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Anti Aging

Anti Aging: Our body is in a constant and never ending battle for survival. Cells are birthed, cells are destroyed. Scientists estimate that each of our cells must withstand over 10,000 individual assaults from reactive oxygen species (ROS) or free radicals. Without Fail, the body has an incredible system of self-healing that withstands the attack and rebuilds what has been damaged or destroyed. This is the beauty of our design. To understand the biology of aging and to translate scientific insight into interventions that improve late life health through anti-aging treatments. It is useful to have a clear, consensus view on what exactly constitutes anti-aging treatment.  Chiropractic care with its health movement, has been shown to be a powerful method of stabilizing and enhancing this self-healing ability. Dr. Alex Jimenez discusses concepts surrounding the anti-aging pandora. Since before the days of Ponce de Leon’s search for longevity man has always been enticed by the chance of eternal youth.


The 4Rs Protocol For a Healthy Gut

The 4Rs Protocol For a Healthy Gut

Do you feel:

  • Like you have been diagnosed with Celiac Disease, Irritable Bowel Syndrome, Diverticulosis/Diverticulitis, or Leaky Gut Syndrome?
  • Excessive belching, burping, or bloating?
  • Abnormal distention after certain probiotics or natural supplements?
  • Suspicion of nutritional malabsorption?
  • Do digestive problems subside with relaxation?

If you are experiencing any of these situations, then you might be experiencing gut problems and might have to try the 4R Protocol.

Food sensitivities, rheumatoid arthritis, and anxiety have one thing in common. These various conditions have all been associated with impaired gastrointestinal health. These conditions can happen from a poor diet to excess stress and many factors that can negatively impact the digestive function. It can potentially be the result of increased intestinal permeability, systemic inflammation, and the development of certain health conditions. The 4R protocol can be utilized to restore optimal digestive health and involves the four steps, which are: remove, replace, reinoculate, and repair.

Intestinal Permeability

The intestinal tract is the body’s primary physical barrier from the outside world. It protects the body from potentially harmful environmental factors that are passing through the digestive tract. It can be either toxin, pathogenic microorganisms, and other antigens that can harm the digestive tract causing problems. The intestinal lining is consisting of a single layer of epithelial cells that are separated by protein complexes known as tight junctions. In a healthy gut, the tight junction regulates the intestinal permeability by selectively allowing the transport of substances like water, electrolytes, and nutrients from the gut lumen, traveling across the intestinal barrier, while also preventing the absorption of harmful substances.

Certain environmental factors can damage the tight junction, and the result is that it can increase the intestinal permeability, which is referred to as intestinal hyperpermeability or leaky gut. Contributing factors to increased intestinal permeability include dietary excesses (saturated fats and alcohol), nutrient deficiencies (vitamin D and fiber), stress, and infections (Helicobacter pylori and bacterial infections.)

With an increased intestinal permeability, it can enable antigens to cross the gut mucosa into the systemic circulation. This is resulting in an immune response and a low-grade inflammation. Intestinal hyperpermeability has been associated with certain gastrointestinal conditions like IBS (irritable bowel syndrome), ulcerative colitis, and Crohn’s disease. It can also trigger certain autoimmune conditions like celiac disease, type 1 diabetes, and rheumatoid arthritis, causing harm to the body.

What are the 4Rs?

The 4Rs is a four-step protocol that healthcare professionals advised individuals to use when they address digestive conditions and to support gut healing.

Step 1: Remove

Food allergies

The first step is to remove pathogens and other inflammatory triggers that are associated with increased intestinal permeability. Triggers like stress and chronic alcohol consumption can do much harm to an individual’s body. So targeting pathogens may involve treatment with pharmaceutical medication, antibiotics, or antimicrobial herbal supplements and removing inflammatory foods from the diet is advised, including:

  • Alcohol
  • Gluten
  • Food additives
  • Refined starches and sugar
  • Saturated and trans-fatty acids
  • Food sensitivities, which may be identified through the elimination diet

Step 2: Replace

The second step is to replace dietary nutrients that can help reduce inflammation and support digestive health. Anti-inflammatory food that is nutritious include:

  • High-fiber foods
  • Omega-3 fatty acids
  • Extra virgin olive oil
  • Mushrooms
  • Anti-inflammatory herbs and spices

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Certain dietary supplements can also be used to support the digestive function by assisting in the digestion and absorption of dietary nutrients. The digestive enzymes assist in the breakdown of fats, proteins, and carbohydrates, while also benefiting individuals with an impaired digestive function, food intolerances, or having celiac disease. Supplements like bile acid supplements can also assist in nutrient absorption by emulsifying lipids. Studies have stated that bile acids have been used to treat the conditions of the liver, gallbladder, and bile duct. Bile acids have been shown to prevent gallstone formation following bariatric surgery.

Step 3: Reinoculate

The third step is to reinoculate the gut microbiota with beneficial bacteria. Studies have been shown that probiotic supplementation has been used to improve the composition of the gut microbiota by restoring the beneficial Bifidobacterium and the Lactobacillus bacteria species. With probiotic supplements, they can help improve the gut by enhancing the secretion of anti-inflammatory substances, supporting the immune system, altering the microbial composition, and reducing the intestinal permeability.

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Probiotics are found in fermented foods like yogurt, fermented vegetables, fermented soy products, and kombucha. Foods that have probiotics in them are considered as transient as they do not persist in the gastrointestinal tract. Surprisingly, they may still have an impact on human health by producing vitamins and anti-microbial compounds by influencing the gut microbiota diversity and function.

Step 4: Repair

cooking-with-herbs

The last step is to repair the gut. This step involves repairing the intestinal lining with specific nutrients and medicinal herbs. These herbs and supplements have been shown to decrease intestinal permeability and inflammation. Some of these herbs and supplements include:

  • Aloe vera
  • Chios mastic gum
  • DGL (Deglycyrrhizinated licorice)
  • Marshmallow root
  • L-glutamine
  • Omega-3 fatty acids
  • Polyphenols
  • Vitamin D
  • Zinc

Conclusion

Since many dietary and lifestyle factors can adversely affect the digestive system and can be the contributor to several health conditions. The main goal of the 4Rs protocol is to minimize the factors that can lead the gut to have an increased intestinal permeability and inflammation, as well as introducing the beneficial factors that can promote gut health and healing. Some products are here to help support the gastrointestinal system by supporting the intestines, improving the sugar metabolism, and targeting the amino acids that are intended to support the intestines.

The scope of our information is limited to chiropractic, musculoskeletal, and nervous health issues as well as functional medicine articles, topics, and discussions. We use functional health protocols to treat injuries or chronic disorders of the musculoskeletal system. To further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900 .


References:

De Santis, Stefania, et al. “Nutritional Keys for Intestinal Barrier Modulation.” Frontiers in Immunology, Frontiers Media S.A., 7 Dec. 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4670985/.

Ianiro, Gianluca, et al. “Digestive Enzyme Supplementation in Gastrointestinal Diseases.” Current Drug Metabolism, Bentham Science Publishers, 2016, www.ncbi.nlm.nih.gov/pmc/articles/PMC4923703/.

Mu, Qinghui, et al. “Leaky Gut As a Danger Signal for Autoimmune Diseases.” Frontiers, Frontiers, 5 May 2017, www.frontiersin.org/articles/10.3389/fimmu.2017.00598/full.

Rezac, Shannon, et al. “Fermented Foods as a Dietary Source of Live Organisms.” Frontiers in Microbiology, Frontiers Media S.A., 24 Aug. 2018, www.ncbi.nlm.nih.gov/pmc/articles/PMC6117398/.

Sander, Guy R., et al. “Rapid Disruption of Intestinal Barrier Function by Gliadin Involves Altered Expression of Apical Junctional Proteins.” FEBS Press, John Wiley & Sons, Ltd, 8 Aug. 2005, febs.onlinelibrary.wiley.com/doi/full/10.1016/j.febslet.2005.07.066.

Sartor, R Balfour. “Therapeutic Manipulation of the Enteric Microflora in Inflammatory Bowel Diseases: Antibiotics, Probiotics, and Prebiotics.” Gastroenterology, U.S. National Library of Medicine, May 2004, www.ncbi.nlm.nih.gov/pubmed/15168372.

Zaremba, Karolina. “The 4Rs: How To Heal The Gut Naturally.” Fullscript, 24 Sept. 2019, fullscript.com/blog/natural-gut-healing.

Fasting and Chronic Pain

Fasting and Chronic Pain

Chronic pain is a common health issue which affects many people in the United States. While several medical conditions, such as fibromyalgia and myofascial pain syndrome, can cause chronic pain, it may also develop due to a variety of other health issues. Research studies have found that widespread inflammation is the leading cause of chronic pain. Inflammation is a natural defense mechanism to injury, illness, or infection. But, if the inflammatory process continues for too long, it can become problematic.

Inflammation signals the immune system to heal and repair damaged tissue as well as to protect itself against bacteria and viruses. As mentioned above, however, chronic inflammation can cause a variety of health issues, including chronic pain symptoms. Healthy lifestyle modifications can help manage chronic pain, but first, let’s understand the common causes of chronic pain.

What is Acute Inflammation?

Acute inflammation, by way of instance, occurs following an injury or something as simple as a sore throat. It is a natural response with adverse effects, meaning it works locally in the region where the health issue is found. The common signs of acute inflammation include swelling, redness, warmth, pain and loss of function, as stated by the National Library of Medicine. When acute inflammation develops, the blood vessels dilate causing blood flow to increase, and white blood cells in the injured region promote recovery.

During severe inflammation, compounds called cytokines are released by the damaged tissue. The cytokines act as “emergency signals” which bring on the human body’s own immune cells, as well as hormones and numerous nutrients to repair the health issue. Additionally, hormone-like substances, known as prostaglandins, cause blood clots to heal damaged tissue, and these may also trigger fever and pain as part of the inflammatory procedure. As the damage or injury recovers, the inflammation subsides.

What is Chronic Inflammation?

Unlike acute inflammation, chronic inflammation has long-term effects. Chronic inflammation, also known as persistent inflammation, produces low-levels of inflammation throughout the human body, as demonstrated by an increase in immune system markers located in blood and cell tissues. Chronic inflammation may also cause the progression of various diseases and conditions. Elevated levels of inflammation may sometimes trigger even if there is no injury, illness, or infection, which may also cause the immune system to react.

As a result, the human body’s immune system could begin attacking healthy cells, tissues, or organs. Researchers are still trying to understand the consequences of chronic inflammation in the human body and the mechanisms involved in this natural defense process. By way of instance, chronic inflammation has been associated with a variety of health issues, such as heart disease, and stroke.

One theory suggests that when inflammation remains in the blood vessels, it can encourage the accumulation of plaque. According to the American Heart Association, or the AHA, if the immune system identifies plaque as a foreign invader, the white blood cells can attempt to wall off the plaque found in the blood flowing through the arteries. This can create a blood clot which may block the blood flow to the heart or brain, causing it to become unstable and rupture. Cancer is another health issue associated with chronic inflammation. Furthermore, according to the National Cancer Institute, DNA damage can also be caused by chronic inflammation.

Persistent, low-grade inflammation frequently doesn’t have any symptoms, but healthcare professionals can check for a C-reactive protein, or CRP, known as lipoic acid, a marker for inflammation found in the blood. Elevated levels of CRP are associated with an increased risk of cardiovascular disease. Elevated CRP levels may be found in chronic disorders like lupus or rheumatoid arthritis.

In the case of other chronic conditions, such as fibromyalgia, the nervous system over-reacts to specific stimulation, however, it’s inflammation which causes chronic pain symptoms. Subjectively, it’s almost impossible to tell the difference between the chronic pain caused by an oversensitive nervous system and the chronic pain caused by widespread inflammation. Apart from searching for clues in the bloodstream, a person’s nutrition, lifestyle habits, and environmental exposures, can also promote chronic inflammation.

Dr Jimenez White Coat

Inflammation is the immune system’s natural defense mechanism against injury, illness, or infection. While this inflammatory response can help heal and repair tissues, chronic, widespread inflammation can cause a variety of health issues, including chronic pain symptoms. A balanced nutrition, including a variety of diets and fasting, can help reduce inflammation. Fasting, also known as caloric restriction, promotes cell apoptosis and mitochondrial recovery. The fasting mimicking diet, which is a part of the longevity diet plan, is a dietary program which “tricks” the human body into a fasting state to experience the benefits of traditional fasting. Before following any of the diets described in this article, make sure to consult a doctor.

Dr. Alex Jimenez D.C., C.C.S.T. Insight

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Nutrition, Diets, Fasting and Chronic Pain

Anti-inflammatory diets mainly consist of eating fresh fruits and vegetables, fish, and fats. The Mediterranean diet plan, by way of instance, is an anti-inflammatory diet which promotes eating moderate amounts of nuts, ingesting very little meat, and drinking wine. Anti-inflammatory food parts, such as omega-3 fatty acids, protect the human body against the damage brought on by inflammation.

An anti-inflammatory diet also involves staying away from foods which could promote inflammation. It is ideal to decrease the amount of foods you eat which are high in trans and saturated fats, such as meats. Additionally, an anti-inflammatory diet limits the consumption of refined carbohydrates and foods, such as bread and rice. These also promote cutting back on the utilization of margarine and oils that are packed with omega-6 fatty acids, such as sunflower, safflower and corn oils.

Fasting, or caloric restriction, has long been known to decrease oxidative stress and slow down the mechanisms of aging in various organisms. The effects of fasting involve programmed cell death, or apoptosis, transcription, mobile energy efficiency, mitochondrial biogenesis, antioxidant mechanisms, and circadian rhythm. Fasting also contributes to mitochondrial autophagy, known as mitophagy, where genes in the mitochondria are stimulated to undergo apoptosis, which promotes mitochondrial recovery.

Intermittent fasting can help you fight inflammation, improve digestion, and boost your longevity. The human body is designed to be able to survive for extended periods of time without food. Research studies have demonstrated that intermittent fasting can have positive changes in the overall composition of your gut microbiota. Moreover, intermittent fasting can reduce insulin resistance while increasing the immune system response. Finally, intermittent fasting can promote the production of a substance, known as β-hydroxybutyrate, that blocks a portion of the immune system involved in inflammatory ailments as well as substantially reducing the production of inflammatory markers, such as cytokines and the C-reactive protein, or CRP, previously mentioned above.

The Longevity Diet Plan, presented in the book by Dr. Valter Longo, eliminates the consumption of processed foods which can cause inflammation, promoting well-being and longevity. This unique dietary program, unlike most traditional diets, doesn’t promote weight loss. Although you may experience weight reduction, the emphasis of this unique dietary program is on eating healthier. The Longevity Diet Plan has been demonstrated to help activate stem cell-based renewal, reduce abdominal fat, and prevent age-related bone and muscle loss, as well as build resistance to developing cardiovascular disease, Alzheimer’s disease, diabetes, and cancer.

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The fasting mimicking diet, or FMD, allows you to experience the benefits of traditional fasting without depriving your body of food. The main difference of the FMD is that instead of completely eliminating all food for several days or even weeks, you only restrict your calorie intake for five days out of the month. The FMD can be practiced once a month to help promote overall health and wellness.

While anyone can follow the FMD on their own, the ProLon® fasting mimicking diet offers a 5-day meal program which has been individually packed and labeled for each day, that serves the foods you need for the FMD in precise quantities and combinations. The meal program is made up of ready-to-eat or easy-to-prepare, plant-based foods, including bars, soups, snacks, supplements, a drink concentrate, and teas. Before starting the ProLon® fasting mimicking diet, 5-day meal program, or any of the lifestyle modifications described above, please make sure to talk to a healthcare professional to find out which chronic pain treatment is right for you.

The scope of our information is limited to chiropractic, spinal health issues, and functional medicine articles, topics, and discussions. To further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900 .

Curated by Dr. Alex Jimenez

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Additional Topic Discussion: Acute Back Pain

Back pain is one of the most prevalent causes of disability and missed days at work worldwide. Back pain attributes to the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience back pain at least once throughout their life. Your spine is a complex structure made up of bones, joints, ligaments, and muscles, among other soft tissues. Injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.

Xymogen Formulas - El Paso, TX

XYMOGEN’s Exclusive Professional Formulas are available through select licensed health care professionals. The internet sale and discounting of XYMOGEN formulas are strictly prohibited.

Proudly, Dr. Alexander Jimenez makes XYMOGEN formulas available only to patients under our care.

Please call our office in order for us to assign a doctor consultation for immediate access.

If you are a patient of Injury Medical & Chiropractic Clinic, you may inquire about XYMOGEN by calling 915-850-0900.

xymogen el paso, tx

For your convenience and review of the XYMOGEN products please review the following link.*XYMOGEN-Catalog-Download

* All the above XYMOGEN policies remain strictly in force.

***

What is the Longevity Diet Plan?

What is the Longevity Diet Plan?

Adhering to a specific diet to maintain proper nutrition can sometimes make eating stressful. Natural lifestyle modifications are the key to changing your eating habits and this can help you live a longer, healthier life. The Longevity Diet Plan, created by Dr. Valter Longo, is a selection of practical eating guidelines which focuses on changing your eating patterns to achieve overall health and wellness.

The Rules of The Longevity Diet Plan

By merely following the nutritional tips below, you can overhaul your current diet plan and start eating healthier without all the stress of a traditional diet. The Longevity Diet Plan eliminates the consumption of processed foods that can cause a variety of health issues and boosts the consumption of nutrients that promote longevity. This unique dietary program shares the results of approximately 25 years of research studies all on a simple solution which can help people experience overall well-being through proper nutrition.

However, unlike most traditional diets, the Longevity Diet Plan doesn’t promote weight loss. Although you may experience weight reduction, the emphasis of this unique dietary program is on eating healthier. The Longevity Diet Plan has been demonstrated to help you activate stem cell-based renewal, lose weight and reduce abdominal fat, prevent age-related bone and muscle loss, build resistance to developing cardiovascular disease, Alzheimer’s disease, diabetes, and cancer, as well as extend longevity. Below, we will summarize the 8 most common nutritional tips of the Longevity Diet Plan which can ultimately help make your life longer and healthier.

Dr Jimenez White Coat

The Longevity Diet Plan is a unique dietary program designed by Dr. Valter Longo to promote overall health, wellness, and longevity. Through simple lifestyle modifications, people can change their eating habits and take advantage of the many health benefits of this dietary program. By following a pescatarian diet and following the ProLon® Fasting Mimicking Diet, among the other nutritional tips described below, people can live longer and healthier lives. Traditional diets can often be difficult and stressful to follow, however, the Longevity Diet Plan is a practical and unique dietary program which can be suitable for many people.

Dr. Alex Jimenez D.C., C.C.S.T. Insight

8 Nutritional Tips of the Longevity Diet Plan

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Follow a Pescatarian Diet

As a part of the Longevity Diet Plan, follow a pescatarian diet, which is almost 100 percent plant and fish-based. Also, make sure to limit fish consumption to two or three servings every week, avoiding fish with higher mercury content, such as tuna, swordfish, mackerel, and halibut. If you’re over 65 and you begin to experience reduced muscle mass, strength, and fat, add more fish into your diet alongside other animal-based foods, including eggs and specific cheeses, such as feta or pecorino, and yogurt made from goat’s milk.

Don’t Eat Too Much Protein

According to the Longevity Diet Plan, we should eat 0.31 to 0.36 grams of protein per pound of body fat every day. If you weigh 130lbs, you should eat about 40 to 47 grams of protein per day, or an equivalent of 1.5 filets of salmon, 1 cup of chickpeas or 2 1/2 cups of lentils, of which 30 grams should be consumed in one meal. If you weigh 200 to 220lbs, you should eat about 60 to 70 grams of protein per day, or an equivalent of two fillets of salmon, 3 1/2 cups of lentils or 1 1/2 cups of chickpeas. Protein consumption should be increased after age 65. For the majority of us, a 10 to 20 percent increase, or 5 to 10 grams more each day, is enough. Finally, the Longevity Diet is free of animal proteins like red meat, white meat, and poultry, with the exception of animal proteins in fish. This unique dietary program instead is comparatively high in vegetable proteins like legumes and nuts to optimize health and wellness.

Increase Good Fats and Complex Carbohydrates

As a part of the Longevity Diet Plan, you should eat higher amounts of polyunsaturated fats, such as those found in salmon, almonds, walnuts, and olive oil, while you should eat lower amounts of saturated, hydrogenated, and trans fats. Likewise, as a part of the Longevity Diet Plan, you should also eat complex carbohydrates, such as those found in whole wheat bread, legumes, and vegetables. Make sure to limit eating pasta, rice, bread, fruit, and fruit juices, which can be converted to sugars by the time they reach your gut.

Take Dietary Supplements

The human body needs proteins, essential fatty acids like omega-3 and omega-6, vitamins, minerals, and even sugars to function correctly. Whenever your intake of certain nutrients becomes too low, the repair, replacement, and defense methods of the human body can slow down or stop, allowing fungi, bacteria, and viruses to cause damage which can lead to a variety of health issues. Take vitamin and mineral dietary supplements, especially for omega-3, as recommended by your healthcare professional.

Eat Various Foods from your Ancestry

To take in all of the necessary nutrients you need, you have to eat a wide variety of foods, but it’s best to choose foods that were common on your parents’, grandparents’, and great-grandparents’ table. By way of instance, in many northern European countries where milk has been generally consumed, lactose intolerance is relatively rare, whereas lactose intolerance is quite common in southern European and Asian countries, where milk was not historically part of the conventional diet of adults. If a person of Japanese ancestry residing in the United States suddenly decides to begin drinking milk, which was probably rarely served in their grandparents’ dining table, they will probably start feeling sick. The most common problems in these cases are intolerances or autoimmunities, such as the response to gluten-rich foods like bread and pasta seen in people with celiac disease. Although further evidence is needed, it is possible that food intolerances could be related to many autoimmune disorders, including diabetes, colitis, and Crohn’s disease.

Eat Two Meals a Day and a Snack

According to the Longevity Diet Plan, it is ideal to eat breakfast and one major meal plus a nourishing low-calorie, low-sugar snack every day. While for some people it may be recommended to eat three meals and a snack every day. Many nutritional guidelines recommend that we should eat five to six meals every day. When people are advised to eat frequently, it can often become difficult for them to regulate their calorie intake. Over the last twenty years, approximately 70 percent of the population in the United States is considered to be overweight or obese. It’s much more difficult to overeat on the Longevity Diet Plan if you eat only two and a half meals every day. It would take massive portions of legumes, vegetables, and fish to reach the amount that would lead to weight gain. The high nourishment of the meals, plus the amount of the meal, sends a signal to your stomach and your brain that you have had enough food. This one major meal system may sometimes have to be broken down into two meals to avoid digestion issues. Adults and older people prone to weight loss should eat three meals a day. For people trying to lose weight as well as for people who are overweight or obese, the best nutritional advice would be to eat breakfast daily; have dinner or lunch, but not both, and substitute for the missed meal with one snack containing fewer than 100 calories and no more than 3 to 5 g of sugar. Which meal you skip depends upon your lifestyle, however, it’s not recommended to skip breakfast due to its adverse health issues. The benefit of skipping lunch is more free time and energy. But, there is a drawback for eating a large dinner, particularly for people who suffer from acid reflux or sleeping problems. The drawback for skipping dinner, however, is that it may eliminate the social meal of their day.

Eat Within a 12-Hour Window Every Day

Another common eating habit adopted by many centenarians is time-restricted eating or limiting all meals and snacks within a 12-hour window every day. The efficiency of this method was demonstrated in both human and animal research studies. Generally, you would eat breakfast at 8 a.m. and then eat dinner by 8 p.m.. A briefer eating window of ten hours or less can be even better for weight loss, but it’s considerably harder to maintain and it might increase the risk of developing side effects, such as gallstones and even potentially increasing the chance of developing cardiovascular disease. You should not eat three to four hours before sleeping.

Follow the ProLon® Fasting Mimicking Diet

Healthy people under the age of 65 should follow the ProLon® Fasting Mimicking Diet, 5-day meal program at least twice every year. The FMD is one of the key principles promoted by the Longevity Diet Plan. The fasting mimicking diet offers the same health benefits of fasting without actually fasting. By eating 800 to 1,100 calories in precise quantities and combinations of foods which have been individually packed and labeled for each day, you can “trick” the human body into a fasting state. Through various research studies, Dr. Valter Longo discovered that by depriving the body of food in this manner, our cells begin breaking down and regenerating our internal tissues, through a process known as autophagy, killing and replacing, or regenerating, damaged cells. Additionally, fasting can reverse various health issues, destroy cancer cells and significantly reduce the possibility of developing Alzheimer’s disease.

