Unlike dietary restriction, rapamycin fails to extend lifespan and reduce transcription stress in progeroid DNA repair-deficient mice
| Autor: | Harry van Steeg, Jan H.J. Hoeijmakers, Sander Barnhoorn, Renata M. C. Brandt, Anton J.M. Roks, Ype Elgersma, Bhawani Nagarajah, Dick Jaarsma, Jeroen L. A. Pennings, Martijn E.T. Dollé, José A. Ferreira, Eliana Portilla Fernandez, Wilbert P. Vermeij, María B. Birkisdóttir, Sandra Imholz, Conny T. M. van Oostrom, Nicole van Vliet |
|---|---|
| Přispěvatelé: | Neurosciences, Molecular Genetics, Internal Medicine |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
DNA Repair DNA damage DNA repair Logic Longevity Mice Inbred Strains Biology Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Transcription (biology) Deficient mouse Animals DNA damage repair Mode of action PI3K/AKT/mTOR pathway Caloric Restriction Mice Knockout Sirolimus Original Paper rapamycin aging dietary restriction Cell Biology Endonucleases Multiple species Original Papers Cell biology DNA-Binding Proteins 030104 developmental biology transcription stress chemistry Geriatrics 030217 neurology & neurosurgery DNA |
| Zdroj: | Aging Cell Aging Cell, 20(2):e13302. Wiley-Blackwell Publishing Ltd |
| ISSN: | 1474-9718 |
| Popis: | Dietary restriction (DR) and rapamycin extend healthspan and life span across multiple species. We have recently shown that DR in progeroid DNA repair‐deficient mice dramatically extended healthspan and trippled life span. Here, we show that rapamycin, while significantly lowering mTOR signaling, failed to improve life span nor healthspan of DNA repair‐deficient Ercc1 ∆/− mice, contrary to DR tested in parallel. Rapamycin interventions focusing on dosage, gender, and timing all were unable to alter life span. Even genetically modifying mTOR signaling failed to increase life span of DNA repair‐deficient mice. The absence of effects by rapamycin on P53 in brain and transcription stress in liver is in sharp contrast with results obtained by DR, and appoints reducing DNA damage and transcription stress as an important mode of action of DR, lacking by rapamycin. Together, this indicates that mTOR inhibition does not mediate the beneficial effects of DR in progeroid mice, revealing that DR and rapamycin strongly differ in their modes of action. In this study, we have subjected Ercc1 Δ/− progeroid DNA repair‐deficient mice to rapamycin and dietary restriction (DR), two well‐known interventions for extending life span across multiple species. DR again resulted in extreme benefits for these mice while rapamycin interventions, focusing on dosage, gender, and timing as well as modulation of mTor via genetic means, all failed to improve life span, healthspan, or the DNA damage indicator transcription stress. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text