Cold temperatures induce progenitor cells within white adipose tissue to form beige adipocytes that burn energy and generate heat; this is a potential anti-diabesity therapy. However, the potential to form cold-induced beige adipocytes declines with age. This creates a clinical roadblock to potential therapeutic use in older individuals, who constitute a large percentage of the obesity epidemic. Here we show that aging murine and human beige progenitor cells display a cellular aging, senescence-like phenotype that accounts for their age-dependent failure. Activating the senescence pathway, either genetically or pharmacologically, in young beige progenitors induces premature cellular senescence and blocks their potential to form cold-induced beige adipocytes. Conversely, genetically or pharmacologically reversing cellular aging by targeting the p38/MAPK-p16Ink4a pathway in aged mouse or human beige progenitor cells rejuvenates cold-induced beiging. This in turn increases glucose sensitivity. Collectively, these data indicate that anti-aging or senescence modalities could be a strategy to induce beiging, thereby improving metabolic health in aging humans.
Bibliographical noteFunding Information:
This study was supported by grants to J.M.G. from the National Institutes of Health and the National Institute of Diabetes and Digestive and Kidney Disease ( R01 DK066556 , R01 DK064261 , and R01 DK088220 ). D.C.B. is supported by the National Institute of Diabetes and Digestive and Kidney Disease grant K01 DK109027 . Correspondence and requests for materials should be addressed to D.C.B. and J.M.G. J.M.G. is a co-founder and shareholder of Reata Pharmaceuticals.
- beige adipocytes
- cellular aging
- cold exposure
- mural cells