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Anti Aging

Back Clinic Anti Aging Chiropractic and Functional Medicine Team. Our body is in a constant and never-ending battle for survival. Cells are birthed, cells are destroyed. Scientists estimate that each cell 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 translate scientific insight into interventions that improve late-life health through treatments. It is useful to have a clear, consensus view on what exactly constitutes anti-aging treatment.

Since before the days of Ponce de Leon’s search for longevity, man has always been enticed by the chance of eternal youth. Chiropractic care with its health movement is a powerful method of stabilizing and enhancing this self-healing ability. Dr. Alex Jimenez discusses concepts surrounding the anti-aging pandora.


Aging and A Few Ways To Keep The Spine In Top Form

Aging and A Few Ways To Keep The Spine In Top Form

Keeping an individual’s spine in top form equals less pain and more mobility, flexibility, and freedom. The body wears down and is a natural effect of aging that happens to every single one of us. Spinal issues related to aging can become serious if not addressed and enacted upon with exercises, stretching, and chiropractic maintenance.  

Aging and The Back

It is normal for the spinal discs and joints to deteriorate with age. Spinal stenosis or the narrowing of the spinal canal can also be part of the aging process. Two conditions brought on by aging are degenerative disc disease and arthritis that can also include stiffening of the spinal ligaments and osteoporosis.
  • Degenerative disc disease is experienced by 40% of individuals 40 years of age
  • Increases to 80% for individuals 80 years of age and older.
  • It centers around discs that gradually change from being mostly water to mostly fat.
  • When it is fat, the discs become narrowed and lose elasticity.
11860 Vista Del Sol, Ste. 128 Aging and A Few Ways To Keep The Spine In Top Form
The Centers for Disease Control and Prevention say that 23% of American adults have arthritis. This is a condition that mainly affects the facet joints. The joints become swollen, which reduces the range of motion and can impinge on the spinal nerves, causing pain, weakness, and sciatica. With time the ligaments around and in the spine stiffen, reducing the range of motion, causing stenosis. Bone loss, or osteoporosis, is brought on by changes in hormones and other factors like nutrition. Aging is a natural process, but individuals can help their spines stay in top form no matter how old they are.  
11860 Vista Del Sol, Ste. 128 Aging and A Few Ways To Keep The Spine In Top Form

Practicing Healthy Posture

Right off the bat proper healthy body mechanics is a must. Staying aware and mindful of body posture maintains alignment and keeps the body balanced. Healthy posture will help reduce the effects of:
  • Spinal stenosis
  • Degenerative disc disease
  • Herniation
  • Risk of spinal fractures
Practicing proper posture includes:
  • Reduce slouching
  • Make sure the workstation is in top form and ergonomically sound
  • Whatever activity an individual is engaged in, try to elongate and make the spine long.
  • This approach also carries over to lifting.
  • Make sure to bend the knees when lifting and keep the spine as vertical as possible.


Yoga can be highly beneficial for a healthier, more youthful spine. Yoga fulfills three areas for keeping the spine in top form. This includes:
  • Regular exercise
  • Maintains flexibility
  • Achieves ideal body weight
Yoga is an age-defying activity for the spine. Because it:
  • Maintains strength
  • Flexibility
  • Posture
  • Balance
  • Can be helpful for a variety of spinal conditions, specifically arthritis pain
  • Falls can cause serious injuries. Yoga can also help work on balance as well.

See a Chiropractor

Preventive medicine is key to keeping the body healthy, youthful, and as strong as possible. A chiropractic examination can determine if there are any spinal problems and a diagnosis to develop an optimal treatment plan. If body function is limited because of pain in the back and/or legs, contact Injury Medical Chiropractic and Functional Medicine Clinic and get the spine back in top form.

