Researchers have discovered a new drug that targets the mTOR pathway, which is involved in aging and metabolism. It could function as a caloric restriction mimetic, bringing about similar health benefits.
The mTOR pathway
The mechanistic target of rapamycin (mTOR) pathway is a part of metabolism and is one of the four major pathways that control it; collectively, the four pathways are affected by deregulated nutrient sensing, which is a hallmark of aging.
The mTOR pathway includes two distinct protein complexes: mTORC1 and mTORC2. The pathway senses amino acids and is associated with nutrient abundance. It is a kinase, which means that it adds phosphates to molecules. mTOR is a master regulator of anabolic metabolism, the process of creating new proteins and tissues.
Studies show that less mTOR activity increases lifespan in various species, including mice, yeast, worms, and flies. High mTOR activity is a rough analog of the phrase “Live fast, die young”, because too much activity is good for growth but bad for lifespan. However, too little mTOR activity is not beneficial either, as it can disrupt healing and insulin sensitivity and can cause cataracts in mouse models .
mTOR has been well studied in the last few years, particularly for its role in caloric restriction. It is encountered as two specific protein complexes, mTORC1 and mTORC2. mTORC1 supports cell growth, ribosomal biogenesis, and the regulation of autophagy. The mTORC2 complex functions primarily as a downstream effector of the insulin/IGF-1 signaling pathway, another major metabolic pathway involved in aging.
Of the two complexes, mTORC1 appears to the most beneficial to target, as doing so appears to emulate some of the positive effects of caloric restriction. In studies that targeted mTORC1 in mice, the animals saw increased healthy lifespan due to the activation of stress response mechanisms and boosted levels of autophagy, a recycling system for unwanted cellular components.
The trouble with rapamycin
Rapamycin and its related rapalogs (drugs that are similar to rapamycin) are the best-known substances that target the mTOR pathway; unfortunately, their use as anti-aging therapies is limited due to the side effects that they can cause, including immunosuppression, glucose intolerance, an increased risk of type 2 diabetes, and disruption of lipid homeostasis. The problem is that these compounds are not selective and target both mTORC1 and mTORC2 complexes, which leads to various negative side effects.
A recent study has discovered a new rapalog called DL001, which appears to be far more selective in its ability to target mTORC1 and avoid interfering with the mTORC2 complex .
The researchers suggest that it is forty times more selective for the mTORC1 complex than rapamycin and is able to potently inhibit that complex in both cell culture as well as in ordinary, normally aging Black 6 lab mice, which were chosen instead of a progeric mouse strain that experiences accelerated aging. These mice are closer analogs of human aging, meaning that the findings are more likely to translate.
DL001 was apparently able to reduce the activity of the mTORC1 complex without harming glucose homeostasis or lipid metabolism. Perhaps most importantly, it also did not negatively impact the immune systems of the study mice.
Rapamycin, an inhibitor of mechanistic Target Of Rapamycin Complex 1 (mTORC1), extends lifespan and shows strong potential for the treatment of age-related diseases. However, rapamycin exerts metabolic and immunological side effects mediated by off-target inhibition of a second mTOR-containing complex, mTOR complex 2. Here, we report the identification of DL001, a FKBP12-dependent rapamycin analog 40x more selective for mTORC1 than rapamycin. DL001 inhibits mTORC1 in cell culture lines and in vivo in C57BL/6J mice, in which DL001 inhibits mTORC1 signaling without impairing glucose homeostasis and with substantially reduced or no side effects on lipid metabolism and the immune system. In cells, DL001 efficiently represses elevated mTORC1 activity and restores normal gene expression to cells lacking a functional tuberous sclerosis complex. Our results demonstrate that highly selective pharmacological inhibition of mTORC1 can be achieved in vivo, and that selective inhibition of mTORC1 significantly reduces the side effects associated with conventional rapalogs.
The discovery of a more selective rapalog is of scientific interest; however, given what we know about the effects of caloric restriction on lifespan in multiple species, we should probably not be holding our breath that this will lead to dramatically longer lives.
We already know that caloric restriction targets the same complex and can increase lifespan up to around 40% in mice, but that does not scale well to humans, where we might expect a few years of additional lifespan at best from following a caloric restriction diet. Some researchers suggest that the difference in scale of effect between mice and humans with caloric restriction is due to the influence of famines. For a human, a year of famine is relatively short in comparison to total lifespan; for a mouse, a year is a considerable portion of its entire life. Evolution has therefore apparently seen fit to give shorter-lived animals, such as mice, greater flexibility of lifespan to adjust for seasonal factors like famine and the scarcity of food in order to ensure that the next generation of offspring is born.
A number of companies are engaged in developing mTOR-targeting therapies; however, these efforts are likely to, at best, lead to a pill that simply mimics caloric restriction, which has limited effects in humans. This would not be entirely useless, of course; caloric restriction has a number of health benefits despite not leading to greatly increased life spans in humans, plus caloric restriction is not an easy lifestyle to practice, so a pill that could emulate it may prove useful on the road to developing more direct interventions against aging in the coming decades.
 López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.
 Schreiber, K. H., Apelo, S. I. A., Yu, D., Brinkman, J. A., Velarde, M. C., Syed, F. A., … & Ortiz, D. (2019). A novel rapamycin analog is highly selective for mTORC1 in vivo. Nature Communications, 10(1), 3194.