Senolytic Nutrition and the Molecular Biology of Wellness

There are two sides to medicine.  One side is treating disease; the other side is maintaining wellness.  We currently define disease by its symptoms and then use drugs to treat those symptoms.  That sounds very high-tech.  But how do you define wellness?  One definition might be the lack of symptoms associated with disease, especially chronic disease.  That’s not a very good definition of wellness since the classic symptoms of chronic disease often take years, if not decades, of continuing organ damage before they appear.  By that time, the organ in question is generally significantly damaged.  What is required is a readily determined blood marker to let you know you are no longer well as early as possible to avert long-term future organ damage.

A strong argument can be made that the first blood marker that indicates you are no longer well is the measurement of insulin resistance, which can be quantified by a blood test called Homeostatic Assessment of Insulin Resistance, or HOMA-IR.  This simple blood test only requires knowing your fasting insulin and glucose levels and then putting their values into a simple equation.  If the HOMA-IR is less than 1, then you have no insulin resistance.  This indicates that your metabolism is running at peak efficiency, and you can be considered well.  The higher your level of HOMA-IR, the less well you are and the more likely you are to develop a chronic disease condition at an earlier age.  Which disease and when it will manifest, no one knows.  But the sure thing is that many Americans are well along the pathway to earlier future chronic diseases because the first physical indication of increased insulin resistance is the accumulation of excess body fat which continues to proliferate in every segment of our society.

Insulin resistance is not a disease per se but a marker that your metabolism is being disrupted.  Our metabolism keeps us alive, controls our immune system, and repairs damaged tissue.  Metabolism is an incredibly complex example of systems-based biology that makes supercomputers look like toys in comparison.  A simple description of metabolism might be “the food you put into your mouth can control your ability to stay well.”   That sounds lame.  So how about this for a better definition of metabolism:  “Your diet controls your body’s ability to immunologically remove senescent cells that are the underlying cause of age-related chronic disease.”  Now that sounds like cutting-edge biotechnology.

Senescent cells are transformed cells that are immortal unless the immune system removes them.  In this sense, they are like cancer cells.  However, unlike cancer cells which are characterized by uncontrolled growth, senescent cells are marked by the generation of increased inflammation.   To live longer, you want your immune system to remove senescent cells and replace those damaged cells with new healthy ones to maintain organ function.   But before I get too far ahead of myself, let’s return to understand how the diet causes the generation of senescent cells that accelerate aging and the chronic diseases associated with aging.

The transformation of normal cells into senescent cells starts with a pro-inflammatory diet.  A pro-inflammatory diet can be defined as any diet that contains any one of these three dietary components:

  1. A deficiency in the intake of omega-3 fatty acids and polyphenols.
  2. An excess intake of total calories, glucose, omega-6 fatty acids, and palmitic acid.
  3. An imbalance in the ratio of protein to carbohydrate.

The more of these three dietary components in your current diet, the more pro-inflammatory your diet becomes, and the more rapidly you develop insulin resistance.

However, the initial metabolic consequence of a pro-inflammatory diet before insulin resistance develops is the inhibition of the master regulator of metabolism found in every living cell in the body.  That master regulator is the protein AMPK.  AMPK acts as the molecular traffic cop that keeps metabolism flowing efficiently and, in turn, keeps us well.

Insulin resistance can be best understood as a general term to indicate that the efficacy of converting food into new living tissue has become compromised.  Although it is challenging to measure your AMPK levels because your need tissue biopsies, you can quickly determine your level of insulin resistance by the level of HOMA-IR in the blood.  Thus, determining the level of insulin resistance in the blood is the earliest clinical marker you can do that indicates you are no longer well.  One of the first consequences of increasing insulin resistance is the appearance of excess body fat, especially in the midsection area.  This is because as AMPK activity becomes inhibited, the ability of an organ to convert stored fat into energy is compromised, and fat begins to accumulate in that organ.  Unfortunately, this is not the only consequence of insulin resistance.  Insulin resistance causes the cells to become metabolically stressed, creating genetic damage to your DNA.  The cell’s response to such genetic damage is to activate a survival mechanism to stop such damaged cells from becoming cancerous.  This process is called senescence.  An even more graphic description of this transformation is that a senescent cell becomes an immortal “zombie cell.”  Zombie cells not only don’t die but also begin to transform other cells into new zombie cells.

Furthermore, your stored body fat is the best “breeding ground” for new zombie cell formation.   Therefore, the more excess body fat you have, the faster you build up a growing population of zombie cells, causing you to age more quickly.  You age more rapidly because zombie cells generate high levels of inflammation.

Usually, this increased inflammation generated by zombie cells would signal the immune system to remove them.  Unfortunately, the immune response that controls the selective removal of senescent cells can be blocked in the presence of insulin resistance.  Now, senescent cells can escape detection by the immune system and continue to generate more zombie cells in every organ in the body, including the brain. This explains why virtually every chronic condition and a decreased ability to fight off infectious disease are strongly associated with increased insulin resistance, which is strongly associated with increased body fat.

