JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age |
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Authors: | Ming Xu Tamara Tchkonia Husheng Ding Mikolaj Ogrodnik Ellen R. Lubbers Tamar Pirtskhalava Thomas A. White Kurt O. Johnson Michael B. Stout Vojtech Mezera Nino Giorgadze Michael D. Jensen Nathan K. LeBrasseur James L. Kirkland |
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Affiliation: | aRobert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN, 55905;;bNewcastle University Institute for Ageing, Newcastle University, Newcastle Upon Tyne, NE4 5PL, United Kingdom |
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Abstract: | Chronic, low grade, sterile inflammation frequently accompanies aging and age-related diseases. Cellular senescence is associated with the production of proinflammatory chemokines, cytokines, and extracellular matrix (ECM) remodeling proteases, which comprise the senescence-associated secretory phenotype (SASP). We found a higher burden of senescent cells in adipose tissue with aging. Senescent human primary preadipocytes as well as human umbilical vein endothelial cells (HUVECs) developed a SASP that could be suppressed by targeting the JAK pathway using RNAi or JAK inhibitors. Conditioned medium (CM) from senescent human preadipocytes induced macrophage migration in vitro and inflammation in healthy adipose tissue and preadipocytes. When the senescent cells from which CM was derived had been treated with JAK inhibitors, the resulting CM was much less proinflammatory. The administration of JAK inhibitor to aged mice for 10 wk alleviated both adipose tissue and systemic inflammation and enhanced physical function. Our findings are consistent with a possible contribution of senescent cells and the SASP to age-related inflammation and frailty. We speculate that SASP inhibition by JAK inhibitors may contribute to alleviating frailty. Targeting the JAK pathway holds promise for treating age-related dysfunction.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. |
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Keywords: | JAK/STAT pathway cellular senescence ruxolitinib interleukin-6 frailty |
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