Open AccessUnlike dietary restriction, rapamycin fails to extend lifespan and reduce transcription stress in progeroid DNA repair‐deficient mice
Author(s) -
Birkisdóttir María B.,
Jaarsma Dick,
Brandt Renata M. C.,
Barnhoorn Sander,
Vliet Nicole,
Imholz Sandra,
Oostrom Conny T.,
Nagarajah Bhawani,
Portilla Fernández Eliana,
Roks Anton J. M.,
Elgersma Ype,
Steeg Harry,
Ferreira José A.,
Pennings Jeroen L. A.,
Hoeijmakers Jan H. J.,
Vermeij Wilbert P.,
Dollé Martijn E. T.
Publication year - 2021
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.13302
Subject(s) - biology , pi3k/akt/mtor pathway , transcription (linguistics) , dna repair , life span , werner syndrome , dna damage , microbiology and biotechnology , sirolimus , dna , longevity , genetics , signal transduction , gene , evolutionary biology , biochemistry , rna , helicase , linguistics , philosophy
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.