Why do we have to die?

If we are to understand aging and death, the primary question is why should there be aging and death in the first place?  What evolutionary purpose might they serve?  First let me say that I’m discouraged that I don’t have any formal education in evolutionary biology, I think it’s a fascinating field and I’m frustrated by my status as a dilettante.  Yet I proceed in the spirit of an amateur.

Established evolutionary theory holds that genes that lead to the death of an organism would not be adaptive and so aging and death are not part of some program.  Current accepted theories fall under two broad categories, both animated by the spirit that aging is a product of evolutionary neglect, not intent.

The first theory is that of “accumulated mutations,” which holds that the organism accrues wear and tear from the processes of life, primarily genetic mutations that compromise function and lead to aging and death.  Given the evolving understanding of genetics as well as our new awareness that the hallmarks of aging extend beyond simple genetic mutations, this is theory is now a non-starter.

The second theory that is typically offered is “antagonistic pleiotropy,” meaning that survival to reproduction is prioritized by evolution and the very genes that improve survival to reproductive age lead to aging and death with the passage of time.  Or put differently, genes that code to preserve the organism do not improve fitness.  This theory is of a different class than the first one—while the first one is mechanistic and has been disproven, this one is teleological, offering an unverifiable story.

Neither of these theories supports the idea that aging and death are evolved and part of some program.  I’m suggesting that the field of evolutionary biology is wrong and I want to argue instead that dying is a way to promote evolutionary fitness.  Let me just make it clear:  I believe that aging is an extension of the same program as development and this program has evolved because it increased iterations of natural selection and evolutionary fitness.

The only way I can make this point is with a story, so let us consider the example of a nonhuman organism, an early mammal, though we could just as well pick a reptile or something else that is subject to sexual reproduction.  Also one presumption–that a given population lives in a particular geography with limited natural resources.

Consider first the non-aging organism.  At a certain point, the mature male will be competing for mating partners with males of the next generation.  Given the evolutionary imperative to pass on genes, there will be competition, and since our mature male is larger and more experienced than the next generation, it will kill them.  Alternatively, it will simply scare them off and prohibit them from mating.  But killing them is better as it will prevent them from getting larger one day and becoming a legitimate adversary.  Which is to say, those populations that evolve to infanticide will be better off.  So now you have an immortal infanticidal creature that continues to mate forever.  And if there is an accident or some lethal event, perhaps the accumulation of damage, the younger offspring can finally take his place.  But you have a real limit on the amount of natural selection because the population genetics are all deriving from the same male, who is presumably the one mating with all the females.

On the other hand, in an aging organism, the old male always gets weaker with time and is superseded by the young males, who fight it out for the right to mate with the females.  Because there is death, this arrangement maximizes iterations of natural selection which selects for better evolutionary fitness.  Invariably this population will evolve more rapidly and will likely be better suited to survive in a difficult environment.

So aging and death can be considered an evolutionary advantage.  Why couldn’t it be this simple?

Why Nature Wants Us to be Fat by Richard Johnson

The two popular theories that purport to explain the obesity pandemic are the carbohydrate insulin model and the standard model of energy balance.  In Why Nature Wants Us to be Fat, nephrologist Richard Johnson bravely proposes another theory:  the survival switch.

In his formulation, nature has evolved a survival mechanism allowing organisms to rapidly gain weight in response to stress or in preparation for periods of scarcity.  It is meant to be turned on occasionally in response to adversity, but our food environment has interacted with our evolutionary biology to turn the switch on continuously, leading to widespread obesity.  The survival switch is mediated by the molecule fructose, and Johnson pins much of the blame on pervasive consumption of high fructose containing foods and beverages which were introduced in the 1970’s.  Fructose metabolism triggers an intracellular starvation type response in the liver that ultimately leads to leptin resistance and diminished satiety, which then causes persistently disordered appetite.  Fructose causes obesity not because of its caloric or nutritive value, but rather by hijacking appetite.  Sucrose too is implicated, as it is broken down to equal parts fructose and glucose.

The book impressively draws from biochemistry and clinical science as well as comparative biology, evolutionary science, bio-anthropology and paleontology to synthesize a coherent theory to explain our current global metabolic perdicament.  According to Johnson, a classic example of the survival switch is mammalian hibernation.  To take that example, in preparation for winter the bear markedly ramps up its consumption of fructose-containing blueberries in order to build fat stores, which become a source of both calories and water during its hibernation.  Similarly, birds often switch from insect diets to fruit and nectar-filled diets as winter approaches in order to gain fat.  In this way animal and fruit-bearing plant life are in seasonal harmony.