Body Composition


Exercise/Stability Ball Curls

This exercise works muscle groups specific to spinal strength and includes the:
  • Hamstrings
  • Glutes
  • Deep abdominals
  • Hip abductors and rotators
Exercises like this are one of the most effective ways to build functional strength and endurance in the hamstrings, hips and prevent injuries. To do this workout:
  • Lie on your back with the knees bent
  • Lift legs up so the bottom of the feet rests on top of an exercise ball
  • Roll your legs out until they are straight
  • Hold the position for a second or two
  • Return to the top of the movement while squeezing the hamstrings
Working these muscles will help make squatting, lunging, or bending motions easier on the spine.  

Dr. Alex Jimenez�s Blog Post Disclaimer

The scope of our information is limited to chiropractic, musculoskeletal, physical medicines, wellness, and sensitive health issues and/or functional medicine articles, topics, and discussions. We use functional health & wellness protocols to treat and support care for injuries or disorders of the musculoskeletal system. Our posts, topics, subjects, and insights cover clinical matters, issues, and topics that relate and support directly or indirectly our clinical scope of practice.* Our office has made a reasonable attempt to provide supportive citations and has identified the relevant research study or studies supporting our posts. We also make copies of supporting research studies available to the board and or the public upon request. We understand that we cover matters that require an additional explanation as to how it may assist in a particular care plan or treatment protocol; therefore, to further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900. The provider(s) Licensed in Texas& New Mexico*  
Intro:�Ontario Health Technology Assessment�Series.�(April 2006) �Artificial discs for lumbar and cervical degenerative disc disease -update: an evidence-based analysis�� Intro:�Centers for Disease Control and Prevention.�(November 2020) �Arthritis��
Good Foods to Help Promote Longevity

Good Foods to Help Promote Longevity

The foods we eat can have the potential to be beneficial or harmful to our health. Poor nutrition can cause a variety of health issues, including obesity, cardiovascular disease, and type 2 diabetes. Meanwhile, proper nutrition can make you feel energized, reduce your risk of health issues, as well as help maintain and regulate a healthy weight. If you want to promote longevity, you have to fuel your body with good foods. In the following article, we will list several good foods that can ultimately help promote longevity by also helping to improve overall health and wellness.


Cruciferous Vegetables


Cruciferous vegetables have the unique ability to change our hormones, trigger the body�s natural detoxification system, and even reduce the growth of cancerous cells. These must be chewed thoroughly or eaten shredded, chopped, juiced, or blended in order to release their beneficial properties. Sulforaphane, found in cruciferous vegetables, has also been found to help protect the blood vessel wall from inflammation that can cause heart disease. Cruciferous vegetables, such as kale, cabbage, Brussels sprouts, cauliflower, and broccoli are several of the most nutrient-dense foods in the world.


Salad Greens


Raw leafy greens have less than 100 calories per pound, which makes them the perfect food for weight loss. Eating more salad greens has also been associated with the reduced risk of heart attack, stroke, diabetes, and several types of cancers. Raw leafy greens are also rich in the essential B-vitamin folate, plus lutein and zeaxanthin, carotenoids that can help protect the eyes. Fat-soluble phytochemicals, such as carotenoids, found in salad greens like lettuce, spinach, kale, collard greens, and mustard greens also have antioxidant and anti-inflammatory effects in the body.




Nuts are a low-glycemic food and a great source of healthy fats, plant protein, fiber, antioxidants, phytosterols, and minerals, which also helps to reduce the glycemic load of an entire meal, making them an essential part of an anti-diabetes diet. Regardless of their caloric density, eating nuts can help promote weight loss. Nuts can also reduce cholesterol and help reduce the risk of heart disease.




Seeds, much like nuts, also provide healthy fats, antioxidants, and minerals, however, these have more protein and are rich in trace minerals. Chia, flax, and hemp seeds are rich in omega-3 fats. Chia, flax, and sesame seeds are also rich lignans or breast cancer-fighting phytoestrogens. Moreover, sesame seeds are rich in calcium and vitamin E, and pumpkin seeds are rich in zinc.




Berries are antioxidant-rich fruits that can help promote heart health. Research studies where participants ate strawberries or blueberries daily for several weeks reported improvements in blood pressure, total and LDL cholesterol, and even signs of oxidative stress. Berries also have anti-cancer properties and have been shown to help prevent cognitive decline associated with aging.




