Estrogen-Related Receptor Agonism Reverses Mitochondrial Dysfunction and Inflammation in the Aging Kidney.
Wang. Xiaoxin X XX; Myakala. Komuraiah K; Libby. Andrew E AE; Krawczyk. Ewa E; Panov. Julia J; Jones. Bryce A BA; Bhasin. Kanchan K; Shults. Nataliia N; Qi. Yue Y; Krausz. Kristopher W KW; Zerfas. Patricia M PM; Takahashi. Shogo S; Daneshpajouhnejad. Parnaz P; Titievsky. Avi A; Taranenko. Elizaveta E; Billon. Cyrielle C; Chatterjee. Arindam A; Elgendy. Bahaa B; Walker. John K JK; Albanese. Chris C; Kopp. Jeffrey B JB; Rosenberg. Avi Z AZ; Gonzalez. Frank J FJ; Guha. Udayan U; Brodsky. Leonid L; Burris. Thomas P TP; Levi. Moshe M
Key Findings
- ERR levels drop with age in kidneys, but stay high in calorie‑restricted mice.
- An 8‑week treatment with the pan‑ERR agonist SLU‑PP‑332 reversed age‑related kidney damage, mitochondrial dysfunction, and inflammation in 21‑month‑old mice.
- Both the ERR agonist and a STING inhibitor improved kidney health via the cGAS‑STING‑STAT3 pathway, suggesting ERR activation mimics calorie restriction.
Practical Outcomes
- For biohackers, this study highlights estrogen‑related receptor activation as a potential anti‑aging target for kidney health, but the work is still in mice and the compound isn’t commercially available. It suggests that strategies mimicking calorie restriction (e.g., intermittent fasting, CR‑mimetic compounds) may support mitochondrial function and reduce inflammation, which could be explored with existing supplements or lifestyle approaches while awaiting human data on ERR agonists.
Summary
In old mice, a drug called SLU‑PP‑332 that activates estrogen‑related receptors (ERRs) acted like lifelong calorie restriction: it lowered kidney leak (albuminuria), protected kidney cells, improved mitochondrial health, and cut inflammation. The benefits seemed to work through the STING‑STAT3 signaling pathway. A separate STING inhibitor also helped, but unexpectedly boosted the same mitochondrial and ERR markers.
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.
Study Information
pubmed
2023
2023-09-17T00:00:00.000Z
10.1016/j.ajpath.2023.07.008
24
85