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With the Longevity Diet Plan presented in the book by Dr. Valter Longo, you’ll eat better, feel better and, although it’s not designed as a weight loss plan, you may even shed a few pounds. You’re not going to have to consider complex food rules and make difficult choices with this unique dietary program. Once you get the hang of these lifestyle modifications, you’ll be able to improve your overall health and wellness as well as your longevity. The scope of our information is limited to chiropractic, spinal health issues, and functional medicine topics. To further discuss the subject matter, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900 .

Curated by Dr. Alex Jimenez

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Additional Topic Discussion: Acute Back Pain

Back pain is one of the most prevalent causes of disability and missed days at work worldwide. Back pain attributes to the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience back pain at least once throughout their life. Your spine is a complex structure made up of bones, joints, ligaments, and muscles, among other soft tissues. Injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.

Xymogen Formulas - El Paso, TX

XYMOGEN’s Exclusive Professional Formulas are available through select licensed health care professionals. The internet sale and discounting of XYMOGEN formulas are strictly prohibited.

Proudly, Dr. Alexander Jimenez makes XYMOGEN formulas available only to patients under our care.

Please call our office in order for us to assign a doctor consultation for immediate access.

If you are a patient of Injury Medical & Chiropractic Clinic, you may inquire about XYMOGEN by calling 915-850-0900.

xymogen el paso, tx

For your convenience and review of the XYMOGEN products please review the following link.*XYMOGEN-Catalog-Download

* All the above XYMOGEN policies remain strictly in force.

***

Multi-Dimensional Roles of Ketone Bodies

Multi-Dimensional Roles of Ketone Bodies

Ketone bodies are created by the liver and utilized as an energy source when glucose is not readily available in the human body. The two main ketone bodies are acetoacetate (AcAc) and 3-beta-hydroxybutyrate (3HB), while acetone is the third and least abundant, ketone body. Ketones are always present in the blood and their levels increase during fasting and prolonged exercise. Ketogenesis is the biochemical process by which organisms produce ketone bodies through the breakdown of fatty acids and ketogenic amino acids.

Ketone bodies are mainly generated in the mitochondria of liver cells. Ketogenesis occurs when there are low glucose levels in the blood, particularly after other cellular carbohydrate stores, such as glycogen, have been exhausted. This mechanism can also occur when there is insufficient amounts of insulin. The production of ketone bodies is ultimately initiated to make available energy which is stored in the human body as fatty acids. Ketogenesis occurs in the mitochondria where it is independently regulated.

Abstract

Ketone body metabolism is a central node in physiological homeostasis. In this review, we discuss how ketones serve discrete fine-tuning metabolic roles that optimize organ and organism performance in varying nutrient remains and protect from inflammation and injury in multiple organ systems. Traditionally viewed as metabolic substrates enlisted only in carbohydrate restriction, recent observations underscore the importance of ketone bodies as vital metabolic and signaling mediators when carbohydrates are abundant. Complementing a repertoire of known therapeutic options for diseases of the nervous system, prospective roles for ketone bodies in cancer have arisen, as have intriguing protective roles in heart and liver, opening therapeutic options in obesity-related and cardiovascular disease. Controversies in ketone metabolism and signaling are discussed to reconcile classical dogma with contemporary observations.

Introduction

Ketone bodies are a vital alternative metabolic fuel source for all the domains of life, eukarya, bacteria, and archaea (Aneja et al., 2002; Cahill GF Jr, 2006; Krishnakumar et al., 2008). Ketone body metabolism in humans has been leveraged to fuel the brain during episodic periods of nutrient deprivation. Ketone bodies are interwoven with crucial mammalian metabolic pathways such as β-oxidation (FAO), the tricarboxylic acid cycle (TCA), gluconeogenesis, de novo lipogenesis (DNL), and biosynthesis of sterols. In mammals, ketone bodies are produced predominantly in the liver from FAO-derived acetyl-CoA, and they are transported to extrahepatic tissues for terminal oxidation. This physiology provides an alternative fuel that is augmented by relatively brief periods of fasting, which increases fatty acid availability and diminishes carbohydrate availability (Cahill GF Jr, 2006; McGarry and Foster, 1980; Robinson and Williamson, 1980). Ketone body oxidation becomes a significant contributor to overall energy mammalian metabolism within extrahepatic tissues in a myriad of physiological states, including fasting, starvation, the neonatal period, post-exercise, pregnancy, and adherence to low carbohydrate diets. Circulating total ketone body concentrations in healthy adult humans normally exhibit circadian oscillations between approximately 100–250 µM, rise to ~1 mM after prolonged exercise or 24h of fasting, and can accumulate to as high as 20 mM in pathological states like diabetic ketoacidosis (Cahill GF Jr, 2006; Johnson et al., 1969b; Koeslag et al., 1980; Robinson and Williamson, 1980; Wildenhoff et al., 1974). The human liver produces up to 300 g of ketone bodies per day (Balasse and Fery, 1989), which contribute between 5–20% of total energy expenditure in fed, fasted, and starved states (Balasse et al., 1978; Cox et al., 2016).

Recent studies now highlight imperative roles for ketone bodies in mammalian cell metabolism, homeostasis, and signaling under a wide variety of physiological and pathological states. Apart from serving as energy fuels for extrahepatic tissues like brain, heart, or skeletal muscle, ketone bodies play pivotal roles as signaling mediators, drivers of protein post-translational modification (PTM), and modulators of inflammation and oxidative stress. In this review, we provide both classical and modern views of the pleiotropic roles of ketone bodies and their metabolism.

Overview of Ketone Body Metabolism

The rate of hepatic ketogenesis is governed by an orchestrated series of physiological and biochemical transformations of fat. Primary regulators include lipolysis of fatty acids from triacylglycerols, transport to and across the hepatocyte plasma membrane, transport into mitochondria via carnitine palmitoyltransferase 1 (CPT1), the β-oxidation spiral, TCA cycle activity and intermediate concentrations, redox potential, and the hormonal regulators of these processes, predominantly glucagon and insulin [reviewed in (Arias et al., 1995; Ayte et al., 1993; Ehara et al., 2015; Ferre et al., 1983; Kahn et al., 2005; McGarry and Foster, 1980; Williamson et al., 1969)]. Classically ketogenesis is viewed as a spillover pathway, in which β-oxidation-derived acetyl-CoA exceeds citrate synthase activity and/or oxaloacetate availability for condensation to form citrate. Three-carbon intermediates exhibit anti-ketogenic activity, presumably due to their ability to expand the oxaloacetate pool for acetyl-CoA consumption, but hepatic acetyl-CoA concentration alone does not determine ketogenic rate (Foster, 1967; Rawat and Menahan, 1975; Williamson et al., 1969). The regulation of ketogenesis by hormonal, transcriptional, and post-translational events together support the notion that the molecular mechanisms that fine-tune ketogenic rate remain incompletely understood (see Regulation of HMGCS2 and SCOT/OXCT1).

Ketogenesis occurs primarily in hepatic mitochondrial matrix at rates proportional to total fat oxidation. After transport of acyl chains across the mitochondrial membranes and β-oxidation, the mitochondrial isoform of 3-hydroxymethylglutaryl-CoA synthase (HMGCS2) catalyzes the fate committing condensation of acetoacetyl-CoA (AcAc-CoA) and acetyl-CoA to generate HMG-CoA (Fig. 1A). HMG-CoA lyase (HMGCL) cleaves HMG-CoA to liberate acetyl-CoA and acetoacetate (AcAc), and the latter is reduced to d-β-hydroxybutyrate (d-βOHB) by phosphatidylcholine-dependent mitochondrial d-βOHB dehydrogenase (BDH1) in a NAD+/NADH-coupled near-equilibrium reaction (Bock and Fleischer, 1975; LEHNINGER et al., 1960). The BDH1 equilibrium constant favors d-βOHB production, but the ratio of AcAc/d-βOHB ketone bodies is directly proportional to mitochondrial NAD+/NADH ratio, and thus BDH1 oxidoreductase activity modulates mitochondrial redox potential (Krebs et al., 1969; Williamson et al., 1967). AcAc can also spontaneously decarboxylate to acetone (Pedersen, 1929), the source of sweet odor in humans suffering ketoacidosis (i.e., total serum ketone bodies > ~7 mM; AcAc pKa 3.6, βOHB pKa 4.7). The mechanisms through which ketone bodies are transported across the mitochondrial inner membrane are not known, but AcAc/d-βOHB are released from cells via monocarboxylate transporters (in mammals, MCT 1 and 2, also known as solute carrier 16A family members 1 and 7) and transported in the circulation to extrahepatic tissues for terminal oxidation (Cotter et al., 2011; Halestrap and Wilson, 2012; Halestrap, 2012; Hugo et al., 2012). Concentrations of circulating ketone bodies are higher than those in the extrahepatic tissues (Harrison and Long, 1940) indicating ketone bodies are transported down a concentration gradient. Loss-of-function mutations in MCT1 are associated with spontaneous bouts of ketoacidosis, suggesting a critical role in ketone body import.

  With the exception of potential diversion of ketone bodies into non-oxidative fates (see Non-oxidative metabolic fates of ketone bodies), hepatocytes lack the ability to metabolize the ketone bodies they produce. Ketone bodies synthesized de novo by liver are (i) catabolized in mitochondria of extrahepatic tissues to acetyl-CoA, which is available to the TCA cycle for terminal oxidation (Fig. 1A), (ii) diverted to the lipogenesis or sterol synthesis pathways (Fig. 1B), or (iii) excreted in the urine. As an alternative energetic fuel, ketone bodies are avidly oxidized in heart, skeletal muscle, and brain (Balasse and Fery, 1989; Bentourkia et al., 2009; Owen et al., 1967; Reichard et al., 1974; Sultan, 1988). Extrahepatic mitochondrial BDH1 catalyzes the first reaction of βOHB oxidation, converting it to back AcAc (LEHNINGER et al., 1960; Sandermann et al., 1986). A cytoplasmic d-βOHB-dehydrogenase (BDH2) with only 20% sequence identity to BDH1 has a high Km for ketone bodies, and also plays a role in iron homeostasis (Davuluri et al., 2016; Guo et al., 2006). In extrahepatic mitochondrial matrix, AcAc is activated to AcAc-CoA through exchange of a CoA-moiety from succinyl-CoA in a reaction catalyzed by a unique mammalian CoA transferase, succinyl-CoA:3-oxoacid-CoA transferase (SCOT, CoA transferase; encoded by OXCT1), through a near equilibrium reaction. The free energy released by hydrolysis of AcAc-CoA is greater than that of succinyl-CoA, favoring AcAc formation. Thus ketone body oxidative flux occurs due to mass action: an abundant supply of AcAc and rapid consumption of acetyl-CoA through citrate synthase favors AcAc-CoA (+ succinate) formation by SCOT. Notably, in contrast to glucose (hexokinase) and fatty acids (acyl-CoA synthetases), the activation of ketone bodies (SCOT) into an oxidizable form does not require the investment of ATP. A reversible AcAc-CoA thiolase reaction [catalyzed by any of the four mitochondrial thiolases encoded by either ACAA2 (encoding an enzyme known as T1 or CT), ACAT1 (encoding T2), HADHA, or HADHB] yields two molecules of acetyl-CoA, which enter the TCA cycle (Hersh and Jencks, 1967; Stern et al., 1956; Williamson et al., 1971). During ketotic states (i.e., total serum ketones > 500 µM), ketone bodies become significant contributors to energy expenditure and are utilized in tissues rapidly until uptake or saturation of oxidation occurs (Balasse et al., 1978; Balasse and Fery, 1989; Edmond et al., 1987). A very small fraction of liver-derived ketone bodies can be readily measured in the urine, and utilization and reabsorption rates by the kidney are proportionate to circulating concentration (Goldstein, 1987; Robinson and Williamson, 1980). During highly ketotic states (> 1 mM in plasma), ketonuria serves as a semi-quantitative reporter of ketosis, although most clinical assays of urine ketone bodies detect AcAc but not βOHB (Klocker et al., 2013).

Ketogenic Substrates and their Impact on Hepatocyte Metabolism

Ketogenic substrates include fatty acids and amino acids (Fig. 1B). The catabolism of amino acids, especially leucine, generates about 4% of ketone bodies in post-absorptive state (Thomas et al., 1982). Thus the acetyl-CoA substrate pool to generate ketone bodies mainly derives from fatty acids, because during states of diminished carbohydrate supply, pyruvate enters the hepatic TCA cycle primarily via anaplerosis, i.e., ATP-dependent carboxylation to oxaloacetate (OAA), or to malate (MAL), and not oxidative decarboxylation to acetyl-CoA (Jeoung et al., 2012; Magnusson et al., 1991; Merritt et al., 2011). In liver, glucose and pyruvate contribute negligibly to ketogenesis, even when pyruvate decarboxylation to acetyl-CoA is maximal (Jeoung et al., 2012).

Acetyl-CoA subsumes several roles integral to hepatic intermediary metabolism beyond ATP generation via terminal oxidation (also see The integration of ketone body metabolism, post-translational modification, and cell physiology). Acetyl-CoA allosterically activates (i) pyruvate carboxylase (PC), thereby activating a metabolic control mechanism that augments anaplerotic entry of metabolites into the TCA cycle (Owen et al., 2002; Scrutton and Utter, 1967) and (ii) pyruvate dehydrogenase kinase, which phosphorylates and inhibits pyruvate dehydrogenase (PDH) (Cooper et al., 1975), thereby further enhancing flow of pyruvate into the TCA cycle via anaplerosis. Furthermore, cytoplasmic acetyl-CoA, whose pool is augmented by mechanisms that convert mitochondrial acetyl-CoA to transportable metabolites, inhibits fatty acid oxidation: acetyl-CoA carboxylase (ACC) catalyzes the conversion of acetyl-CoA to malonyl-CoA, the lipogenic substrate and allosteric inhibitor of mitochondrial CPT1 [reviewed in (Kahn et al., 2005; McGarry and Foster, 1980)]. Thus, the mitochondrial acetyl-CoA pool both regulates and is regulated by the spillover pathway of ketogenesis, which orchestrates key aspects of hepatic intermediary metabolism.

Non-Oxidative Metabolic Fates of Ketone Bodies

The predominant fate of liver-derived ketones is SCOT-dependent extrahepatic oxidation. However, AcAc can be exported from mitochondria and utilized in anabolic pathways via conversion to AcAc-CoA by an ATP-dependent reaction catalyzed by cytoplasmic acetoacetyl-CoA synthetase (AACS, Fig. 1B). This pathway is active during brain development and in lactating mammary gland (Morris, 2005; Robinson and Williamson, 1978; Ohgami et al., 2003). AACS is also highly expressed in adipose tissue, and activated osteoclasts (Aguilo et al., 2010; Yamasaki et al., 2016). Cytoplasmic AcAc-CoA can be either directed by cytosolic HMGCS1 toward sterol biosynthesis, or cleaved by either of two cytoplasmic thiolases to acetyl-CoA (ACAA1 and ACAT2), carboxylated to malonyl-CoA, and contribute to the synthesis of fatty acids (Bergstrom et al., 1984; Edmond, 1974; Endemann et al., 1982; Geelen et al., 1983; Webber and Edmond, 1977).

While the physiological significance is yet to be established, ketones can serve as anabolic substrates even in the liver. In artificial experimental contexts, AcAc can contribute to as much as half of newly synthesized lipid, and up to 75% of new synthesized cholesterol (Endemann et al., 1982; Geelen et al., 1983; Freed et al., 1988). Because AcAc is derived from incomplete hepatic fat oxidation, the ability of AcAc to contribute to lipogenesis in vivo would imply hepatic futile cycling, where fat-derived ketones can be utilized for lipid production, a notion whose physiological significance requires experimental validation, but could serve adaptive or maladaptive roles (Solinas et al., 2015). AcAc avidly supplies cholesterogenesis, with a low AACS Km-AcAc (~50 µM) favoring AcAc activation even in the fed state (Bergstrom et al., 1984). The dynamic role of cytoplasmic ketone metabolism has been suggested in primary mouse embryonic neurons and in 3T3-L1 derived-adipocytes, as AACS knockdown impaired differentiation of each cell type (Hasegawa et al., 2012a; Hasegawa et al., 2012b). Knockdown of AACS in mice in vivo decreased serum cholesterol (Hasegawa et al., 2012c). SREBP-2, a master transcriptional regulator of cholesterol biosynthesis, and peroxisome proliferator activated receptor (PPAR)-γ are AACS transcriptional activators, and regulate its transcription during neurite development and in the liver (Aguilo et al., 2010; Hasegawa et al., 2012c). Taken together, cytoplasmic ketone body metabolism may be important in select conditions or disease natural histories, but are inadequate to dispose of liver-derived ketone bodies, as massive hyperketonemia occurs in the setting of selective impairment of the primary oxidative fate via loss of function mutations to SCOT (Berry et al., 2001; Cotter et al., 2011).

Regulation of HMGCS2 and SCOT/OXCT1

The divergence of a mitochondrial from the gene encoding cytosolic HMGCS occurred early in vertebrate evolution due to the need to support hepatic ketogenesis in species with higher brain to body weight ratios (Boukaftane et al., 1994; Cunnane and Crawford, 2003). Naturally occurring loss-of-function HMGCS2 mutations in humans cause bouts of hypoketotic hypoglycemia (Pitt et al., 2015; Thompson et al., 1997). Robust HMGCS2 expression is restricted to hepatocytes and colonic epithelium, and its expression and enzymatic activity are coordinated through diverse mechanisms (Mascaro et al., 1995; McGarry and Foster, 1980; Robinson and Williamson, 1980). While the full scope of physiological states that influence HMGCS2 requires further elucidation, its expression and/or activity is regulated during the early postnatal period, aging, diabetes, starvation or ingestion of ketogenic diet (Balasse and Fery, 1989; Cahill GF Jr, 2006; Girard et al., 1992; Hegardt, 1999; Satapati et al., 2012; Sengupta et al., 2010). In the fetus, methylation of 5’ flanking region of Hmgcs2 gene inversely correlates with its transcription, and is partially reversed after birth (Arias et al., 1995; Ayte et al., 1993; Ehara et al., 2015; Ferre et al., 1983). Similarly, hepatic Bdh1 exhibits a developmental expression pattern, increasing from birth to weaning, and is also induced by ketogenic diet in a fibroblast growth factor (FGF)-21-dependent manner (Badman et al., 2007; Zhang et al., 1989). Ketogenesis in mammals is highly responsive to both insulin and glucagon, being suppressed and stimulated, respectively (McGarry and Foster, 1977). Insulin suppresses adipose tissue lipolysis, thus depriving ketogenesis of its substrate, while glucagon increases ketogenic flux through a direct effect on the liver (Hegardt, 1999). Hmgcs2 transcription is stimulated by forkhead transcriptional factor FOXA2, which is inhibited via insulin-phosphatidylinositol-3-kinase/Akt, and is induced by glucagon-cAMP-p300 signaling (Arias et al., 1995; Hegardt, 1999; Quant et al., 1990; Thumelin et al., 1993; von Meyenn et al., 2013; Wolfrum et al., 2004; Wolfrum et al., 2003). PPARα (Rodriguez et al., 1994) together with its target, FGF21 (Badman et al., 2007) also induce Hmgcs2 transcription in the liver during starvation or administration of ketogenic diet (Badman et al., 2007; Inagaki et al., 2007). Induction of PPARα may occur before the transition from fetal to neonatal physiology, while FGF21 activation may be favored in the early neonatal period via βOHB-mediated inhibition of histone deacetylase (HDAC)-3 (Rando et al., 2016). mTORC1 (mammalian target of rapamycin complex 1) dependent inhibition of PPARα transcriptional activity is also a key regulator of Hmgcs2 gene expression (Sengupta et al., 2010), and liver PER2, a master circadian oscillator, indirectly regulates Hmgcs2 expression (Chavan et al., 2016). Recent observations indicate that extrahepatic tumor-induced interleukin-6 impairs ketogenesis via PPARα suppression (Flint et al., 2016). Despite these observations, it is important to note that physiological shifts in Hmgcs2 gene expression have not been mechanistically linked to HMGCS2 protein abundance or to variations of ketogenic rate.

HMGCS2 enzyme activity is regulated through multiple PTMs. HMGCS2 serine phosphorylation enhanced its activity in vitro (Grimsrud et al., 2012). HMGCS2 activity is allosterically inhibited by succinyl-CoA and lysine residue succinylation (Arias et al., 1995; Hegardt, 1999; Lowe and Tubbs, 1985; Quant et al., 1990; Rardin et al., 2013; Reed et al., 1975; Thumelin et al., 1993). Succinylation of HMGCS2, HMGCL, and BDH1 lysine residues in hepatic mitochondria are targets of the NAD+ dependent deacylase sirtuin 5 (SIRT5) (Rardin et al., 2013). HMGCS2 activity is also enhanced by SIRT3 lysine deacetylation, and it is possible that crosstalk between acetylation and succinylation regulates HMGCS2 activity (Rardin et al., 2013; Shimazu et al., 2013). Despite the ability of these PTMs to regulate HMGCS2 Km and Vmax, fluctuations of these PTMs have not yet been carefully mapped and have not been confirmed as mechanistic drivers of ketogenesis in vivo.

SCOT is expressed in all mammalian cells that harbor mitochondria, except those of hepatocytes. The importance of SCOT activity and ketolysis was demonstrated in SCOT-KO mice, which exhibited uniform lethality due to hyperketonemic hypoglycemia within 48h after birth (Cotter et al., 2011). Tissue-specific loss of SCOT in neurons or skeletal myocytes induces metabolic abnormalities during starvation but is not lethal (Cotter et al., 2013b). In humans, SCOT deficiency presents early in life with severe ketoacidosis, causing lethargy, vomiting, and coma (Berry et al., 2001; Fukao et al., 2000; Kassovska-Bratinova et al., 1996; Niezen-Koning et al., 1997; Saudubray et al., 1987; Snyderman et al., 1998; Tildon and Cornblath, 1972). Relatively little is known at the cellular level about SCOT gene and protein expression regulators. Oxct1 mRNA expression and SCOT protein and activity are diminished in ketotic states, possibly through PPAR-dependent mechanisms (Fenselau and Wallis, 1974; Fenselau and Wallis, 1976; Grinblat et al., 1986; Okuda et al., 1991; Turko et al., 2001; Wentz et al., 2010). In diabetic ketoacidosis, the mismatch between hepatic ketogenesis and extrahepatic oxidation becomes exacerbated by impairment of SCOT activity. Overexpression of insulin-independent glucose transporter (GLUT1/SLC2A1) in cardiomyocytes also inhibits Oxct1 gene expression and downregulates ketones terminal oxidation in a non-ketotic state (Yan et al., 2009). In liver, Oxct1 mRNA abundance is suppressed by microRNA-122 and histone methylation H3K27me3 that are evident during the transition from fetal to the neonatal period (Thorrez et al., 2011). However, suppression of hepatic Oxct1 expression in the postnatal period is primarily attributable to the evacuation of Oxct1-expressing hematopoietic progenitors from the liver, rather than a loss of previously existing Oxct1 expression in terminally differentiated hepatocytes. In fact, expression of Oxct1 mRNA and SCOT protein in differentiated hepatocytes are extremely low (Orii et al., 2008).

SCOT is also regulated by PTMs. The enzyme is hyper-acetylated in brains of SIRT3 KO mice, which also exhibit diminished AcAc dependent acetyl-CoA production (Dittenhafer-Reed et al., 2015). Non-enzymatic nitration of tyrosine residues of SCOT also attenuates its activity, which has been reported in hearts of various diabetic mice models (Marcondes et al., 2001; Turko et al., 2001; Wang et al., 2010a). In contrast, tryptophan residue nitration augments SCOT activity (Brégère et al., 2010; Rebrin et al., 2007). Molecular mechanisms of residue-specific nitration or de-nitration designed to modulate SCOT activity may exist and require elucidation.

Controversies in Extrahepatic Ketogenesis

In mammals the primary ketogenic organ is liver, and only hepatocytes and gut epithelial cells abundantly express the mitochondrial isoform of HMGCS2 (Cotter et al., 2013a; Cotter et al., 2014; McGarry and Foster, 1980; Robinson and Williamson, 1980). Anaerobic bacterial fermentation of complex polysaccharides yields butyrate, which is absorbed by colonocytes in mammalians for terminal oxidation or ketogenesis (Cherbuy et al., 1995), which may play a role in colonocyte differentiation (Wang et al., 2016). Excluding gut epithelial cells and hepatocytes, HMGCS2 is nearly absent in almost all other mammalian cells, but the prospect of extrahepatic ketogenesis has been raised in tumor cells, astrocytes of the central nervous system, the kidney, pancreatic β cells, retinal pigment epithelium (RPE), and even in skeletal muscle (Adijanto et al., 2014; Avogaro et al., 1992; El Azzouny et al., 2016; Grabacka et al., 2016; Kang et al., 2015; Le Foll et al., 2014; Nonaka et al., 2016; Takagi et al., 2016a; Thevenet et al., 2016; Zhang et al., 2011). Ectopic HMGCS2 has been observed in tissues that lack net ketogenic capacity (Cook et al., 2016; Wentz et al., 2010), and HMGCS2 exhibits prospective ketogenesis-independent ‘moonlighting’ activities, including within the cell nucleus (Chen et al., 2016; Kostiuk et al., 2010; Meertens et al., 1998).

