JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age

TLDR

Chronic sterile inflammation is a hallmark of aging and is closely linked to frailty and age‑related diseases. In aging adipose tissue, the JAK pathway is activated and can be inhibited to suppress the senescence‑associated secretory phenotype in senescent cells. Senescent fat progenitor cells accumulate with age, produce a proinflammatory SASP that drives adipose inflammation and macrophage recruitment, and JAK1/2 inhibition suppresses this SASP, reducing inflammation and alleviating frailty in aged mice, highlighting the JAK pathway as a therapeutic target for age‑related dysfunction.

Abstract

Significance A hallmark of aging is chronic sterile inflammation, which is closely associated with frailty and age-related diseases. We found that senescent fat progenitor cells accumulate in adipose tissue with aging and acquire a senescence-associated secretory phenotype (SASP), with increased production of proinflammatory cytokines compared with nonsenescent cells. These cells provoked inflammation in adipose tissue and induced macrophage migration. The JAK pathway is activated in adipose tissue with aging, and the SASP can be suppressed by inhibiting the JAK pathway in senescent cells. JAK1/2 inhibitors reduced inflammation and alleviated frailty in aged mice. One possible mechanism contributing to reduced frailty is SASP inhibition. Our study points to the JAK pathway as a potential target for countering age-related dysfunction.