The most well-known phytochemical in pomegranates, punicalagin, is responsible for more than half of the fruit’s antioxidant activity. Pomegranate phytochemicals have anti-cancer, cardioprotective, and brain-healthy benefits. In one research study, older adults who drank pomegranate juice daily for 28 days performed better on a memory test compared to those who drank a placebo beverage.




Eating beans and other legumes can help balance blood sugar, reduce your appetite, and protect against colon cancer. Beans are an anti-diabetes food that can help promote weight loss because they are digested slowly, which slows down the increase of blood sugar after a meal and helps prevent food cravings by promoting satiety. Eating beans and other legumes twice a week has been found to decrease the risk of colon cancer. Eating beans and other legumes, such as red beans, black beans, chickpeas, lentils, and split peas, also provides significant protection against other cancers.




Eating mushrooms regularly is associated with a reduced risk of breast cancer. White and Portobello mushrooms are especially beneficial against breast cancer because they have aromatase inhibitors or compounds that inhibit the production of estrogen. Mushrooms have shown to have anti-inflammatory effects as well as provide enhanced immune cell activity, prevention of DNA damage, slowed cancer cell growth, and angiogenesis inhibition. Mushrooms should always be cooked as raw mushrooms have a potentially carcinogenic chemical known as agaritine that is significantly reduced by cooking.


Onions and Garlic


Onions and garlic provide cardiovascular and immune system benefits as well as provide anti-diabetic and anti-cancer effects. These have also been associated with a lower risk of gastric and prostate cancers. Onions and garlic are known for their organosulfur compounds which help to prevent the development of cancers by detoxifying carcinogens, decreasing cancer cell growth, and blocking angiogenesis. Onions and garlic also have high concentrations of health-promoting flavonoid antioxidants, which have anti-inflammatory effects that may help provide cancer prevention.




Tomatoes are rich in a variety of nutrients, such as lycopene, vitamin C and E, beta-carotene, and flavonol antioxidants. Lycopene can help protect against prostate cancer, UV skin damage, and? cardiovascular disease. Lycopene is better absorbed when tomatoes are cooked. One cup of tomato sauce has about 10 times the amount of lycopene as a cup of raw, chopped tomatoes. Also keep in mind that carotenoids, like lycopene, are best absorbed when accompanied by healthy fats, so enjoy your tomatoes in a salad with nuts or a nut-based dressing for extra nutritional benefits.



The foods we eat can have the potential to be beneficial or harmful to our health. Poor nutrition can cause a variety of health issues, including obesity, cardiovascular disease, and type 2 diabetes. Meanwhile, proper nutrition can make you feel energized, reduce your risk of health issues, as well as help maintain and regulate a healthy weight. If you want to promote longevity, you have to fuel your body with good foods. Good foods can also help reduce inflammation associated with a variety of health issues, including joint pain and arthritis. Healthcare professionals, such as chiropractors, can offer diet and lifestyle advice to help promote health and wellness. In the following article, we will list several good foods that can ultimately help promote longevity. – Dr. Alex Jimenez D.C., C.C.S.T. Insight



Image of zesty beet juice.


Zesty Beet Juice

Servings: 1
Cook time: 5-10 minutes

� 1 grapefruit, peeled and sliced
� 1 apple, washed and sliced
� 1 whole beet, and leaves if you have them, washed and sliced
� 1-inch knob of ginger, rinsed, peeled and chopped

Juice all ingredients in a high-quality juicer. Best served immediately.



Image of carrots.


Just one carrot gives you all of your daily vitamin A intake


Yes, eating just one boiled 80g (2�oz) carrot gives you enough beta carotene for your body to produce 1,480 micrograms (mcg) of vitamin A (necessary for skin cell renewal). That’s more than the recommended daily intake of vitamin A in the United States, which is about 900mcg. It’s best to eat carrots cooked, as this softens the cell walls allowing more beta carotene to be absorbed. Adding healthier foods into your diet is a great way to improve your overall health.