The fundamental issue is that fructose metabolism simulates an intracellular energy deficit in a dose dependent fashion by rapidly diminishing intracellular ATP by 20-60%.  As a result, appetite and fat deposition are stimulated.  Fructose is known to cause central leptin resistance by hypothalamic inflammation, which would naturally increase appetite.  Additionally, in the presence of fructose, saturated fats are particularly obesogenic.  Finally, mitochondria suffer oxidative stress because of fructose.

In the absence of fructose, other stimuli such as high salt, dehydration and umami (glutamate) can also trigger the survival switch by pushing conversion of glucose to sorbitol and then to fructose through the polyol pathway. High glycemic carbs will  increase fructose production as well, and this is probably the number one way in which people are exposed to fructose today outside of supplemented HFCS.

According to Johnson, animals are drawn to salt-licks because the salt triggers the conversion of glucose to fructose, which in turn helps them put on weight. To the extent that ultra-processed foods are formulated with high concentrations of salt and sugar, they are continually triggering this metabolic switch on a global scale.

Johnson suggests inhibitors of fructose metabolism would prevent the adverse consequences of the western diet and would by themselves prevent NAFLD.  There happens to be a number of Pharma groups working on fructokinase inhibitors.  Luteolin is a naturally occurring flavone that blocks fructose metabolism and has been associated with renal protection.

This is a fascinating book by a researcher who has stature and standing in the field, but his identification of the survival switch as the cause of the majority of  maladies afflicting mankind gives pause.    Yet the theory is cohesive, supported by empirical evidence and powerfully explains much of our current predicament.  I am swayed.

Muscle, Protein and Aging

Muscle is a metabolically active tissue that plays a central role in health and longevity.  Beyond functional roles such as helping one get up from a chair, going up stairs and avoiding falls as we age, muscle accounts for 75% of glucose disposal and makes the greatest contribution to resting energy expenditure of any tissue in the body.  For these reasons, we need to be mindful of preserving our muscle mass if we are to age well.  Unfortunately, it becomes harder to maintain (let alone build) muscle as we get older.  There is evidence of anabolic resistance in the elderly, a barrier to building muscle, and it is not uncommon for the elderly become sarcopenic.  Sarcopenia (from the Greek “loss of flesh”) can be a tremendous burden on geriatric populations and is the leading cause of frailty and deterioration.  What follows is a discussion of muscle metabolism that owes a debt of gratitude to the food industry scientist Don Layman and also to a review article by Tezze et. al.

Protein
The main drivers of muscle synthesis and retention are resistance exercise and to a lesser extent, protein intake.   But what kind of exercise?  And what kind of protein?  And how much?  And when?

Not all protein is equal.  

  • Protein is made of amino acids, some of which are categorized as essential because they cannot be manufactured by our body and must be consumed.
  • The essential amino acids are: histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine.
    • Leucine in particular is thought to be a notable driver of muscle protein synthesis
    • Leucine is also a primary driver of the enzyme mtorc1.
  • Proteins differ in their amino acid composition and degree of binding / accessibility.
  • Typically, meats and fish have a complete assortment of essential amino acids that are easily accessible for use in the body.
  • All essential amino acids are derived from bacteria.
    • Plants will absorb them as part of their root system to incorporate into plant protein.
    • Ruminative animals like cows have nitrogen fixing bacteria in their stomachs that very efficiently convert plant protein in grass / grain to essential amino acids, accounting for the high protein of herbivores who themselves consume very little protein.
  • Plants are often deficient in various essential amino acids and plant protein is more likely to present difficulties with extraction. They have a lower protein digestibility corrected amino acid score.
      • DIAAS is the digestible indispensable amino acid score.
      • To take an example, whey protein, a byproduct of cheesemaking, is 20% better than a soy protein isolate on the basis of its essential amino acids

Muscle Homeostasis

  • Muscle tissue is in a constant state of turnover characterized by rates of muscle protein breakdown and muscle protein synthesis.
  • The relationship of building muscle tissue to fostering longevity is seemingly paradoxical.  On the one hand, having muscle mass is good for aging and associated with less frailty.  On the other hand, it requires the anabolic activation of mtorc1, which is a driver of aging and frailty.  How do we reconcile these realities?
    • Muscle protein breakdown is inhibited by insulin, which is the body’s main anabolic hormone.
    • Beyond that, muscle protein synthesis is more heavily regulated and amenable to modification, typically stimulated by agents that increase the activity of mtor, which is believed to accelerate aging. We know that branched chain amino acids such as leucine drive mTORC1 and drive muscle growth.
    • Yet ITP studies in mice suggest L-leucine enriched diets reduce lifespan (ITP 2017) and chronic activation of mTORC1 stimulates progressive muscle damage and loss. Moreover, inhibition of mTORC1 with rapamycin prevents age-related muscle loss (1).
  • The resolution of this paradox is lies in the complexity of muscle homeostasis and the mTORC1 enzyme and there are various explanations.  Some authors (1) have suggested that Akt dependent activation of mTORC1 prevents muscle atrophy whereas Akt independent pathways will induce muscle atrophy, largely mediated by mitochondrial oxidative stress.  Others (2) have suggested that mTORC1 inhibition rejuvenates muscle stem cells by preventing senescence.

