As a companion piece to an earlier post on the relationship between the mechanistic target of rapamycin (mTOR) gene and cellular senescence in aging, you might take a look at the research here that investigates the relationship between mTOR and the characteristic decline in stem cell activity that occurs with advancing age. In addition to the large body of research focused on insulin and growth hormone metabolism, work on mTOR is among the most active areas of study resulting from investigations of calorie restriction. The practice of calorie restriction has been shown to slow aging in near all species and lineages studied to date, so insofar as the response to calorie restriction is partially mediated through mTOR, we should expect mTOR to have some connection to most of the causes of aging.
Unfortunately, calorie restriction has only a small effect on life span in our species. The research community doesn't yet know exactly how small, but it would be very surprising for it to be greater than five years or so. It would be hard for an effect much larger than that to remain hidden over the length of human history. The health effects are worth it in all other respects; calorie restriction greatly reduces the risk of age-related disease in our species, just as in others. Why are the effects on longevity so much less in humans than in mice? The response to calorie restriction most likely evolved because it grants a greater chance of survival through seasonal famine. The famine is the same length regardless of species, and thus short-lived species evolve under selection pressure to develop a proportionally greater extension of life span, while longer-lived species do not. The result is mice that live 40% longer if they eat less, and humans that do not.
Stem cells of many varied types are responsible for maintaining our tissues in good condition. Their activity declines with age, however, due to some combination of (a) intrinsic damage of the sort listed in the SENS view of aging, and (b) reactions to rising levels of damage elsewhere. It is thought that stem cells become less active with age because this acts to reduce the risk of cancer; the more cells that replicate, the greater the risk that one of those cells acquires mutations that lead to a tumor. That risk rises as the damage of aging grows, as the environment becomes more inflamed and dysfunctional, and the immune system, responsible for destroying potentially cancerous cells, falters. Our life span, longer than that of other primates, came to its present position by balancing the slow decline due to failing tissue maintenance against the fast end due to cancerous growth.
In calorie restricted individuals, the decline in stem cell activity tends to be a little bit slower. So if this effect is in part mediated by mTOR, what exactly is going on under the hood? It is a complex business, trying to reverse engineer the operation of metabolism. Even when it is possible to identify lynchpin genes, such as mTOR, it usually turns out that they are influential in dozens of important low-level cellular operations that can in turn slightly speed or slow the aging process in any number of ways. That just means it is challenging work, however. I think my greater objection to putting such a large focus on this way forward towards potential therapies to treat aging is that, based on what is known of calorie restriction, we shouldn't expect the results in mice to in any way translate to similarly sized results in humans. The effects should be analogous to one another, but in humans the size of those effects will be small.
In most of our tissues, adult stem cells hang out in a quiet state - ready to be activated in case of infection or injury. In response to such injury, however, stem cells have to be able to rapidly divide, to generate daughter cells that differentiate into cells that repair the tissue. Previous research showed that TOR needs to be maintained at a low level in order to preserve stem cells in a quiet state and prevent their differentiation. But in this study, researchers discovered that TOR signaling becomes activated in many stem cell types when they are engaged in a regenerative response.
This activation is important for rapid tissue repair, but at the same time it also increases the probability that stem cells will differentiate, thus losing their stem cell status. This loss - in this case in the fly intestine, mouse muscle and mouse trachea - is particularly prevalent when the tissue is under heavy or chronic pressure to regenerate, which occurs in response to infections or other trauma to the tissue. During aging, repeated or chronic activation of TOR signaling contributes to the gradual loss of stem cells. Accordingly, by performing genetic or pharmacological interventions to limit TOR activity chronically, the researchers were able to prevent or reverse stem cell loss in tracheae and muscle of aging mice.
Mice were put on differing regimens of the mTOR inhibitor rapamycin starting at different stages of life. Rapamycin was able to rescue stem cells even when given to mice starting at 15 months of age - the human equivalent of 50 years of age. "In every case we saw a decline in the number of stem cells, and rapamycin would bring it back." Whether this recovery of tissue stem cell numbers is due to a replenishment of the stem cell pool from more differentiated cells, or due to an increase in "asymmetric" stem cell divisions that allow one stem cell to generate two new ones, remains to be answered.
The balance between self-renewal and differentiation ensures long-term maintenance of stem cell (SC) pools in regenerating epithelial tissues. This balance is challenged during periods of high regenerative pressure and is often compromised in aged animals. Here, we show that target of rapamycin (TOR) signaling is a key regulator of SC loss during repeated regenerative episodes. In response to regenerative stimuli, SCs in the intestinal epithelium of the fly and in the tracheal epithelium of mice exhibit transient activation of TOR signaling.
Although this activation is required for SCs to rapidly proliferate in response to damage, repeated rounds of damage lead to SC loss. Consistently, age-related SC loss in the mouse trachea and in muscle can be prevented by pharmacologic or genetic inhibition, respectively, of mammalian target of rapamycin complex 1 (mTORC1) signaling. These findings highlight an evolutionarily conserved role of TOR signaling in SC function and identify repeated rounds of mTORC1 activation as a driver of age-related SC decline.