The scope of our information is limited to chiropractic, musculoskeletal, physical medicines, wellness, and sensitive health issues and/or functional medicine articles, topics, and discussions. We use functional health & wellness protocols to treat and support care for injuries or disorders of the musculoskeletal system. Our posts, topics, subjects, and insights cover clinical matters, issues, and topics that relate and support directly or indirectly our clinical scope of practice.* Our office has made a reasonable attempt to provide supportive citations and has identified the relevant research study or studies supporting our posts. We also make copies of supporting research studies available to the board and or the public upon request. We understand that we cover matters that require an additional explanation as to how it may assist in a particular care plan or treatment protocol; therefore, to further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900. The provider(s) Licensed in Texas*& New Mexico*�


Curated by Dr. Alex Jimenez D.C., C.C.S.T.




  • Joel Fuhrman, MD. �10 Best Foods You Can Eat to Live Longer and Stay Healthy.� Verywell Health, 6 June 2020,
  • Dowden, Angela. �Coffee Is a Fruit and Other Unbelievably True Food Facts.� MSN Lifestyle, 4 June 2020,
How Collagen Improves Body Composition

How Collagen Improves Body Composition

Do you feel:

  • Redden skin, especially in the palms?
  • Dry or flakey skin or hair?
  • Acne or unhealthy skin?
  • Weak nails?
  • Edema?

If you are experiencing any of these situations, then your collagen peptides might be low.

There have been new studies on how collagen can improve body composition when it is combined with daily exercises. Collagen in the body has a unique amino acid composition that plays an essential role in the body’s anatomy. Collagen protein is a concentrated source of glycine, proline, and hydroxyproline, and when it is being compared to all the other dietary proteins, it makes collagen a potential practical choice as a structural protein.


In a 2015 study, researchers have demonstrated how efficient collagen supplements can improve body composition in active males. The results show how each male individuals are participating in weight training at least three times a week and have to supplement with at least 15 grams of collagen peptides to achieve maximum health. The assessments that the test provide are strength test, bioimpedance analysis (BIA), and muscle biopsies. These tests make sure that the male individuals are performing well after taking the collagen supplements, and the results show how their body mass had an increase of fat-free body mass. Another study showed how collagen protein supplementation when it is combined with resistance training that can increase muscle mass and muscle strength with the elderly as well as people with sarcopenia.

Beneficial Properties With Collagen

There are many beneficial properties that collagen supplements can provide to the body when it is consumed. There are hydrolyzed collagen and gelatin and can help improve a person’s skin structure. Even though there are not many studies on collagen supplements, there are excellent promises for the areas on the body. They are:

  • Muscles mass: Collagen supplements, when combined with strength training, can increase muscle mass and strength in the body.
  • Arthritis: Collagen supplements can help people with osteoarthritis. Studies show that when people osteoarthritis take collagen supplements, they discovered a massive decline in the pain they were experiencing.
  • Skin elasticity: In a 2014 study, it stated that women who took collagen supplements and has shown improvements in skin elasticity. Collagen can also be used in topical treatments to help improve the appearance of a person�s skin by minimizing fine lines and wrinkles.

Not only collagen supplements provide beneficial properties to the specific areas on the body, but there are the four main types of collagen and what is their roles in the human body as well as their functions:

  • Type 1: Type 1 collagen took account of 90% of the body’s collagen and made up of densely packed fibers that provide structures to the skin, bones, connective tissues, and teeth that are in the body.
  • Type 2: Type 2 collagen is made up of loosely packed fibers that are found in the elastic cartilage, which helps cushion the joints in the body.
  • Type 3: Type 3 collagen helps support the structure of the muscles, organs, and arteries that make sure that the body is functioning correctly.
  • Type 4: Type 4 collagen is found in the layers of everyone�s skin and helps with the filtration in the body.

Since these four types of collagen are in the body, it is essential to know that collagen can naturally decrease over time with age since the body will produce a lesser lower quality of collagen. One of the visible signs of decrease collagen is when the skin on the human body becomes less firm and supple as well as weaken cartilage due to aging.

