High protein intake causes gene-length-dependent transcriptional decline, shortens lifespan and accelerates ageing in progeroid DNA repair-deficient mice
van Galen, Ivar Birkisdóttir, Maria B Ozinga, Rutger A Brandt, Renata MC Barnhoorn, Sander Imholz, Sandra van Oostrom, Conny T van der Marel, Ricfrid WGN Smit, Kimberly Rijksen, Yvonne MA
van Galen, Ivar
Birkisdóttir, Maria B
Ozinga, Rutger A
Brandt, Renata MC
Barnhoorn, Sander
Imholz, Sandra
van Oostrom, Conny T
van der Marel, Ricfrid WGN
Smit, Kimberly
Rijksen, Yvonne MA
Series / Report no.
Open Access
Type
Journal Article
Article
Article
Language
en
Date of publication
2025-05-22
Year of publication
Research Projects
Organizational Units
Journal Issue
Title
High protein intake causes gene-length-dependent transcriptional decline, shortens lifespan and accelerates ageing in progeroid DNA repair-deficient mice
Translated Title
Published in
NPJ Metab Health Dis 2025; 3:20
Abstract
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 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 reflect 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, warrant the use of excessive protein intake for sustaining health, and suggests GLTD as a sensitive read-out of overall health and predictor of biological ageing.