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mTOR and Cellular Senescence

Now that the research community has finally woken up to the significance of cellular senescence in aging, a point long advocated for by the SENS Research Foundation and Methuselah Foundation, scientists are busily patching it in to their existing understanding and models of aging. This is just as true for studies of mechanistic target of rapamycin (mTOR) as elsewhere. This is one of the more popular areas of research to emerge from the study of calorie restriction, an intervention that slows aging in near all species tested to date. There is a sizable contingent of researchers interested in finding ways to mimic some fraction of the benefits of calorie restriction through therapies that target mTOR.

Since calorie restriction slows aging, albeit to a much larger degree in short-lived animals than in humans, it is generally agreed that it also slows the accumulation of senescent cells, one of the causes of aging. Thus to the degree that mTOR is involved in the calorie restriction response, we should also expect mTOR to be relevant in some ways to the harms done by cellular senescence: either reducing the number of cells that become senescent, or reducing the harm done by cells once they are senescent. Since we know that calorie restriction doesn't greatly extend life in humans (though it is very good for long term health), we should not expect these effects to be large. Certainly, senolytic therapies that clear out senescent cells should have a much greater positive impact on health and longevity.

The mechanistic target of rapamycin (mTOR) is an evolutionary conserved serine-threonine kinase that senses and integrates a diverse set of environmental and intracellular signals, such as growth factors and nutrients to direct cellular and organismal responses. The name TOR (target of rapamycin) is derived from its inhibitor rapamycin. We now know that the role of mTOR goes far beyond proliferation and coordinates a cell-tailored metabolic program to control cell growth and many biological processes including aging, cellular senescence, and lifespan.

Rapamycin is currently the only known pharmacological substance to prolong lifespan in all studied model organisms and the only one in mammals. Rapamycin was shown to extend the lifespan of genetically heterogeneous mice at three independent test locations by about 10-18% depending on sex. Interestingly, treatment was only started late when the mice were 600 days of age equivalent to roughly 60 years of age in a human person. This proposes that inhibition of mTOR in the elderly might be enough to prolong life. The findings were confirmed and extended in mice, in which rapamycin treatment started earlier. However, they failed to substantially observe larger effects on longevity.

It is now accepted that mTOR inhibition increases lifespan; yet, the mechanism through which this occurs is still uncertain. mTORC1 inhibition may not delay aging itself, but may delay age-related diseases. However, many researchers directly link the longevity effects of mTOR inhibitors to a decrease in aging. Conserved hallmarks of aging have recently been proposed and include telomere attrition, epigenetic alterations, genomic instability, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. The mTOR network is known to regulate some of these aging hallmarks. Ultimately, the prominence of mTORC1 signaling in aging likely reflects its exceptional capacity to regulate such a wide variety of key cellular functions.

Cellular senescence has been suggested to function as a tumor suppressor mechanism and promotor of tissue remodeling after wounding. However, senescent cells may also directly contribute to aging. Senescent cells show marked changes in morphology including an enlarged size, irregular cell shape, prominent and sometimes multiple nuclei, accumulation of mitochondrial and lysosomal mass, increased granularity and highly prominent stress fibers that are accompanied by shifts in metabolism and a failure of autophagy. Interestingly, many of these phenotypes are regulated by mTORC1 in various cell types. The secretion of proinflammatory mediators by senescent cells contributes to aging and has been termed senescence-associated secretory phenotype (SASP). Recent data identified a main role of mTORC1 to promote the SASP. Rapamycin blunts the proinflammatory phenotype of senescent cells by specifically suppressing translation of IL1A.

Despite maintaining a nondividing state, senescent cells display a high metabolic rate. Metabolic changes characteristic of replicative senescence often show a shift to glycolytic metabolism away from oxidative phosphorylation (which is also observed in proliferative cells), despite a marked increase in mitochondrial mass and markers of mitochondrial activity. This might stem from a rise in lysosomal pH as a consequence of proton pump failure, which leads to an inability to get rid of damaged organelles such as mitochondria caused by a failure of autophagy. Dysfunctional mitochondria not cleared by autophagy in senescent cells produce reactive oxygen species, which cause cellular damage including DNA damage. mTORC1 has been postulated as main driver of these metabolic changes. Hence, rapamycin treatment prevents metabolic stress and delays cellular senescence.

Link: https://doi.org/10.1159/000484629

Comments

You know what? I've got a lot of questions about Senolytics and I was hoping I could get some answers. Maybe the crew here can help me out.

Seems that the drug candidates so far can hit only very specific cell-types. Will we need a cocktail of senolytics to get whole body rejuvenation? Oisin has something that looks like it can hit many different cell targets.

I know that Unity mentioned that it found 22 beneficial indicators in animal models. They published 9. Anyone have any idea what the other 13 are?

What are the most educated guesses involving what the impact will be on human health? We've often seen fantastic things in animal models, but when it comes to humans, we get shafted. There should be some idea of what we should see.

Thanks guys. I come here for the straight dope.

Posted by: Mark Borbely at December 7th, 2017 9:48 AM

You have also the possibility to ask Aubrey on Reddit today.

Posted by: Antonio at December 7th, 2017 10:48 AM

MTOR driven aging theory has always incorporated within it cellular senescence, as can be read in any of Blagosklonny's papers starting in 2006. Whenever a cell is arrested for any reason it is basically a race to repair to damage so it can continue proliferation before MTOR forces beyond the point of no return. That is why you get lots of mitochondrial biogenesis and the consequent overload of the lysosomes trying to deal with it, because the MTOR is trying to force growth, when growth has been arrested.

It also fits in very well with telomere depletion, either through proliferative loss, or damage from ROS. Either way MTOR converts arrest to permanent senescence.

Even post mitotic cells have some MTOR pressure on them to senesce, but it is much lower as they are often inhibited by contact inhibition, or low oxygen and also other mechanisms.

The great thing about SENS is that it is theory agnostic. It just states such and such wasn't here in a young cell/organ/organism, so it must be bad, i.e. accumulating senescent cells. But SENS doesn't know about the underlying mechanism of why such and such has happened. So we can expect lots more of this is the future as the underlying mechanisms are elucidated. It doesn't mean SENS knew this all along, it just pointed out the changes from young to old and said 'that's bad!'

Posted by: Mark at December 7th, 2017 11:05 AM

@Mark: Thats the beauty of SENS. It has categorised types of damages and comes up with solutions.

Posted by: Gekki at December 7th, 2017 12:10 PM

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