Factors That Can Damage Collagen

Even though collagen can decrease naturally with age, many factors can destroy collagens that are harmful to the skin. The harmful factors can include:

  • Sugar and Carbs: Refined sugars and carb can interfere with collagen�s ability to repair itself on the skin. So by minimizing sugar and carb consumption in the body, it can reduce the effects of vascular, renal, and cutaneous tissue dysfunction.
  • Sun Exposure: Even though getting enough sun can help a person enjoy the day, however, being exposed to the sun for an extended period can cause damaged to the skin and destroy collagen peptides. The effects of overexposure of the sun can cause the skin to photo age and produce oxidative stress in the body.
  • Smoking: When a person smokes, it can reduce collagen production in the body, causing the body to have premature wrinkles, and if the body is wounded, the healing process will be slower and can lead to ailments in the body.
  • Autoimmune Diseases: Some autoimmune diseases can also damage collagen production like lupus.


Collagen is vital for the body as it helps the skin be gentle and firm. Naturally, it will decrease as a person gets older, so taking collagen supplements can make sure that the body can function correctly. When harmful factors are affecting the body, they can stop or even damage collagen production and accelerate the process of premature wrinkles from forming, making a person look older than they are. Some products can help the body’s cellular activity by providing more excellent stability, bioavailability, and digestive comfort.

The scope of our information is limited to chiropractic, musculoskeletal, and nervous health issues or functional medicine articles, topics, and discussions. We use functional health protocols to treat injuries or disorders of the musculoskeletal system. Our office has made a reasonable attempt to provide supportive citations and has identified the relevant research study or studies supporting our posts. We also make copies of supporting research studies available to the board and or the public upon request. To further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900.


Bosch, Ricardo, et al. �Mechanisms of Photoaging and Cutaneous Photocarcinogenesis, and Photoprotective Strategies with Phytochemicals.� Antioxidants (Basel, Switzerland), MDPI, 26 Mar. 2015,

Danby, F William. �Nutrition and Aging Skin: Sugar and Glycation.� Clinics in Dermatology, U.S. National Library of Medicine, 2010,

Jennings, Kerri-Ann. � Collagen – What Is It and What Is It Good For?� Healthline, 9 Sept. 2016,

Jurgelewicz, Michael. �New Study Demonstrates the Benefits of Collagen Peptides for Improving Body Composition Combined with Exercise.� Designs for Health, 31 May 2019,

Knuutinen, A, et al. �Smoking Affects Collagen Synthesis and Extracellular Matrix Turnover in Human Skin.� The British Journal of Dermatology, U.S. National Library of Medicine, Apr. 2002,

Proksch, E, et al. �Oral Supplementation of Specific Collagen Peptides Has Beneficial Effects on Human Skin Physiology: a Double-Blind, Placebo-Controlled Study.� Skin Pharmacology and Physiology, U.S. National Library of Medicine, 2014,

Schauss, Alexander G, et al. �Effect of the Novel Low Molecular Weight Hydrolyzed Chicken Sternal Cartilage Extract, BioCell Collagen, on Improving Osteoarthritis-Related Symptoms: a Randomized, Double-Blind, Placebo-Controlled Trial.� Journal of Agricultural and Food Chemistry, U.S. National Library of Medicine, 25 Apr. 2012,

Zdzieblik, Denise, et al. �Collagen Peptide Supplementation in Combination with Resistance Training Improves Body Composition and Increases Muscle Strength in Elderly Sarcopenic Men: a Randomised Controlled Trial.� The British Journal of Nutrition, Cambridge University Press, 28 Oct. 2015,

Modern Integrative Wellness- Esse Quam Videri

By informing individuals about how the National University of Health Sciences provides the knowledge for future generations, the University offers a wide variety of medical professions for functional medicine.



The 4Rs Program

The 4Rs Program

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 Program.

