Low protein-induced-FGF-21 signaling remodels adipose tissue on reduced markers of senescence during aging

Cellular senescence and metabolic impairment occur during aging, with adipose tissue decline playing a key role in this process. Furthermore, the detriments of aging on adipose tissue function are further exacerbated by obesity. Dietary protein restriction (DPR), without reducing calorie intake, protects against age-related metabolic decline and extends lifespan through the metabolic hormone FGF21. Here, we demonstrate that protein restriction significantly decreases pro-oncogenic and senescence-related markers in adipose tissue, including SASP, Cdkn1a Cdkn1a, and SA-βgal staining. Additionally, mice fed a low-protein diet during diet-induced obesity demonstrated significant decreases in tumorigenic and cell cycle markers compared with mice fed a control protein and high-fat diet, suggesting that a low-protein diet decreases the burden of cellular senescence on adipose tissue in aged mice and aged obese mice. Conversely, mice lacking FGF21 failed to exhibit the benefits of protein restriction on markers of senescence in white and brown adipose tissue. These data demonstrate that protein restriction exerts distinct beneficial effects on white and brown adipose tissue remodeling on senescence and other markers associated with improvements in lifespan and particularly health span. Given the negative impact of cellular senescence on adipose tissue, protein restriction offers a potential dietary intervention to prevent the detriments of cellular senescence on adipose tissue function during obesity and aging.