Type 2 cytokine signaling in macrophages protects from cellular senescence and organismal aging

Accumulation of senescent cells in organs and tissues is a hallmark of aging and known to contribute to age-related diseases. Although aging-associated immune dysfunction, or immunosenescence, is known to contribute to this process, the underlying mechanism remains elusive. Here, we report that type 2 cytokine signaling deficiency accelerated aging and, conversely, that the interleukin-4 (IL-4)-STAT6 pathway protected macrophages from senescence. Mechanistically, activated STAT6 promoted the expression of genes involved in DNA repair both via homologous recombination and Fanconi anemia pathways. Conversely, STAT6 deficiency induced release of nuclear DNA into the cytoplasm to promote tissue inflammation and organismal aging. Importantly, we demonstrate that IL-4 treatment prevented macrophage senescence and improved the health span of aged mice to an extent comparable to senolytic treatment, with further additive effects when combined. Together, our findings support that type 2 cytokine signaling protects macrophages from immunosenescence and thus hold therapeutic potential for improving healthy aging. [Display omitted] •Deficiency of IL-4 signaling accelerates organismal aging•Loss of Stat6 induces macrophage senescence•The IL-4-STAT6 axis regulates DNA repair in macrophages•IL-4 treatment improves health span of aged mice Aging induces cellular senescence of immune cells, yet the underlying mechanism is poorly understood. Here, Zhou et al. reveal that type 2 cytokine signaling protects macrophages from senescence by directly sustaining DNA repair. They further show that IL-4 treatment alleviates cellular senescence and improves health span of aged mice.