Any extrahepatic tissue that oxidizes ketone bodies also has the potential to accumulate ketone bodies via HMGCS2 independent mechanisms (Fig. 2A). However, there is no extrahepatic tissue in which a steady state ketone body concentration exceeds that in the circulation (Cotter et al., 2011; Cotter et al., 2013b; Harrison and Long, 1940), underscoring that ketone bodies are transported down a concentration gradient via MCT1/2-dependent mechanisms. One mechanism of apparent extrahepatic ketogenesis may actually reflect relative impairment of ketone oxidation. Additional potential explanations fall within the realm of ketone body formation. First, de novo ketogenesis may occur via reversible enzymatic activity of thiolase and SCOT (Weidemann and Krebs, 1969). When the concentration of acetyl-CoA is relatively high, reactions normally responsible for AcAc oxidation operate in the reverse direction (GOLDMAN, 1954). A second mechanism occurs when β-oxidation-derived intermediates accumulate due to a TCA cycle bottleneck, AcAc-CoA is converted to l-βOHB-CoA through a reaction catalyzed by mitochondrial 3-hydroxyacyl-CoA dehydrogenase, and further by 3-hydroxybutyryl CoA deacylase to l-βOHB, which is indistinguishable by mass spectrometry or resonance spectroscopy from the physiological enantiomer d-βOHB (Reed and Ozand, 1980). l-βOHB can be chromatographically or enzymatically distinguished from d-βOHB, and is present in extrahepatic tissues, but not in liver or blood (Hsu et al., 2011). Hepatic ketogenesis produces only d-βOHB, the only enantiomer that is a BDH substrate (Ito et al., 1984; Lincoln et al., 1987; Reed and Ozand, 1980; Scofield et al., 1982; Scofield et al., 1982). A third HMGCS2-independent mechanism generates d-βOHB through amino acid catabolism, particularly that of leucine and lysine. A fourth mechanism is only apparent because it is due to a labeling artifact and is thus termed pseudoketogenesis. This phenomenon is attributable to the reversibility of the SCOT and thiolase reactions, and can cause overestimation of ketone body turnover due to the isotopic dilution of ketone body tracer in extrahepatic tissue (Des Rosiers et al., 1990; Fink et al., 1988). Nonetheless, pseudoketogenesis may be negligible in most contexts (Bailey et al., 1990; Keller et al., 1978). A schematic (Fig. 2A) indicates a useful approach to apply while considering elevated tissue steady state concentration of ketones.

  Kidney has recently received attention as a potentially ketogenic organ. In the vast majority of states, the kidney is a net consumer of liver-derived ketone bodies, excreting or reabsorbing ketone bodies from the bloodstream, and kidney is generally not a net ketone body generator or concentrator (Robinson and Williamson, 1980). The authors of a classical study concluded that minimal renal ketogenesis quantified in an artificial experimental system was not physiologically relevant (Weidemann and Krebs, 1969). Recently, renal ketogenesis has been inferred in diabetic and autophagy deficient mouse models, but it is more likely that multi-organ shifts in metabolic homeostasis alter integrative ketone metabolism through inputs on multiple organs (Takagi et al., 2016a; Takagi et al., 2016b; Zhang et al., 2011). One recent publication suggested renal ketogenesis as a protective mechanism against ischemia-reperfusion injury in the kidney (Tran et al., 2016). Absolute steady state concentrations of βOHB from extracts of mice renal tissue were reported at ~4–12 mM. To test whether this was tenable, we quantified βOHB concentrations in renal extracts from fed and 24h fasted mice. Serum βOHB concentrations increased from ~100 µM to 2 mM with 24h fasting (Fig. 2B), while renal steady state βOHB concentrations approximate 100 µM in the fed state, and only 1 mM in the 24h fasted state (Fig. 2C–E), observations that are consistent with concentrations quantified over 45 years ago (Hems and Brosnan, 1970). It remains possible that in ketotic states, liver-derived ketone bodies could be renoprotective, but evidence for renal ketogenesis requires further substantiation. Compelling evidence that supports true extrahepatic ketogenesis was presented in RPE (Adijanto et al., 2014). This intriguing metabolic transformation was suggested to potentially allow RPE-derived ketones to flow to photoreceptor or Müller glia cells, which could aid in the regeneration of photoreceptor outer segment.

βOHB as a Signaling Mediator

Although they are energetically rich, ketone bodies exert provocative ‘non-canonical’ signaling roles in cellular homeostasis (Fig. 3) (Newman and Verdin, 2014; Rojas-Morales et al., 2016). For example, βOHB inhibits Class I HDACs, which increases histone acetylation and thereby induces the expression of genes that curtail oxidative stress (Shimazu et al., 2013). βOHB itself is a histone covalent modifier at lysine residues in livers of fasted or streptozotocin induced diabetic mice (Xie et al., 2016) (also see below, The integration of ketone body metabolism, post-translational modification, and cell physiology, and Ketone bodies, oxidative stress, and neuroprotection).

 

βOHB is also an effector via G-protein coupled receptors. Through unclear molecular mechanisms, it suppresses sympathetic nervous system activity and reduces total energy expenditure and heart rate by inhibiting short chain fatty acid signaling through G protein coupled receptor 41 (GPR41) (Kimura et al., 2011). One of the most studied signaling effects of βOHB proceeds through GPR109A (also known as HCAR2), a member of the hydrocarboxylic acid GPCR sub-family expressed in adipose tissues (white and brown) (Tunaru et al., 2003), and in immune cells (Ahmed et al., 2009). βOHB is the only known endogenous ligand of GPR109A receptor (EC50 ~770 µM) activated by d-βOHB, l-βOHB, and butyrate, but not AcAc (Taggart et al., 2005). The high concentration threshold for GPR109A activation is achieved through adherence to a ketogenic diet, starvation, or during ketoacidosis, leading to inhibition of adipose tissue lipolysis. The anti-lipolytic effect of GPR109A proceeds through inhibition of adenylyl cyclase and decreased cAMP, inhibiting hormone sensitive triglyceride lipase (Ahmed et al., 2009; Tunaru et al., 2003). This creates a negative feedback loop in which ketosis places a modulatory brake on ketogenesis by diminishing the release of non-esterified fatty acids from adipocytes (Ahmed et al., 2009; Taggart et al., 2005), an effect that can be counterbalanced by the sympathetic drive that stimulates lipolysis. Niacin (vitamin B3, nicotinic acid) is a potent (EC50 ~ 0.1 µM) ligand for GRP109A, effectively employed for decades for dyslipidemias (Benyo et al., 2005; Benyo et al., 2006; Fabbrini et al., 2010a; Lukasova et al., 2011; Tunaru et al., 2003). While niacin enhances reverse cholesterol transport in macrophages and reduces atherosclerotic lesions (Lukasova et al., 2011), the effects of βOHB on atherosclerotic lesions remain unknown. Although GPR109A receptor exerts protective roles, and intriguing connections exist between ketogenic diet use in stroke and neurodegenerative diseases (Fu et al., 2015; Rahman et al., 2014), a protective role of βOHB via GPR109A has not been demonstrated in vivo.

Finally, βOHB may influence appetite and satiety. A meta-analysis of studies that measured the effects of ketogenic and very low energy diets concluded that participants consuming these diets exhibit higher satiety, compared to control diets (Gibson et al., 2015). However, a plausible explanation for this effect is the additional metabolic or hormonal elements that might modulate appetite. For example, mice maintained on a rodent ketogenic diet exhibited increased energy expenditure compared to chow control-fed mice, despite similar caloric intake, and circulating leptin or genes of peptides regulating feeding behavior were not changed (Kennedy et al., 2007). Among proposed mechanisms that suggest appetite suppression by βOHB includes both signaling and oxidation (Laeger et al., 2010). Hepatocyte specific deletion of circadian rhythm gene (Per2) and chromatin immunoprecipitation studies revealed that PER2 directly activates the Cpt1a gene, and indirectly regulates Hmgcs2, leading to impaired ketosis in Per2 knockout mice (Chavan et al., 2016). These mice exhibited impaired food anticipation, which was partially restored by systemic βOHB administration. Future studies will be needed to confirm the central nervous system as a direct βOHB target, and whether ketone oxidation is required for the observed effects, or whether another signaling mechanism is involved. Other investigators have invoked the possibility of local astrocyte-derived ketogenesis within the ventromedial hypothalamus as a regulator of food intake, but these preliminary observations also will benefit from genetic and flux-based assessments (Le Foll et al., 2014). The relationship between ketosis and nutrient deprivation remains of interest because hunger and satiety are important elements in failed weight loss attempts.

Integration of Ketone Body Metabolism, Post-Translational Modification, and Cell Physiology

Ketone bodies contribute to compartmentalized pools of acetyl-CoA, a key intermediate that exhibits prominent roles in cellular metabolism (Pietrocola et al., 2015). One role of acetyl-CoA is to serve as a substrate for acetylation, an enzymatically-catalyzed histone covalent modification (Choudhary et al., 2014; Dutta et al., 2016; Fan et al., 2015; Menzies et al., 2016). A large number of dynamically acetylated mitochondrial proteins, many of which may occur through non-enzymatic mechanisms, have also emerged from computational proteomics studies (Dittenhafer-Reed et al., 2015; Hebert et al., 2013; Rardin et al., 2013; Shimazu et al., 2010). Lysine deacetylases use a zinc cofactor (e.g., nucleocytosolic HDACs) or NAD+ as co-substrate (sirtuins, SIRTs) (Choudhary et al., 2014; Menzies et al., 2016). The acetylproteome serves as both sensor and effector of the total cellular acetyl-CoA pool, as physiological and genetic manipulations each result in non-enzymatic global variations of acetylation (Weinert et al., 2014). As intracellular metabolites serve as modulators of lysine residue acetylation, it is important to consider the role of ketone bodies, whose abundance is highly dynamic.

βOHB is an epigenetic modifier through at least two mechanisms. Increased βOHB levels induced by fasting, caloric restriction, direct administration or prolonged exercise provoke HDAC inhibition or histone acetyltransferase activation (Marosi et al., 2016; Sleiman et al., 2016) or to oxidative stress (Shimazu et al., 2013). βOHB inhibition of HDAC3 could regulate newborn metabolic physiology (Rando et al., 2016). Independently, βOHB itself directly modifies histone lysine residues (Xie et al., 2016). Prolonged fasting, or steptozotocin-induced diabetic ketoacidosis increased histone β-hydroxybutyrylation. Although the number of lysine β-hydroxybutyrylation and acetylation sites was comparable, stoichiometrically greater histone β-hydroxybutyrylation than acetylation was observed. Distinct genes were impacted by histone lysine β-hydroxybutyrylation, versus acetylation or methylation, suggesting distinct cellular functions. Whether β-hydroxybutyrylation is spontaneous or enzymatic is not known, but expands the range of mechanisms through ketone bodies dynamically influence transcription.

Essential cell reprogramming events during caloric restriction and nutrient deprivation may be mediated in SIRT3- and SIRT5-dependent mitochondrial deacetylation and desuccinylation, respectively, regulating ketogenic and ketolytic proteins at post-translational level in liver and extrahepatic tissues (Dittenhafer-Reed et al., 2015; Hebert et al., 2013; Rardin et al., 2013; Shimazu et al., 2010). Even though stoichiometric comparison of occupied sites does not necessarily link directly to shifts in metabolic flux, mitochondrial acetylation is dynamic and may be driven by acetyl-CoA concentration or mitochondrial pH, rather than enzymatic acetyltransferases (Wagner and Payne, 2013). That SIRT3 and SIRT5 modulate activities of ketone body metabolizing enzymes provokes the question of the reciprocal role of ketones in sculpting the acetylproteome, succinylproteome, and other dynamic cellular targets. Indeed, as variations of ketogenesis reflect NAD+ concentrations, ketone production and abundance could regulate sirtuin activity, thereby influencing total acetyl-CoA/succinyl-CoA pools, the acylproteome, and thus mitochondrial and cell physiology. β-hydroxybutyrylation of enzyme lysine residues could add another layer to cellular reprogramming. In extrahepatic tissues, ketone body oxidation may stimulate analogous changes in cell homeostasis. While compartmentation of acetyl-CoA pools is highly regulated and coordinates a broad spectrum of cellular changes, the ability of ketone bodies to directly shape both mitochondrial and cytoplasmic acetyl-CoA concentrations requires elucidation (Chen et al., 2012; Corbet et al., 2016; Pougovkina et al., 2014; Schwer et al., 2009; Wellen and Thompson, 2012). Because acetyl-CoA concentrations are tightly regulated, and acetyl-CoA is membrane impermeant, it is crucial to consider the driver mechanisms coordinating acetyl-CoA homeostasis, including the rates of production and terminal oxidation in the TCA cycle, conversion into ketone bodies, mitochondrial efflux via carnitine acetyltransferase (CrAT), or acetyl-CoA export to cytosol after conversion to citrate and release by ATP citrate lyase (ACLY). The key roles of these latter mechanisms in cell acetylproteome and homeostasis require matched understanding of the roles of ketogenesis and ketone oxidation (Das et al., 2015; McDonnell et al., 2016; Moussaieff et al., 2015; Overmyer et al., 2015; Seiler et al., 2014; Seiler et al., 2015; Wellen et al., 2009; Wellen and Thompson, 2012). Convergent technologies in metabolomics and acylproteomics in the setting of genetically manipulated models will be required to specify targets and outcomes.

Anti- and Pro-Inflammatory Responses to Ketone Bodies

Ketosis and ketone bodies modulate inflammation and immune cell function, but varied and even discrepant mechanisms have been proposed. Prolonged nutrient deprivation reduces inflammation (Youm et al., 2015), but the chronic ketosis of type 1 diabetes is a pro-inflammatory state (Jain et al., 2002; Kanikarla-Marie and Jain, 2015; Kurepa et al., 2012). Mechanism-based signaling roles for βOHB in inflammation emerge because many immune system cells, including macrophages or monocytes, abundantly express GPR109A. While βOHB exerts a predominantly anti-inflammatory response (Fu et al., 2014; Gambhir et al., 2012; Rahman et al., 2014; Youm et al., 2015), high concentrations of ketone bodies, particularly AcAc, may trigger a pro-inflammatory response (Jain et al., 2002; Kanikarla-Marie and Jain, 2015; Kurepa et al., 2012).

Anti-inflammatory roles of GPR109A ligands in atherosclerosis, obesity, inflammatory bowel disease, neurological disease, and cancer have been reviewed (Graff et al., 2016). GPR109A expression is augmented in RPE cells of diabetic models, human diabetic patients (Gambhir et al., 2012), and in microglia during neurodegeneration (Fu et al., 2014). Anti-inflammatory effects of βOHB are enhanced by GPR109A overexpression in RPE cells, and abrogated by pharmacological inhibition or genetic knockout of GPR109A (Gambhir et al., 2012). βOHB and exogenous nicotinic acid (Taggart et al., 2005), both confer anti-inflammatory effects in TNFα or LPS-induced inflammation by decreasing the levels of pro-inflammatory proteins (iNOS, COX-2), or secreted cytokines (TNFα, IL-1β, IL-6, CCL2/MCP-1), in part through inhibiting NF-κB translocation (Fu et al., 2014; Gambhir et al., 2012). βOHB decreases ER stress and the NLRP3 inflammasome, activating the antioxidative stress response (Bae et al., 2016; Youm et al., 2015). However, in neurodegenerative inflammation, GPR109A-dependent βOHB-mediated protection does not involve inflammatory mediators like MAPK pathway signaling (e.g., ERK, JNK, p38) (Fu et al., 2014), but may require COX-1-dependent PGD2 production (Rahman et al., 2014). It is intriguing that macrophage GPR109A is required to exert a neuroprotective effect in an ischemic stroke model (Rahman et al., 2014), but the ability of βOHB to inhibit the NLRP3 inflammasome in bone marrow derived macrophages is GPR109A independent (Youm et al., 2015). Although most studies link βOHB to anti-inflammatory effects, βOHB may be pro-inflammatory and increase markers of lipid peroxidation in calf hepatocytes (Shi et al., 2014). Anti- versus pro-inflammatory effects of βOHB may thus depend on cell type, βOHB concentration, exposure duration, and the presence or absence of co-modulators.

Unlike βOHB, AcAc may activate pro-inflammatory signaling. Elevated AcAc, especially with a high glucose concentration, intensifies endothelial cell injury through an NADPH oxidase/oxidative stress dependent mechanism (Kanikarla-Marie and Jain, 2015). High AcAc concentrations in umbilical cord of diabetic mothers were correlated with higher protein oxidation rate and MCP-1 concentration (Kurepa et al., 2012). High AcAc in diabetic patients was correlated with TNFα expression (Jain et al., 2002), and AcAc, but not βOHB, induced TNFα, MCP-1 expression, ROS accumulation, and diminished cAMP level in U937 human monocyte cells (Jain et al., 2002; Kurepa et al., 2012).

Ketone body dependent signaling phenomena are frequently triggered only with high ketone body concentrations (> 5 mM), and in the case of many studies linking ketones to pro- or anti-inflammatory effects, through unclear mechanisms. In addition, due to the contradictory effects of βOHB versus AcAc on inflammation, and the ability of AcAc/βOHB ratio to influence mitochondrial redox potential, the best experiments assessing the roles of ketone bodies on cellular phenotypes compare the effects of AcAc and βOHB in varying ratios, and at varying cumulative concentrations [e.g., (Saito et al., 2016)]. Finally, AcAc can be purchased commercially only as a lithium salt or as an ethyl ester that requires base hydrolysis before use. Lithium cation independently induces signal transduction cascades (Manji et al., 1995), and AcAc anion is labile. Finally, studies using racemic d/l-βOHB can be confounded, as only the d-βOHB stereoisomer can be oxidized to AcAc, but d-βOHB and l-βOHB can each signal through GPR109A, inhibit the NLRP3 inflammasome, and serve as lipogenic substrates.

Ketone Bodies, Oxidative Stress, and Neuroprotection

Oxidative stress is typically defined as a state in which ROS are presented in excess, due to excessive production and/or impaired elimination. Antioxidant and oxidative stress mitigating roles of ketone bodies have been widely described both in vitro and in vivo, particularly in the context of neuroprotection. As most neurons do not effectively generate high-energy phosphates from fatty acids but do oxidize ketone bodies when carbohydrates are in short supply, neuroprotective effects of ketone bodies are especially important (Cahill GF Jr, 2006; Edmond et al., 1987; Yang et al., 1987). In oxidative stress models, BDH1 induction and SCOT suppression suggest that ketone body metabolism can be reprogrammed to sustain diverse cell signaling, redox potential, or metabolic requirements (Nagao et al., 2016; Tieu et al., 2003).

Ketone bodies decrease the grades of cellular damage, injury, death and lower apoptosis in neurons and cardiomyocytes (Haces et al., 2008; Maalouf et al., 2007; Nagao et al., 2016; Tieu et al., 2003). Invoked mechanisms are varied and not always linearly related to concentration. Low millimolar concentrations of (d or l)-βOHB scavenge ROS (hydroxyl anion), while AcAc scavenges numerous ROS species, but only at concentrations that exceed the physiological range (IC50 20–67 mM) (Haces et al., 2008). Conversely, a beneficial influence over the electron transport chain’s redox potential is a mechanism commonly linked to d-βOHB. While all three ketone bodies (d/l-βOHB and AcAc) reduced neuronal cell death and ROS accumulation triggered by chemical inhibition of glycolysis, only d-βOHB and AcAc prevented neuronal ATP decline. Conversely, in a hypoglycemic in vivo model, (d or l)-βOHB, but not AcAc prevented hippocampal lipid peroxidation (Haces et al., 2008; Maalouf et al., 2007; Marosi et al., 2016; Murphy, 2009; Tieu et al., 2003). In vivo studies of mice fed a ketogenic diet (87% kcal fat and 13% protein) exhibited neuroanatomical variation of antioxidant capacity (Ziegler et al., 2003), where the most profound changes were observed in hippocampus, with increase glutathione peroxidase and total antioxidant capacities.

Ketogenic diet, ketone esters (also see Therapeutic use of ketogenic diet and exogenous ketone bodies), or βOHB administration exert neuroprotection in models of ischemic stroke (Rahman et al., 2014); Parkinson’s disease (Tieu et al., 2003); central nervous system oxygen toxicity seizure (D’Agostino et al., 2013); epileptic spasms (Yum et al., 2015); mitochondrial encephalomyopathy, lactic acidosis and stroke-like (MELAS) episodes syndrome (Frey et al., 2016) and Alzheimer’s disease (Cunnane and Crawford, 2003; Yin et al., 2016). Conversely, a recent report demonstrated histopathological evidence of neurodegenerative progression by a ketogenic diet in a transgenic mouse model of abnormal mitochondrial DNA repair, despite increases in mitochondrial biogenesis and antioxidant signatures (Lauritzen et al., 2016). Other conflicting reports suggest that exposure to high ketone body concentrations elicits oxidative stress. High βOHB or AcAc doses induced nitric oxide secretion, lipid peroxidation, reduced expression of SOD, glutathione peroxidase and catalase in calf hepatocytes, while in rat hepatocytes the MAPK pathway induction was attributed to AcAc but not βOHB (Abdelmegeed et al., 2004; Shi et al., 2014; Shi et al., 2016).

Taken together, most reports link βOHB to attenuation of oxidative stress, as its administration inhibits ROS/superoxide production, prevents lipid peroxidation and protein oxidation, increases antioxidant protein levels, and improves mitochondrial respiration and ATP production (Abdelmegeed et al., 2004; Haces et al., 2008; Jain et al., 1998; Jain et al., 2002; Kanikarla-Marie and Jain, 2015; Maalouf et al., 2007; Maalouf and Rho, 2008; Marosi et al., 2016; Tieu et al., 2003; Yin et al., 2016; Ziegler et al., 2003). While AcAc has been more directly correlated than βOHB with the induction of oxidative stress, these effects are not always easily dissected from prospective pro-inflammatory responses (Jain et al., 2002; Kanikarla-Marie and Jain, 2015; Kanikarla-Marie and Jain, 2016). Moreover, it is critical to consider that the apparent antioxidative benefit conferred by pleiotropic ketogenic diets may not be transduced by ketone bodies themselves, and neuroprotection conferred by ketone bodies may not entirely be attributable to oxidative stress. For example during glucose deprivation, in a model of glucose deprivation in cortical neurons, βOHB stimulated autophagic flux and prevented autophagosome accumulation, which was associated with decreased neuronal death (Camberos-Luna et al., 2016). d-βOHB induces also the canonical antioxidant proteins FOXO3a, SOD, MnSOD, and catalase, prospectively through HDAC inhibition (Nagao et al., 2016; Shimazu et al., 2013).

Non-Alcoholic Fatty Liver Disease (NAFLD) and Ketone Body Metabolism

Obesity-associated NAFLD and nonalcoholic steatohepatitis (NASH) are the most common causes of liver disease in Western countries (Rinella and Sanyal, 2016), and NASH-induced liver failure is one of the most common reasons for liver transplantation. While excess storage of triacylglycerols in hepatocytes >5% of liver weight (NAFL) alone does not cause degenerative liver function, the progression to NAFLD in humans correlates with systemic insulin resistance and increased risk of type 2 diabetes, and may contribute to the pathogenesis of cardiovascular disease and chronic kidney disease (Fabbrini et al., 2009; Targher et al., 2010; Targher and Byrne, 2013). The pathogenic mechanisms of NAFLD and NASH are incompletely understood but include abnormalities of hepatocyte metabolism, hepatocyte autophagy and endoplasmic reticulum stress, hepatic immune cell function, adipose tissue inflammation, and systemic inflammatory mediators (Fabbrini et al., 2009; Masuoka and Chalasani, 2013; Targher et al., 2010; Yang et al., 2010). Perturbations of carbohydrate, lipid, and amino acid metabolism occur in and contribute to obesity, diabetes, and NAFLD in humans and in model organisms [reviewed in (Farese et al., 2012; Lin and Accili, 2011; Newgard, 2012; Samuel and Shulman, 2012; Sun and Lazar, 2013)]. While hepatocyte abnormalities in cytoplasmic lipid metabolism are commonly observed in NAFLD (Fabbrini et al., 2010b), the role of mitochondrial metabolism, which governs oxidative disposal of fats is less clear in NAFLD pathogenesis. Abnormalities of mitochondrial metabolism occur in and contribute to NAFLD/NASH pathogenesis (Hyotylainen et al., 2016; Serviddio et al., 2011; Serviddio et al., 2008; Wei et al., 2008). There is general (Felig et al., 1974; Iozzo et al., 2010; Koliaki et al., 2015; Satapati et al., 2015; Satapati et al., 2012; Sunny et al., 2011) but not uniform (Koliaki and Roden, 2013; Perry et al., 2016; Rector et al., 2010) consensus that, prior to the development of bona fide NASH, hepatic mitochondrial oxidation, and in particular fat oxidation, is augmented in obesity, systemic insulin resistance, and NAFLD. It is likely that as NAFLD progresses, oxidative capacity heterogenity, even among individual mitochondria, emerges, and ultimately oxidative function becomes impaired (Koliaki et al., 2015; Rector et al., 2010; Satapati et al., 2008; Satapati et al., 2012).

