Inhibition of mTORC1 as a Treatment to Slow the Consequences of Muscle Aging

Inhibition of mTOR, and more specifically only its activities as a part of the mTORC1 protein complex, has been shown to slow aging in mice. This is a class of calorie restriction mimetic treatment, in that it works through many of the same beneficial stress response mechanisms as does a restricted nutrient intake. Many of the specific effects of mTORC1 inhibition in various different tissues in the body are still incompletely investigated, however. Researchers here discuss the effects of mTORC1 inhibition on the aging of muscle tissue. With age, muscle mass and strength are lost, leading to the onset of sarcopenia and contributing greatly to the condition of age-related frailty. Means to prevent this deterioration of muscle would provide a great benefit to the older population, but mTORC1 inhibition is unfortunately only a small step towards that goal.

A decade ago, rapamycin, an mTORC1 inhibitor, was reported to extend the lifespan of mice. Consistent with this, rapamycin and other mTORC1 inhibitors also protect several organs and tissues against age-related functional decline. Rapamycin's effect on aging skeletal muscle, however, was not explored until recently. It has long been known that mTORC1 activity is induced in aging muscle. Two recent reports with genetic and pharmacological evidence reveal important findings: 1) Chronic activation of mTORC1 stimulates progressive muscle damage and loss, and 2) Inhibition of mTORC1 with rapamycin prevents age-related muscle loss.

Consistent with the observation that the hyperactive mTORC1 induces muscle damage and loss, inhibition of mTORC1 activity with rapamycin or rapalogs protects aging muscle from atrophy in mice and rats. For example, treatment with rapamycin from 9 months to 30 months of age reduced apoptosis and promoted retention of peripherally located nuclei, and this was associated with reduced fiber loss in aging skeletal muscle. In a separate study, a shorter duration of rapalog treatment for 6-weeks, starting from 22 month of age, preserved both fiber size and muscle weight. These data suggest that mTORC1 is necessary and sufficient to drive skeletal muscle aging.

Do these findings conflict with the current understanding of the anabolic function of mTORC1? We do not think so. We believe the ultimate effect of mTORC1 depends upon: 1) how mTORC1 is activated, and 2) for how long mTORC1 remains activated. Akt-dependent, short-term activation of mTORC1 appears usually to be beneficial to cells, whereas Akt-independent, chronic activation of mTORC1 appears to be detrimental to cells. Akt-independent activation of mTORC1 induces catabolism in addition to its conventional anabolic activity. The progressive myopathy seen in the mTORC1-hyperactive muscle is the net outcome of a complex process that perturbs the balance between anabolism and catabolism, with catabolism winning out and leading to muscle fiber damage and loss.

Link: https://doi.org/10.18632/aging.102176

Comments

I hope everyone reading this blog and writing for it takes a minute to take pride in the fact that we are at the tip of the spear.

The theory of controlling the cells in your body from a synthesizing and building mode (mtorc1 stimulation/ activation/IGF-1) to a more "clean up and clear out" recycling mode (AMPK / autophagy/ cell hermetic stress) will be one of the most significant biohacks accessible to the average person.

Although you will not look like Brock Lesnar or Arnold who lived off mtorc1 activation all day everyday, you will be functioning at a higher level for longer.

Posted by: Steven at September 9th, 2019 10:31 AM

I'm fine with not looking like Brock Lesnar, Steven; he hasn't had that much of a muscular physique for a while... I don't expect to look like Luchasaurus, either. But I agree with you about how we are
getting really close to having rejuvenation therapies.

Posted by: Quinn at September 9th, 2019 12:16 PM

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.