The Roles of mTOR in Aging

Next to insulin signaling, the biochemistry surrounding mechanistic target of rapamycin (mTOR) is probably the greatest point of study for that part of the mainstream research community interested in modestly slowing aging through pharmaceuticals, researchers who generally show little interest in the alternative approach of repairing the causes of aging to produce rejuvenation. Drugs and drug candidates to slow aging are largely intended to adjust the operation of cellular metabolism involved in nutrient sensing to mimic some of the beneficial response to calorie restriction, such as increased autophagy. mTOR is, as one might imagine, the primary target for the action of rapamycin, and similar pharmaceuticals known as rapalogs, that inhibit mTOR and have been shown to slow aging in mice. The paper here is a good summary of present knowledge on the subject.

The most studied and best understood longevity pathways govern metabolism according to available nutrient levels. The fundamental mechanisms from signaling cascades to protein complexes are conserved across phyla. A controlling hub at the center of nutrient sensing and signaling is the mechanistic target of rapamycin (mTOR) that governs cellular growth, protein synthesis, and degradation. mTOR acts upstream of several transcription factors, such as TFEB, FOXO, FOXA, and Nrf, that are essential for lifespan-extending strategies such as dietary restriction. These transcription factors also control autophagy, a cellular process that clears proteins and dysfunctional organelles, and reduces proteotoxic and oxidative stress while maintaining a pool of amino acids for protein synthesis. mTOR responds to amino acids, a pathway modulated by proteins such as sestrins.

Here we will review the current knowledge on the best-known longevity pathways across animal models, namely insulin/insulin-like signaling and its downstream transcription factor FOXO, and transcription factor FOXA-dependent signaling. We consider how FOXO and FOXA are regulated by mTOR, and what role autophagy plays in the lifespan extension they confer. We also consider additional longevity mechanisms that rely on lipid signaling and the proteasome. We conclude with a discussion of how advancements in technologies such as induced pluripotent stem cells can enable the study of longevity-regulating mechanisms in human systems, and how emerging ideas on nuclear-cytoplasmic compartmentalization and its loss could contribute to our understanding of transcriptional dysregulation of nutrient-sensing pathways in aging.

The mechanism through which mTOR accelerates cellular and organismal aging is still unclear, but causative elements discussed include increased oxidative and proteotoxic stress associated with mTOR-mediated mRNA translation and inhibition of autophagy resulting in the accumulation of defective organelles, including mitochondria. It is important to emphasize the complexity of the pathway: mTOR regulates metabolic transcription factors and can be regulated by the same transcription factors, such as TFEB and FOXO, and mTOR is able to regulate nuclear morphology and induce epigenetic changes by which it is affected.

Several components of the mTOR pathway have still not been investigated in the context of aging and longevity. It is possible that differential expression or activity of TOR-regulating proteins can be part of the age-associated changes in the base level of mTOR signaling, associated also with a decline in protein turnover and autophagy, and increase in protein aggregation. Another possible way the regulation of these longevity-driving processes could deteriorate over time is the loss of nucleocytoplasmic compartmentalization, as seen in progeria, and also in healthy aged individuals, whose cells show evidence of increased nuclear membrane blebbing and progerin buildup. In addition to the recorded effects of this loss on DNA damage and promotion of cellular senescence, further aggravated with simultaneously increased mTOR signaling, this could possibly disable the highly controlled localization of transcription factors, including those regulating processes related to aging, feeding into a vicious cycle of perturbed metabolism and homeostasis.

Rapamycin has recently been shown to alleviate some aging phenotypes while exacerbating others. These results could be due at least in part to attenuated mTORC2 activity, the loss of which has been shown to reduce longevity in Caenorhabditis elegans and in liver-specific mTORC2 knockout mice, while inhibition of mTORC1 is largely viewed as advantageous. Development of new drugs targeting the amino acid sensing pathway may increase selectivity to mTORC1 and enable assessments of longevity changes upon pharmacological complex-specific mTOR inhibition.



It seems to me that with aging, we have less and less available energy from the mitochondria, and shortening of telomeres, and buildup of mutations and waste material in cells, and increasing numbers of senescent cells, ROS buildup, nutrient deficiencies, and a host of other problems in the cells and leaky and stressed mitochondria. Double-stranded and single-stranded DNA mutations need energy to fix. The proteasomes get overloaded with waste material and with less energy available, the cells and organism eventually dies.

Posted by: Biotechy at October 13th, 2017 1:44 PM

Yes its one of the four metabolic pathways, two catabolic and two anabolic and they are all very important in order to maintain homeostasis and proper metabolic operation. See deregulated nutrient sensing in Hallmarks of aging for more details. And no, deregulated nutrient sensing is not just CR :)

Posted by: Steve Hill at October 13th, 2017 2:54 PM

I have recently read scholarly articles that seem to demonstrate that exercise, which I have always believed to be beneficial to an anti-aging lifestyle (both aerobic and anaerobic) tend to promote TORC!. This would tend to make exercise counter-productive if one is using low dose intermittent rapamycin as an anti-aging protocol. Does this mean that exercise is not beneficial and not a recommended part of an anti-aging program or am I being overly simplistic?

Posted by: Lawrence Rosen at October 24th, 2017 9:18 AM

This is pretty sad news. An mTor activator from Navitor Pharmaceuticals, inspired by dissociation-inducing Ketamine, for treatment-resistant depression. No hypothesis-free research leading to a new understanding of the biological roots of depression. And based on useless "promising data" from ridiculous animal models of "depression". I wouldn't count on Navitor Pharmaceuticals for anti-aging medicine, if this is the best they can do.

Navitor Pharmaceuticals to Develop NV-5138, a Specific Activator of mTORC1 for Treatment-Resistant Depression, Based on Promising Data Presented at Society for Neuroscience 2017

Posted by: NY2LA at November 24th, 2017 2:47 PM

About to turn 70 and have been using IF for six years and WHM for three. Recently found out about medicinal mushrooms. I feel forty years younger. My retirement plan is to hang out in Europe for as long as I may. Everything is fine, another five kilos and I am back to my youthful weight. Keep active, learn new languages, make new friends.

Posted by: Christopher Ellis at March 29th, 2019 3:47 PM

What nutritional supplements enhance mTOR I.E. arginine?

Posted by: DELL VANN at January 17th, 2020 11:56 AM
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