Birkisdóttir, María BJaarsma, DickBrandt, Renata M CBarnhoorn, Sandervan Vliet, NicoleImholz, Sandravan Oostrom, Conny TNagarajah, BhawaniPortilla Fernández, ElianaRoks, Anton J MElgersma, Ypevan Steeg, HarryFerreira, José APennings, Jeroen L AHoeijmakers, Jan H JVermeij, Wilbert PDollé, Martijn E T2021-02-072021-02-072021-01-233348448010.1111/acel.13302http://hdl.handle.net/10029/624666Dietary 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.en© 2021 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.DNA damage repairagingdietary restrictionrapamycintranscription stressArticle1474-9726Aging Cell 2021; e13302 advance online publication (ahead of print)