Protein Intake and Longevity

Post in Progress 

Aging is associated with a progressive loss of muscle mass and loss of mobility. For these reasons, many health professionals recommend eating more protein to maintain muscle mass and reduce frailty.

However, there appears to be an inverse relationship between increased protein intake and cellular longevity (R).

Proteins are complex macromolecules made of amino acids. When we ingest protein, our body breaks them down into individual amino acids, which then circulate in our bloodstream and are utilized in every cell of our body for many different functions besides building muscle (R).

Of these circulating amino acids, leucine and arginine have the greatest ability to stimulate muscle growth (R). They are potent activators of the mammalian target of rapamycin (mTOR), which is a highly conserved gene, important for efficiently converting food into new tissue and other crucial functions.

While this is important to help our food more efficiently be converted into new tissue, when excessively activated, it can lead to reduced cellular health by inhibiting autophagy. When autophagy is inhibited, proteins within the cells are not recycled, leading to a build-up of damaged proteins which negatively impact cell function and lead to decreased cell lifespan, and thus decreased cellular and organismal lifespan (R, R2, R3).

Some studies in other organisms found that reducing protein intake, but keeping total calories the same had a similar effect on longevity as caloric restriction.

So, how can we maintain muscle and still have healthy cells as we age?

We need to properly balance hypertrophy with autophagy.

To do this, there are many ways to activate autophagy. The most widely know is fasting (R). Fortunately, long bouts of hunger aren’t necessary to gain the benefits of fasting. Even intermittent fasting is effective at increasing autophagy, allowing the body to remove protein aggregates inside of cells while limiting the amount of catabolism (muscle and weight loss).

If intermittent fasting sounds too annoying, you may not even need to fast in order to obtain many of the benefits of fasting. There are compounds which can mimic many of the effects of fasting without excessive caloric restriction.

Some of these calorie restriction mimetics include:

Berberine – ↑AMPK activation, lowers insulin response post meal (R)

Curcumin – boosts autophagy by inhibiting the Akt/mTOR pathway (R R2)

Coffee – (R)

EGCG – found in green tea (R)

Exercise – (R)

Fish oil – autophagy – (R)

Ginger – (R)

Ginseng – Increased autophagy and lowered mTOR – R

HCA – hydroxycitric acid – found in garcinia cambogia – common weight loss supplement. Blocks part of the citric acid cycle, tricking the body’s food sensors.

Ketones – (R)

Lithium – GSK-3 inhibitor, autophagy booster – (R)

Melatonin – autophagy activation (R)

MCT oils – (found in coconuts and palm oil) (R)

Nicotinamide – NAD+ substrate which is required for SIRT1 expression (R)

Nicotinamide Dinucleotide – NAD+ – substrate for Sirtuins, which boost autophagy.

Olive oil – tyrosol and oleuropein ↑autophagy (R R2)

Pterostilbene – a more bioavailable and longer lasting form of resveratrol, has slightly different effects than resveratrol, but also significantly boosts SIRT1 (R)

Trehalose – mTOR independent autophagy – (R)

Vitamin D – influences hundreds of genes, some of which regulate autophagy (R)

Sleep – (R)

Sulforaphane – found in broccoli sprouts is a potent activator of pGC-1a and nrf2 (RR2)

Spermidine (found in wheat germ oil) – (R)

Reishi Mushroom – (R)

Resveratrol – activates SIRT1, which boosts autophagy (R)


Rapamycin – mTOR inhibitor

Metformin – boosts AMPK in the liver, which activates autophagy.


mTOR and other autophagy regulating pathways. image sourced from Wikimedia Image made  by Charles betz

Here are some resources that can help you learn more:

A related article by Dave Asprey that describes one method of improving autophagy by protein restriction.

Podcasts by Dr. Rhoda Patrick. In this interview, she talks with the respected cellular biologist Guido Kroemer about autophagy, calorie-restriction mimetics, fasting, and protein acetylation.

mTOR inhibitors


A comprehensive review of autophagy detection methods and research