Abstract Sestrins drive immune senescence, and their inhibition may restore immunity in the elderly and improve vaccine responses.

How important is the decline of the immune system in the context of mortality and aging? Can we actually ask Charon to turn the boat around as we are taken to the gates of Hades? The elderly frequently succumb to infections because immunity declines with age and T-B collaboration is compromised in older individuals.

Sestrins are proteins that have been shown to have anti-aging properties in various tissues and organisms, but Lanna et al. suggest that sestrins have pro-aging properties in human CD4+ T cells. They demonstrate an increase in expression of sestrins 1, 2, and 3 in human CD27-CD28-CD4+ T cells, frequently considered to be senescent cells. Sestrins form a complex with and simultaneously activate the extracellular signal–regulated (Erk), c-Jun N-terminal (Jnk), and p38 mitogen-activated protein (MAP) kinases, which each induce different pathways relevant to senescence. Erk can increase endogenous DNA damage foci, p38 can decrease telomerase activity, and Jnk can suppress the expression of Lck, a tyrosine kinase that initiates T cell receptor activation. Sestrin expression increases with age and can be substantially higher in the elderly (above the age of 65) compared with adults under the age of 35. Expansion of varicella zoster virus– and cytomegalovirus-specific T cells is compromised in older adults, but the expansion occurred readily when the three sestrins were knocked down. In mice, MAPK inhibition phenocopied sestrin deficiency in vivo, leading to a sizable increase in the numbers of CD4+IFN-γ+ T cells and IgG+ B cells.

The ability of sestrin and MAPK inhibitors to potentially reverse CD4+ T cell senescence opens the door to the restoration of some immune functions that decline with age. It remains to be seen how broad the effects of attenuating sestrin function will be in vivo. Sestrin inhibition could perhaps be used to boost vaccine responses in the elderly, obviating the need for revaccination, and it could also potentially help to generate sustained immune responses in immune-compromised hosts. It could also be part of that long-sought elixir that holds Charon at bay and delays the inevitable crossing of the Styx.