mTOR inhibition improves immune function in the elderly

Abstract

Inhibition of the mammalian target of rapamycin (mTOR) pathway extends life span in all species studied to date, and in mice delays the onset of age-related diseases and comorbidities. However, it is unknown if mTOR inhibition affects aging or its consequences in humans. To begin to assess the effects of mTOR inhibition on human aging-related conditions, we evaluated whether the mTOR inhibitor RAD001 ameliorated immunosenescence (the decline in immune function during aging) in elderly volunteers, as assessed by their response to influenza vaccination. RAD001 enhanced the response to the influenza vaccine by about 20% at doses that were relatively well tolerated. RAD001 also reduced the percentage of CD4 and CD8 T lymphocytes expressing the programmed death-1 (PD-1) receptor, which inhibits T cell signaling and is more highly expressed with age. These results raise the possibility that mTOR inhibition may have beneficial effects on immunosenescence in the elderly.

Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity

“…To our knowledge, this data represents the first evidence of a dose-dependent immune potentiating impact of mTOR signalling in primary effector T-cells. These findings are in keeping with evidence that rapamycin promotes the accumulation of T-cell memory cells during viral infection or vaccination, 36,48 and that mTOR plays a generalized role to limit biological lifespan. 49 In addition, given that mTOR inhibition is known to promote autophagy, 50 our results may extend findings by Xu et al., who linked autophagy to enhanced effector T-cell survival and differentiation during immune responses to chronic viral infection, 51 Further study will be required to delineate the contributions of downstream mTOR-dependent processes that limit intratumoral immunity.…”

Gene expression‐based drug repurposing to target aging

“…These findings are consistent with the mechanism of action for the most well‐known prolongevity drugs. For example, sirolimus (rapamycin) is an immunosuppressant approved for human use, and similar drugs can enhance the response of elderly humans to immunization against influenza (Mannick et al, 2014). …”

The interconnectedness of ageing: does the convoy principal apply?

“…This concept of improving the biological performance of individual ageing systems should be seen as achievable in the short term. Recent evidence on the use of rapamycin in improving the immune performance of older adults is an excellent case in point (Mannick, Del Giudice et al 2014) and provides evidence of the first small steps towards an 'anti-ageing' drug in humans.In this special issue the latest knowledge about ageing of several systems is reviewed. Cobley et al (Cobley, Moult et al 2014) provide fascinating insight into how exercise can support muscle function in older adults in their review of mitochondrial responses to physical activity in ageing muscle, providing a potential mechanism for the protective effect of exercise training on age-related musculoskeletal decline.…”

“…This concept of improving the biological performance of individual ageing systems should be seen as achievable in the short term. Recent evidence on the use of rapamycin in improving the immune performance of older adults is an excellent case in point (Mannick, Del Giudice et al 2014) and provides evidence of the first small steps towards an 'anti-ageing' drug in humans.…”