Ketogenesis is often used as a proxy for hepatic fat oxidation. Impairments of ketogenesis emerge as NAFLD progresses in animal models, and likely in humans. Through incompletely defined mechanisms, hyperinsulinemia suppresses ketogenesis, possibly contributing to hypoketonemia compared to lean controls (Bergman et al., 2007; Bickerton et al., 2008; Satapati et al., 2012; Soeters et al., 2009; Sunny et al., 2011; Vice et al., 2005). Nonetheless, the ability of circulating ketone body concentrations to predict NAFLD is controversial (Männistö et al., 2015; Sanyal et al., 2001). Robust quantitative magnetic resonance spectroscopic methods in animal models revealed increased ketone turnover rate with moderate insulin resistance, but decreased rates were evident with more severe insulin resistance (Satapati et al., 2012; Sunny et al., 2010). In obese humans with fatty liver, ketogenic rate is normal (Bickerton et al., 2008; Sunny et al., 2011), and hence, the rates of ketogenesis are diminished relative to the increased fatty acid load within hepatocytes. Consequently, β-oxidation-derived acetyl-CoA may be directed to terminal oxidation in the TCA cycle, increasing terminal oxidation, phosphoenolpyruvate-driven gluconeogenesis via anaplerosis/cataplerosis, and oxidative stress. Acetyl-CoA also possibly undergoes export from mitochondria as citrate, a precursor substrate for lipogenesis (Fig. 4) (Satapati et al., 2015; Satapati et al., 2012; Solinas et al., 2015). While ketogenesis becomes less responsive to insulin or fasting with prolonged obesity (Satapati et al., 2012), the underlying mechanisms and downstream consequences of this remain incompletely understood. Recent evidence indicates that mTORC1 suppresses ketogenesis in a manner that may be downstream of insulin signaling (Kucejova et al., 2016), which is concordant with the observations that mTORC1 inhibits PPARα-mediated Hmgcs2 induction (Sengupta et al., 2010) (also see Regulation of HMGCS2 and SCOT/OXCT1).

 

Preliminary observations from our group suggest adverse hepatic consequences of ketogenic insufficiency (Cotter et al., 2014). To test the hypothesis that impaired ketogenesis, even in carbohydrate-replete and thus ‘non-ketogenic’ states, contributes to abnormal glucose metabolism and provokes steatohepatitis, we generated a mouse model of marked ketogenic insufficiency by administration of antisense oligonucleotides (ASO) targeted to Hmgcs2. Loss of HMGCS2 in standard low-fat chow-fed adult mice caused mild hyperglycemia and markedly increased production of hundreds of hepatic metabolites, a suite of which strongly suggested lipogenesis activation. High-fat diet feeding of mice with insufficient ketogenesis resulted in extensive hepatocyte injury and inflammation. These findings support the central hypotheses that (i) ketogenesis is not a passive overflow pathway but rather a dynamic node in hepatic and integrated physiological homeostasis, and (ii) prudent ketogenic augmentation to mitigate NAFLD/NASH and disordered hepatic glucose metabolism is worthy of exploration.

How might impaired ketogenesis contribute to hepatic injury and altered glucose homeostasis? The first consideration is whether the culprit is deficiency of ketogenic flux, or ketones themselves. A recent report suggests that ketone bodies may mitigate oxidative stress-induced hepatic injury in response to n-3 polyunsaturated fatty acids (Pawlak et al., 2015). Recall that due to lack of SCOT expression in hepatocytes, ketone bodies are not oxidized, but they can contribute to lipogenesis, and serve a variety of signaling roles independent of their oxidation (also see Non-oxidative metabolic fates of ketone bodies and βOHB as a signaling mediator). It is also possible that hepatocyte-derived ketone bodies may serve as a signal and/or metabolite for neighboring cell types within the hepatic acinus, including stellate cells and Kupffer cell macrophages. While the limited literature available suggests that macrophages are unable to oxidize ketone bodies, this has only been measured using classical methodologies, and only in peritoneal macrophages (Newsholme et al., 1986; Newsholme et al., 1987), indicating that a re-assessment is appropriate given abundant SCOT expression in bone marrow-derived macrophages (Youm et al., 2015).

Hepatocyte ketogenic flux may also be cytoprotective. While salutary mechanisms may not depend on ketogenesis per se, low carbohydrate ketogenic diets have been associated with amelioration of NAFLD (Browning et al., 2011; Foster et al., 2010; Kani et al., 2014; Schugar and Crawford, 2012). Our observations indicate that hepatocyte ketogenesis may feedback and regulate TCA cycle flux, anaplerotic flux, phosphoenolpyruvate-derived gluconeogenesis (Cotter et al., 2014), and even glycogen turnover. Ketogenic impairment directs acetyl-CoA to increase TCA flux, which in liver has been linked to increased ROS-mediated injury (Satapati et al., 2015; Satapati et al., 2012); forces diversion of carbon into de novo synthesized lipid species that could prove cytotoxic; and prevents NADH re-oxidation to NAD+ (Cotter et al., 2014) (Fig. 4). Taken together, future experiments are required to address mechanisms through which relative ketogenic insufficiency may become maladaptive, contribute to hyperglycemia, provoke steatohepatitis, and whether these mechanisms are operant in human NAFLD/NASH. As epidemiological evidence suggests impaired ketogenesis during the progression of steatohepatitis (Embade et al., 2016; Marinou et al., 2011; Männistö et al., 2015; Pramfalk et al., 2015; Safaei et al., 2016) therapies that increase hepatic ketogenesis could prove salutary (Degirolamo et al., 2016; Honda et al., 2016).

Ketone Bodies and Heart Failure (HF)

With a metabolic rate exceeding 400 kcal/kg/day, and a turnover of 6–35 kg ATP/day, the heart is the organ with the highest energy expenditure and oxidative demand (Ashrafian et al., 2007; Wang et al., 2010b). The vast majority of myocardial energy turnover resides within mitochondria, and 70% of this supply originates from FAO. The heart is omnivorous and flexible under normal conditions, but the pathologically remodeling heart (e.g., due to hypertension or myocardial infarction) and the diabetic heart each become metabolically inflexible (Balasse and Fery, 1989; BING, 1954; Fukao et al., 2004; Lopaschuk et al., 2010; Taegtmeyer et al., 1980; Taegtmeyer et al., 2002; Young et al., 2002). Indeed, genetically programmed abnormalities of cardiac fuel metabolism in mouse models provoke cardiomyopathy (Carley et al., 2014; Neubauer, 2007). Under physiological conditions normal hearts oxidize ketone bodies in proportion to their delivery, at the expense of fatty acid and glucose oxidation, and myocardium is the highest ketone body consumer per unit mass (BING, 1954; Crawford et al., 2009; GARLAND et al., 1962; Hasselbaink et al., 2003; Jeffrey et al., 1995; Pelletier et al., 2007; Tardif et al., 2001; Yan et al., 2009). Compared to fatty acid oxidation, ketone bodies are more energetically efficient, yielding more energy available for ATP synthesis per molecule of oxygen invested (P/O ratio) (Kashiwaya et al., 2010; Sato et al., 1995; Veech, 2004). Ketone body oxidation also yields potentially higher energy than FAO, keeping ubiquinone oxidized, which raises redox span in the electron transport chain and makes more energy available to synthetize ATP (Sato et al., 1995; Veech, 2004). Oxidation of ketone bodies may also curtail ROS production, and thus oxidative stress (Veech, 2004).

Preliminary interventional and observational studies indicate a potential salutary role of ketone bodies in the heart. In the experimental ischemia/reperfusion injury context, ketone bodies conferred potential cardioprotective effects (Al-Zaid et al., 2007; Wang et al., 2008), possibly due to the increase mitochondrial abundance in heart or up-regulation of crucial oxidative phosphorylation mediators (Snorek et al., 2012; Zou et al., 2002). Recent studies indicate that ketone body utilization is increased in failing hearts of mice (Aubert et al., 2016) and humans (Bedi et al., 2016), supporting prior observations in humans (BING, 1954; Fukao et al., 2000; Janardhan et al., 2011; Longo et al., 2004; Rudolph and Schinz, 1973; Tildon and Cornblath, 1972). Circulating ketone body concentrations are increased in heart failure patients, in direct proportion to filling pressures, observations whose mechanism and significance remains unknown (Kupari et al., 1995; Lommi et al., 1996; Lommi et al., 1997; Neely et al., 1972), but mice with selective SCOT deficiency in cardiomyocytes exhibit accelerated pathological ventricular remodeling and ROS signatures in response to surgically induced pressure overload injury (Schugar et al., 2014).

Recent intriguing observations in diabetes therapy have revealed a potential link between myocardial ketone metabolism and pathological ventricular remodeling (Fig. 5). Inhibition of the renal proximal tubular sodium/glucose co-transporter 2 (SGLT2i) increases circulating ketone body concentrations in humans (Ferrannini et al., 2016a; Inagaki et al., 2015) and mice (Suzuki et al., 2014) via increased hepatic ketogenesis (Ferrannini et al., 2014; Ferrannini et al., 2016a; Katz and Leiter, 2015; Mudaliar et al., 2015). Strikingly, at least one of these agents decreased HF hospitalization (e.g., as revealed by the EMPA-REG OUTCOME trial), and improved cardiovascular mortality (Fitchett et al., 2016; Sonesson et al., 2016; Wu et al., 2016a; Zinman et al., 2015). While the driver mechanisms behind beneficial HF outcomes to linked SGLT2i remain actively debated, the survival benefit is likely multifactorial, prospectively including ketosis but also salutary effects on weight, blood pressure, glucose and uric acid levels, arterial stiffness, the sympathetic nervous system, osmotic diuresis/reduced plasma volume, and increased hematocrit (Raz and Cahn, 2016; Vallon and Thomson, 2016). Taken together, the notion that therapeutically increasing ketonemia either in HF patients, or those at high risk to develop HF, remains controversial but is under active investigation in pre-clinical and clinical studies (Ferrannini et al., 2016b; Kolwicz et al., 2016; Lopaschuk and Verma, 2016; Mudaliar et al., 2016; Taegtmeyer, 2016).

 

Ketone Bodies in Cancer Biology

Connections between ketone bodies and cancer are rapidly emerging, but studies in both animal models and humans have yielded diverse conclusions. Because ketone metabolism is dynamic and nutrient state responsive, it is enticing to pursue biological connections to cancer because of the potential for precision-guided nutritional therapies. Cancer cells undergo metabolic reprogramming in order to maintain rapid cell proliferation and growth (DeNicola and Cantley, 2015; Pavlova and Thompson, 2016). The classical Warburg effect in cancer cell metabolism arises from the dominant role of glycolysis and lactic acid fermentation to transfer energy and compensate for lower dependence on oxidative phosphorylation and limited mitochondrial respiration (De Feyter et al., 2016; Grabacka et al., 2016; Kang et al., 2015; Poff et al., 2014; Shukla et al., 2014). Glucose carbon is primarily directed through glycolysis, the pentose phosphate pathway, and lipogenesis, which together provide intermediates necessary for tumor biomass expansion (Grabacka et al., 2016; Shukla et al., 2014; Yoshii et al., 2015). Adaptation of cancer cells to glucose deprivation occurs through the ability to exploit alternative fuel sources, including acetate, glutamine, and aspartate (Jaworski et al., 2016; Sullivan et al., 2015). For example, restricted access to pyruvate reveals the ability of cancer cells to convert glutamine into acetyl-CoA by carboxylation, maintaining both energetic and anabolic needs (Yang et al., 2014). An interesting adaptation of cancer cells is the utilization of acetate as a fuel (Comerford et al., 2014; Jaworski et al., 2016; Mashimo et al., 2014; Wright and Simone, 2016; Yoshii et al., 2015). Acetate is also a substrate for lipogenesis, which is critical for tumor cell proliferation, and gain of this lipogenic conduit is associated with shorter patient survival and greater tumor burden (Comerford et al., 2014; Mashimo et al., 2014; Yoshii et al., 2015).

Non-cancer cells easily shift their energy source from glucose to ketone bodies during glucose deprivation. This plasticity may be more variable among cancer cell types, but in vivo implanted brain tumors oxidized [2,4-13C2]-βOHB to a similar degree as surrounding brain tissue (De Feyter et al., 2016). ‘Reverse Warburg effect’ or ‘two compartment tumor metabolism’ models hypothesize that cancer cells induce βOHB production in adjacent fibroblasts, furnishing the tumor cell’s energy needs (Bonuccelli et al., 2010; Martinez-Outschoorn et al., 2012). In liver, a shift in hepatocytes from ketogenesis to ketone oxidation in hepatocellular carcinoma (hepatoma) cells is consistent with activation of BDH1 and SCOT activities observed in two hepatoma cell lines (Zhang et al., 1989). Indeed, hepatoma cells express OXCT1 and BDH1 and oxidize ketones, but only when serum starved (Huang et al., 2016). Alternatively, tumor cell ketogenesis has also been proposed. Dynamic shifts in ketogenic gene expression are exhibited during cancerous transformation of colonic epithelium, a cell type that normally expresses HMGCS2, and a recent report suggested that HMGCS2 may be a prognostic marker of poor prognosis in colorectal and squamous cell carcinomas (Camarero et al., 2006; Chen et al., 2016). Whether this association requires or involves ketogenesis, or a moonlighting function of HMGCS2, remains to be determined. Conversely, apparent βOHB production by melanoma and glioblastoma cells, stimulated by the PPARα agonist fenofibrate, was associated with growth arrest (Grabacka et al., 2016). Further studies are required to characterize roles of HMGCS2/SCOT expression, ketogenesis, and ketone oxidation in cancer cells.

Beyond the realm of fuel metabolism, ketones have recently been implicated in cancer cell biology via a signaling mechanism. Analysis of BRAF-V600E+ melanoma indicated OCT1-dependent induction of HMGCL in an oncogenic BRAF-dependent manner (Kang et al., 2015). HMGCL augmentation was correlated with higher cellular AcAc concentration, which in turn enhanced BRAFV600E-MEK1 interaction, amplifying MEK-ERK signaling in a feed-forward loop that drives tumor cell proliferation and growth. These observations raise the intriguing question of prospective extrahepatic ketogenesis that then supports a signaling mechanism (also see βOHB as a signaling mediator and Controversies in extrahepatic ketogenesis). It is also important to consider independent effects of AcAc, d-βOHB, and l-βOHB on cancer metabolism, and when considering HMGCL, leucine catabolism may also be deranged.

The effects of ketogenic diets (also see Therapeutic use of ketogenic diet and exogenous ketone bodies) in cancer animal models are varied (De Feyter et al., 2016; Klement et al., 2016; Meidenbauer et al., 2015; Poff et al., 2014; Seyfried et al., 2011; Shukla et al., 2014). While epidemiological associations among obesity, cancer, and ketogenic diets are debated (Liskiewicz et al., 2016; Wright and Simone, 2016), a meta-analysis using ketogenic diets in animal models and in human studies suggested a salutary impact on survival, with benefits prospectively linked to the magnitude of ketosis, time of diet initiation, and tumor location (Klement et al., 2016; Woolf et al., 2016). Treatment of pancreatic cancer cells with ketone bodies (d-βOHB or AcAc) inhibited growth, proliferation and glycolysis, and a ketogenic diet (81% kcal fat, 18% protein, 1% carbohydrate) reduced in vivo tumor weight, glycemia, and increased muscle and body weight in animals with implanted cancer (Shukla et al., 2014). Similar results were observed using a metastatic glioblastoma cell model in mice that received ketone supplementation in the diet (Poff et al., 2014). Conversely, a ketogenic diet (91% kcal fat, 9% protein) increased circulating βOHB concentration and diminished glycemia but had no impact on either tumor volume or survival duration in glioma-bearing rats (De Feyter et al., 2016). A glucose ketone index has been proposed as a clinical indicator that improves metabolic management of ketogenic diet-induced brain cancer therapy in humans and mice (Meidenbauer et al., 2015). Taken together, roles of ketone body metabolism and ketone bodies in cancer biology are tantalizing because they each pose tractable therapeutic options, but fundamental aspects remain to be elucidated, with clear influences emerging from a matrix of variables, including (i) differences between exogenous ketone bodies versus ketogenic diet, (ii) cancer cell type, genomic polymorphisms, grade, and stage; and (iii) timing and duration of exposure to the ketotic state.

Dr Jimenez White Coat
Ketogenesis is created by ketone bodies through the breakdown of fatty acids and ketogenic amino acids. This biochemical process provides energy to various organs, specifically the brain, under circumstances of fasting as a response to an unavailability of blood glucose. Ketone bodies are mainly produced in the mitochondria of liver cells. While other cells are capable of carrying out ketogenesis, they are not as effective at doing so as liver cells. Because ketogenesis occurs in the mitochondria, its processes are regulated independently. Dr. Alex Jimenez D.C., C.C.S.T. Insight

Therapeutic Application of Ketogenic Diet and Exogenous Ketone Bodies

The applications of ketogenic diets and ketone bodies as therapeutic tools have also arisen in non-cancerous contexts including obesity and NAFLD/NASH (Browning et al., 2011; Foster et al., 2010; Schugar and Crawford, 2012); heart failure (Huynh, 2016; Kolwicz et al., 2016; Taegtmeyer, 2016); neurological and neurodegenerative disease (Martin et al., 2016; McNally and Hartman, 2012; Rho, 2015; Rogawski et al., 2016; Yang and Cheng, 2010; Yao et al., 2011); inborn errors of metabolism (Scholl-Bürgi et al, 2015); and exercise performance (Cox et al., 2016). The efficacy of ketogenic diets has been especially appreciated in therapy of epileptic seizure, particularly in drug-resistant patients. Most studies have evaluated ketogenic diets in pediatric patients, and reveal up to a ~50% reduction in seizure frequency after 3 months, with improved effectiveness in select syndromes (Wu et al., 2016b). The experience is more limited in adult epilepsy, but a similar reduction is evident, with better response in symptomatic generalized epilepsy patients (Nei et al., 2014). Underlying anti-convulsant mechanisms remain unclear, although postulated hypotheses include reduced glucose utilization/glycolysis, reprogrammed glutamate transport, indirect impact on ATP-sensitive potassium channel or adenosine A1 receptor, alteration of sodium channel isoform expression, or effects on circulating hormones including leptin (Lambrechts et al., 2016; Lin et al., 2017; Lutas and Yellen, 2013). It remains unclear whether the anti-convulsant effect is primarily attributable to ketone bodies, or due to the cascade metabolic consequences of low carbohydrate diets. Nonetheless, ketone esters (see below) appear to elevate the seizure threshold in animal models of provoked seizures (Ciarlone et al., 2016; D’Agostino et al., 2013; Viggiano et al., 2015).

Atkins-style and ketogenic, low carbohydrate diets are often deemed unpleasant, and can cause constipation, hyperuricemia, hypocalcemia, hypomagnesemia, lead to nephrolithiasis, ketoacidosis, cause hyperglycemia, and raise circulating cholesterol and free fatty acid concentrations (Bisschop et al., 2001; Kossoff and Hartman, 2012; Kwiterovich et al., 2003; Suzuki et al., 2002). For these reasons, long-term adherence poses challenges. Rodent studies commonly use a distinctive macronutrient distribution (94% kcal fat, 1% kcal carbohydrate, 5% kcal protein, Bio-Serv F3666), which provokes a robust ketosis. However, increasing the protein content, even to 10% kcal substantially diminishes the ketosis, and 5% kcal protein restriction confers confounding metabolic and physiological effects. This diet formulation is also choline depleted, another variable that influences susceptibility to liver injury, and even ketogenesis (Garbow et al., 2011; Jornayvaz et al., 2010; Kennedy et al., 2007; Pissios et al., 2013; Schugar et al., 2013). Effects of long-term consumption of ketogenic diets in mice remain incompletely defined, but recent studies in mice revealed normal survival and the absence of liver injury markers in mice on ketogenic diets over their lifespan, although amino acid metabolism, energy expenditure, and insulin signaling were markedly reprogrammed (Douris et al., 2015).

Mechanisms increasing ketosis through mechanisms alternative to ketogenic diets include the use of ingestible ketone body precursors. Administration of exogenous ketone bodies could create a unique physiological state not encountered in normal physiology, because circulating glucose and insulin concentrations are relatively normal, while cells might spare glucose uptake and utilization. Ketone bodies themselves have short half-lives, and ingestion or infusion of sodium βOHB salt to achieve therapeutic ketosis provokes an untoward sodium load. R/S-1,3-butanediol is a non-toxic dialcohol that is readily oxidized in the liver to yield d/l-βOHB (Desrochers et al., 1992). In distinct experimental contexts, this dose has been administered daily to mice or rats for as long as seven weeks, yielding circulating βOHB concentrations of up to 5 mM within 2 h of administration, which is stable for at least an additional 3h (D’Agostino et al., 2013). Partial suppression of food intake has been observed in rodents given R/S-1,3-butanediol (Carpenter and Grossman, 1983). In addition, three chemically distinct ketone esters (KEs), (i) monoester of R-1,3-butanediol and d-βOHB (R-3-hydroxybutyl R-βOHB); (ii) glyceryl-tris-βOHB; and (iii) R,S-1,3-butanediol acetoacetate diester, have also been extensively studied (Brunengraber, 1997; Clarke et al., 2012a; Clarke et al., 2012b; Desrochers et al., 1995a; Desrochers et al., 1995b; Kashiwaya et al., 2010). An inherent advantage of the former is that 2 moles of physiological d-βOHB are produced per mole of KE, following esterase hydrolysis in the intestine or liver. Safety, pharmacokinetics, and tolerance have been most extensively studied in humans ingesting R-3-hydroxybutyl R-βOHB, at doses up to 714 mg/kg, yielding circulating d-βOHB concentrations up to 6 mM (Clarke et al., 2012a; Cox et al., 2016; Kemper et al., 2015; Shivva et al., 2016). In rodents, this KE decreases caloric intake and plasma total cholesterol, stimulates brown adipose tissue, and improves insulin resistance (Kashiwaya et al., 2010; Kemper et al., 2015; Veech, 2013). Recent findings indicate that during exercise in trained athletes, R-3-hydroxybutyl R-βOHB ingestion decreased skeletal muscle glycolysis and plasma lactate concentrations, increased intramuscular triacylglycerol oxidation, and preserved muscle glycogen content, even when co-ingested carbohydrate stimulated insulin secretion (Cox et al., 2016). Further development of these intriguing results is required, because the improvement in endurance exercise performance was predominantly driven by a robust response to the KE in 2/8 subjects. Nonetheless, these results do support classical studies that indicate a preference for ketone oxidation over other substrates (GARLAND et al., 1962; Hasselbaink et al., 2003; Stanley et al., 2003; Valente-Silva et al., 2015), including during exercise, and that trained athletes may be more primed to utilize ketones (Johnson et al., 1969a; Johnson and Walton, 1972; Winder et al., 1974; Winder et al., 1975). Finally, the mechanisms that might support improved exercise performance following equal caloric intake (differentially distributed among macronutrients) and equal oxygen consumption rates remain to be determined. Clues may emerge from animal studies, as temporary exposure to R-3-hydroxybutyl R-βOHB in rats was associated with increased treadmill time, improved cognitive function, and an apparent energetic benefit in ex vivo perfused hearts (Murray et al., 2016).

Future Perspective

Once largely stigmatized as an overflow pathway capable of accumulating toxic emissions from fat combustion in carbohydrate restricted states (the ‘ketotoxic’ paradigm), recent observations support the notion that ketone body metabolism serves salutary roles even in carbohydrate-laden states, opening a ‘ketohormetic’ hypothesis. While the facile nutritional and pharmacological approaches to manipulate ketone metabolism make it an attractive therapeutic target, aggressively posed but prudent experiments remain in both the basic and translational research laboratories. Unmet needs have emerged in the domains of defining the role of leveraging ketone metabolism in heart failure, obesity, NAFLD/NASH, type 2 diabetes, and cancer. The scope and impact of ‘non-canonical’ signaling roles of ketone bodies, including regulation of PTMs that likely feed back and forward into metabolic and signaling pathways, require deeper exploration. Finally, extrahepatic ketogenesis could open intriguing paracrine and autocrine signaling mechanisms and opportunities to influence co-metabolism within the nervous system and tumors to achieve therapeutic ends.