Food sensitivities, rheumatoid arthritis, and anxiety have been associated with impaired gastrointestinal permeability. These various conditions can happen from many factors that can impact the digestive tract. If left untreated it can potentially be the result of dysfunction of the intestinal permeability barrier, causing inflammation, and severe health conditions that the gut can develop. The 4R program is used to restore a healthy gut in the body and involves four steps. They are: remove, replace, reinoculated, and repair.

Intestinal Permeability

The intestinal permeability helps protects the body and makes sure that harmful bacteria do not enter the gut. It protects the body from potential environmental factors that can be harmful and are entering 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 layer of epithelial cells that are separated by tight junctions. In a healthy gut, the tight junction regulates the intestinal permeability by selectively allowing substances to enter and travel across the intestinal barrier and preventing harmful factors from being absorbed.

blog picture of doctor and elderly patient speak

Certain environmental factors can damage the tight junction, and the result is that it can increase the intestinal permeability, which causes intestinal hyperpermeability or leaky gut in the body. Contributing factors can increase intestinal permeability like an excessive amount of saturated fats and alcohol, deficiencies in nutrients, chronic stress, and infectious diseases.

With an increased intestinal permeability in the gut, it can enable antigens to cross the gut mucosa and enter the bloodstream causing an immune response and inflammation to the body. There are certain gastrointestinal conditions that are associated with intestinal hyperpermeability and if left untreated it can trigger certain autoimmune conditions that can cause harm to the body.

4Rs Program

The 4Rs is a program that healthcare professionals advise their patients to use when they are addressing disruptive digestive issues and help support gut healing.

Removing the Problem

The first step in the 4Rs program is to remove harmful pathogens and inflammation 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 these harmful factors from the body is to treat it with medication, antibiotics, supplements, and the removal of inflammatory foods from the diet is advised, including:

  • – Alcohol
  • – Gluten
  • – Food additives
  • – Starches
  • – Certain fatty acids
  • – Certain foods that a person is sensitive to

Replacing the Nutrients

The second step of the 4Rs program is to replace the nutrients that are causing the gut problems through inflammation. Certain nutrients can help reducing inflammation in the gut while making sure that the digestive tract is being supported. There are some anti-inflammatory foods that are nutritious. These include:

  • – High-fiber foods
  • – Omega-3s
  • – Olive oil
  • – Mushrooms
  • – Anti-inflammatory herbs

There are certain supplements can be used to support digestive function by assisting and absorbing the nutrients to promote a healthy gut. What the digestive enzymes do is that they assist in helping to break down fats, proteins, and carbohydrates in the gut. This will help benefit individuals that have an impaired digestive tract, food intolerances, or having celiac disease. Supplements like bile acid supplements can help assist in nutrient absorption by merging lipids together. Studies have stated that bile acids have been used to treat the liver, gallbladder, and bile duct while preventing gallstone formation after bariatric surgery.

Reinoculated The Gut

The third step is of the 4rs program to reinoculated the gut microbe with beneficial bacteria to promote a healthy gut function. Studies have been shown that probiotic supplements have been used to improve the gut by restoring beneficial bacteria. With these supplements, they provide the gut an enhancement by secreting anti-inflammatory substances into the body, help support the immune system, altering the body’s microbial composition, and reducing the intestinal permeability in the gut system.

Since probiotics are found in fermented foods and are considered as a transient since they are not persistent in the gastrointestinal tract and are beneficial. Surprisingly, they still have an impact on human health due to influencing the gut by producing vitamins and anti-microbial compounds, thus providing diversity and gut function.

Repairing the Gut

The last step of the 4Rs program is to repair the gut. This step involves repairing the intestinal lining of the gut with specific nutrients and herbs. These herbs and supplements can help decrease intestinal permeability and inflammation in the body. Some of these herbs and supplements include:

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


Since many factors can adversely affect the digestive system in a harmful way and can be the contributor to several health conditions. The main goal of the 4Rs program is to minimize these factors that are harming the gut and reducing inflammation and increased intestinal permeability. When the patient is being introduced to the beneficial factors that the 4Rs provide, it can lead to a healthy, healed gut. 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 or functional medicine articles, topics, and discussions. We use functional health protocols to treat injuries or disorders of the musculoskeletal system. Our office has made a reasonable attempt to provide supportive citations and has identified the relevant research study or studies supporting our posts. We also make copies of supporting research studies available to the board and or the public upon request. To further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900.


