# Protective Role of p66Shc Deletion in Physiological Renal Aging: Effects on G Protein-Coupled Receptor 124 Expression and Associated Cellular Senescence

## TL;DR

Deleting the p66Shc protein in mice slows kidney aging by reducing oxidative stress and cellular senescence, possibly through preserving GPR124 levels.

## Contribution

This study identifies p66Shc and GPR124 as key players in natural kidney aging and senescence.

## Key findings

- p66Shc deletion in mice improves kidney function and reduces aging-related damage.
- GPR124 levels decline less in p66Shc−/− mice, correlating with reduced cellular senescence markers.
- p66Shc deletion may protect kidneys by limiting oxidative stress and preserving GPR124.

## Abstract

The adaptor protein p66Shc regulates oxidative stress and aging, but its role in renal aging is unclear. We investigated the effects of p66Shc deletion on age-related kidney changes, focusing on G protein-coupled receptor 124 (GPR124) and cellular senescence. Using kidney and urine samples from p66Shc−/− and wild-type mice aged 5–24 months, we found that p66Shc deficiency slows renal aging. Compared to wild-type mice, p66Shc−/− mice showed better kidney function and reduced glomerular sclerosis and mesangial expansion from 18 months, alongside attenuated fibrosis, oxidative stress, and podocyte loss. Age-related declines in GPR124 were also smaller in p66Shc−/− mice, correlating with lower p16INK4a levels in glomeruli and cultured podocytes. These findings suggest that p66Shc deletion provides kidney protection by limiting oxidative stress and senescence, potentially through the preservation of GPR124. This study links p66Shc to natural kidney aging and identifies GPR124 as a mediator of p66Shc-driven senescence, suggesting potential targets for interventions in age-related renal decline.