We have heard about so-called “longevity genes” that are over a billion years old. A number of these in humans (15 or so) are also found in primitive species such as nematode roundworms (c-elegans), and are associated with the target of rapamycin (TOR) signaling pathway. The mammalian counterpart of TOR is known as mTOR. My purpose here is to lay out a plain-language overview of TOR and mTOR-related longevity research and see what light this research might throw on the theories of aging in my Anti-Aging Firewalls treatise. It turns out that the new findings are relevant to at least the Oxidative damage and Mitochondrial damage theories of aging.
Mammalian target of rapamycin (mTOR) is a protein encoded in humans by the FRAP1 gene. As the name suggests, mTOR is targeted by the immunosuppressive drug rapamycin, a drug used clinically to treat graft rejection and restenosis and being tested as a treatment for autoimmune diseases. “The mTOR pathway integrates signals from nutrients, energy status and growth factors to regulate many processes, including autophagy, ribosome biogenesis and metabolism(ref, ref).” The mTOR pathway is “a central controller of cellular and organism growth that integrates nutrient and hormonal signals, and regulates diverse cellular processes(ref).”
The mTOR pathway plays important role in diseases. Recent studies link mTOR to several age-related human diseases including diabetes, cancer, obesity, atherosclerosis, nephrotoxicity, cardiovascular diseases and neurological disorders. Inhibiting mTOR using rapamycin or derivative drugs offers a promising therapeutic approach for dealing with several diseases and cancer lines(ref,ref,ref). “Dysregulation of mTOR signaling occurs in diverse human tumours, and can confer higher susceptibility to inhibitors of mTOR(ref).”
Inhibiting mTOR may also offer an approach to enhancing human longevity. Decreasing TOR signaling can extend the lifespans of flies and worms. It does this by upregulation of mitochondrial gene expression resulting in decreased production of reactive oxygen species. “Reduced TOR Signaling Extends Chronological Life Span via Increased Respiration and Upregulation of Mitochondrial Gene Expression(ref)” With respect to humans, much of the machinery of TOR signaling found in more primitive species is conserved. “Recent data have also revealed that mTOR is involved in the regulation of lifespan and in age-related diseases(ref).” TOR also plays a role in the longevity-producing effects of calorie restriction(ref).
There are some tantalizing hints about how the mTOR pathway may relate to the other theories of aging. For example, there are complex feedback interactions between the pathways involving NF-kappaB, mTOR and PI3K-Akt related to both treatment of cancers and longevity(ref). A cancer treatment leads to simultaneous down-regulation of mTOR and telomerase activity in cancer cells(ref). Inhibiting mTOR via rapamycin resulted in impairment of pluripotency and prevention of adult stem cell differentiation, among other effects(ref). As far as I can tell, however, discussions of human life extension via mTOR inhibition are at this point conjectural. Based on what I have seen in fact, there have been no experiments so far to try mTOR inhibition for life extension on any mammals, even mice. There are plenty of adverse effects associated with rapamycin, some possibly quite serious. These are enough to throw cold water on any idea of healthy people using this substance in an effort to enhance their longevity
Does the mTOR story lend light on whether mitochondrial activity is more important than cell signaling or protection against oxidation damage for determining longevity? The story actually lends light on the fact that this is the wrong kind of question to ask “Such notions are slowly giving way to a more nuanced view in which cellular signaling pathways intersect with the mitochondria, creating a two-way network of interactions between the consumer (the cell) and the supplier (the mitochondria) of energy(ref).” Instead of just focusing on the health of the inner operations of the cell or the mitochondria, perhaps we need to look more at what they are saying to each other.
So what does the mTOR story contribute to the longevity picture beyond what I have discussed before? I see it as yet-another interesting area of the longevity puzzle still to be well-integrated with the other ones.