Acknowledgments

Ncbi.nlm.nih.gov/pmc/articles/PMC5313038/

Footnotes

Ncbi.nlm.nih.gov

In conclusion, ketone bodies are created by the liver in order to be used as an energy source when there is not enough glucose readily available in the human body. Ketogenesis occurs when there are low glucose levels in the blood, particularly after other cellular carbohydrate stores have been exhausted. The purpose of the article above was to discuss the multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. The scope of our information is limited to chiropractic and spinal health issues. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .

Curated by Dr. Alex Jimenez

Referenced from: Ncbi.nlm.nih.gov/pmc/articles/PMC5313038/

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Additional Topic Discussion: Acute Back Pain

Back pain is one of the most prevalent causes of disability and missed days at work worldwide. Back pain attributes to the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments, and muscles, among other soft tissues. Injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.  

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The Function Of Ketones In Ketosis

The Function Of Ketones In Ketosis

Ketosis is a natural procedure the human body goes through on a regular basis. This method provides the cells with energy from ketones if sugar isn’t readily available. A moderate degree of ketosis occurs when we skip a meal or two, do not consume many carbohydrates throughout the day or exercise for an extended amount of time. When there is an increased demand for energy and carbohydrates are not immediately available to meet that need, the human body will subsequently begin to raise its ketone levels.

If carbohydrates continue to be limited for a considerable amount of time, ketone levels may increase further. These deeper degrees of ketosis provide many favorable effects throughout the entire body. These benefits can be taken advantage of by following the ketogenic diet. However, the majority of people are seldom in ketosis since the human body prefers to utilize sugar, or glucose, as its principal fuel supply. Below, we will discuss ketosis, ketones, and how these procedures work together to keep the cells healthy.

How Nutrients are Converted into Energy

The human body processes several kinds of nutrients to produce the energy it requires. Carbohydrates, proteins, and fats can be converted to energy in order to fuel various metabolic processes. If you consume high-carbohydrate foods or excessive amounts of protein, your cells will break these down into a simple sugar called glucose. This occurs because sugar provides the cells with the fastest source of ATP, which one of the main energy molecules required to fuel virtually every system within the human body.

By way of instance, more ATP means more cell energy and more calories result in more ATP. As a matter of fact, each calorie consumed from carbohydrates, proteins, and fats may be utilized to maximize ATP levels. The human body consumes a lot of these nutrients to maintain the proper function of all its structures. If you consume more than sufficient food, nevertheless, there’ll be too much sugar which your system does not need. But, considering this, what does the human body do with all this excess sugar? Instead of eliminating excess calories which the body does not need, it will store them as fat where it can be used later once the cells require energy.

The human body stores energy in two ways:

  • Glycogenesis. Through this procedure, excess glucose is converted into glycogen, or the stored form of glucose, which is stored in the liver and muscles. Researchers estimate that the entire human body stores about 2000 calories in the shape of muscle and liver glycogen. This generally means that glycogen levels will be used within 6 to 24 hours if no additional calories are consumed. An alternate system of energy storage may help sustain the human body when glycogen levels are reduced: lipogenesis.
  • Lipogenesis. When there are sufficient amounts of glycogen in the muscles and liver, any excess glucose is converted into fats and stores through a procedure called lipogenesis. Compared to our limited glycogen stores, our fat stores are almost infinite. These supply us with the capability to sustain ourselves for weeks to even months without enough food being available.

When food is limited and the intake of nutrients like carbohydrates are restricted, glycogenesis and lipogenesis is no longer active. Rather, these procedures are replaced with glycogenolysis and lipolysis which free energy from glycogen and fat stores throughout the human body. However, something unexpected occurs when the cells no longer have stored sugar, fat or glycogen. Fat will continue to be used as fuel but an alternate fuel source known as ketones is produced as well. Because of this, the process of ketosis occurs.

Why Does Ketosis Occur?

When you don’t have any access to foods, such as when you’re sleeping, fasting, or following the ketogenic diet, then the human body will convert some of its stored fat into exceptionally efficient energy molecules known as ketones. Ketones are synthesized following the entire breakdown of fats into fatty acids and glycerol, where we can thank our cell’s capacity to change metabolic pathways for this. Although fatty acids and glycerol are turned into fuel throughout the entire body, they’re not utilized as energy by brain cells.

Because these nutrients are converted into energy too slowly to support the function of the brain, sugar is still considered to be the principal source of fuel for the brain. This process also helps us understand why we create ketones. Without an alternate energy supply, the brain would be exceedingly vulnerable if we don’t consume enough calories. Our muscles would be broken down instantly and converted into sugar to feed our hungry brains. Without ketones, the human race would have most probably been extinct.

Dr Jimenez White Coat
Low-carbohydrate modified ketogenic diets have been demonstrated to have many health benefits, including weight loss and the increased ability to help fight diabetes. These type of diets have a remarkable way of providing energy for the brain. Research studies have discovered that entering ketosis has the ability to reduce insulin levels, freeing fat from fat cells. Researchers have also shown that the ketogenic diet can have a significant metabolic advantage, which leads to more calories burned than with any other diet. Dr. Alex Jimenez D.C., C.C.S.T. Insight

The Way Ketones are Produced

The human body breaks down fat into fatty acids and glycerol which may be utilized for fuel in the cells directly but not by the brain. To fulfill the requirements of the brain, the fatty acids from fats and glycerol go through the liver where they’re then converted into glucose, or sugar, and ketones. Glycerol undergoes a process called gluconeogenesis, which transforms it into glucose, where fatty acids are converted to ketone bodies through a procedure called ketogenesis. As a consequence of ketogenesis, a ketone body called acetoacetate is generated. Acetoacetate is then converted to two different types of ketone bodies:

  • Beta-hydroxybutyrate (BHB). After being keto-adapted for several weeks, the cells will start to convert acetoacetate into BHB because it’s a more efficient source of fuel where it destroys an extra chemical reaction which provides more energy to the cell compared to acetoacetate. Research studies have demonstrated that the human body and brain favor utilizing BHB and acetoacetate for energy because the cells can utilize it 70 percent better than they can sugar or glucose.
  • Acetone. This substance can occasionally be metabolized into glucose, however, it is largely eliminated as waste. This is what specifically provides the distinctly smelling breath which many ketogenic dieters have learned to understand.

Over time, the human body will release less surplus ketone bodies, or acetone, and, should you utilize keto sticks to monitor your degree of ketosis, you might believe it’s slowing down. As the brain burns off BHB as fuel, the cells attempt to present the brain with as much effective energy as they can. This is why long-term low-carbohydrate users won’t show profound levels of ketosis in their urine tests. As a matter of fact, long-term keto dieters can endure around 50 percent of their basal energy demands and 70 percent of their brain’s energy demands from ketones. Therefore, you shouldn’t allow the urine tests to fool you.

The Significance of Gluconeogenesis

Regardless of how keto-adapted the human body may become, the cells will still require glucose to function properly. To satisfy the energy demands of the human mind and body which can’t be fulfilled by ketones, the liver will initiate a process called gluconeogenesis. Amino acids in proteins and lactate in the muscles may also be transformed into glucose.

By converting amino acids, glycerol, and lactate into glucose, the liver can satisfy the glucose demands of the human body and brain during times of fasting and carbohydrate limitation. That is the reason why there’s not any crucial requirement for carbohydrates to be included in our diet. The liver will, generally, make sure to have sufficient sugar in the blood for your own cells to survive.

It’s important to remember, however, that certain variables, such as eating too much protein, may get in the way of ketosis and boost the demand for gluconeogenesis. Insulin levels and ketone production are closely connected. Protein sources, which are generally consumed on the ketogenic diet, can also increase insulin levels. In response to a rise in insulin levels, ketogenesis is downregulated, which raises the demand for gluconeogenesis to generate more sugar.

This is the reason why eating too much protein may impair your ability to enter ketosis. But this doesn’t necessarily mean you ought to limit your protein intake either. By restricting protein intake, your muscle cells will be employed to generate the sugar your body and brain demand for fuel. With proper guidance, you can consum the perfect quantity of protein your body needs to maintain muscle mass and fulfill your glucose needs when you’re on the road to ketosis.

Recognizing the Path to Ketosis

Almost all of our understanding behind ketosis originates from research studies on people who have fasted from all foods, not only from ketogenic dieters. However, we could make many inferences concerning the ketogenic diet out of what the researchers discovered from the research studies on fasting. First, let us look at the phases the body goes through during fasting:

Stage 1 – The glycogen depletion phase – 6 to 24 hours of fasting

In this phase, most energy is produced by glycogen. During this time, hormone levels begin to change, causing increases in gluconeogenesis and fat burning, however, ketone generation isn’t active yet.

Stage 2 – The gluconeogenic stage – 2 to 10 days of fasting

In this phase, glycogen is totally depleted and gluconeogenesis supplies the cells with energy. Ketones begin to be generated at reduced levels. You will notice you have keto breath and are urinating more frequently due to greater acetone levels in your blood. The timeframe for this phase is so extensive (two to ten days) since it is dependent upon who is fasting. By way of instance, healthy men and obese people have a tendency to remain in the gluconeogenic phase for extended periods of time compared to healthy women.

Stage 3 – The ketogenic stage – after 2 days of fasting or more

This phase is characterized by a decrease in protein breakdown for energy through an increase in fat and ketone usage. At this phase, you will surely be in ketosis. Every individual can enter this point at various rates based on lifestyle and genetic variables, their physical activity levels, and the number of times they fasted and/or restricted carbohydrates before. Whether you’re following the ketogenic diet or fasting, you may go through these phases, but this doesn’t guarantee the same benefits fasting as you do from the keto diet.

Ketogenic Diet Ketosis vs Starvation Ketosis

The ketosis which you experience on the ketogenic diet is considered to be a lot safer and healthier compared to the ketosis you get to when fasting. During the time you’re fasting, the human body doesn’t have any food resources, therefore it begins converting the protein from your muscles into sugar. This induces rapid muscle reduction.

The ketogenic diet, on the other hand, provides us with the healthiest and safest way to experience the advantages of ketosis. Limiting carbohydrates while keeping sufficient caloric intake from protein and fat permits the ketogenic procedure to sustain muscle tissue by employing ketosis and the ketone bodies we generate for fuel without having to utilize valuable muscle mass. Many research studies have discovered that ketones can also have an array of beneficial effects throughout the entire body too.

Ketoacidosis: The Bad Side of Ketosis

Ketoacidosis is a potentially lethal condition which occurs when excessive ketones accumulate in the blood. Some healthcare professionals may advise against increasing your ketone levels with the ketogenic diet because they fear you could enter ketoacidosis. The practice of ketosis is closely governed by the liver, and also the entire body infrequently generates more ketones then it requires for fuel. That is the reason why the ketogenic diet has been referred to as a safe and effective way to enter ketosis.

Ketoacidosis, on the other hand, is more likely to occur in type 1 and type 2 diabetics who don’t have their glucose under control. The mix of insulin deficiency and higher glucose levels, which are generally found in people with diabetes, produce a vicious cycle which causes ketones to build up in the blood. By limiting carbohydrates, nevertheless, healthy people and patients with diabetes may continue to keep their glucose under control and also experience the advantages of utilizing ketones for fuel.

Putting It All Together

Ketogenesis takes fatty acids from stored fat and transforms it into ketones. The ketones are subsequently released into the bloodstream. The procedure where the body burns off ketones for fuel is known as ketosis. However, not all cells can utilize ketones as fuel. Some cells will always utilize glucose to function accordingly. To satisfy the energy requirements which can’t be fulfilled by ketones, your liver utilizes a process called gluconeogenesis. Gluconeogenesis is the procedure where the liver converts glycerol from fatty acids, amino acids from proteins, and lactate from muscles, into glucose. Collectively, ketogenesis and gluconeogenesis produce the ketones and glucose which fulfill all the body’s energy demands when food is not available or when carbohydrates are limited.

Though ketones are well-known for being an alternate fuel supply, they supply us with several unique advantages too. The best and safest way to receive all the advantages of ketosis is by simply adhering to the ketogenic diet. In that way, you won’t encounter the chance of losing valuable muscle mass or inducing the potentially lethal condition of ketoacidosis. But, the ketogenic diet is somewhat more nuanced than a lot of men and women think. It is not just about restricting carbohydrates, it’s about making sure sufficient fat, protein, and overall calorie intake are consumed, which are ultimately vital. The scope of our information is limited to chiropractic and spinal health issues. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .

Curated by Dr. Alex Jimenez

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Additional Topic Discussion: Acute Back Pain

Back pain is one of the most prevalent causes of disability and missed days at work worldwide. Back pain attributes to the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments, and muscles, among other soft tissues. Injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.  

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EXTRA EXTRA | IMPORTANT TOPIC: Recommended El Paso, TX Chiropractor

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What Are The Risks Of Nrf2 Overexpression?

What Are The Risks Of Nrf2 Overexpression?

The nuclear erythroid 2-related factor 2 signaling pathway, best known as Nrf2, is a protective mechanism which functions as a “master regulator” of the human body’s antioxidant response. Nrf2 senses the levels of oxidative stress within the cells and triggers protective antioxidant mechanisms. While Nrf2 activation can have many benefits, Nrf2 “overexpression” can have several risks. It appears that a balanced degree of NRF2 is essential towards preventing the overall development of a variety of diseases in addition to the general improvement of these health issues. However, NRF2 can also cause complications. The main cause behind NRF2 “overexpression” is due to a genetic mutation or a continuing chronic exposure to a chemical or oxidative stress, among others. Below, we will discuss the downsides of Nrf2 overexpression and demonstrate its mechanisms of action within the human body.

Cancer

Research studies found that mice that don’t express NRF2 are more inclined to develop cancer in response to physical and chemical stimulation. Similar research studies, however, showed that NRF2 over-activation, or even KEAP1 inactivation, can result in the exacerbation of certain cancers, particularly if those pathways have been interrupted. Overactive NRF2 can occur through smoking, where continuous NRF2 activation is believed to be the cause of lung cancer in smokers. Nrf2 overexpression might cause cancerous cells not to self-destruct, while intermittent NRF2 activation can prevent cancerous cells from triggering toxin induction. Additionally, because NRF2 overexpression increases the human body’s antioxidant ability to function beyond redox homeostasis, this boosts cell division and generates an unnatural pattern of DNA and histone methylation. This can ultimately make chemotherapy and radiotherapy less effective against cancer. Therefore, limiting NRF2 activation with substances like DIM, Luteolin, Zi Cao, or salinomycin could be ideal for patients with cancer although Nrf2 overactivation should not be considered to be the only cause for cancer. Nutrient deficiencies can affect genes, including NRF2. This might be one way as to how deficiencies contribute to tumors.

Liver

The overactivation of Nrf2, can also affect the function of specific organs in the human body. NRF2 overexpression can ultimately block the production of the insulin-like growth factor 1, or IGF-1, from the liver, which is essential for the regeneration of the liver.

Heart

While the acute overexpression of Nrf2 may have its benefits, continuous overexpression of NRF2 may cause long-term harmful effects on the heart, such as cardiomyopathy. NRF2 expression can be increased through high levels of cholesterol, or the activation of HO-1. This is believed to be the reason why chronic elevated levels of cholesterol might cause cardiovascular health issues.

Vitiligo

NRF2 overexpression has also been demonstrated to inhibit the capability to repigment in vitiligo as it might obstruct Tyrosinase, or TYR, action which is essential for repigmentation through melaninogenesis. Research studies have demonstrated that this process may be one of the primary reasons as to why people with vitiligo don’t seem to activate Nrf2 as efficiently as people without vitiligo.

Why NRF2 May Not Function Properly

Hormesis

NRF2 has to be hormetically activated in order to be able to take advantage of its benefits. In other words, Nrf2 shouldn’t trigger every minute or every day, therefore, it’s a great idea to take breaks from it, by way of instance, 5 days on 5 days off or every other day. NRF2 must also accomplish a specific threshold to trigger its hormetic response, where a small stressor may not be enough to trigger it.

DJ-1 Oxidation

Protein deglycase DJ-1, or just DJ-1, also called the Parkinson’s disease protein, or PARK7, is a master regulator and detector of the redox status in the human body. DJ-1 is essential towards regulating how long NRF2 can perform its function and produce an antioxidant response. In the case that DJ-1 becomes overoxidized, the cells will make the DJ-1 protein less accessible. This process induces NRF2 activation to expire too fast since DJ-1 is paramount for maintaining balanced levels of NRF2 and preventing them from being broken down in the cell. In case the DJ-1 protein is non-existent or overoxidized, NRF2 expression will probably be minimal, even using DIM or alternative NRF2 activators. DJ-1 expression is imperative to restore impaired NRF2 action.

Chronic Illness

If you have a chronic illness, including CIRS, chronic infections/dysbiosis/SIBO, or heavy metal build up, such as mercury and/or that from root canals, these can obstruct the systems of NRF2 and phase two detoxification. Rather than oxidative stress turning NRF2 into an antioxidant, NRF2 will not trigger and oxidative stress can remain in the cell and cause damage, meaning, there is no antioxidant response. This is a significant reason why many people with CIRS have several sensitivities and reach to numerous factors. Some people believe they may be having a herx response, however, this reaction may only be damaging the cells farther. Treating chronic illness, however, will permit the liver to discharge toxins into the bile, gradually developing the hormetic response of NRF2 activation. If the bile remains toxic and it’s not excreted from the human body, it will reactivate NRF2’s oxidative stress and cause you to feel worse once it’s reabsorbed from the gastrointestinal, or GI, tract. For example, ochratoxin A may block NRF2. Aside from treating the problem, histone deacetylase inhibitors can block the oxidative reaction from a number of the factors which trigger NRF2 activation but it might also prevent NRF2 from triggerring normally, which might ultimately fail to serve its purpose.

Fish Oil Dysregulation

Cholinergics are substances which boost acetylcholine, or ACh, and choline in the brain through the increase of ACh, particularly when inhibiting the breakdown of ACh. Patients with CIRS often have problems with the dysregulation of acetylcholine levels in the human body, especially in the brain. Fish oil triggers NRF2, activating its protective antioxidant mechanism within the cells. People with chronic illnesses might have problems with cognitive stress and acetylcholine excitotoxicity, from organophosphate accumulation, which might cause fish oil to create inflammation within the human body. Choline deficiency additionally induces NRF2 activation. Including choline into your diet, (polyphenols, eggs, etc.) can help enhance the effects of cholinergic dysregulation.

What Decreases NRF2?

Decreasing NRF2 overexpression is best for people that have cancer, although it may be beneficial for a variety of other health issues.

Diet, Supplements, and Common Medicines:

  • Apigenin (higher doses)
  • Brucea javanica
  • Chestnuts
  • EGCG (high doses increase NRF2)
  • Fenugreek (Trigonelline)
  • Hiba (Hinokitiol / β-thujaplicin)
  • High Salt Diet
  • Luteolin (Celery, green pepper, parsley, perilla leaf, and chamomile tea – higher doses may increase NRF2 – 40 mg/kg luteolin three times per week )
  • Metformin (chronic intake)
  • N-Acetyl-L-Cysteine (NAC, by blocking the oxidative response, esp at high doses)
  • Orange Peel (have polymethoxylated flavonoids)
  • Quercetin (higher doses may increase NRF2 – 50 mg/kg/d quercetin)
  • Salinomycin (drug)
  • Retinol (all-trans retinoic acid)
  • Vitamin C when combined with Quercetin
  • Zi Cao (Purple Gromwel has Shikonin/Alkannin)

Pathways and Other:

  • Bach1
  • BET
  • Biofilms
  • Brusatol
  • Camptothecin
  • DNMT
  • DPP-23
  • EZH2
  • Glucocorticoid Receptor signaling (Dexamethasone and Betamethasone as well)
  • GSK-3β (regulatory feedback)
  • HDAC activation?
  • Halofuginone
  • Homocysteine (ALCAR can reverse this homocysteine induce low levels of NRF2)
  • IL-24
  • Keap1
  • MDA-7
  • NFκB
  • Ochratoxin A(aspergillus and pencicllium species)
  • Promyelocytic leukemia protein
  • p38
  • p53
  • p97
  • Retinoic acid receptor alpha
  • Selenite
  • SYVN1 (Hrd1)
  • STAT3 inhibition (such as Cryptotanshinone)
  • Testosterone (and Testosterone propionate, although TP intranasally may increase NRF2)
  • Trecator (Ethionamide)
  • Trx1 (via reduction of Cys151 in Keap1 or of Cys506 in the NLS region of Nrf2)
  • Trolox
  • Vorinostat
  • Zinc Deficiency (makes it worse in the brain)

Nrf2 Mechanism Of Action

Oxidative stress triggers through CUL3 where NRF2 from KEAP1, a negative inhibitor, subsequently enters the nucleus of these cells, stimulating the transcription of the AREs, turning sulfides into disulfides, and turning them into more antioxidant genes, leading to the upregulation of antioxidants, such as GSH, GPX, GST, SOD, etc.. The rest of these can be seen in the list below:
  • Increases AKR
  • Increases ARE
  • Increases ATF4
  • Increases Bcl-xL
  • Increases Bcl-2
  • Increases BDNF
  • Increases BRCA1
  • Increases c-Jun
  • Increases CAT
  • Increases cGMP
  • Increases CKIP-1
  • Increases CYP450
  • Increases Cul3
  • Increases GCL
  • Increases GCLC
  • Increases GCLM
  • Increases GCS
  • Increases GPx
  • Increases GR
  • Increases GSH
  • Increases GST
  • Increases HIF1
  • Increases HO-1
  • Increases HQO1
  • Increases HSP70
  • Increases IL-4
  • Increases IL-5
  • Increases IL-10
  • Increases IL-13
  • Increases K6
  • Increases K16
  • Increases K17
  • Increases mEH
  • Increases Mrp2-5
  • Increases NADPH
  • Increases Notch 1
  • Increases NQO1
  • Increases PPAR-alpha
  • Increases Prx
  • Increases p62
  • Increases Sesn2
  • Increases Slco1b2
  • Increases sMafs
  • Increases SOD
  • Increases Trx
  • Increases Txn(d)
  • Increases UGT1(A1/6)
  • Increases VEGF
  • Reduces ADAMTS(4/5)
  • Reduces alpha-SMA
  • Reduces ALT
  • Reduces AP1
  • Reduces AST
  • Reduces Bach1
  • Reduces COX-2
  • Reduces DNMT
  • Reduces FASN
  • Reduces FGF
  • Reduces HDAC
  • Reduces IFN-γ
  • Reduces IgE
  • Reduces IGF-1
  • Reduces IL-1b
  • Reduces IL-2
  • Reduces IL-6
  • Reduces IL-8
  • Reduces IL-25
  • Reduces IL-33
  • Reduces iNOS
  • Reduces LT
  • Reduces Keap1
  • Reduces MCP-1
  • Reduces MIP-2
  • Reduces MMP-1
  • Reduces MMP-2
  • Reduces MMP-3
  • Reduces MMP-9
  • Reduces MMP-13
  • Reduces NfkB
  • Reduces NO
  • Reduces SIRT1
  • Reduces TGF-b1
  • Reduces TNF-alpha
  • Reduces Tyr
  • Reduces VCAM-1
  • Encoded from the NFE2L2 gene, NRF2, or nuclear erythroid 2-related factor 2, is a transcription factor in the basic leucine zipper, or bZIP, superfamily which utilizes a Cap’n’Collar, or CNC structure.
  • It promotes nitric enzymes, biotransformation enzymes, and xenobiotic efflux transporters.
  • It is an essential regulator at the induction of the phase II antioxidant and detoxification enzyme genes, which protect cells from damage caused by oxidative stress and electrophilic attacks.
  • During homeostatic conditions, Nrf2 is sequestered in the cytosol through bodily attachment of the N-terminal domain of Nrf2, or the Kelch-like ECH-associated protein or Keap1, also referred to as INrf2 or Inhibitor of Nrf2, inhibiting Nrf2 activation.
  • It may also be controlled by mammalian selenoprotein thioredoxin reductase 1, or TrxR1, which functions as a negative regulator.
  • Upon vulnerability to electrophilic stressors, Nrf2 dissociates from Keap1, translocating into the nucleus, where it then heterodimerizes with a range of transcriptional regulatory protein.
  • Frequent interactions comprise with those of transcription authorities Jun and Fos, which can be members of the activator protein family of transcription factors.
  • After dimerization, these complexes then bind to antioxidant/electrophile responsive components ARE/EpRE and activate transcription, as is true with the Jun-Nrf2 complex, or suppress transcription, much like the Fos-Nrf2 complex.
  • The positioning of the ARE, which is triggered or inhibited, will determine which genes are transcriptionally controlled by these variables.
  • When ARE is triggered:
  1. Activation of the synthesis of antioxidants is capable of detoxifying ROS like catalase, superoxide-dismutase, or SOD, GSH-peroxidases, GSH-reductase, GSH-transferase, NADPH-quinone oxidoreductase, or NQO1, Cytochrome P450 monooxygenase system, thioredoxin, thioredoxin reductase, and HSP70.
  2. Activation of this GSH synthase permits a noticeable growth of the GSH intracellular degree, which is quite protective.
  3. The augmentation of this synthesis and degrees of phase II enzymes like UDP-glucuronosyltransferase, N-acetyltransferases, and sulfotransferases.
  4. The upregulation of HO-1, which is a really protective receptor with a potential growth of CO that in conjunction with NO allows vasodilation of ischemic cells.
  5. Reduction of iron overload through elevated ferritin and bilirubin as a lipophilic antioxidant. Both the phase II proteins along with the antioxidants are able to fix the chronic oxidative stress and also to revive a normal redox system.
  • GSK3β under the management of AKT and PI3K, phosphorylates Fyn resulting in Fyn nuclear localization, which Fyn phosphorylates Nrf2Y568 leading to nuclear export and degradation of Nrf2.
  • NRF2 also dampens the TH1/TH17 response and enriches the TH2 response.
  • HDAC inhibitors triggered the Nrf2 signaling pathway and up-regulated that the Nrf2 downstream targets HO-1, NQO1, and glutamate-cysteine ligase catalytic subunit, or GCLC, by curbing Keap1 and encouraging dissociation of Keap1 from Nrf2, Nrf2 nuclear translocation, and Nrf2-ARE binding.
  • Nrf2 includes a half-life of about 20 minutes under basal conditions.
  • Diminishing the IKKβ pool through Keap1 binding reduces IκBα degradation and might be the elusive mechanism by which Nrf2 activation is proven to inhibit NFκB activation.
  • Keap1 does not always have to be downregulated to get NRF2 to operate, such as chlorophyllin, blueberry, ellagic acid, astaxanthin, and tea polyphenols may boost NRF2 and KEAP1 at 400 percent.
  • Nrf2 regulates negatively through the term of stearoyl CoA desaturase, or SCD, and citrate lyase, or CL.

