Study summary · research use only
Estrogen-Related Receptor Agonism Reverses Mitochondrial Dysfunction and Inflammation in the Aging Kidney
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This study in aging human and mouse kidneys, with intervention experiments in mice, examined estrogen-related receptors (ERRs) in age-related kidney mitochondrial dysfunction and inflammation. ERR levels were decreased in aging human and mouse kidneys and preserved in mice with lifelong caloric restriction. Treating 21-month-old mice with the pan-ERR agonist SLU-PP-332 for 8 weeks reversed age-related increases in albuminuria, podocyte loss, mitochondrial dysfunction, and inflammatory cytokines, acting through the cyclic GMP-AMP synthase-STING and STAT3 signaling pathways. Treating 21-month-old mice with the STING inhibitor C-176 for 3 weeks reduced inflammatory cytokines and the senescence marker p21/Cdkn1a, and also reversed age-related decreases in PGC-1α, ERRα, mitochondrial complexes, and MCAD expression. The authors describe ERRs as calorie-restriction mimetics and as modulators of age-related kidney mitochondrial dysfunction and inflammation.
Abstract
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 and inflammation, which collectively contribute to age-related kidney dysfunction and disease. This study examined the role of the nuclear hormone receptors, the estrogen-related receptors (ERRs), in regulation of age-related mitochondrial dysfunction and inflammation. The ERRs were decreased in both aging human and mouse kidneys and were preserved in aging mice with lifelong caloric restriction (CR). A pan-ERR agonist, SLU-PP-332, was used to treat 21-month-old mice for 8 weeks. In addition, 21-month-old mice were treated with a stimulator of interferon genes (STING) inhibitor, C-176, for 3 weeks. Remarkably, similar to CR, an 8-week treatment with a pan-ERR agonist reversed the age-related increases in albuminuria, podocyte loss, mitochondrial dysfunction, and inflammatory cytokines, via the cyclic GMP-AMP synthase-STING and STAT3 signaling pathways. A 3-week treatment of 21-month-old mice with a STING inhibitor reversed the increases in inflammatory cytokines and the senescence marker, p21/cyclin dependent kinase inhibitor 1A (Cdkn1a), but also unexpectedly reversed the age-related decreases in PPARG coactivator (PGC)-1α, ERRα, mitochondrial complexes, and medium chain acyl coenzyme A dehydrogenase (MCAD) expression. These studies identified ERRs as CR mimetics and as important modulators of age-related mitochondrial dysfunction and inflammation. These findings highlight novel druggable pathways that can be further evaluated to prevent progression of age-related kidney disease.
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