ERR agonism reverses mitochondrial dysfunction and inflammation in aging

A gradual decline in renal function occurs even in healthy aging individuals. In addition to aging per se, concurrent metabolic syndrome and hypertension, which are common in the aging population, can induce mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, inflammation, altered lipid metabolism, and profibrotic growth factors in the kidney, which collectively contribute to age-related kidney disease. With increasing population of older individuals and the increasing incidence of acute kidney injury and chronic kidney disease, identifying preventable or treatable aspects of age-related nephropathy becomes of critical importance. In this regard we studied the role of the nuclear hormone receptors, the estrogen related receptors (ERRs), whose expression levels are decreased in aging human and mouse kidneys. Our studies have identified the estrogen related receptors ERRα, ERRβ, and ERRγ as important modulators of age-related mitochondrial dysfunction, cellular senescence, and inflammation. Significantly these pathways are also regulated by lifelong caloric restriction (CR), which is known to prevent several age-related complications including kidney disease. ERRα, ERRβ, and ERRγ expression levels are decreased in the aging kidney, and CR and pharmacological treatment with a pan ERR agonist results in increases in expression of ERRα, ERRβ, and ERRγ in the kidney. Remarkably, only a 4-week treatment of 21-month-old mice with the pan ERR agonist reversed the age-related mitochondrial dysfunction, the cellular senescence marker p21, and inflammatory cytokines, including the STAT3 and STING signaling pathways.