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

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

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 relat...

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Main Authors: Karunadharma, Pabalu P, Basisty, Nathan, Dai, Dao-Fu, Chiao, Ying A, Quarles, Ellen K, Hsieh, Edward J, Crispin, David, Bielas, Jason H, Ericson, Nolan G, Beyer, Richard P, MacKay, Vivian L, MacCoss, Michael J, Rabinovitch, Peter S
Format: Online
Language:English
Published: John Wiley & Sons, Ltd 2015
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531069/
id pubmed-4531069
recordtype oai_dc
spelling pubmed-45310692015-08-13 Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects Karunadharma, Pabalu P Basisty, Nathan Dai, Dao-Fu Chiao, Ying A Quarles, Ellen K Hsieh, Edward J Crispin, David Bielas, Jason H Ericson, Nolan G Beyer, Richard P MacKay, Vivian L MacCoss, Michael J Rabinovitch, Peter S Original Articles 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 2H3–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. John Wiley & Sons, Ltd 2015-08 2015-03-23 /pmc/articles/PMC4531069/ /pubmed/25807975 http://dx.doi.org/10.1111/acel.12317 Text en © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Karunadharma, Pabalu P
Basisty, Nathan
Dai, Dao-Fu
Chiao, Ying A
Quarles, Ellen K
Hsieh, Edward J
Crispin, David
Bielas, Jason H
Ericson, Nolan G
Beyer, Richard P
MacKay, Vivian L
MacCoss, Michael J
Rabinovitch, Peter S
spellingShingle Karunadharma, Pabalu P
Basisty, Nathan
Dai, Dao-Fu
Chiao, Ying A
Quarles, Ellen K
Hsieh, Edward J
Crispin, David
Bielas, Jason H
Ericson, Nolan G
Beyer, Richard P
MacKay, Vivian L
MacCoss, Michael J
Rabinovitch, Peter S
Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects
author_facet Karunadharma, Pabalu P
Basisty, Nathan
Dai, Dao-Fu
Chiao, Ying A
Quarles, Ellen K
Hsieh, Edward J
Crispin, David
Bielas, Jason H
Ericson, Nolan G
Beyer, Richard P
MacKay, Vivian L
MacCoss, Michael J
Rabinovitch, Peter S
author_sort Karunadharma, Pabalu P
title Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects
title_short Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects
title_full Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects
title_fullStr Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects
title_full_unstemmed Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects
title_sort subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects
description 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 2H3–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.
publisher John Wiley & Sons, Ltd
publishDate 2015
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531069/
_version_ 1613257675269734400

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