Examining Cellular Senescence and Brown Adipose-Like Features of Cardiac Adipose Tissue in Female Mice

Abstract

Cardiovascular disease (CVD) is an age- and obesity-associated disease that is the leading cause of death in the world. During aging, white adipose tissue (AT) expands and becomes more inflammatory, driving systemic changes to lipid metabolism and increasing CVD risk. Senescent cells accumulate in white AT with age and secrete pro-inflammatory cytokines, chemokines, and proteases that constitute the senescence-associated secretory phenotype (SASP) and contribute to chronic inflammation and disease during aging. Epicardial and pericardial AT are beige, thermogenic tissues that surround the heart and can produce heat through metabolic activation by β3 adrenergic stimulation. The thermogenic capacity of other AT depots (i.e., subcutaneous and brown) declines with age, but it is unknown if thermogenic capacity and senescence in epicardial and pericardial AT changes with age. Therefore, we measured markers of senescence (p16, p21, Il6, Il1b) and thermogenesis (Ucp1, Ppargc1α) in epicardial and pericardial AT in young and old female mice. The old mice exhibited a basal reduction in Ucp1 and Ppargc1α expression in both tissues compared to the young, suggesting that basal thermogenesis declines with age. In contrast, β3 adrenergic stimulation induced greater expression of Ucp1 in old pericardial AT compared to young. Senescence factors including p16 and p21 increased in the AT from old mice compared to the young, indicating increased senescence in old pericardial and epicardial AT. However, cytokine expression was unchanged or reduced with age. Notably, epicardial AT showed greater p16 and loss of thermogenic markers compared to pericardial AT during aging, suggesting differential aging of these tissues. Ultimately, our results showed that cardiac AT thermogenesis is impaired basally, but not under stimulation, and may be more senescent during aging. Additionally, epicardial AT shows greater age-related metabolic dysfunction. These data provide more insight into the heterogeneity of adipose tissue depots, which will benefit research in CVD.