Unlike Dietary Restriction, Rapamycin Fails to Extend Lifespan and Reduce Transcription Stress in Progeroid DNA Repair-deficient Mice

Overview

Journal Aging Cell

Specialties Cell Biology
Geriatrics

Date 2021 Jan 23

PMID 33484480

Citations 17

Authors

Maria B Birkisdottir

Dick Jaarsma

Renata M C Brandt

Sander Barnhoorn

Nicole van Vliet

Sandra Imholz

Conny T van Oostrom

Bhawani Nagarajah

Eliana Portilla Fernandez

Anton J M Roks

Ype Elgersma

Harry van Steeg

Jose A Ferreira

Jeroen L A Pennings

Jan H J Hoeijmakers

Wilbert P Vermeij

Martijn E T Dolle

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Improved health by combining dietary restriction and promoting muscle growth in DNA repair-deficient progeroid mice.

Vermeij W, Alyodawi K, van Galen I, von der Heide J, Birkisdottir M, Vant Sant L J Cachexia Sarcopenia Muscle. 2024; 15(6):2361-2374.

PMID: 39245994 PMC: 11634475. DOI: 10.1002/jcsm.13570.

Initiation phase cellular reprogramming ameliorates DNA damage in the ERCC1 mouse model of premature aging.

Paine P, Rechsteiner C, Morandini F, Desdin-Mico G, Mrabti C, Parras A Front Aging. 2024; 4():1323194.

PMID: 38322248 PMC: 10844398. DOI: 10.3389/fragi.2023.1323194.

The central role of DNA damage in immunosenescence.

Kell L, Simon A, Alsaleh G, Cox L Front Aging. 2023; 4:1202152.

PMID: 37465119 PMC: 10351018. DOI: 10.3389/fragi.2023.1202152.

Gene expression changes in cerebellum induced by dietary restriction.

Vant Sant L, Birkisdottir M, Ozinga R, Gyenis A, Hoeijmakers J, Vermeij W Front Mol Neurosci. 2023; 16:1185665.

PMID: 37293544 PMC: 10244750. DOI: 10.3389/fnmol.2023.1185665.

Hypoxia extends lifespan and neurological function in a mouse model of aging.

Rogers R, Wang H, Durham T, Stefely J, Owiti N, Markhard A PLoS Biol. 2023; 21(5):e3002117.

PMID: 37220109 PMC: 10204955. DOI: 10.1371/journal.pbio.3002117.

References

Thompson M, Chwialkowska K, Rubbi L, Lusis A, Davis R, Srivastava A . A multi-tissue full lifespan epigenetic clock for mice. Aging (Albany NY). 2018; 10(10):2832-2854. PMC: 6224226. DOI: 10.18632/aging.101590. View

Vellai T, Takacs-Vellai K, Zhang Y, Kovacs A, Orosz L, Muller F . Genetics: influence of TOR kinase on lifespan in C. elegans. Nature. 2003; 426(6967):620. DOI: 10.1038/426620a. View

Sharp Z, Bartke A . Evidence for down-regulation of phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR)-dependent translation regulatory signaling pathways in Ames dwarf mice. J Gerontol A Biol Sci Med Sci. 2005; 60(3):293-300. DOI: 10.1093/gerona/60.3.293. View

de Waard M, van der Pluijm I, Zuiderveen Borgesius N, Comley L, Haasdijk E, Rijksen Y . Age-related motor neuron degeneration in DNA repair-deficient Ercc1 mice. Acta Neuropathol. 2010; 120(4):461-75. PMC: 2923326. DOI: 10.1007/s00401-010-0715-9. View

Lans H, Hoeijmakers J, Vermeulen W, Marteijn J . The DNA damage response to transcription stress. Nat Rev Mol Cell Biol. 2019; 20(12):766-784. DOI: 10.1038/s41580-019-0169-4. View

