October 20, 2022

Muscle, Protein and Aging

by mert in Uncategorized

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.

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, which is thought to advance the ticking of the clock (aging).
  • Proteins differ in their amino acid composition and degree of binding / accessibility.
  • 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.
  • Typically, meats and fish have a complete assortment of essential amino acids that are easily accessible for use in the body.
  • 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
  • This doesn’t mean that plant protein is not good for you.  Scientists like Walter Longo suggest that low protein / plant based diets throughout life may limit inflammation and slow the ticking of the clock.
  • The case of frailty / sarcopenia is a separate issue considered below.

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.
  • Plant or animal protein?  In one recent prospective cohort study from Hong Kong, older patients who ate plant protein were less likely to develop sarcopenia than those who ate animal protein whereas those who ate predominantly animal protein were more effectively rescued from sarcopenia.
  • 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/

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