De Santis, Stefania, et al. �Nutritional Keys for Intestinal Barrier Modulation.� Frontiers in Immunology, Frontiers Media S.A., 7 Dec. 2015,

Ianiro, Gianluca, et al. �Digestive Enzyme Supplementation in Gastrointestinal Diseases.� Current Drug Metabolism, Bentham Science Publishers, 2016,

Mu, Qinghui, et al. �Leaky Gut As a Danger Signal for Autoimmune Diseases.� Frontiers, Frontiers, 5 May 2017,

Rezac, Shannon, et al. �Fermented Foods as a Dietary Source of Live Organisms.� Frontiers in Microbiology, Frontiers Media S.A., 24 Aug. 2018,

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,

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,



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 ?-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.


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.

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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.


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

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. 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.


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.


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 ?-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 �M, 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 ?-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 ?-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 ?-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-?-hydroxybutyrate (d-?OHB) by phosphatidylcholine-dependent mitochondrial d-?OHB dehydrogenase (BDH1) in a NAD+/NADH-coupled near-equilibrium reaction (Bock and Fleischer, 1975; LEHNINGER et al., 1960). The BDH1 equilibrium constant favors d-?OHB production, but the ratio of AcAc/d-?OHB 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, ?OHB pKa 4.7). The mechanisms through which ketone bodies are transported across the mitochondrial inner membrane are not known, but AcAc/d-?OHB 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 ?OHB oxidation, converting it to back AcAc (LEHNINGER et al., 1960; Sandermann et al., 1986). A cytoplasmic d-?OHB-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 �M), 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 ?OHB (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 �M) 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)-? 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). PPAR? (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 PPAR? may occur before the transition from fetal to neonatal physiology, while FGF21 activation may be favored in the early neonatal period via ?OHB-mediated inhibition of histone deacetylase (HDAC)-3 (Rando et al., 2016). mTORC1 (mammalian target of rapamycin complex 1) dependent inhibition of PPAR? 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 PPAR? 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 (Br�g�re 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 ? 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 ?-oxidation-derived intermediates accumulate due to a TCA cycle bottleneck, AcAc-CoA is converted to l-?OHB-CoA through a reaction catalyzed by mitochondrial 3-hydroxyacyl-CoA dehydrogenase, and further by 3-hydroxybutyryl CoA deacylase to l-?OHB, which is indistinguishable by mass spectrometry or resonance spectroscopy from the physiological enantiomer d-?OHB (Reed and Ozand, 1980). l-?OHB can be chromatographically or enzymatically distinguished from d-?OHB, and is present in extrahepatic tissues, but not in liver or blood (Hsu et al., 2011). Hepatic ketogenesis produces only d-?OHB, 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-?OHB 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 ?OHB from extracts of mice renal tissue were reported at ~4�12 mM. To test whether this was tenable, we quantified ?OHB concentrations in renal extracts from fed and 24h fasted mice. Serum ?OHB concentrations increased from ~100 �M to 2 mM with 24h fasting (Fig. 2B), while renal steady state ?OHB concentrations approximate 100 �M 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 M�ller glia cells, which could aid in the regeneration of photoreceptor outer segment.

?OHB 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, ?OHB inhibits Class I HDACs, which increases histone acetylation and thereby induces the expression of genes that curtail oxidative stress (Shimazu et al., 2013). ?OHB 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).

?OHB 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 ?OHB 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). ?OHB is the only known endogenous ligand of GPR109A receptor (EC50 ~770 �M) activated by d-?OHB, l-?OHB, 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 �M) 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 ?OHB 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 ?OHB via GPR109A has not been demonstrated in vivo.

Finally, ?OHB 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 ?OHB 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 ?OHB administration. Future studies will be needed to confirm the central nervous system as a direct ?OHB 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.

