Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects.

Autor: Karunadharma PP; Department of Pathology, University of Washington, Seattle, WA, 98195, USA., Basisty N; Department of Pathology, University of Washington, Seattle, WA, 98195, USA., Dai DF; Department of Pathology, University of Washington, Seattle, WA, 98195, USA., Chiao YA; Department of Pathology, University of Washington, Seattle, WA, 98195, USA., Quarles EK; Department of Pathology, University of Washington, Seattle, WA, 98195, USA., Hsieh EJ; Department of Genome Sciences, University of Washington, Seattle, WA, 98195, USA., Crispin D; Department of Pathology, University of Washington, Seattle, WA, 98195, USA., Bielas JH; Department of Pathology, University of Washington, Seattle, WA, 98195, USA.; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA., Ericson NG; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA., Beyer RP; Department of Environmental Health and Biostatistics, University of Washington, Seattle, WA, 98195, USA., MacKay VL; Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA., MacCoss MJ; Department of Genome Sciences, University of Washington, Seattle, WA, 98195, USA., Rabinovitch PS; Department of Pathology, University of Washington, Seattle, WA, 98195, USA.
Jazyk: angličtina
Zdroj: Aging cell [Aging Cell] 2015 Aug; Vol. 14 (4), pp. 547-57. Date of Electronic Publication: 2015 Mar 23.
DOI: 10.1111/acel.12317
Abstrakt: Calorie restriction (CR) and rapamycin (RP) extend lifespan and improve health across model organisms. Both treatments inhibit mammalian target of rapamycin (mTOR) signaling, a conserved longevity pathway and a key regulator of protein homeostasis, yet their effects on proteome homeostasis are relatively unknown. To comprehensively study the effects of aging, CR, and RP on protein homeostasis, we performed the first simultaneous measurement of mRNA translation, protein turnover, and abundance in livers of young (3 month) and old (25 month) mice subjected to 10-week RP or 40% CR. Protein abundance and turnover were measured in vivo using (2) H3 -leucine heavy isotope labeling followed by LC-MS/MS, and translation was assessed by polysome profiling. We observed 35-60% increased protein half-lives after CR and 15% increased half-lives after RP compared to age-matched controls. Surprisingly, the effects of RP and CR on protein turnover and abundance differed greatly between canonical pathways, with opposite effects in mitochondrial (mt) dysfunction and eIF2 signaling pathways. CR most closely recapitulated the young phenotype in the top pathways. Polysome profiles indicated that CR reduced polysome loading while RP increased polysome loading in young and old mice, suggesting distinct mechanisms of reduced protein synthesis. CR and RP both attenuated protein oxidative damage. Our findings collectively suggest that CR and RP extend lifespan in part through the reduction of protein synthetic burden and damage and a concomitant increase in protein quality. However, these results challenge the notion that RP is a faithful CR mimetic and highlight mechanistic differences between the two interventions.
(© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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