SIRT3 deficiency decreases oxidative metabolism capacity but increases lifespan in male mice under caloric restriction

Rashpal S Dhillon; Yiming Amy Qin; Paul R van Ginkel; Vivian X Fu; James M Vann; Alexis J Lawton; Cara L Green; Fúlvia B Manchado-Gobatto; Claudio A Gobatto; Dudley W Lamming; Tomas A Prolla; John M Denu

doi:10.1111/acel.13721

SIRT3 deficiency decreases oxidative metabolism capacity but increases lifespan in male mice under caloric restriction

Rashpal S Dhillon
, Yiming Amy Qin
, Paul R van Ginkel
, Vivian X Fu
, James M Vann
, Alexis J Lawton
, Cara L Green
, Fúlvia B Manchado-Gobatto
, Claudio A Gobatto
, Dudley W Lamming
, Tomas A Prolla
, John M Denu

University of Wisconsin-Madison
University of California, Los Angeles
Wisconsin Institute for Discovery
Interdepartmental Graduate Program in Nutritional Sciences
Department of Medicine
SMPH
William S. Middleton Memorial Veterans Hospital
Universidade Estadual de Campinas

Research output: Contribution to journal › Article › peer-review

23 Citations (SciVal)

Abstract

Mitochondrial NAD+ -dependent protein deacetylase Sirtuin3 (SIRT3) has been proposed to mediate calorie restriction (CR)-dependent metabolic regulation and lifespan extension. Here, we investigated the role of SIRT3 in CR-mediated longevity, mitochondrial function, and aerobic fitness. We report that SIRT3 is required for whole-body aerobic capacity but is dispensable for CR-dependent lifespan extension. Under CR, loss of SIRT3 (Sirt3-/- ) yielded a longer overall and maximum lifespan as compared to Sirt3+/+ mice. This unexpected lifespan extension was associated with altered mitochondrial protein acetylation in oxidative metabolic pathways, reduced mitochondrial respiration, and reduced aerobic exercise capacity. Also, Sirt3-/- CR mice exhibit lower spontaneous activity and a trend favoring fatty acid oxidation during the postprandial period. This study shows the uncoupling of lifespan and healthspan parameters (aerobic fitness and spontaneous activity) and provides new insights into SIRT3 function in CR adaptation, fuel utilization, and aging.

Original language	English
Pages (from-to)	e13721
Number of pages	15
Journal	Aging Cell
Volume	21
Issue number	12
Early online date	5 Oct 2022
DOIs	https://doi.org/10.1111/acel.13721
Publication status	Published - 31 Dec 2022

Data Availability Statement

The raw data, processed data, spectral library, and the analysis logs describing the settings for the Spectronaut analyses have been deposited to the Proteome Xchange Consortium via the MassIVE partner repository with the dataset identifier MSV000087085 andPXD024961 (DOI: 10.25345/C59Z2Q). The data were processed and cleaned using an in-house R script, which can be accessed through the GitHub link: (DOI: 10.5281/zenodo.3360892). Other data are available upon request

Funding

This work was supported by NIA grant AG038679 and GM65386to T.A.P and J.M.D. The Lamming lab is supported in part by the NIA(AG056771, AG062328, and AG061635), the NIDDK (DK125859),and startup funds from UW-Madison to D.W.L. C.L.G. was sup-ported in part a Glenn/AFAR Postdoctoral Fellowship from the Glenn Foundation for Medical Research. Support for this research was provided by the University of Wisconsin–Madison Office of the Vice Chancellor for Research and Graduate Education with funding from the Wisconsin Alumni Research Foundation. The Lamming lab is supported in part by the U.S. Department of Veterans Affairs(I01-BX004031), and this work was supported using facilities and re-sources from the William S. Middleton Memorial Veterans Hospital. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work does not represent the views of the Department of Veterans Affairs or the United States Government F.B.M.-G. and C.A.G. were supported by FAPESP (#2015/00272- 6, #2015/01362-9) for their working period at University of Wisconsin-Madison. We would like to thank Randall Massey at the Medical School Electron Microscope Facility for his help in transmission electron microscopy. We thank Dr. Melissa Skala, Dr. Alex Walsh, and Kelsey Tweed for the insightful discussions and comments. We also thank Eric Armstrong for his help with the metabolomic analysis.

Keywords

Animals
Male
Mice
Acetylation
Aging/metabolism
Caloric Restriction
Longevity/genetics
Mitochondria/metabolism
Sirtuin 3/genetics
Oxidative Stress/genetics

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10.1111/acel.13721Licence: CC BY

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Dhillon, R. S., Qin, Y. A., van Ginkel, P. R., Fu, V. X., Vann, J. M., Lawton, A. J., Green, C. L., Manchado-Gobatto, F. B., Gobatto, C. A., Lamming, D. W., Prolla, T. A., & Denu, J. M. (2022). SIRT3 deficiency decreases oxidative metabolism capacity but increases lifespan in male mice under caloric restriction. Aging Cell, 21(12), e13721. https://doi.org/10.1111/acel.13721

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abstract = "Mitochondrial NAD+ -dependent protein deacetylase Sirtuin3 (SIRT3) has been proposed to mediate calorie restriction (CR)-dependent metabolic regulation and lifespan extension. Here, we investigated the role of SIRT3 in CR-mediated longevity, mitochondrial function, and aerobic fitness. We report that SIRT3 is required for whole-body aerobic capacity but is dispensable for CR-dependent lifespan extension. Under CR, loss of SIRT3 (Sirt3-/- ) yielded a longer overall and maximum lifespan as compared to Sirt3+/+ mice. This unexpected lifespan extension was associated with altered mitochondrial protein acetylation in oxidative metabolic pathways, reduced mitochondrial respiration, and reduced aerobic exercise capacity. Also, Sirt3-/- CR mice exhibit lower spontaneous activity and a trend favoring fatty acid oxidation during the postprandial period. This study shows the uncoupling of lifespan and healthspan parameters (aerobic fitness and spontaneous activity) and provides new insights into SIRT3 function in CR adaptation, fuel utilization, and aging.",

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AU - Lawton, Alexis J

AU - Green, Cara L

AU - Manchado-Gobatto, Fúlvia B

AU - Gobatto, Claudio A

AU - Lamming, Dudley W

AU - Prolla, Tomas A

AU - Denu, John M

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KW - Mice

KW - Acetylation

KW - Aging/metabolism

KW - Caloric Restriction

KW - Longevity/genetics

KW - Mitochondria/metabolism

KW - Sirtuin 3/genetics

KW - Oxidative Stress/genetics

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ER -

SIRT3 deficiency decreases oxidative metabolism capacity but increases lifespan in male mice under caloric restriction

Abstract

Data Availability Statement

Funding

Keywords

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