mTOR Inhibitors Reduce DNA Damage and Consequent Cellular Senescence in Immune Cells
Rapamycin and other mTOR inhibitors mimic some of the mechanisms making up the response to calorie restriction. Their most interesting effect is to increase the operation of autophagy in cells. Autophagy is a collection of processes responsible for recycling damaged or unwanted proteins and structures in the cell. A large proportion of the approaches shown to modestly slow aging in yeast, worms, flies, and mice are characterized by increased or more efficient autophagy; it is a universal response to stress of any sort placed upon a cell. Too much autophagy can be a bad thing, but a modest increase improves health in the context of the dysfunctional, damaged environment of aged tissues.
Another feature of mTOR inhibitors, and the age-slowing interventions that are characterized by upregulated autophagy, is that the burden of harmful, inflammatory senescent cells that linger in aged tissues is reduced. The present thinking on this topic is that this reduction does not occur because senescent cells are destroyed by the intervention, but rather that the pace at which cells become senescent is reduced. This seems sensible: more autophagy allows cells to better maintain function and resist damage, and thus fewer cells will be tipped over the line into senescence in response to damage.
Here, however, researchers argue that, at least in immune cells, the effects of mTOR inhibition on cellular senescence do not emerge from autophagy. Instead, there is a direct effect on the burden of DNA damage in these cells, and it is that reduced DNA damage that leads to a reduced number of cells becoming senescent. Further work will have to be conducted in order to fully understand how exactly mTOR inhibition produces this outcome.
mTOR inhibitors such as rapamycin are among the most robust life-extending interventions known, yet the mechanisms underlying their geroprotective effects in humans remain incompletely understood. At non-immunosuppressive doses, these drugs are senomorphic, that is, they mitigate cellular senescence, but whether they protect genome stability itself has been unclear. Given that DNA damage is a major driver of immune ageing, and immune decline accelerates whole-organism ageing, we tested whether mTOR inhibition enhances genome stability.
In human T cells exposed to acute genotoxic stress, we found that rapamycin and other mTOR inhibitors suppressed senescence not by slowing protein synthesis, halting cell division, or stimulating autophagy, but by directly reducing DNA lesional burden and improving cell survival. Ex vivo analysis of aged immune cells from healthy donors revealed a stark enrichment of markers for DNA damage, senescence, and mTORC hyperactivation, suggesting that human immune ageing may be amenable to intervention by low-dose mTOR inhibition.
To test this in vivo, we conducted a placebo-controlled experimental medicine study in older adults administered with low-dose rapamycin. p21, a marker of DNA damage-induced senescence, was significantly reduced in immune cells from the rapamycin compared to placebo group. These findings reveal a previously unrecognised role for mTOR inhibition: direct genoprotection. This mechanism may help explain rapamycin's exceptional geroprotective profile and opens new avenues for its use in contexts where genome instability drives pathology, ranging from healthy ageing, clinical radiation exposure and even the hazards of cosmic radiation in space travel.