JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age
A hallmark of aging is chronic, low-grade, “sterile” inflammation (1–3). Elevated proinflammatory cytokines and chemokines are closely associated with mortality (4, 5) and with a variety of age-related diseases, including atherosclerosis (6), depression (7), cancers (8), diabetes (9), and neurodegenerative diseases (10, 11). Inflammation also is associated with frailty, a geriatric syndrome characterized by decreased strength and incapacity to respond to stress (2).
The underlying mechanisms of age-related chronic inflammation, tissue dysfunction, and frailty remain elusive. Cellular senescence, stable arrest of cell growth in replication-competent cells, is a plausible contributor. Senescence can be induced by a number of stimuli and stresses, including telomere dysfunction, genomic instability, oncogenic and metabolic insults, and epigenetic changes (12). Senescent cells accumulate with aging in the skin (13, 14), liver (15, 16), kidney (17), the cardiovascular system (18), and other tissues in various species (16). The senescence-associated secretory phenotype (SASP), largely comprised of proinflammatory cytokines and chemokines (19, 20), links senescent cells to age-related inflammation and diseases. We found that elimination of senescent cells delayed the onset of age-related phenotypes and enhanced healthspan (21, 22). Therefore, senescent cells and the SASP could play a role in age-related pathologies, particularly those that involve systemic inflammation.
The JAK/STAT pathway plays an important role in regulating cytokine production (23, 24). We hypothesized that it may directly affect the SASP. The JAK family has four members: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). JAK1 and 2 are involved in inflammatory signaling and in the action of growth hormone and other endocrine and paracrine signals (25). JAK3 is expressed primarily in blood cells and mediates erythropoietin signaling and immune cell generation (26–29). TYK2 plays an important role in white blood cell function and host defenses (30, 31). A number of inhibitors that target different JAKs have been approved or are in phase I–III studies for treating myelofibrosis (23, 32–34), acute myeloid leukemia (23), lymphoma (23), and rheumatoid arthritis (23, 35, 36). JAK inhibitors recently have been found to reprogram the SASP in senescent tumor cells, contributing to improved antitumor response (37). Therefore, we investigated the role of the JAK pathway in age-related inflammation and dysfunction.
We demonstrate here that senescent preadipocytes, fat cell progenitors, accumulate in adipose tissue with aging and can contribute to adipose tissue inflammation. We found that JAK inhibitors decrease the SASP in preadipocytes and human umbilical vein endothelial cells (HUVECs). They also decrease age-related adipose tissue and systemic inflammation as well as frailty. Our findings provide insights into the possible contribution of senescent cells to age-related inflammation and, in turn, to age-related pathologies, as well as potential therapeutic targets to alleviate age-related dysfunction.