High protein intake causes gene-length-dependent transcriptional decline, shortens lifespan and accelerates ageing in progeroid DNA repair-deficient mice
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 Ercc1 Δ/− DNA-repair-deficient...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-05-01
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| Series: | npj Metabolic Health and Disease |
| Online Access: | https://doi.org/10.1038/s44324-025-00064-3 |
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| author | Ivar van Galen Maria B. Birkisdóttir Rutger A. Ozinga Renata M. C. Brandt Sander Barnhoorn Sandra Imholz Conny T. van Oostrom Ricfrid W. G. N. van der Marel Kimberly Smit Yvonne M. A. Rijksen Erwin Reiling Harry van Steeg Jan H. J. Hoeijmakers Martijn E. T. Dollé Wilbert P. Vermeij |
| author_facet | Ivar van Galen Maria B. Birkisdóttir Rutger A. Ozinga Renata M. C. Brandt Sander Barnhoorn Sandra Imholz Conny T. van Oostrom Ricfrid W. G. N. van der Marel Kimberly Smit Yvonne M. A. Rijksen Erwin Reiling Harry van Steeg Jan H. J. Hoeijmakers Martijn E. T. Dollé Wilbert P. Vermeij |
| author_sort | Ivar van Galen |
| collection | DOAJ |
| description | 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 Ercc1 Δ/− 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. |
| format | Article |
| id | doaj-art-cbc24cbc24e246538d9f861ae036dc26 |
| institution | DOAJ |
| issn | 2948-2828 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Metabolic Health and Disease |
| spelling | doaj-art-cbc24cbc24e246538d9f861ae036dc262025-08-20T03:08:40ZengNature Portfolionpj Metabolic Health and Disease2948-28282025-05-013111110.1038/s44324-025-00064-3High protein intake causes gene-length-dependent transcriptional decline, shortens lifespan and accelerates ageing in progeroid DNA repair-deficient miceIvar van Galen0Maria B. Birkisdóttir1Rutger A. Ozinga2Renata M. C. Brandt3Sander Barnhoorn4Sandra Imholz5Conny T. van Oostrom6Ricfrid W. G. N. van der Marel7Kimberly Smit8Yvonne M. A. Rijksen9Erwin Reiling10Harry van Steeg11Jan H. J. Hoeijmakers12Martijn E. T. Dollé13Wilbert P. Vermeij14Princess Máxima Center for Pediatric OncologyPrincess Máxima Center for Pediatric OncologyPrincess Máxima Center for Pediatric OncologyDepartment of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center RotterdamDepartment of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center RotterdamCentre for Health Protection, National Institute for Public Health and the Environment, (RIVM)Centre for Health Protection, National Institute for Public Health and the Environment, (RIVM)Princess Máxima Center for Pediatric OncologyPrincess Máxima Center for Pediatric OncologyPrincess Máxima Center for Pediatric OncologyCentre for Health Protection, National Institute for Public Health and the Environment, (RIVM)Centre for Health Protection, National Institute for Public Health and the Environment, (RIVM)Princess Máxima Center for Pediatric OncologyCentre for Health Protection, National Institute for Public Health and the Environment, (RIVM)Princess Máxima Center for Pediatric OncologyAbstract 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 Ercc1 Δ/− 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.https://doi.org/10.1038/s44324-025-00064-3 |
| spellingShingle | Ivar van Galen Maria B. Birkisdóttir Rutger A. Ozinga Renata M. C. Brandt Sander Barnhoorn Sandra Imholz Conny T. van Oostrom Ricfrid W. G. N. van der Marel Kimberly Smit Yvonne M. A. Rijksen Erwin Reiling Harry van Steeg Jan H. J. Hoeijmakers Martijn E. T. Dollé Wilbert P. Vermeij High protein intake causes gene-length-dependent transcriptional decline, shortens lifespan and accelerates ageing in progeroid DNA repair-deficient mice npj Metabolic Health and Disease |
| title | High protein intake causes gene-length-dependent transcriptional decline, shortens lifespan and accelerates ageing in progeroid DNA repair-deficient mice |
| title_full | High protein intake causes gene-length-dependent transcriptional decline, shortens lifespan and accelerates ageing in progeroid DNA repair-deficient mice |
| title_fullStr | High protein intake causes gene-length-dependent transcriptional decline, shortens lifespan and accelerates ageing in progeroid DNA repair-deficient mice |
| title_full_unstemmed | High protein intake causes gene-length-dependent transcriptional decline, shortens lifespan and accelerates ageing in progeroid DNA repair-deficient mice |
| title_short | High protein intake causes gene-length-dependent transcriptional decline, shortens lifespan and accelerates ageing in progeroid DNA repair-deficient mice |
| title_sort | high protein intake causes gene length dependent transcriptional decline shortens lifespan and accelerates ageing in progeroid dna repair deficient mice |
| url | https://doi.org/10.1038/s44324-025-00064-3 |
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