Another way of looking at this issue is to consider the essential amino acid leucine, which is a relatively muscle-specific activator of mtor.  Insulin on the other hand activates mtor in a range of tissues.  What this means functionally is that people who eat a lot of small carbohydrate meals, each of which leads to the secretion of insulin, continuously activate mTOR and drive anabolic pathways / aging across tissues.  This is probably the worst-case scenario and a real justification not to snack.   On the other hand, infrequent / periodic high protein meals with large leucine loads will stimulate muscle growth while reducing broader mtor activation associated with snacking.  Does this mean there is no role for carbs in the diet?  Of course, not, but that is a matter for another time.

Timing of protein consumption—is it better to spread your intake across the day or consume the bulk of your protein in one or two meal?

  • To build muscle you need large individual servings of protein.  Muscle anabolism is not stimulated until you have a significant ingestion. Muscle tissue senses the concentration of amino acids in the blood that serve as a signal that a meal has adequate quality for muscle to trigger the very expensive process of protein synthesis.
  • Protein should be front loaded in the day, ~30g for breakfast to interrupt overnight catabolism and then at dinner to forestall overnight catabolism. Ideally, we pair this with some resistance activity.
  • For the rest of your physiological needs (cardiac, liver, etc.), you don’t need large individual servings.
  • This is not true for kids—their muscle growth is more insulin oriented. They can use protein regardless of the absorption schedule.

Exercise and muscle

  • Resistance exercise is a necessary co-factor for muscle growth along with protein.
    • Resistance exercise stresses the muscle, disrupting homeostasis and leading to protein turnover. With protein turnover, there is protein misfolding, leading to endoplasmic reticulum stress.
    • ER stress leads to the activation of the “integrated stress response” a signaling pathway whose goal is to restore muscle homeostasis.
    • How? via upregulation of ATF4, which controls LARS, a leucine sensor.  Clearly more complicated than this, but here’s your broad outline.
  • Exercise induces both hyperplasia and hypertrophy of muscle fibers. In other words, it increases both the number of fibers and their size.
  • Exercise enhances the ability of the muscle to take-up more amino acids from the bloodstream, and this effect lasts multiple days.

Protein as a diet food

  • Protein is also the most satiating food.
  • It also has a higher thermogenic effect (burns more calories) than either carbs or fat. So eating protein it increases energy consumption.
  • Hi protein percentages during dieting preserves muscle mass.

Protein use / reversing catabolism with age

  • As we get older, our ability to use protein is diminished, referred to as “anabolic inflexibility.”
  • This is partly due to diminished physical activity with age, but also because of features intrinsic to the muscle tissue.
  • This anabolic resistance can be largely overcome by increasing protein intake.  Yet you also need resistance–it doesn’t matter how much protein you consume if you don’t also engage in some degree of muscle exercise. You need both.
  • Older adults need more protein.  There are varying recommendations between, 1-1.5 mg/kg/day (3), keeping in mind that not all protein is created equal.
  • I would rather that an older adult work hard to ensure adequate protein intake, eat meat fish and eggs every day, even if it means taking a statin for dyslipidemia. Obviously, this would be a case-by-case decision, but I’m far less interested in treating obesity, for instance in an older adult.

Cautionary thought:

  • Beyond driving muscle synthesis, certain branched chain amino acids found in animal sources such as isoleucine and isoleucine may actually drive mtor and accelerate aging.  In which case, in the setting of tonically activated mtor (middle/old age), a diet high in protein from vegetable sources makes most sense.
  1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738401/?fbclid=IwAR3vAqW1MLIF-kY1utROauhs2i8xHFSlqjeL95SRN02Cdgoif-FW1PWXw0c
  2. https://www.mikhailblagosklonny.com/blog/how-rapamycin-prevents-muscle-loss-and-sarcopenia-first-draft/
  3. https://pubmed.ncbi.nlm.nih.gov/24039411/