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

Pabalu P Karunadharma; Nathan Basisty; Dao-Fu Dai; Ying A Chiao; Ellen K Quarles; Edward J Hsieh; David Crispin; Jason H Bielas; Nolan G Ericson; Richard P Beyer; Vivian L MacKay; Michael J MacCoss; Peter S Rabinovitch

doi:10.1111/acel.12317

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

Journal article

Open access

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

Pabalu P Karunadharma, Nathan Basisty, Dao-Fu Dai, Ying A Chiao, Ellen K Quarles, Edward J Hsieh, David Crispin, Jason H Bielas, Nolan G Ericson, Richard P Beyer, …

Aging cell, Vol.14(4), pp.547-557

08/2015

DOI: 10.1111/acel.12317

PMCID: PMC4531069

PMID: 25807975

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Abstract

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.

Deuterium

Proteome - genetics

TOR Serine-Threonine Kinases - metabolism

Caloric Restriction

Half-Life

Homeostasis

TOR Serine-Threonine Kinases - antagonists & inhibitors

Tandem Mass Spectrometry

TOR Serine-Threonine Kinases - genetics

Aging - genetics

Liver - drug effects

Proteolysis

Eukaryotic Initiation Factor-2 - metabolism

Isotope Labeling

Female

Protein Stability

Leucine - metabolism

Signal Transduction

Liver - metabolism

Mice, Inbred C57BL

Gene Expression Regulation

Sirolimus - pharmacology

Animals

Eukaryotic Initiation Factor-2 - genetics

Polyribosomes - metabolism

Protein Biosynthesis - drug effects

Mice

Polyribosomes - drug effects

Proteome - metabolism

Aging - metabolism

Details

Title: Subtitle: Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects
Creators: Pabalu P Karunadharma - Department of Pathology, University of Washington, Seattle, WA, 98195, USA
Nathan Basisty - Department of Pathology, University of Washington, Seattle, WA, 98195, USA
Dao-Fu Dai - Department of Pathology, University of Washington, Seattle, WA, 98195, USA
Ying A Chiao - Department of Pathology, University of Washington, Seattle, WA, 98195, USA
Ellen K Quarles - Department of Pathology, University of Washington, Seattle, WA, 98195, USA
Edward J Hsieh - Department of Genome Sciences, University of Washington, Seattle, WA, 98195, USA
David Crispin - Department of Pathology, University of Washington, Seattle, WA, 98195, USA
Jason H Bielas - Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
Nolan G Ericson - Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
Richard P Beyer - Department of Environmental Health and Biostatistics, University of Washington, Seattle, WA, 98195, USA
Vivian L MacKay - Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA
Michael J MacCoss - Department of Genome Sciences, University of Washington, Seattle, WA, 98195, USA
Peter S Rabinovitch - Department of Pathology, University of Washington, Seattle, WA, 98195, USA
Resource Type: Journal article
Publication Details: Aging cell, Vol.14(4), pp.547-557
DOI: 10.1111/acel.12317
PMID: 25807975
PMCID: PMC4531069
NLM abbreviation: Aging Cell
ISSN: 1474-9718
eISSN: 1474-9726
Publisher: England
Grant note: R01ES019319 / NIEHS NIH HHS R01HL101186 / NHLBI NIH HHS R13AG046104 / NIA NIH HHS T32 AG000057 / NIA NIH HHS P30 AG013280 / NIA NIH HHS R01 ES019319 / NIEHS NIH HHS R01 HL101186 / NHLBI NIH HHS R01 AG038550 / NIA NIH HHS
Language: English
Date published: 08/2015
Academic Unit: Pathology; Iowa Neuroscience Institute; Radiation Oncology
Record Identifier: 9984047742902771

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