?OHB is an epigenetic modifier through at least two mechanisms. Increased ?OHB 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). ?OHB inhibition of HDAC3 could regulate newborn metabolic physiology (Rando et al., 2016). Independently, ?OHB itself directly modifies histone lysine residues (Xie et al., 2016). Prolonged fasting, or steptozotocin-induced diabetic ketoacidosis increased histone ?-hydroxybutyrylation. Although the number of lysine ?-hydroxybutyrylation and acetylation sites was comparable, stoichiometrically greater histone ?-hydroxybutyrylation than acetylation was observed. Distinct genes were impacted by histone lysine ?-hydroxybutyrylation, versus acetylation or methylation, suggesting distinct cellular functions. Whether ?-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. ?-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 ?OHB in inflammation emerge because many immune system cells, including macrophages or monocytes, abundantly express GPR109A. While ?OHB 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 ?OHB are enhanced by GPR109A overexpression in RPE cells, and abrogated by pharmacological inhibition or genetic knockout of GPR109A (Gambhir et al., 2012). ?OHB and exogenous nicotinic acid (Taggart et al., 2005), both confer anti-inflammatory effects in TNF? or LPS-induced inflammation by decreasing the levels of pro-inflammatory proteins (iNOS, COX-2), or secreted cytokines (TNF?, IL-1?, IL-6, CCL2/MCP-1), in part through inhibiting NF-?B translocation (Fu et al., 2014; Gambhir et al., 2012). ?OHB 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 ?OHB-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 ?OHB to inhibit the NLRP3 inflammasome in bone marrow derived macrophages is GPR109A independent (Youm et al., 2015). Although most studies link ?OHB to anti-inflammatory effects, ?OHB may be pro-inflammatory and increase markers of lipid peroxidation in calf hepatocytes (Shi et al., 2014). Anti- versus pro-inflammatory effects of ?OHB may thus depend on cell type, ?OHB concentration, exposure duration, and the presence or absence of co-modulators.

Unlike ?OHB, 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 TNF? expression (Jain et al., 2002), and AcAc, but not ?OHB, induced TNF?, 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 ?OHB versus AcAc on inflammation, and the ability of AcAc/?OHB ratio to influence mitochondrial redox potential, the best experiments assessing the roles of ketone bodies on cellular phenotypes compare the effects of AcAc and ?OHB 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-?OHB can be confounded, as only the d-?OHB stereoisomer can be oxidized to AcAc, but d-?OHB and l-?OHB 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)-?OHB 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-?OHB. While all three ketone bodies (d/l-?OHB and AcAc) reduced neuronal cell death and ROS accumulation triggered by chemical inhibition of glycolysis, only d-?OHB and AcAc prevented neuronal ATP decline. Conversely, in a hypoglycemic in vivo model, (d or l)-?OHB, 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 ?OHB 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 ?OHB 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 ?OHB (Abdelmegeed et al., 2004; Shi et al., 2014; Shi et al., 2016).

Taken together, most reports link ?OHB 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 ?OHB 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, ?OHB stimulated autophagic flux and prevented autophagosome accumulation, which was associated with decreased neuronal death (Camberos-Luna et al., 2016). d-?OHB 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 (M�nnist� 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, ?-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 PPAR?-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 ?OHB 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; M�nnist� 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]-?OHB 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 ?OHB 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 ?OHB production by melanoma and glioblastoma cells, stimulated by the PPAR? 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 ?OHB as a signaling mediator and Controversies in extrahepatic ketogenesis). It is also important to consider independent effects of AcAc, d-?OHB, and l-?OHB 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-?OHB 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 ?OHB 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.

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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-B�rgi 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 ?OHB 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-?OHB (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 ?OHB 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-?OHB (R-3-hydroxybutyl R-?OHB); (ii) glyceryl-tris-?OHB; 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-?OHB 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-?OHB, at doses up to 714 mg/kg, yielding circulating d-?OHB 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-?OHB 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-?OHB 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.



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

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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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