Genetics

KEAP1

rs1048290

  • C allele – showed a significant risk for and a protective effect against drug resistant epilepsy (DRE)

rs11085735 (I’m AC)

  • associated with rate of decline of lung function in the LHS

MAPT

rs242561

  • T allele – protective allele for Parkinsonian disorders – had stronger NRF2/sMAF binding and was associated with the higher MAPT mRNA levels in 3 different regions in brain, including cerebellar cortex (CRBL), temporal cortex (TCTX), intralobular white matter (WHMT)

NFE2L2 (NRF2)

rs10183914 (I’m CT)

  • T allele – increased levels of Nrf2 protein and delayed age of onset of Parkinson’s by four years

rs16865105 (I’m AC)

  • C allele – had higher risk of Parkinson’s Disease

rs1806649 (I’m CT)

  • C allele – has been identified and may be relevant for breast cancer etiology.
  • associated with increased risk of hospital admissions during periods of high PM10 levels

rs1962142 (I’m GG)

  • T allele – was associated with a low level of cytoplasmic NRF2 expression (P = 0.036) and negative sulfiredoxin expression (P = 0.042)
  • A allele – protected from forearm blood flow (FEV) decline (forced expiratory volume in one second) in relation to cigarette smoking status (p = 0.004)

rs2001350 (I’m TT)

  • T allele – protected from FEV decline (forced expiratory volume in one second) in relation to cigarette smoking status (p = 0.004)

rs2364722 (I’m AA)

  • A allele – protected from FEV decline (forced expiratory volume in one second) in relation to cigarette smoking status (p = 0.004)

rs2364723

  • C allele – associated with significantly reduced FEV in Japanese smokers with lung cancer

rs2706110

  • G allele – showed a significant risk for and a protective effect against drug resistant epilepsy (DRE)
  • AA alleles – showed significantly reduced KEAP1 expression
  • AA alleles – was associated with an increased risk of breast cancer (P = 0.011)

rs2886161 (I’m TT)

  • T allele – associated with Parkinson’s Disease

rs2886162

  • A allele – was associated with low NRF2 expression (P = 0.011; OR, 1.988; CI, 1.162–3.400) and the AA genotype was associated with a worse survival (P = 0.032; HR, 1.687; CI, 1.047–2.748)

rs35652124 (I’m TT)

  • A allele – associated with higher associated with age at onset for Parkinson’s Disease vs G allele
  • C allele – had increase NRF2 protein
  • T allele – had less NRF2 protein and greater risk of heart disease and blood pressure

rs6706649 (I’m CC)

  • C allele – had lower NRF2 protein and increase risk for Parkinson’s Disease

rs6721961 (I’m GG)

  • T allele – had lower NRF2 protein
  • TT alleles – association between cigarette smoking in heavy smokers and a decrease in semen quality
  • TT allele – was associated with increased risk of breast cancer [P = 0.008; OR, 4.656; confidence interval (CI), 1.350–16.063] and the T allele was associated with a low extent of NRF2 protein expression (P = 0.0003; OR, 2.420; CI, 1.491–3.926) and negative SRXN1 expression (P = 0.047; OR, 1.867; CI = 1.002–3.478)
  • T allele – allele was also nominally associated with ALI-related 28-day mortality following systemic inflammatory response syndrome
  • T allele – protected from FEV decline (forced expiratory volume in one second) in relation to cigarette smoking status (p = 0.004)
  • G allele – associated with increased risk of ALI following major trauma in European and African-Americans (odds ratio, OR 6.44; 95% confidence interval
  • AA alleles – associated with infection-induced asthma
  • AA alleles – exhibited significantly diminished NRF2 gene expression and, consequently, an increased risk of lung cancer, especially those who had ever smoked
  • AA alleles – had a significantly higher risk for developing T2DM (OR 1.77; 95% CI 1.26, 2.49; p = 0.011) relative to those with the CC genotype
  • AA alleles – strong association between wound repair and late toxicities of radiation (associated with a significantly higher risk for developing late effects in African-Americans with a trend in Caucasians)
  • associated with oral estrogen therapy and risk of venous thromboembolism in postmenopausal women

rs6726395 (I’m AG)

  • A allele – protected from FEV1 decline (forced expiratory volume in one second) in relation to cigarette smoking status (p = 0.004)
  • A allele – associated with significantly reduced FEV1 in Japanese smokers with lung cancer
  • GG alleles – had higher NRF2 levels and decreased risk of macular degeneration
  • GG alleles – had higher survival with Cholangiocarcinoma

rs7557529 (I’m CT)

  • C allele – associated with Parkinson’s Disease
Dr Jimenez White Coat
Oxidative stress and other stressors can cause cell damage which may eventually lead to a variety of health issues. Research studies have demonstrated that Nrf2 activation can promote the human body’s protective antioxidant mechanism, however, researchers have discussed that Nrf2 overexpression can have tremendous risks towards overall health and wellness. Various types of cancer can also occur with Nrf2 overactivation. Dr. Alex Jimenez D.C., C.C.S.T. Insight

Sulforaphane and Its Effects on Cancer, Mortality, Aging, Brain and Behavior, Heart Disease & More

Isothiocyanates are some of the most important plant compounds you can get in your diet. In this video I make the most comprehensive case for them that has ever been made. Short attention span? Skip to your favorite topic by clicking one of the time points below. Full timeline below. Key sections:
  • 00:01:14 – Cancer and mortality
  • 00:19:04 – Aging
  • 00:26:30 – Brain and behavior
  • 00:38:06 – Final recap
  • 00:40:27 – Dose
Full timeline:
  • 00:00:34 – Introduction of sulforaphane, a major focus of the video.
  • 00:01:14 – Cruciferous vegetable consumption and reductions in all-cause mortality.
  • 00:02:12 – Prostate cancer risk.
  • 00:02:23 – Bladder cancer risk.
  • 00:02:34 – Lung cancer in smokers risk.
  • 00:02:48 – Breast cancer risk.
  • 00:03:13 – Hypothetical: what if you already have cancer? (interventional)
  • 00:03:35 – Plausible mechanism driving the cancer and mortality associative data.
  • 00:04:38 – Sulforaphane and cancer.
  • 00:05:32 – Animal evidence showing strong effect of broccoli sprout extract on bladder tumor development in rats.
  • 00:06:06 – Effect of direct supplementation of sulforaphane in prostate cancer patients.
  • 00:07:09 – Bioaccumulation of isothiocyanate metabolites in actual breast tissue.
  • 00:08:32 – Inhibition of breast cancer stem cells.
  • 00:08:53 – History lesson: brassicas were established as having health properties even in ancient Rome.
  • 00:09:16 – Sulforaphane’s ability to enhance carcinogen excretion (benzene, acrolein).
  • 00:09:51 – NRF2 as a genetic switch via antioxidant response elements.
  • 00:10:10 – How NRF2 activation enhances carcinogen excretion via glutathione-S-conjugates.
  • 00:10:34 – Brussels sprouts increase glutathione-S-transferase and reduce DNA damage.
  • 00:11:20 – Broccoli sprout drink increases benzene excretion by 61%.
  • 00:13:31 – Broccoli sprout homogenate increases antioxidant enzymes in the upper airway.
  • 00:15:45 – Cruciferous vegetable consumption and heart disease mortality.
  • 00:16:55 – Broccoli sprout powder improves blood lipids and overall heart disease risk in type 2 diabetics.
  • 00:19:04 – Beginning of aging section.
  • 00:19:21 – Sulforaphane-enriched diet enhances lifespan of beetles from 15 to 30% (in certain conditions).
  • 00:20:34 – Importance of low inflammation for longevity.
  • 00:22:05 – Cruciferous vegetables and broccoli sprout powder seem to reduce a wide variety of inflammatory markers in humans.
  • 00:23:40 – Mid-video recap: cancer, aging sections
  • 00:24:14 – Mouse studies suggest sulforaphane might improve adaptive immune function in old age.
  • 00:25:18 – Sulforaphane improved hair growth in a mouse model of balding. Picture at 00:26:10.
  • 00:26:30 – Beginning of brain and behavior section.
  • 00:27:18 – Effect of broccoli sprout extract on autism.
  • 00:27:48 – Effect of glucoraphanin on schizophrenia.
  • 00:28:17 – Start of depression discussion (plausible mechanism and studies).
  • 00:31:21 – Mouse study using 10 different models of stress-induced depression show sulforaphane similarly effective as fluoxetine (prozac).
  • 00:32:00 – Study shows direct ingestion of glucoraphanin in mice is similarly effective at preventing depression from social defeat stress model.
  • 00:33:01 – Beginning of neurodegeneration section.
  • 00:33:30 – Sulforaphane and Alzheimer’s disease.
  • 00:33:44 – Sulforaphane and Parkinson’s disease.
  • 00:33:51 – Sulforaphane and Hungtington’s disease.
  • 00:34:13 – Sulforaphane increases heat shock proteins.
  • 00:34:43 – Beginning of traumatic brain injury section.
  • 00:35:01 – Sulforaphane injected immediately after TBI improves memory (mouse study).
  • 00:35:55 – Sulforaphane and neuronal plasticity.
  • 00:36:32 – Sulforaphane improves learning in model of type II diabetes in mice.
  • 00:37:19 – Sulforaphane and duchenne muscular dystrophy.
  • 00:37:44 – Myostatin inhibition in muscle satellite cells (in vitro).
  • 00:38:06 – Late-video recap: mortality and cancer, DNA damage, oxidative stress and inflammation, benzene excretion, cardiovascular disease, type II diabetes, effects on the brain (depression, autism, schizophrenia, neurodegeneration), NRF2 pathway.
  • 00:40:27 – Thoughts on figuring out a dose of broccoli sprouts or sulforaphane.
  • 00:41:01 – Anecdotes on sprouting at home.
  • 00:43:14 – On cooking temperatures and sulforaphane activity.
  • 00:43:45 – Gut bacteria conversion of sulforaphane from glucoraphanin.
  • 00:44:24 – Supplements work better when combined with active myrosinase from vegetables.
  • 00:44:56 – Cooking techniques and cruciferous vegetables.
  • 00:46:06 – Isothiocyanates as goitrogens.
According to research studies, Nrf2, is a fundamental transcription factor which activates the cells’ protective antioxidant mechanisms to detoxify the human body. The overexpression of Nrf2, however, can cause health issues. The scope of our information is limited to chiropractic and spinal health issues. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 . Curated by Dr. Alex Jimenez
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Additional Topic Discussion: Acute Back Pain

Back pain is one of the most prevalent causes of disability and missed days at work worldwide. Back pain attributes to the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments, and muscles, among other soft tissues. Injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.  
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EXTRA EXTRA | IMPORTANT TOPIC: Recommended El Paso, TX Chiropractor

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The Role Of Nrf2 Activation

The Role Of Nrf2 Activation

Many current research studies on cancer have allowed health professionals to understand the way the body detoxes. By analyzing upregulated genes in tumorous cells, researchers discovered the nuclear erythroid 2-related factor 2 signaling pathway, best known as Nrf2. NRF2 is an important transcription factor which activates the human body’s protective antioxidant mechanisms in order to regulate oxidation from both external and internal factors to prevent increased levels of oxidative stress.

Principles of Nrf2

NRF2 is essential towards maintaining overall health and wellness because it serves the primary purpose of regulating how we manage everything we’re exposed to on a daily basis and not become sick. NRF2 activation plays a role in the phase II detoxification system. Phase II detoxification takes lipophilic, or fat soluble, free radicals and converts them into hydrophilic, or water soluble, substances for excretion while inactivating exceptionally reactive metabolites and chemicals as a consequence of phase I.

NRF2 activation reduces overall oxidation and inflammation of the human body through a hormetic effect. To trigger NRF2, an inflammatory reaction due to oxidation must occur in order for the cells to produce an adaptive response and create antioxidants, such as glutathione. To break down the principle of Nrf2, essentially, oxidative stress activates NRF2 which then activates an antioxidant response in the human body. NRF2 functions to balance redox signaling, or the equilibrium of oxidant and antioxidant levels in the cell.

A great illustration of how this process functions can be demonstrated with exercise. Through every workout, the muscle adapts so that it can accommodate another workout session. If NRF2 becomes under- or over-expressed due to chronic infections or increased exposure to toxins, which may be observed in patients who have chronic inflammatory response syndrome, or CIRS, the health issues may worsen following NRF2 activation. Above all, if DJ-1 becomes over-oxidized, NRF2 activation will end too quickly.

Effects of NRF2 Activation

NRF2 activation is highly expressed in the lungs, liver, and kidneys. Nuclear erythroid 2-related factor 2, or NRF2, most commonly functions by counteracting increased levels of oxidation in the human body which can lead to oxidative stress. Nrf2 activation can help treat a variety of health issues, however, over-activation of Nrf2 may worsen various problems, which are demonstrated below.

Periodic activation of Nrf2 can help:

  • Aging (ie Longevity)
  • Autoimmunity and Overall Inflammation (ie Arthritis, Autism)
  • Cancer and Chemoprotection (ie EMF Exposure)
  • Depression and Anxiety (ie PTSD)
  • Drug Exposure (Alcohol, NSAIDs )
  • Exercise and Endurance Performance
  • Gut Disease (ie SIBO, Dysbiosis, Ulcerative Colitis)
  • Kidney Disease (ie Acute Kidney Injury, Chronic Kidney Disease, Lupus Nephritis)
  • Liver Disease (ie Alcoholic Liver Disease, Acute Hepatitis, Nonalcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis, Cirrhosis)
  • Lung Disease (ie Asthma, Fibrosis)
  • Metabolic And Vascular Disease (ie Atherosclerosis, Hypertension, Stroke, Diabetes)
  • Neurodegeneration (ie Alzheimer’s, Parkinson’s, Huntington’s and ALS)
  • Pain (ie Neuropathy)
  • Skin Disorders (ie Psoriasis, UVB/Sun Protection)
  • Toxin Exposure (Arsenic, Asbestos, Cadmium, Fluoride, Glyphosate, Mercury, Sepsis, Smoke)
  • Vision (ie Bright Light, Sensitivity, Cataracts, Corneal Dystrophy)

Hyperactivation of Nrf2 can worsen:

  • Atherosclerosis
  • Cancer (ie Brain, Breast, Head, Neck Pancreatic, Prostate, Liver, Thyroid)
  • Chronic Inflammatory Response Syndrome (CIRS)
  • Heart Transplant (while open NRF2 may be bad, NRF2 can help with repair)
  • Hepatitis C
  • Nephritis (severe cases)
  • Vitiligo

Furthermore, NRF2 can help make specific nutritional supplements, drugs, and medications work. Many natural supplements can also help trigger NRF2. Through current research studies, researchers have demonstrated that a large number of compounds which were once believed to be antioxidants were really pro-oxidants. That’s because nearly all of them need NRF2 to function, even supplements like curcumin and fish oil. Cocoa, for example, was shown to generate antioxidant effects in mice which possess the NRF2 gene.

Ways To Activate NRF2

In the case of neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, stroke or even autoimmune diseases, it’s probably best to have Nrf2 upregulated, but in a hormetic fashion. Mixing NRF2 activators may also have an additive or synergistic effect, as occasionally it can be dose-dependent. The top ways to increase Nrf2 expression are listed below:

  • HIST (Exercise) + CoQ10 + Sun (these synergize very well)
  • Broccoli Sprouts + LLLT on my head and gut
  • Butyrate + Super Coffee + Morning Sun
  • Acupuncture (this is an alternative method, laser acupuncture may also be used)
  • Fasting
  • Cannabidiol (CBD)
  • Lion’s Mane + Melatonin
  • Alpha-lipoic acid + DIM
  • Wormwood
  • PPAR-gamma Activation

The following comprehensive listing containing over 350 other ways to activate Nrf2 through diet, lifestyle and devices, probiotics, supplements, herbs and oils, hormones and neurotransmitters, drugs/medications and chemicals, pathways/transcription factors, as well as other ways, is only a brief guide as to what can trigger Nrf2. For the sake of brevity in this article, we have left out over 500 other foods, nutritional supplements and compounds which can help activate Nrf2. The following are listed below:

Diet:

  • Acai Berries
  • Alcohol (Red wine is better, especially if there is a cork in it, as protocatechuic aldehyde from corks can also activate NRF2. In general, alcohol is not recommended, although acute intake increases NRF2. Chronic intake may decrease NRF2.
  • Algae (kelp)
  • Apples
  • Black Tea
  • Brazil Nuts
  • Broccoli Sprouts (and other isothiocyanates, sulforaphane as well as cruciferous vegetables like bok choy that have D3T)
  • Blueberries (0.6-10 g/day)
  • Carrots (falcarinone)
  • Cayenne Pepper (Capsaicin)
  • Celery (Butylphthalide)
  • Chaga (Betulin)
  • Chamomile Tea
  • Chia
  • Chinese Potato
  • Chokeberries (Aronia)
  • Chocolate (Dark or Cocoa)
  • Cinnamon
  • Coffee (such as chlorogenic acid, Cafestol and Kahweol)
  • Cordyceps
  • Fish (and Shellfish)
  • Flaxseed
  • Garlic
  • Ghee (possibly)
  • Ginger (and Cardamonin)
  • Gojiberries
  • Grapefruit (Naringenin – 50 mg/kg/d naringenin)
  • Grapes
  • Green Tea
  • Guava
  • Heart Of Palm
  • Hijiki/Wakame
  • Honeycomb
  • Kiwi
  • Legumes
  • Lion’s Mane
  • Mahuwa
  • Mangos (Mangiferin)
  • Mangosteen
  • Milk (goat, cow – via regulation of microbiome)
  • Mulberries
  • Olive Oil (pomace – hydroxytyrosol and Oleanolic Acid)
  • Omega 6 Fatty Acids (Lipoxin A4)
  • Osange Oranges (Morin)
  • Oyster Mushrooms
  • Papaya
  • Peanuts
  • Pigeon Peas
  • Pomegranate (Punicalagin, Ellagic Acid)
  • Propolis (Pinocembrin)
  • Purple Sweet Potatoes
  • Rambutan (Geraniin)
  • Onions
  • Reishi
  • Rhodiola Rosea (Salidroside)
  • Rice Bran (cycloartenyl ferulate)
  • Riceberry
  • Rooibos Tea
  • Rosemary
  • Sage
  • Safflower
  • Sesame Oil
  • Soy (and isoflavones, Daidzein, Genistein)
  • Squash
  • Strawberries
  • Tartary Buckwheat
  • Thyme
  • Tomatoes
  • Tonka Beans
  • Turmeric
  • Wasabi
  • Watermelon

Lifestyle and Devices:

  • Acupuncture and Electroacupuncture (via collagen cascade on ECM)
  • Blue light
  • Brain Games (increases NRF2 in the hippocampus)
  • Caloric Restriction
  • Cold (showers, plunges, ice bath, gear, cryotheraphy)
  • EMFs (low frequency, such as PEMF)
  • Exercise (Acute exercise like HIST or HIIT seems to be more beneficial for inducing NRF2, while longer exercise doesn’t induce NRF2, but does increase glutathione levels)
  • High Fat Diet (diet)
  • High Heat (Sauna)
  • Hydrogen Inhalation and Hydrogen Water
  • Hyperbaric Oxygen Therapy
  • Infrared Therapy (such as Joovv)
  • Intravenous Vitamin C
  • Ketogenic Diet
  • Ozone
  • Smoking (not recommended – acutely smoking increase NRF2, chronically smoking decreases NRF2. If you choose to smoke, Holy Basil may help protect against downregulation of NRF2)
  • Sun (UVB and Infrared)

Probiotics:

  • Bacillus subtilis (fmbJ)
  • Clostridium butyricum (MIYAIRI 588)
  • Lactobacillus brevis
  • Lactobacillus casei (SC4 and 114001)
  • Lactobacillus collinoides
  • Lactobacillus gasseri (OLL2809, L13-Ia, and SBT2055)
  • Lactobacillus helveticus (NS8)
  • Lactobacillus paracasei (NTU 101)
  • Lactobacillus plantarum (C88, CAI6, FC225, SC4)
  • Lactobacillus rhamnosus (GG)

Supplements, Herbs, and Oils:

  • Acetyl-L-Carnitine (ALCAR) and Carnitine
  • Allicin
  • Alpha-lipoic acid
  • Amentoflavone
  • Andrographis paniculata
  • Agmatine
  • Apigenin
  • Arginine
  • Artichoke (Cyanropicrin)
  • Ashwaganda
  • Astragalus
  • Bacopa
  • Beefsteak (Isogemaketone)
  • Berberine
  • Beta-caryophyllene
  • Bidens Pilosa
  • Black Cumin Seed Oil (Thymoquinone)
  • Boswellia
  • Butein
  • Butyrate
  • Cannabidiol (CBD)
  • Carotenioids (like Beta-carotene [synergy with Lycopene – 2 × 15 mg/d lycopene], Fucoxanthin, Zeaxanthin, Astaxanthin, and Lutein)
  • Chitrak
  • Chlorella
  • Chlorophyll
  • Chrysanthemum zawadskii
  • Cinnamomea
  • Common Sundew
  • Copper
  • Coptis
  • CoQ10
  • Curcumin
  • Damiana
  • Dan Shen/Red Sage (Miltirone)
  • DIM
  • Dioscin
  • Dong Ling Cao
  • Dong Quai (female ginseng)
  • Ecklonia Cava
  • EGCG
  • Elecampane / Inula
  • Eucommia Bark
  • Ferulic Acid
  • Fisetin
  • Fish Oil (DHA/EPA – 3 × 1 g/d fish oil containing 1098 mg EPA and 549 mg DHA)
  • Galangal
  • Gastrodin (Tian Ma)
  • Gentiana
  • Geranium
  • Ginkgo Biloba (Ginkgolide B)
  • Glasswort
  • Gotu Kola
  • Grape Seed Extract
  • Hairy Agrimony
  • Haritaki (Triphala)
  • Hawthorn
  • Helichrysum
  • Henna (Juglone)
  • Hibiscus
  • Higenamine
  • Holy Basil/Tulsi (Ursolic Acid)
  • Hops
  • Horny Goat Weed (Icariin/Icariside)
  • Indigo Naturalis
  • Iron (not recommended unless essential)
  • I3C
  • Job’s Tears
  • Moringa Oleifera (such as Kaempferol)
  • Inchinkoto (combo of Zhi Zi and Wormwood)
  • Kudzu Root
  • Licorice Root
  • Lindera Root
  • Luteolin (high doses for activation, lower doses inhibit NRF2 in cancer though)
  • Magnolia
  • Manjistha
  • Maximowiczianum (Acerogenin A)
  • Mexican Arnica
  • Milk Thistle
  • MitoQ
  • Mu Xiang
  • Mucuna Pruriens
  • Nicotinamide and NAD+
  • Panax Ginseng
  • Passionflower (such as Chrysin, but chyrisin may also reduce NRF2 via dysregulation of PI3K/Akt signaling)
  • Pau d’arco (Lapacho)
  • Phloretin
  • Piceatannol
  • PQQ
  • Procyanidin
  • Pterostilbene
  • Pueraria
  • Quercetin (high doses only, lower doses inhibit NRF2)
  • Qiang Huo
  • Red Clover
  • Resveratrol (Piceid and other phytoestrogens essentially, Knotweed)
  • Rose Hips
  • Rosewood
  • Rutin
  • Sappanwood
  • Sarsaparilla
  • Saururus chinensis
  • SC-E1 (Gypsum, Jasmine, Licorice, Kudzu, and Balloon Flower)
  • Schisandra
  • Self Heal (prunella)
  • Skullcap (Baicalin and Wogonin)
  • Sheep Sorrel
  • Si Wu Tang
  • Sideritis
  • Spikenard (Aralia)
  • Spirulina
  • St. John’s Wort
  • Sulforaphane
  • Sutherlandia
  • Tao Hong Si Wu
  • Taurine
  • Thunder God Vine (Triptolide)
  • Tocopherols (such as Vitamin E or Linalool)
  • Tribulus R
  • Tu Si Zi
  • TUDCA
  • Vitamin A (although other retinoids inhibit NRF2)
  • Vitamin C (high dose only, low dose does inhibit NRF2)
  • Vitex/Chaste Tree
  • White Peony (Paeoniflorin from Paeonia lactiflora)
  • Wormwood (Hispidulin and Artemisinin)
  • Xiao Yao Wan (Free and Easy Wanderer)
  • Yerba Santa (Eriodictyol)
  • Yuan Zhi (Tenuigenin)
  • Zi Cao (will reduce NRF2 in cancer)
  • Zinc
  • Ziziphus Jujube

