Abstract
Senescent cells accumulate in fat with aging. We previously found genetic clearance of senescent cells from progeroid INK-ATTAC mice prevents lipodystrophy. Here we show that primary human senescent fat progenitors secrete activin A and directly inhibit adipogenesis in non-senescent progenitors. Blocking activin A partially restored lipid accumulation and expression of key adipogenic markers in differentiating progenitors exposed to senescent cells. Mouse fat tissue activin A increased with aging. Clearing senescent cells from 18-month-old naturally-aged INK-ATTAC mice reduced circulating activin A, blunted fat loss, and enhanced adipogenic transcription factor expression within 3 weeks. JAK inhibitor suppressed senescent cell activin A production and blunted senescent cell-mediated inhibition of adipogenesis. Eight weeks-treatment with ruxolitinib, an FDA-approved JAK1/2 inhibitor, reduced circulating activin A, preserved fat mass, reduced lipotoxicity, and increased insulin sensitivity in 22-month-old mice. Our study indicates targeting senescent cells or their products may alleviate age-related dysfunction of progenitors, adipose tissue, and metabolism.
Highlights
A major function of adipose tissue is to store potentially cytotoxic lipids, including fatty acids (FAs), as less reactive neutral triglycerides (TG) within fat droplets (Listenberger et al, 2003)
We considered a cell to be differentiated if it contained doubly refractile lipid droplets visible by low power phase contrast microscopy, a change that occurs in fat cell progenitors following differentiation medium (DM) exposure, but not in other cell types (Karagiannides et al, 2006)
When co-cultured with senescent source cells, only 20% of target progenitors accumulated lipid compared to more than 50% when co-cultured with non-senescent source cells (Figure 1b), indicating that senescent cells can directly impair lipid accumulation by nearby fat progenitors
Summary
A major function of adipose tissue is to store potentially cytotoxic lipids, including fatty acids (FAs), as less reactive neutral triglycerides (TG) within fat droplets (Listenberger et al, 2003). Capacity for adipogenesis, PPARg and C/EBPa expression, adipose tissue mass, and metabolic function begin to decline in experimental animals and humans
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