It often takes years, if not decades, for the symptoms of many chronic conditions to manifest themselves to allow a physician to diagnose something is wrong, usually resulting in a lifetime of prescription medications to treat the symptoms of this new emerging chronic disease.  However, the initial step of that long journey began with a pro-inflammatory diet that inhibited AMPK activity, thus creating insulin resistance, and leading to increased cellular senescence.

The logical solution is to follow a dietary pathway to reverse insulin resistance, thus reducing cellular senescence.  Although no drug or magic supplement can do that, a specific dietary system can be designed to activate AMPK.  This multi-component dietary system consists of (1) the highly defined calorie-restricted Zone diet, (2) omega-3 fatty acids, and (3) polyphenols all working as a team to eliminate zombie cells by activating AMPK.  This is the foundation of Senolytic Nutrition.

You should consider Senolytic Nutrition as a dietary form of gene therapy whose results can be easily monitored by reductions in HOMA-IR levels in the blood.  It is estimated that 150 million Americans have significant insulin resistance, which means they are fast-tracking to many potential chronic conditions at an earlier age.  Senolytic Nutrition can be viewed as a “longevity drug” potentially reversing this oncoming tidal wave of age-related chronic diseases associated with cellular senescence.  This is because Senolytic Nutrition offers a far more elegant, efficient, and utterly non-toxic way to reduce the rapidly growing cost of healthcare.

Senolytic Nutrition goes back to the founding of medicine some 2,500 years ago when Hippocrates said, “let food be your medicine, and let medicine be your food.”  Although it has taken an incredibly long time to understand the complex molecular biology of metabolism, using Senolytic Nutrition offers a pathway based on the biotechnology of systems-based biology to maintain wellness for as long as possible.  That should be the primary goal of medicine in the future, as it has been in the past.


4 replies
  1. chris stephens says:

    You’ve always emphasized a 3/4 ratio of protein/carb intake. I think you’ve softened on that a little over the years emphasizing a few soft metrics like hunger and mental clarity between meals as a way to calibrate the ratio up or down as well as object blood markers like HbA1c, TG/HDL and EPA/AA. How much wiggle room do you currently think there is for personalizing the P/C ratio? Is there something more there than the fact that the math works out to minimize calories while supplying enough protein to maintain muscle mass and glucose to maintain energy and cognitive health? I assume the farther you stray, the less AMPK activation you get but I’m unsure what the window is around 3/4 ratio.

    Also, what is the relative strength of AMK activation through nutrition vs through exercise? There has been a lot of press lately spotlighting the importance of maintaining VO2max and strength in successfully increasing healthspan and possibly lifespan. I continue to struggle to keep calories as low as you recommend but all of the above blood markers are well within your recommendations and I really enjoy exercising vigorously (semi-competitive indoor rower). I *could* eat less but when I do, my energy suffers and I end up scaling back on the exercise. I end up consuming slightly more carbs at most meals and that does the trick so ratio is closer to 3/5 (some days 1/2 when i feel i’ve been restricting too much and energy is affected). I continue to work on this and have been thoroughly enjoy the new zone bars as a way to keep caloric intake slightly lower than i otherwise would be.

    This new angle of senolytics and the zone is fascinating. I am really looking forward to the new book.

    • chris stephens says:

      i’m going to post this over on dr sear’s zoneliving blog which i think is a more appropriate place for this type of question. feel free to delete. thanks!

  2. Tana Webber says:

    I just read your first book from 1995 “Enter the Zone” and here I am on your site. I am very happy to see that you are alive and flourishing! That is a good sign for me to go ahead with this plan. I am 70 years old and have multiple chronic diseases including Asthma, Chronic Fatigue, Fibromyalgia, Arthritis, Heart Disease and Non-alcoholic Fatty Liver Disease along with not one but two Brain Aneurysms. Figuring my protein requirements came out at 57 gm. Looking at that I thought “I’m going to starve and have fat layers hanging off my body if I follow this diet.” I took your Insulin Quiz and got an 8 result. Can you give me any help in managing my problems? BTW my father, brother & sister all had Heart Disease and my brother and grandmother had Diabetes. I have not been tested in awhile but did not test positive. I also weigh 168# at 63.5″. Please help!

    • Barry Sears says:

      The Zone concept has significantly evolved since 1995. Your health problems are interrelated due to a blocked Resolution Response as described in my latest book, The Resolution Zone.. The ultimate cause decreased AMPK activity leading to insulin resistance and then to those other associated problems.

      I like to have to minimum protein intake being 75 grams per day. spread evenly throughout the day or about 25 grams of protein per meal. Then you balance that protein at each meal with about 35 grams of low glycemic carbs and a dash of fat to activate AMPK which is the master regulator of your metabolism and the immune system.. I promise you will not starve, and in fact you will be hard pressed to eat all the food. If you go, you get more information.

      You also likely will require extra omega-3 fatty acids and polyphenols to also activate AMPK. I would normally send you my most recent article, but I am working on a back-up computer as my primary computer in being repaired and should be back next week.


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