High protein intake causes gene-length-dependent transcriptional decline, shortens lifespan and accelerates ageing in progeroid DNA repair‐deficient mice

Dietary composition can significantly influence health and lifespan, however, robust knowledge on which food components, at what concentration exert which long-term health effects is still incomplete. Here, we explored the effects of dietary protein intake on Ercc1Δ/- DNA-repair-deficient mice, which are an excellent model for accelerated ageing and are hyperresponsive to the anti-ageing effect of dietary restriction. Restricting dietary protein by 50% extended lifespan in male mice, but not in females. Restricting protein levels beyond 80% improved various neurological health parameters, while a further reduction to 95% affected appetite and became distinctly detrimental. Conversely, a near doubling of protein intake and isocaloric compensatory lowering with carbohydrates significantly shortened lifespan in both sexes. Gene expression analysis of liver from mice on a high-protein, low-carbohydrate diet to those on high-carbohydrate, low-protein revealed increased expression of oxidative phosphorylation, enrichment of processes associated with tissue injury, inflammation, and gene-length-dependent transcriptional decline (GLTD), recently shown to be indicative of DNA damage accumulation causing transcription stress, and cellular ageing. Finally, GLTD was also identified by reanalysis of publicly available data of wild-type mice, rats and humans on high-protein diets, suggesting that increased dietary protein enhances GLTD and accelerates systemic ageing. Together, our findings have implications for nutritional guidelines for progeroid DNA-repair-deficient human syndromes, caution against excessive protein intake in the context of sustaining health, and suggest GLTD as a sensitive read-out of overall health and a predictor of biological ageing.