The Role of mTOR as a Regulator of Lifespan

The mTOR gene is deeply involved in the regulation of cellular activities in response to nutrient sensing. It is also implicated in the many, many changes that occur to slow aging in response to a restricted calorie intake, including processes known to be important to aging such as mitochondrial function and cellular senescence. Given that most research to date on intervention in the aging process has focused on the calorie restriction response and related upregulation of stress response mechanisms, it is no surprise that mTOR has attracted a lot of attention. The first mTOR inhibitor drugs are already going through clinical trials, developed by companies such as resTORbio and Navitor Pharmaceuticals.

It is unfortunate that this strategy for modulating the pace of aging has far larger effects on life span in short-lived species than in long-lived species such as our own: calorie restriction extends life by 40% in mice, but by no more than a few years for us. This is thought to be a consequence of the seasonal nature of famine. A famine lasts a large fraction of a mouse life span, but very little of a human life span, so only the mouse has the evolutionary pressure to develop a large plasticity of life span in response to calorie restriction.

The end result of these factors is that upregulation of stress response mechanisms just doesn't do as much in our species as it does in mice, or in any other short-lived laboratory species. Thus we shouldn't expect therapies targeting mTOR to do much more than can already be achieved via the practice of calorie restriction. That means some degree of improved health, as illustrated in clinical trials for immune function in later life, for example, but no great extension of life span.

mTOR as a central regulator of lifespan and aging

Consistent with its role in coordinating protein synthesis, energy metabolism, and autophagy in cancer, emerging evidence suggests that mTOR may act as a central node that orchestrates many aspects of cellular and organismal biology related to aging phenotypes. Inhibition of the mTOR pathway by rapamycin or genetic means has profound effects on life span and age-associated phenotypes across a wide array of organisms. However, the underlying mechanisms are still unclear as it has been reported that during aging mTOR activity is both increased and decreased, depending on, for example, tissue or sex. It was suggested that, in spite of these variations, overall aging does not result in a generalized increase in mTOR signaling. If this is the case, it is possible that mTOR activity aligns with the antagonistic pleiotropy theory of aging, whereby its levels are beneficial during development but limit the health span in adult life.

Owing to its central role in age-related processes, mTOR represents an appealing target to ameliorate age-related pathologies. Despite its capacity to expand life span, the function of rapamycin (and of rapalogs) as an immunosuppressant might be of concern, as a decline in immune function (immunosenescence) already occurs in the elderly, leading to infection-related morbidity and mortality. Intriguingly, several studies in both mice and humans suggest that mTOR inhibitors could reduce immunosenescence. In mice, rapamycin can restore the self-renewal and hematopoiesis of hematopoietic stem cells and enable effective vaccination against the influenza virus. A randomized trial testing the effects of rapalog RAD001 in a cohort of healthy elderly patients also showed an enhanced response to the influenza vaccination.

Another limitation of rapamycin is that its chronic exposure in mice leads to mTORC2 inhibition in, for example, hepatocytes. Active-site mTOR inhibitors also inhibit mTORC2. Strikingly, selective suppression of mTORC2 reduces life span and is associated with changes in endocrinology and metabolism (for example, insulin resistance), which have a negative impact on health span. Thus, developing specific inhibitors which effectively suppress all mTORC1 outputs, but do not exert a major effect on mTORC2, appears to be warranted as a strategy to target age-related pathologies and improve health span. Interestingly, in a recent trial of healthy elderly patients, the combination of low-dose RAD001 (rapalog) and BEZ235 (dual mTOR/PI3K catalytic inhibitor) was proposed to selectively inhibit mTORC1 and not mTORC2 and led to enhanced immune function and a reduction in infections. However, it is important to note that complete inhibition of mTORC1 can be deleterious.

Biguanides (for example, metformin) are pharmaceuticals which are thought to have a beneficiary effect (in aging) that indirectly impinges on mTOR. Metformin is a first-line anti-diabetic drug which has been used for more than 60 years in the clinic and has very few side effects. It was shown to modulate life span in model organisms, to affect several processes dysregulated in aging (for example, cellular senescence, inflammation, autophagy, and protein synthesis), and to improve cognitive function and neurodegeneration in humans. By inhibiting mitochondrial complex I, metformin causes energetic stress which results in mTORC1 inhibition through AMPK-dependent and independent mechanisms.

Although many studies have uncovered possible targets of metformin action in the cell in the context of aging, the full extent of metformin's mechanism of action at the cellular and organismal levels is still incompletely understood. Nonetheless, clinical trials in which metformin is used to improve health span or aging-related conditions are being proposed. For instance, in the TAME (targeting aging with metformin) clinical trial, a placebo-controlled multi-center study of about 3000 elderly patients who are 65 to 79 years old, the effects of metformin on the development of age-associated outcomes like cardiovascular events, cancer, dementia, and mortality will be monitored.

Comments

mTOR inhibitors have been on market since 1999. The current interest to develop new mTOR inhibitors is to replace generic drugs with expensive brand name drugs.The new companies will then have the financial incentive to do expensive clinical trials. However, the information gained can be applied to all rapalogs. Currently, those familiar with rapalogs know how to use dose and interval to inhibit mTORC1 and not mTORC2. In 10 years, this may be a huge market. Those with good insurance can then take the expensive brand name rapalogs and those without good insurance to pay for the new brand name rapalogs can continue to use generics rapalogs.

Posted by: alan green at July 28th, 2019 12:03 PM

Unfortunately, CR mimetics can being you just that far. The best you can get is probably the from effects of moderate CR but not the full effects of extremely calorie restriction. Which will give an improvement of health span but not really changing the nature of aging. Still, those are low hanging fruits worth pursuing...

Posted by: Cuberat at July 28th, 2019 12:17 PM

https://www.nature.com/articles/s41467-019-11174-0

I haven't seen this article posted in the major aging blogs I read so I thought I would post a link. Spoofers if it has been posted here. I did a search and was unable to find it. https://www.nature.com/articles/s41467-019-11174-0

Quote:
"Thus, while both rapamycin and DL001 are similarly potent mTORC1 inhibitors, DL001 is over 430× more selective for mTORC1 than mTORC2-and is 44-fold more selective for mTORC1 than rapamycin (Fig. 1f)"

No doubt the cost will be prohibitive-unless it's already off patent.

Posted by: K at August 4th, 2019 10:16 AM

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