Kaeberlein M, Powers 3rd R, Steffen K, Westman E, Hu D, Dang N . Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science. 2005; 310(5751):1193-6. DOI: 10.1126/science.1115535. View

van der Pluijm I, Garinis G, Brandt R, Gorgels T, Wijnhoven S, Diderich K . Impaired genome maintenance suppresses the growth hormone--insulin-like growth factor 1 axis in mice with Cockayne syndrome. PLoS Biol. 2007; 5(1):e2. PMC: 1698505. DOI: 10.1371/journal.pbio.0050002. View

Christy B, Demaria M, Campisi J, Huang J, Jones D, Dodds S . p53 and rapamycin are additive. Oncotarget. 2015; 6(18):15802-13. PMC: 4599238. DOI: 10.18632/oncotarget.4602. View

Kapahi P, Zid B, Harper T, Koslover D, Sapin V, Benzer S . Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol. 2004; 14(10):885-90. PMC: 2754830. DOI: 10.1016/j.cub.2004.03.059. View

10.

Ramos F, Chen S, Garelick M, Dai D, Liao C, Schreiber K . Rapamycin reverses elevated mTORC1 signaling in lamin A/C-deficient mice, rescues cardiac and skeletal muscle function, and extends survival. Sci Transl Med. 2012; 4(144):144ra103. PMC: 3613228. DOI: 10.1126/scitranslmed.3003802. View

11.

Ingram D, Roth G . Calorie restriction mimetics: can you have your cake and eat it, too?. Ageing Res Rev. 2014; 20:46-62. DOI: 10.1016/j.arr.2014.11.005. View

12.

Andersen B, Gundersen H, Pakkenberg B . Aging of the human cerebellum: a stereological study. J Comp Neurol. 2003; 466(3):356-65. DOI: 10.1002/cne.10884. View

13.

Nakazawa Y, Hara Y, Oka Y, Komine O, van den Heuvel D, Guo C . Ubiquitination of DNA Damage-Stalled RNAPII Promotes Transcription-Coupled Repair. Cell. 2020; 180(6):1228-1244.e24. DOI: 10.1016/j.cell.2020.02.010. View

14.

Niedernhofer L, Gurkar A, Wang Y, Vijg J, Hoeijmakers J, Robbins P . Nuclear Genomic Instability and Aging. Annu Rev Biochem. 2018; 87:295-322. DOI: 10.1146/annurev-biochem-062917-012239. View

15.

Weindruch R, Sohal R . Seminars in medicine of the Beth Israel Deaconess Medical Center. Caloric intake and aging. N Engl J Med. 1997; 337(14):986-94. PMC: 2851235. DOI: 10.1056/NEJM199710023371407. View

16.

Marteijn J, Lans H, Vermeulen W, Hoeijmakers J . Understanding nucleotide excision repair and its roles in cancer and ageing. Nat Rev Mol Cell Biol. 2014; 15(7):465-81. DOI: 10.1038/nrm3822. View

17.

Weidenheim K, Dickson D, Rapin I . Neuropathology of Cockayne syndrome: Evidence for impaired development, premature aging, and neurodegeneration. Mech Ageing Dev. 2009; 130(9):619-36. DOI: 10.1016/j.mad.2009.07.006. View

18.

Lopez-Otin C, Blasco M, Partridge L, Serrano M, Kroemer G . The hallmarks of aging. Cell. 2013; 153(6):1194-217. PMC: 3836174. DOI: 10.1016/j.cell.2013.05.039. View

19.

Jabs A, Gobel S, Wenzel P, Kleschyov A, Hortmann M, Oelze M . Sirolimus-induced vascular dysfunction. Increased mitochondrial and nicotinamide adenosine dinucleotide phosphate oxidase-dependent superoxide production and decreased vascular nitric oxide formation. J Am Coll Cardiol. 2008; 51(22):2130-8. DOI: 10.1016/j.jacc.2008.01.058. View

20.

Finkel T . The metabolic regulation of aging. Nat Med. 2015; 21(12):1416-23. DOI: 10.1038/nm.3998. View