Effect of rapamycin on aging and age-related diseases—past and future

Abstract

In 2009, rapamycin was reported to increase the lifespan of mice when implemented later in life. This observation resulted in a sea-change in how researchers viewed aging. This was the first evidence that a pharmacological agent could have an impact on aging when administered later in life, i.e., an intervention that did not have to be implemented early in life before the negative impact of aging. Over the past decade, there has been an explosion in the number of reports studying the effect of rapamycin on various diseases, physiological functions, and biochemical processes in mice. In this review, we focus on those areas in which there is strong evidence for rapamycin’s effect on aging and age-related diseases in mice, e.g., lifespan, cardiac disease/function, central nervous system, immune system, and cell senescence. We conclude that it is time that pre-clinical studies be focused on taking rapamycin to the clinic, e.g., as a potential treatment for Alzheimer’s disease.

Intercellular Transfer of Mitochondria between Senescent Cells through Cytoskeleton-Supported Intercellular Bridges Requires mTOR and CDC42 Signalling

“…Consequently, our findings highlight mTOR signalling as critical in directing the non-cell-autonomous roles of cellular senescence and further emphasise its validity as a therapeutic target for senomodifying therapies, building on reports of beneficial effects of mTOR inhibitors on senescence phenotypes in vitro [ 21 ] and longevity and health in vivo [ 46 , 47 ]. It is tempting to speculate that the utility of mTOR inhibitors in a number of age-related diseases (reviewed in [ 48 ]) including Alzheimer's disease ([ 49 ]; reviewed in [ 50 ]) and immune senescence [ 51 ], as well as their ability to improve ageing human skin structure [ 52 ], may be at least in part through actin cytoskeletal modulation that impacts TNT formation.…”

Necroptosis increases with age in the brain and contributes to age-related neuroinflammation

“…In Alzheimer's disease patients and mouse models, hyperactive mTOR signaling has been reported in the brain regions affected by the disease [67,68]. Feeding AD mice with rapamycin, a mTOR inhibitor, has been shown to improve cognition, reduce Aβ and tau pathology, and reduce neuroinflammation (microglia activation) [69,70]. mTOR activity is reported to increase with age in tissues such as liver, muscle, heart, and adipose tissue [71], whereas in the hippocampus, activity of mTOR and mTOR signaling is reported to decline with age [72].…”

Responsible biology, aging populations and the 50th anniversary of the “War on Cancer”

“…The initial study concludes that rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of aging, or both. Since this initial report in 2009, there have been fourteen additional studies showing that rapamycin increased the lifespans of male and female mice and these studies on mouse data demonstrate that this molecule is effective in preventing, even reversing, a broad rage of age-related conditions and thus warrants being described as an ''anti-aging'' intervention (Selvarani et al 2020).…”