Hormones and Neurotransmitters:

  • Adiponectin
  • Adropin
  • Estrogen (but may decrease NRF2 in breast tissue)
  • Melatonin
  • Progesterone
  • Quinolinic Acid (in protective response to prevent excitotoxicity)
  • Serotonin
  • Thyroid Hormones like T3 (can increase NRF2 in healthy cells, but decrease it in cancer)
  • Vitamin D

Drugs/Medications and Chemicals:

  • Acetaminophen
  • Acetazolamide
  • Amlodipine
  • Auranofin
  • Bardoxolone methyl (BARD)
  • Benznidazole
  • BHA
  • CDDO-imidazolide
  • Ceftriaxone (and beta-lactam antibiotics)
  • Cialis
  • Dexamethasone
  • Diprivan (Propofol)
  • Eriodictyol
  • Exendin-4
  • Ezetimibe
  • Fluoride
  • Fumarate
  • HNE (oxidized)
  • Idazoxan
  • Inorganic arsenic and sodium arsenite
  • JQ1 (may inhibit NRF2 as well, unknown)
  • Letairis
  • Melphalan
  • Methazolamide
  • Methylene Blue
  • Nifedipine
  • NSAIDs
  • Oltipraz
  • PPIs (such as Omeprazole and Lansoprazole)
  • Protandim – great results in vivo, but weak/non-existent at activating NRF2 in humans
  • Probucol
  • Rapamycin
  • Reserpine
  • Ruthenium
  • Sitaxentan
  • Statins (such as Lipitor and Simvastatin)
  • Tamoxifen
  • Tang Luo Ning
  • tBHQ
  • Tecfidera (Dimethyl fumarate)
  • THC (not as strong as CBD)
  • Theophylline
  • Umbelliferone
  • Ursodeoxycholic Acid (UDCA)
  • Verapamil
  • Viagra
  • 4-Acetoxyphenol

Pathways/Transcription Factors:

  • α7 nAChR activation
  • AMPK
  • Bilirubin
  • CDK20
  • CKIP-1
  • CYP2E1
  • EAATs
  • Gankyrin
  • Gremlin
  • GJA1
  • H-ferritin ferroxidase
  • HDAC inhibitors (such as valproic acid and TSA, but can cause NRF2 instability)
  • Heat Shock Proteins
  • IL-17
  • IL-22
  • Klotho
  • let-7 (knocks down mBach1 RNA)
  • MAPK
  • Michael acceptors (most)
  • miR-141
  • miR-153
  • miR-155 (knocks down mBach1 RNA as well)
  • miR-7 (in brain, helps with cancer and schizophrenia)
  • Notch1
  • Oxidatives stress (such as ROS, RNS, H2O2) and Electrophiles
  • PGC-1α
  • PKC-delta
  • PPAR-gamma (synergistic effects)
  • Sigma-1 receptor inhibition
  • SIRT1 (increases NRF2 in the brain and lungs but may decrease it overall)
  • SIRT2
  • SIRT6 (in the liver and brain)
  • SRXN1
  • TrxR1 inhibition (attenuation or depletion as well)
  • Zinc protoporphyrin
  • 4-HHE

Other:

  • Ankaflavin
  • Asbestos
  • Avicins
  • Bacillus amyloliquefaciens (used in agriculture)
  • Carbon Monoxide
  • Daphnetin
  • Glutathione Depletion (depletion of 80%–90% possibly)
  • Gymnaster koraiensis
  • Hepatitis C
  • Herpes (HSV)
  • Indian ash tree
  • Indigowoad Root
  • Isosalipurposide
  • Isorhamentin
  • Monascin
  • Omaveloxolone (strong, aka RTA-408)
  • PDTC
  • Selenium Deficiency (selenium deficiency can increase NRF2)
  • Siberian Larch
  • Sophoraflavanone G
  • Tadehagi triquetrum
  • Toona sinensis (7-DGD)
  • Trumpet Flower
  • 63171 and 63179 (strong)
Dr Jimenez White Coat
The nuclear erythroid 2-related factor 2 signaling pathway, best known by the acronym Nrf2, is a transcription factor which plays the major role of regulating the protective antioxidant mechanisms of the human body, particularly in order to control oxidative stress. While increased levels of oxidative stress can activate Nrf2, its effects are tremendously enhanced through the presence of specific compounds. Certain foods and supplements help activate Nrf2 in the human body, including the isothiocyanate sulforaphane from broccoli sprouts. Dr. Alex Jimenez D.C., C.C.S.T. Insight

Sulforaphane and Its Effects on Cancer, Mortality, Aging, Brain and Behavior, Heart Disease & More

Isothiocyanates are some of the most important plant compounds you can get in your diet. In this video I make the most comprehensive case for them that has ever been made. Short attention span? Skip to your favorite topic by clicking one of the time points below. Full timeline below.

Key sections:

  • 00:01:14 – Cancer and mortality
  • 00:19:04 – Aging
  • 00:26:30 – Brain and behavior
  • 00:38:06 – Final recap
  • 00:40:27 – Dose

Full timeline:

  • 00:00:34 – Introduction of sulforaphane, a major focus of the video.
  • 00:01:14 – Cruciferous vegetable consumption and reductions in all-cause mortality.
  • 00:02:12 – Prostate cancer risk.
  • 00:02:23 – Bladder cancer risk.
  • 00:02:34 – Lung cancer in smokers risk.
  • 00:02:48 – Breast cancer risk.
  • 00:03:13 – Hypothetical: what if you already have cancer? (interventional)
  • 00:03:35 – Plausible mechanism driving the cancer and mortality associative data.
  • 00:04:38 – Sulforaphane and cancer.
  • 00:05:32 – Animal evidence showing strong effect of broccoli sprout extract on bladder tumor development in rats.
  • 00:06:06 – Effect of direct supplementation of sulforaphane in prostate cancer patients.
  • 00:07:09 – Bioaccumulation of isothiocyanate metabolites in actual breast tissue.
  • 00:08:32 – Inhibition of breast cancer stem cells.
  • 00:08:53 – History lesson: brassicas were established as having health properties even in ancient Rome.
  • 00:09:16 – Sulforaphane’s ability to enhance carcinogen excretion (benzene, acrolein).
  • 00:09:51 – NRF2 as a genetic switch via antioxidant response elements.
  • 00:10:10 – How NRF2 activation enhances carcinogen excretion via glutathione-S-conjugates.
  • 00:10:34 – Brussels sprouts increase glutathione-S-transferase and reduce DNA damage.
  • 00:11:20 – Broccoli sprout drink increases benzene excretion by 61%.
  • 00:13:31 – Broccoli sprout homogenate increases antioxidant enzymes in the upper airway.
  • 00:15:45 – Cruciferous vegetable consumption and heart disease mortality.
  • 00:16:55 – Broccoli sprout powder improves blood lipids and overall heart disease risk in type 2 diabetics.
  • 00:19:04 – Beginning of aging section.
  • 00:19:21 – Sulforaphane-enriched diet enhances lifespan of beetles from 15 to 30% (in certain conditions).
  • 00:20:34 – Importance of low inflammation for longevity.
  • 00:22:05 – Cruciferous vegetables and broccoli sprout powder seem to reduce a wide variety of inflammatory markers in humans.
  • 00:23:40 – Mid-video recap: cancer, aging sections
  • 00:24:14 – Mouse studies suggest sulforaphane might improve adaptive immune function in old age.
  • 00:25:18 – Sulforaphane improved hair growth in a mouse model of balding. Picture at 00:26:10.
  • 00:26:30 – Beginning of brain and behavior section.
  • 00:27:18 – Effect of broccoli sprout extract on autism.
  • 00:27:48 – Effect of glucoraphanin on schizophrenia.
  • 00:28:17 – Start of depression discussion (plausible mechanism and studies).
  • 00:31:21 – Mouse study using 10 different models of stress-induced depression show sulforaphane similarly effective as fluoxetine (prozac).
  • 00:32:00 – Study shows direct ingestion of glucoraphanin in mice is similarly effective at preventing depression from social defeat stress model.
  • 00:33:01 – Beginning of neurodegeneration section.
  • 00:33:30 – Sulforaphane and Alzheimer’s disease.
  • 00:33:44 – Sulforaphane and Parkinson’s disease.
  • 00:33:51 – Sulforaphane and Hungtington’s disease.
  • 00:34:13 – Sulforaphane increases heat shock proteins.
  • 00:34:43 – Beginning of traumatic brain injury section.
  • 00:35:01 – Sulforaphane injected immediately after TBI improves memory (mouse study).
  • 00:35:55 – Sulforaphane and neuronal plasticity.
  • 00:36:32 – Sulforaphane improves learning in model of type II diabetes in mice.
  • 00:37:19 – Sulforaphane and duchenne muscular dystrophy.
  • 00:37:44 – Myostatin inhibition in muscle satellite cells (in vitro).
  • 00:38:06 – Late-video recap: mortality and cancer, DNA damage, oxidative stress and inflammation, benzene excretion, cardiovascular disease, type II diabetes, effects on the brain (depression, autism, schizophrenia, neurodegeneration), NRF2 pathway.
  • 00:40:27 – Thoughts on figuring out a dose of broccoli sprouts or sulforaphane.
  • 00:41:01 – Anecdotes on sprouting at home.
  • 00:43:14 – On cooking temperatures and sulforaphane activity.
  • 00:43:45 – Gut bacteria conversion of sulforaphane from glucoraphanin.
  • 00:44:24 – Supplements work better when combined with active myrosinase from vegetables.
  • 00:44:56 – Cooking techniques and cruciferous vegetables.
  • 00:46:06 – Isothiocyanates as goitrogens.

According to many current research studies, the nuclear erythroid 2-related factor 2 signaling pathway, best known as Nrf2, is a fundamental transcription factor which activates the cells’ protective antioxidant mechanisms to detoxify the human body from both external and internal factors and prevent increased levels of oxidative stress. The scope of our information is limited to chiropractic and spinal health issues. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .

Curated by Dr. Alex Jimenez

Green Call Now Button H .png

Additional Topic Discussion: Acute Back Pain

Back pain is one of the most prevalent causes of disability and missed days at work worldwide. Back pain attributes to the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments, and muscles, among other soft tissues. Injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.  

blog picture of cartoon paper boy

EXTRA EXTRA | IMPORTANT TOPIC: Recommended El Paso, TX Chiropractor

***

What Are The Benefits Of Nrf2?

What Are The Benefits Of Nrf2?

Oxidative stress is a major contributor in the development of a variety of health issues, including cancer, heart disease, diabetes, accelerated aging and neurodegeneration. Antioxidant rich foods, herbs and supplements can be utilized to protect the human body from high levels of oxidative stress. Recent research studies have demonstrated that the Nrf2 gene pathway can help amplify the effects of antioxidants. The benefits of Nrf2 are described below.

Protects the Body Against Toxins

NRF2 is an intrinsic substance which can protect the cells from harmful, internal and external compounds. NRF2 may help enrich the human body’s reaction to drugs/medications and toxins, improving the production of proteins that help eliminate compounds from the cell, known as multidrug resistance-associated proteins, or MRPs. By way of instance, NRF2 is triggered upon cigarette smoke inhalation to allow the lungs to detox.

Additionally, it is essential for the lungs to protect themselves against allergens, viral diseases, bacterial endotoxins, hyperoxia, and various environmental pollutants. The constant trigger of Nrf2 however, can decrease the levels of a substance known as glutathione throughout the human body. NRF2 may also protect the liver from toxicity and it can protect the liver from arsenic hepatotoxicity. Moreover, NRF2 protects the liver and brain from alcohol consumption. By way of instance, Nrf2 can protect against acetaminophen toxicity.

Fights Inflammation And Oxidative Stress

NRF2 activation can help battle against inflammation by diminishing inflammatory cytokines, such as those present in psoriasis. NRF2 may also decrease inflammation associated with a variety of health issues like arthritis and fibrosis of the liver, kidney, and lungs. NRF2 may also help control allergies by lowering Th1/Th17 cytokines and raising TH2 cytokines. This can be beneficial for ailments like asthma.

NRF2 additionally protects against cellular damage from blue light and from UVA/UVB  found in sunlight. Nrf2 deficiencies can make it a whole lot easier to get sunburnt. One rationale behind this is because NRF2 is capable of regulating collagen in response to UV radiation. Advanced Glycation End-Products, or AGEs, contribute to the development of many health issues, including diabetes and neurodegenerative diseases. NRF2 can decrease the oxidative stress of AGEs within the body. NRF2 may also protect the human body from higher levels of heat-based stress.

Enhances Mitochondria And Exercise Performance

NRF2 is a mitochondrial booster. NRF2 activation contributes to a rise in ATP energy for mitochondria, in addition to enhanced use of oxygen, or citrate, and fat. With no NRF2, mitochondria would just have the ability to function with sugar, or glucose, rather than fat. NRF2 is also essential for mitochondria to develop through a process known as biogenesis. NRF2 activation is vital in order to take advantage of  the benefits of exercise.

Because of Nrf2’s activity, exercise raises mitochondrial function, where this result may be amplified with CoQ10, Cordyceps, and Caloric Restriction. Moderate exercise or acute exercise induces mitochondrial biogenesis and an elevated synthesis of superoxide dismutase, or SOD, and heme-oxygenase-1, or HO-1, through NRF2 activation. Alpha-Lipoic Acid, or ALA, and Dan Shen can boost NRF2 mediated mitochondrial biogenesis. Furthermore, NRF2 can also improve exercise tolerance where NRF2 deletion makes exercise harmful.

Protects Against Hypoxia

NRF2 also helps protect the human body from cellular oxygen loss/depletion, a health issue called hypoxia. Individuals with CIRS have reduced levels of oxygen since their NRF2 is obstructed, resulting in reduced levels of both VEGF, HIF1, and HO-1. Ordinarily, in healthy individuals with hypoxia, miR-101, which is required for the creation of stem cells, are overexpressed and enhance amounts of NRF2/HO-1 and VEGF/eNOS, therefore preventing brain damage, but that does not appear to occur in CIRS.

Hypoxia, characterized by low HIF1, in CIRS can also result in a leaky blood brain barrier due to an NRF2 imbalance. Salidroside, located in the Rhodiola, functions on NRF2 activation and assists with hypoxia by increasing levels of VEGF and HIF1 within the human body. NRF2 can also ultimately protect against lactate buildup in the heart. NRF2 activation may also stop hypoxia-induced Altitude Motion Sickness, or AMS.

Slows Down Aging

Several compounds which may be fatal in massive quantities may increase longevity in rather tiny quantities due to xenohormesis through NRF2, PPAR-gamma, and FOXO. A very small quantity of toxins raises the cell’s ability to become better equipped for the next time it’s challenged with a toxin, however, this is not an endorsement to consume poisonous chemicals.

A good illustration of this process is with caloric restriction. NRF2 can improve the lifespan of cells by raising their levels of mitochondria and antioxidants as well as lowering the cells’ capability to die. NRF2 declines with aging because NRF2 prevents stem cells from dying and assists them to regenerate. NRF2 plays a part in enhancing wound healing.

Boosts the Vascular System

Done correctly with the production of sulforaphane, NRF2 activation may protect against heart diseases like high blood pressure, or hypertension, and hardening of the arteries, or atherosclerosis. NRF2 can enhance Acetylcholine’s, or ACh, relaxing activity on the vascular system whilst reducing cholesterol-induced stress. Nrf2 activation may strengthen the heart, however, over-activated Nrf2 can raise the probability of cardiovascular disease.

Statins may prevent or lead to cardiovascular disease. NRF2 also plays a major part in balancing iron and calcium which may shield the human body from having elevated levels of iron. By way of instance, Sirtuin 2, or SIRT2, can regulate iron homeostasis in cells by activation of NRF2 which is believed to be required for healthy levels of iron. NRF2 can also help with Sickle Cell Disease, or SCD. NRF2 dysfunction might be a reason behind endotoxemia like with dysbiosis or lectins induced hypertension. Nrf2 may also protect the human body against amphetamine induced damage to the vascular system.

Fights Neuroinflammation

NRF2 can shield against and assist with inflammation of the brain, commonly referred to as neuroinflammation. Furthermore, NRF2 can help with an Assortment of Central Nervous System, or CNS, disorders, including:

  • Alzheimer’s Disease (AD) – reduces amyloid beta stress on mitochondria
  • Amyotrophic Lateral Sclerosis (ALS)
  • Huntington’s Disease (HD)
  • Multiple Sclerosis (MS)
  • Nerve Regeneration
  • Parkinson’s disease (PD) – protects dopamine
  • Spinal Cord Injury (SCI)
  • Stroke (ischemic and hemorrhagic) – aids hypoxia
  • Traumatic Brain Injury

NRF2 has revealed a decrease of neuroinflammation in teens with Autism Spectrum Disorders or ASD. Idebenone pairs properly with NRF2 activators contrary to neuroinflammation. NRF2 may also improve the Blood Brain Barrier, or BBB. By way of instance, NRF2 activation with carnosic acid obtained from rosemary and sage can cross the BBB and cause neurogenesis. NRF2 has also been demonstrated to raise Brain Derived Neurotrophic Factor, or BDNF.

NRF2 also modulates some nutritional supplements capacity to cause Nerve Growth Factor, or NGF as it  can also aid with brain fog and glutamate-induced issues by modulating N-Methyl-D-Aspartate, or NMDA receptors. It may also lower the oxidative stress from quinolinic acid, referred to as QUIN. NRF2 activation can protect against seizures and large doses can decrease the brink of a seizure. At regular doses of stimulation, NRF2 can enhance cognitive abilities following a seizure by lowering extracellular glutamate in the brain and by it’s ability to draw cysteine from glutamate and glutathione.

Relieves Depression

In depression, it’s normal to notice inflammation in the brain, especially from the prefrontal cortex and hippocampus, as well as decreased BDNF. In some versions of depression, NRF2 can improve depressive symptoms by lowering inflammation within the brain and increasing BDNF levels. Agmatine’s capability to decrease depression by raising noradrenaline, dopamine, serotonin, and BDNF in the hippocampus depends upon NRF2 activation.

Contains Anti-Cancer Properties

NRF2 is equally a tumor suppressor as it is a tumor promoter if not managed accordingly. NRF2 can protect against cancer caused by free radicals and oxidative stress, however, NRF2 overexpression can be found in cancer cells as well. Intense activation of NRF2 can assist with a variety of cancers. By way of instance, the supplement Protandim can reduce skin cancer by NRF2 activation.

Relieves Pain

Gulf War Illness, or GWI, a notable illness affecting Gulf War Veterans, is a collection of unexplained, chronic symptoms which may include tiredness, headaches, joint pain, indigestion, insomnia, dizziness, respiratory ailments, and memory issues. NRF2 can improve symptoms of GWI by diminishing hippocampal and general inflammation, in addition to decreasing pain. NRF2 can additionally assist with pain from bodily nerve injury and improve nerve damage from diabetic neuropathy.

Improves Diabetes

High glucose levels, best referred to as hyperglycemia, causes oxidative damage to the cells due to the disruption of mitochondrial function. NRF2 activation may shield the human body against hyperglycemia’s harm to the cell, thereby preventing cell death. NRF2 activation can additionally protect, restore, and enhance pancreatic beta-cell function, while reducing insulin resistance.

Protects Vision And Hearing

NRF2 can protect against harm to the eye from diabetic retinopathy. It might also avoid the formation of cataracts and protect photoreceptors contrary to light-induced death. NRF2 additionally shield the ear, or cochlea, from stress and hearing loss.

Might Help Obesity

NRF2 may help with obesity primarily due to its capacity to regulate variables that operate on fat accumulation in the human body. NRF2 activation with sulforaphane can raise inhibit of Fatty Acid Synthesis, or FAS, and Uncoupling Proteins, or UCP, resulting in less fat accumulation and more brown fat, characterized as fat which includes more mitochondria.

Protects The Gut

NRF2 helps protect the gut by safeguarding the intestine microbiome homeostasis. By way of instance, lactobacillus probiotics will trigger NRF2 to guard the gut from oxidative stress. NRF2 can also help prevent Ulcerative Colitis, or UC.

Protects Sex Organs

NRF2 can shield the testicles and keep sperm count from harm in people with diabetes. It can also assist with Erectile Dysfunction, or ED. Some libido boosting supplements like Mucuna, Tribulus, and Ashwaganda may enhance sexual function via NRF2 activation. Other factors that boost NRF2, such as sunlight or broccoli sprouts, can also help improve libido.

Regulates Bones And Muscles

Oxidative stress may result in bone density and strength reduction, which is normal in osteoporosis. NRF2 activation could have the ability to improve antioxidants in bones and protect against bone aging. NRF2 can also prevent muscle loss and enhance Duchenne Muscular Dystrophy, or DMD.

Contains Anti-Viral Properties

Last but not least, NRF2 activation can ultimately help defend the human body against several viruses. In patients with the dengue virus, symptoms were not as intense in individuals who had greater levels of NRF2 compared to individuals who had less degrees of NRF2. NRF2 can also help people who have Human Immunodeficiency-1 Virus, or HIV. NRF2 can protect against the oxidative stress from Adeno-Associated Virus, or AAV, and H. Pylori. Finally, Lindera Root may suppress Hepatitis C virus with NRF2 activation.

Dr Jimenez White Coat
Nrf2, or NF-E2-related factor 2, is a transcription factor found in humans which regulates the expression of a specific set of antioxidant and detoxifying genes. This signaling pathway is activated due to oxidative stress as it enhances numerous antioxidant and phase II liver detoxification enzymes to restore homeostasis in the human body. Humans are adapted to function throughout a state of homeostasis or balance. When the body is confronted with oxidative stress, Nrf2 activates to regulate oxidation and control the stress it causes. Nrf2 is essential to prevent health issues associated with oxidative stress. Dr. Alex Jimenez D.C., C.C.S.T. Insight

Sulforaphane and Its Effects on Cancer, Mortality, Aging, Brain and Behavior, Heart Disease & More

Isothiocyanates are some of the most important plant compounds you can get in your diet. In this video I make the most comprehensive case for them that has ever been made. Short attention span? Skip to your favorite topic by clicking one of the time points below. Full timeline below.

