Reviewing mTOR Inhibition as a Pharmacological Strategy to Modestly Slow Aging

It is arguably the case that we should look at small molecule mTOR inhibitors, such as rapamycin and its descendant rapalog compounds, as the most effective of the calorie restriction mimetic approaches developed to date. The practice of calorie restriction, eating as much as 40% fewer calories while still obtaining optimal levels of micronutrients, produces sweeping changes to metabolism. Some of these, such as increased autophagy and other forms of cellular housekeeping, appear to be beneficial to long-term health. Keeping cells more free of damage leads to a slowing of aging.

In mice, that slowing of aging can lead to as much as a 40% extension of life span via calorie restriction. Rapamycin, on the other hand, managed a 5% to 10% extension of life span in the very rigorous Interventions Testing Program studies. This illustrates one of the issues with calorie restriction mimetic treatments, which is that they only capture a fraction of the beneficial metabolic change produced by calorie restriction, and are therefore considerably less effective.

The other issue is that the practice of calorie restriction certainly doesn't produce a 40% extension of life span in humans; that would be quite evident, and have been well known since antiquity. Long-lived mammals exhibit very similar short-term metabolic changes and improved measures of health in comparison to short-lived mammals when undergoing calorie restriction, but long-term effects on life span are much more muted.

It seems plausible that many of the metabolic changes caused by calorie restriction in short-lived species became permanent in the course of evolving longer life spans. Thus humans, one of the more long-lived mammals, likely gain only a few years from the practice of calorie restriction. This might lead one to the reasonable conclusion that calorie restriction mimetics are not the way forward to greatly improve late life health in humans. Nonetheless, there is considerable appetite and funding for this line of research and development.

Targeting the biology of aging with mTOR inhibitors

mTOR is an evolutionarily conserved serine-threonine protein kinase found in diverse species including mice and humans. The mTOR kinase forms the catalytic core of two distinct protein complexes, mTORC1 and mTORC2, each of which are composed of shared as well as unique protein subunits and phosphorylate different substrates. mTORC1 is regulated by a wide range of nutrients and hormonal cues, most notably by the availability of amino acids, but also glucose, oxygen, and cholesterol. mTORC1 activity drives a wide variety of anabolic processes, as well autophagy, through phosphorylation of substrates.

Beginning 20 years ago, researchers discovered a role for mTORC1 signaling in the aging process. Studies in yeast, worms, and flies found that genetic inhibition of mTORC1 or signaling pathways downstream of mTORC1 extends lifespan. These results quite logically spurred substantial interest in the possibility that a potent chemical inhibitor of mTORC1, rapamycin, could extend lifespan. This was indeed the case, and there are now numerous studies showing that rapamycin can extend the lifespan not only of model organisms including yeast, worms, and flies but also of both wild-type mice and in many disease models. In this review, we will discuss the results of these studies, as well as the possible mechanism by which reduced mTORC1 signaling via both dietary and pharmacological means may improve healthspan.

There is rapidly growing interest in using mTOR inhibitors to promote healthy aging and to treat, delay or reverse numerous age-related diseases. While there is incredibly strong preclinical evidence in mice that rapamycin can extend lifespan and healthspan, excitement about rapamycin has outpaced rigorous evidence that rapalogs are both safe and efficacious for diseases of aging in humans. There are many unanswered questions from the trials that have been conducted thus far, but a few general lessons can be taken from the clinical trials of mTOR inhibitors that have been performed thus far. In both humans and mice, treatment with low or intermittent doses of rapamycin or everolimus or treatment of mice with the mTORC1-selective inhibitor DL001, is much better tolerated than the high doses of mTOR inhibitors currently approved for organ transplant and oncology indications, with fewer metabolic side effects and less immunosuppression. In addition, low doses of mTOR inhibitors have been shown to have some beneficial effects on the function of aging human organ systems, in particular, the immune system.

There remains much work ahead to bring mTOR inhibitors into the clinic for age-related conditions and many open questions remain. While the safety profile of low-dose rapamycin and rapalogs in humans appears promising, the long-term safety and efficacy of low-dose regimens remain to be determined. A much better understanding is needed of the specific dose and duration of mTOR inhibitors that both maximize efficacy and minimize risk. In humans, higher doses (for example, 3 mg per day) of mTOR inhibitors such as everolimus inhibit T cell function and are therefore are used to suppress immune-mediated organ transplant rejection in patients. By contrast, a sixfold lower dose of everolimus for 6 weeks was associated with improved immune function as assessed by vaccination response. Thus, both dose and duration may contribute to whether mTOR inhibition has positive or negative effects on healthy aging, but, generally speaking, the lower the dose of a drug, the fewer expected side effects.

Over the next 5 years, we expect results from a rapidly expanding list of human clinical trials as well as work in canines and non-human primates to shed light on the viability of mTOR inhibition as a therapy for aging-related conditions. New mTORC1-specific molecules may help to widen the therapeutic window for rapalogs, limiting undesirable side effects resulting in whole or in part from inhibition of mTORC2. Collectively, we expect that researchers will soon be able to determine whether clinicians can safely and effectively bring mTOR inhibitors to the geriatric bedside.

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