Key sections:

  • 00:01:14 – Cancer and mortality
  • 00:19:04 – Aging
  • 00:26:30 – Brain and behavior
  • 00:38:06 – Final recap
  • 00:40:27 – Dose

Full timeline:

  • 00:00:34 – Introduction of sulforaphane, a major focus of the video.
  • 00:01:14 – Cruciferous vegetable consumption and reductions in all-cause mortality.
  • 00:02:12 – Prostate cancer risk.
  • 00:02:23 – Bladder cancer risk.
  • 00:02:34 – Lung cancer in smokers risk.
  • 00:02:48 – Breast cancer risk.
  • 00:03:13 – Hypothetical: what if you already have cancer? (interventional)
  • 00:03:35 – Plausible mechanism driving the cancer and mortality associative data.
  • 00:04:38 – Sulforaphane and cancer.
  • 00:05:32 – Animal evidence showing strong effect of broccoli sprout extract on bladder tumor development in rats.
  • 00:06:06 – Effect of direct supplementation of sulforaphane in prostate cancer patients.
  • 00:07:09 – Bioaccumulation of isothiocyanate metabolites in actual breast tissue.
  • 00:08:32 – Inhibition of breast cancer stem cells.
  • 00:08:53 – History lesson: brassicas were established as having health properties even in ancient Rome.
  • 00:09:16 – Sulforaphane’s ability to enhance carcinogen excretion (benzene, acrolein).
  • 00:09:51 – NRF2 as a genetic switch via antioxidant response elements.
  • 00:10:10 – How NRF2 activation enhances carcinogen excretion via glutathione-S-conjugates.
  • 00:10:34 – Brussels sprouts increase glutathione-S-transferase and reduce DNA damage.
  • 00:11:20 – Broccoli sprout drink increases benzene excretion by 61%.
  • 00:13:31 – Broccoli sprout homogenate increases antioxidant enzymes in the upper airway.
  • 00:15:45 – Cruciferous vegetable consumption and heart disease mortality.
  • 00:16:55 – Broccoli sprout powder improves blood lipids and overall heart disease risk in type 2 diabetics.
  • 00:19:04 – Beginning of aging section.
  • 00:19:21 – Sulforaphane-enriched diet enhances lifespan of beetles from 15 to 30% (in certain conditions).
  • 00:20:34 – Importance of low inflammation for longevity.
  • 00:22:05 – Cruciferous vegetables and broccoli sprout powder seem to reduce a wide variety of inflammatory markers in humans.
  • 00:23:40 – Mid-video recap: cancer, aging sections
  • 00:24:14 – Mouse studies suggest sulforaphane might improve adaptive immune function in old age.
  • 00:25:18 – Sulforaphane improved hair growth in a mouse model of balding. Picture at 00:26:10.
  • 00:26:30 – Beginning of brain and behavior section.
  • 00:27:18 – Effect of broccoli sprout extract on autism.
  • 00:27:48 – Effect of glucoraphanin on schizophrenia.
  • 00:28:17 – Start of depression discussion (plausible mechanism and studies).
  • 00:31:21 – Mouse study using 10 different models of stress-induced depression show sulforaphane similarly effective as fluoxetine (prozac).
  • 00:32:00 – Study shows direct ingestion of glucoraphanin in mice is similarly effective at preventing depression from social defeat stress model.
  • 00:33:01 – Beginning of neurodegeneration section.
  • 00:33:30 – Sulforaphane and Alzheimer’s disease.
  • 00:33:44 – Sulforaphane and Parkinson’s disease.
  • 00:33:51 – Sulforaphane and Hungtington’s disease.
  • 00:34:13 – Sulforaphane increases heat shock proteins.
  • 00:34:43 – Beginning of traumatic brain injury section.
  • 00:35:01 – Sulforaphane injected immediately after TBI improves memory (mouse study).
  • 00:35:55 – Sulforaphane and neuronal plasticity.
  • 00:36:32 – Sulforaphane improves learning in model of type II diabetes in mice.
  • 00:37:19 – Sulforaphane and duchenne muscular dystrophy.
  • 00:37:44 – Myostatin inhibition in muscle satellite cells (in vitro).
  • 00:38:06 – Late-video recap: mortality and cancer, DNA damage, oxidative stress and inflammation, benzene excretion, cardiovascular disease, type II diabetes, effects on the brain (depression, autism, schizophrenia, neurodegeneration), NRF2 pathway.
  • 00:40:27 – Thoughts on figuring out a dose of broccoli sprouts or sulforaphane.
  • 00:41:01 – Anecdotes on sprouting at home.
  • 00:43:14 – On cooking temperatures and sulforaphane activity.
  • 00:43:45 – Gut bacteria conversion of sulforaphane from glucoraphanin.
  • 00:44:24 – Supplements work better when combined with active myrosinase from vegetables.
  • 00:44:56 – Cooking techniques and cruciferous vegetables.
  • 00:46:06 – Isothiocyanates as goitrogens.

When the human body is confronted with harmful internal and external factors like toxins, the cells must rapidly trigger their antioxidant abilities to counteract oxidative stress. Because increased levels of oxidative stress have been determined to cause a variety of health issues, it’s important to use Nrf2 activation to take advantage of its benefits. The scope of our information is limited to chiropractic and spinal health issues. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .

Curated by Dr. Alex Jimenez

Green Call Now Button H .png

Additional Topic Discussion: Acute Back Pain

Back pain is one of the most prevalent causes of disability and missed days at work worldwide. Back pain attributes to the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments, and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.  

blog picture of cartoon paper boy

EXTRA EXTRA | IMPORTANT TOPIC: Recommended El Paso, TX Chiropractor

***

Want to Live to 100? Adopt These Healthy Anti-Aging Habits

Want to Live to 100? Adopt These Healthy Anti-Aging Habits

The number of Americans living to 100 — and beyond — has increased dramatically in recent decades, while those over the age of 80 comprise the world’s fastest-growing segment of the population, according to the latest research.

Between 1980 and 2014, life expectancy in the United States increased from 73.8 years to 79.1 years. Meanwhile, the number of Americans reaching and surpassing age 100 has exceeded 100,000, and that figure is expected to grow eight times — to 800,000 — by 2050, according to the National Institutes of Health and the U.S. Census Bureau.

So what’s the secret to living long enough to celebrate your 100th birthday?

While there are no sure-fire prescriptions for living to an extremely advanced old age, longevity researchers have found the ticket is a mixture of genetics and lifestyle — which means there are steps you can take to up your odds of living longer.

A landmark Swedish study, for example, showed that men who celebrated their 100th birthday all had mothers who lived into their 80s and 90s. But genetics wasn’t the only factor. The study also showed that the men had many controllable lifestyle factors in common. For instance:

  • All of them were non-smokers.
  • They generally stayed fit and trim by eating nutritious diets and exercising regularly.
  • Nearly all had healthy levels of cholesterol and blood pressure, which reduced their risk of developing cardiovascular disease, the No. 1 cause of death worldwide.
  • They owned their own homes or rented expensive residences, allowing them to live independently and stay mentally, physically, and socially active.
  • Most did not retire early, but instead actively worked until at least age 54.
  • None drank more than four cups of coffee per day.
  • Many reported having an optimistic outlook on life, which researchers said helped them embrace the power of positive thinking and combat stress and anxiety.

Studies of American centenarians have reached similar conclusions about the links between healthy lifestyles and longevity.

A recent study that compared and contrasted the lifestyles of Americans with the highest and lowest life expectancy found significant differences the daily habits of those individuals. For the study, researchers examined residents of Summit County, Colo., which has the nation’s highest life expectancy (86.8 years, two years higher than that of Andorra, the tiny country with the world’s highest life expectancy) and Lakota County, S.D. — which has the nation’s lowest life expectancy (66.8 years, comparable to Third World countries such as Sudan.

Researchers concluded that 74 percent of this disparity can be explained by controllable risk factors such as levels of physical activity, diet, tobacco use, and obesity, which increases the risk of developing life-threatening conditions diabetes, high blood pressure, heart disease, and certain cancers.

Worldwide, the rate of chronic illnesses such as heart disease is lowest in the Okinawa Archipelago, a group of 161 coral islands in the East China Sea that are home to the Earth’s longest-living people.

Here are some of the reasons why so many of them live to 100:

Diet. Okinawans primarily rely on plant sources such as sweet potatoes, greens, and whole grains. They supplement their diet with two or three servings per week of freshly caught fish, soya products, and an occasional serving of boiled pork with the fat trimmed off. They also drink antioxidant-rich green tea supplemented with jasmine flowers.

Exercise. Since most Okinawans are fishermen or farmers, they usually work outdoors into extreme old age. They get additional exercise from walking, gardening, martial arts and traditional dance.

Social life. Like other long-lived people, Okinawans maintain close social ties.

Stress. They also engage in stress-relieving strategies such as regular meditation.

Another longevity hot spot is the Greek island of Symi, where residents routinely live into their 90s. They, too, rely on fruits, vegetables, fish, and little meat. But they tend to slather their food tomato sauce, extra virgin olive oil and garlic. They also drink red wine with most meals, which helps account for their low rate of heart attacks.

So how long can life expectancy to continue to grow?

McGill University biologists Bryan G. Hughes and Siegfried Hekimi attempted to answer that question by analyzing the genetics and lifestyles of the longest-living individuals from the U.S., U.K., France, and Japan.

Their findings, published in the journal Nature, explodes the commonly held belief that the upper limit of the human lifespan is around 115 years.

“We just don’t know what the age limit might be. In fact, by extending trend lines, we can show that maximum and average lifespans, could continue to increase far into the foreseeable future,” Hekimi says.

It’s impossible to predict what future lifespans in humans might look like, Hekimi says. Some scientists argue that technology, medical interventions, and improvements in living conditions could all push up the upper limit.

Strawberries Reduce Mental Effects of Aging

Strawberries Reduce Mental Effects of Aging

A natural compound found in strawberries called fisetin reduces the mental effects of aging, says a study published in the Journals of Gerontology Series A. Researchers found it could help treat age-related mental decline and conditions like Alzheimer’s or stroke.

“Companies have put fisetin into various health products but there hasn’t been enough serious testing of the compound,” says Pamela Maher, a senior staff scientist in Salk’s Cellular Neurobiology Laboratory and senior author of the paper.

“Based on our ongoing work, we think fisetin might be helpful as a preventive for many age-associated neurodegenerative diseases, not just Alzheimer’s,” she said.

Maher has been studying fisetin, which is a type of flavonol that has powerful antioxidant properties, for more than a decade. Previous research found that it reduced memory loss related to Alzheimer’s disease (AD) in mice genetically modified to develop the disease.

When the scientists studied mice with Alzheimer’s, they found that the pathways involved in cellular inflammation were turned on. However, when the mice were given fisetin, they began producing anti-inflammatory molecules, and both memory loss and learning impairments were prevented. That particular research focused on genetic AD, which accounts for only 1 to 3 percent of cases.

For the recent study, Maher used a strain of laboratory mice that age prematurely and show signs of the disease at about 10 months in comparison to signs of physical and mental decline not seen in normal mice until two years of age.

The researchers fed the 3-month-old prematurely aging mice a daily dose of fisetin with their food for 7 months. Another group of the prematurely aging mice was fed the same food without fisetin.

During the study period, mice took various activity and memory tests. The team also examined levels of specific proteins related to brain function, as well as stress and inflammation.

“At 10 months, the differences between these two groups were striking,” says Maher, who hopes to conduct human trials. Mice not treated with fisetin had difficulties with all the cognitive tests as well as elevated markers of stress and inflammation. Brain cells called astrocytes and microglia, which are normally anti-inflammatory, were now driving rampant inflammation.

On the other hand, mice treated with fisetin were not noticeably different in behavior, cognitive ability or inflammatory markers at 10 months than a group of untreated 3-month-old mice with the same condition. In addition, fisetin was found to be safe even at high doses.

Strawberries have also been found to fight esophageal cancer. Chinese researchers gave volunteers freeze-dried strawberries each day for six months. A comparison of before-and-after biopsies showed that precancerous lesions in participants were decreased by 80 percent.

Some Over-the-Counter Hearing Aids are Effective

Some Over-the-Counter Hearing Aids are Effective

A handful of over-the-counter “personal sound amplification products” fared as well as an expensive hearing aid in helping people pick up more words in conversation, researchers report.

While the study took place in a sound booth, “in this controlled environment, some of these devices helped people with mild to moderate hearing loss as well as a hearing aid,” said study author Nicholas Reed. He is an audiologist at Johns Hopkins School of Medicine, in Baltimore.

An estimated 16 percent of Americans have trouble hearing, and the U.S. National Institute on Deafness and Other Communication Disorders estimates that almost 30 million people could benefit from hearing aids.

But hearing aids can cost thousands of dollars, and Medicare doesn’t cover them, the researchers noted.

“Hearing aids are regulated medical devices and should all be able to aid someone with hearing loss,” Reed said. “While not all hearing aids are the same, they should all be able to meet this minimum requirement of making sound louder at appropriate frequencies and with minimal distortion.”

In contrast, personal sound amplification products, available at stores and online, aren’t regulated and can’t be marketed as hearing aids. The U.S. Food and Drug Administration says they’re supposed to be used by people without hearing problems to help them hear distant sounds. The devices fit in or around the ear and make use of Bluetooth technology.

People do use the devices as hearing aids, however, said Todd Ricketts, vice chair of graduate studies with the department of hearing and speech sciences at Vanderbilt University Medical Center in Nashville. But these products tend to be less technologically advanced than hearing aids, although some offer advanced features.

Should you go out and buy one of the amplification devices instead of getting a hearing aid from a hearing specialist? Some audiologists will refuse to fit you for one, and the U.S. government doesn’t consider them appropriate for people with hearing loss.

For the study, researchers recruited 42 patients at a university audiology clinic who had mild to moderate hearing loss. Two-thirds were women, and their average age was 72.

In a sound booth, the participants listened to sentences with “speech babble noise” in the background. The participants tried to understand what was said without any hearing assistance; while using a hearing aid (costing $1,910); and while using personal sound amplification products bought online and at a pharmacy (one was $30, and the others cost between $270 and $350).

The researchers measured the average accuracy — the percentage of the time that the participants understood the sentences. It was 77 percent without a hearing aid, 88 percent with the hearing aid, and 81 to 87 percent with four of the amplification devices (Sound World Solutions CS50+, Soundhawk, Etymotic Bean and Tweak Focus).

“The results suggest that the devices are technologically and objectively capable of improving speech understanding in persons with hearing loss,” Reed said.

A fifth amplification device, the $30 MSA 30X Sound Amplifier, scored the worst, with an average accuracy level of 65 percent, the researchers reported. Reed said the device caused distortion.

Reed added that the findings suggest that both hearing aids and the amplification devices should be regulated and available over-the-counter. In that case, he said, “the FDA would set technical standards for all of these devices.”

For now, he said, adults with mild to moderate hearing loss may want to consider using one of the devices and consult an audiologist if needed to adjust it.

Ricketts cautioned that “the downside of just trying these or ordering them is that they may not be appropriate. People aren’t very good at self-diagnosing how much hearing loss they have.”

That’s where an audiologist could be helpful, he said, but some won’t sell these devices.

The study was published in the July 4 issue of the Journal of the American Medical Association.

Chocolate is Good for Your Brain

Chocolate is Good for Your Brain

Is your idea of a balanced diet chocolate in both hands? If so, you may be onto something — at least as far as your brain is concerned, according to a recent review published in Frontiers in Nutrition. Cocoa beans, it found, are a rich source of flavanols, a class of compounds that has neuroprotective effects.

Italian researchers studied available literature on the effects of cocoa flavanols on the brain — what happens to your brain in the hours immediately following eating cocoa, and what happens when you eat a cocoa flavanol enriched diet for a prolonged period of time.

They discovered that most randomized controlled trials found that cocoa flavanols had a beneficial effect on cognitive performance. Participants showed enhancements in working memory performance and improved visual information processing after having had cocoa flavanols.

For women, eating cocoa after a night of total sleep deprivation actually counteracted the cognitive impairment that such a night brings about. The results are promising for people who suffer from chronic sleep deprivation or work shifts.

The effects of relatively long-term ingestion of cocoa flavanols, ranging from five days to three months, has generally been investigated in elderly individuals. For them, cognitive performance was improved by a daily intake of cocoa flavanols.

In the elderly, factors such as attention, processing speed, working memory, and verbal fluency were greatly affected, and were most pronounced in older adults with mild cognitive impairments.

“This result suggests the potential of cocoa flavanols to protect cognition in vulnerable populations over time by improving cognitive performance,” said authors Valentina Socci and Michele Ferrara from the University of L’Aquila in Italy.  

“If you look at the underlying mechanism, the cocoa flavanols have beneficial effects for cardiovascular health and can increase cerebral blood volume in the dentate gyrus of the hippocampus,” they said. “This structure is particularly affected by aging and therefore the potential source of age-related memory decline in humans.”

So should we eat chocolate every day to improve our brains? “Regular intake of cocoa and chocolate could indeed provide beneficial effects on cognitive functioning over time,” said the authors.

“There are, however, potential side effects of eating cocoa and chocolate,” they warned. “Those are generally linked to the caloric value of chocolate, some inherent chemical compounds of the cocoa plant such as caffeine and theobromine, and a variety of additives we add to chocolate such as sugar or milk.”

Nonetheless, the scientists practice their results: “Dark chocolate is a rich source of flavanols. So we always eat some dark chocolate. Every day.”

Recent studies have found that chocolate has additional benefits. British researchers found that magnesium, an essential nutrient found in dark chocolate, helps cells keep track of the natural cycles of day and night.

Need an energy boost? Dark chocolate containing at least 60 percent cacao beans can enhance your energy levels in the afternoon. Volunteers at the University of Northern Arizona University ate dark chocolate or a placebo product, then did thinking and memory activities while undergoing EKGs of their brains. Those who ate the chocolate were more alert.

Popular Prostate Drugs Can Cause Harm

Popular Prostate Drugs Can Cause Harm

Popular hormone-based drugs for treating an enlarged prostate could increase men’s risk of type 2 diabetes, heart disease or stroke, a new study suggests.

A group of German men taking the drug Avodart (dutasteride) for three years wound up with higher blood sugar and cholesterol levels than men taking another class of prostate medication that does not affect male hormones, the researchers reported.

“Our small study suggests there are really adverse effects on metabolic function from these drugs that has not been reported previously,” said lead researcher Abdulmaged Traish. He is a professor of urology with the Boston University School of Medicine.

But Dr. Ashutosh Tewari, chair of urology for the Icahn School of Medicine at Mount Sinai in New York City, said the new findings run counter to prior clinical trials of the drug, and do not warrant any change in use at this time.

Still, Traish believes urologists should talk about these new results with patients before prescribing either Avodart or another hormone-based prostate drug called Proscar (finasteride). Both are in the class of drugs known as 5-alpha-reductase inhibitors.

“They should have a clear, open and honest discussion with their patients,” Traish said. “This drug might cause some of these problems.”

However, according to Tewari, “This is an interesting finding which is a little different than the large ‘controlled’ studies. It needs to be studied in a larger pool of patients in a prospective manner.”

The association seen in the study doesn’t prove a cause-and-effect relationship.

The prostate is a walnut-sized gland surrounding the urethra where it connects to the bladder. The prostate produces fluid that goes into semen, and is essential for male fertility. But as men age, their prostates tend to enlarge, pinching the urethra and making urination more difficult.

Avodart reduces production of dihydrotestosterone (DHT), a hormone linked to enlargement of the prostate gland. Treatment with Avodart can cause a man’s prostate to shrink by roughly 18 percent to 20 percent, Traish noted.

“The men urinate a little bit better,” Traish said. “They don’t have to stand an hour and a half in the bathroom at the airport.”

However, DHT also plays an important role in the function of other organs, particularly the liver, Traish said. He and his colleagues are concerned that reducing DHT could have other unknown health effects.

To examine the issue, Traish’s team reviewed records of 460 men treated at a single urologist’s office in Germany for enlarged prostate.

Half of the men had been prescribed Avodart to treat their problem, and the other half had been prescribed Flomax (tamsulosin). Flomax, in the class of drugs known as alpha-blockers, does not affect hormones, but works by causing the smooth muscle tissue of the prostate to relax, Traish said.

The researchers tracked all of the men for 36 to 42 months, performing blood tests and assessing prostate size and function.

Avodart was linked to an ongoing rise in blood sugar levels among men who received the drug, while men taking Flomax did not experience any such increase, the study authors said.

Further, long-term Avodart treatment was linked to increased “bad” LDL cholesterol levels in men, the investigators found. Men on Flomax experienced a smaller but yet significant increase in their LDL cholesterol levels, but also had an increase in their “good” HDL cholesterol levels, the findings showed.

Based on his findings, Traish said he would lean toward prescribing Flomax first rather than a hormone-based prostate drug.

“I would rather have my patient try something safer, and if it works for him, keep him on that,” Traish said.

Tewari noted that the clinical trials that found Avodart effective in treating enlarged prostate did not show any of these other metabolic problems.

Those clinical trials relied on men being randomly assigned Avodart, Tewari said. The men in this new study were not assigned medication randomly, but were allowed to choose their treatment following discussion with a doctor.

The new study also did not compare men taking Avodart to a control group taking a placebo, and relied on past data rather than an entirely new experiment, Tewari continued.

“This is interesting, yet needs to be verified in a controlled setting with a larger pool of patients,” Tewari explained. “At this time, I’m not too impressed with any clinical significance of this study.”

The study was published online recently in the journal Hormone Molecular Biology and Clinical Investigation.

Is This Hidden Condition Robbing Your Strength?

Is This Hidden Condition Robbing Your Strength?

You may be familiar with osteoporosis, the so-called “brittle bone” disease, but there is another condition – sarcopenia – that can lead to disability as we age, a top expert says.

“Sarcopenia is an age-related condition that can make walking and daily functioning difficult. It can also set the stage for bone fractures but, unlike osteoporosis, few people are aware of it,” Dr. Neerav Padilya, Ph.D., tells Newsmax Health.

Sarcopenia is defined as condition resulting in age-related loss of muscle mass, strength, and function, the National Institutes of Health (NIH) says.

The condition was first described in 1997, and experts – including the NIH – say it is an independent risk factor for physical disability, unrelated to age or other health problems.

Our bones get larger and stronger until the age of 30, when muscle mass begins to diminish, and sarcopenia can begin to set in, says Padilya, vice president of research at Qurr, a New Jersey based company which makes a supplement that targets the condition.

“We rely upon our muscle mass for our mobility, as well as to maintain balance, so if you start to lose it due to sarcopenia, by time you’re in your late 60s or 70s, this will have a direct impact on your life,” adds Padilya, a researcher and patent-holding inventor.

“The condition also causes a lack of hand grip strength, so if this becomes weak, imagine trying to open a jar of pickles,” he adds.

In addition, a loss of muscle mass may increase the risk of diabetes, he says.

Research studies note that increased muscle mass can help the body handle glucose, reducing the risk of the disease, Padilya notes.

But the biggest danger that sarcopenia poses, says Padilya, is that it predisposes people to falling, and suffering a potentially life-threatening fracture.

“About 50 percent of the people over the age of 65 that die have suffered a fracture, so it is a very serious problem,” he adds.

Since muscle mass begins to diminish in your 30s, it’s never too early – or too late – to take steps to prevent sarcopenia, says Padilya.

Here are his recommendations:

  • Make sure you are eating enough protein. Eat foods with protein uniformly at meals throughout the day, not only at dinner. Consume 60 grams of protein daily, or 20 grams at each meal.
  • Get up and move. Even a small amount of activity on a daily basis really helps you reduce body fat and maintain muscle.
  • Introduce weight lifting and resistance training into your exercise program.
  • Make sure you’re getting enough vitamin D. Take a multi-vitamin with vitamin D in it, and also make sure you are getting calcium from milk or eggs. Bone health and muscle health are closely connected.
Drinking Ages Cells

Drinking Ages Cells

The more alcohol people drink, the faster their cells appear to age. Researchers from Japan’s Kobe University Graduate School of Medicine found that alcoholic patients had shortened telomeres which placed them at greater risk for age-related illnesses.

Telomeres are the pieces of DNA that act as protective caps on the ends of chromosomes. Chromosomes, which protect our genes, get shorter every time a cell divides. Once a chromosome gets too short, it dies. Many studies have shown that shortened chromosomes are associated with the diseases of aging, especially cardiovascular disease, dementia, and diabetes.

“Telomeres, the protein caps on the ends of human chromosomes, are markers of aging and overall health,” said Naruhisa Yamaki, M.D. But aging isn’t the only cause of shortened telomeres.

“Our study showed that alcoholic patients have a shortened telomere length, which means that heavy drinking causes biological aging at a cellular level,” he said.

Yamaki and his co-authors recruited 255 study participants from alcoholism treatment services at Kurihama National Hospital in Yokosuka, Japan: 134 alcoholic patients and 121 age-matched controls or non-alcoholics, ranging in age from 41 to 85 years old. DNA samples, as well as drinking histories and habits, were collected from all participants.

“We also found an association between telomere shortening and thiamine deficiency (TD),” said Yamaki. Thiamine is a B vitamin.

 “TD is known to cause neuron impairments such as Wernicke-Korsakoff Syndrome. Although how exactly TD can cause neural impairments is unclear, it is well known that oxidation stress causes telomere shortening and, thus, it is possible that oxidation stress may also cause neuron death.”

According to a study from King’s College London, one in five seniors drinks too much, which could have devastating effects on baby boomers. “As the baby boomer generation become seniors, they represent an ever increasing population of older people drinking at levels that pose a risk to their health,” said lead author Dr. Tony Rao.

“This study shows the need for greater awareness of the potential for alcohol related harm in older people.”