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Sexually dimorphic effects of methionine sulfoxide reductase A (MsrA) on murine longevity and health span during methionine restriction

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Abstract

Methionine restriction (MR) extends lifespan in various model organisms, and understanding the molecular effectors of MR could expand the repertoire of tools targeting the aging process. Here, we address to what extent the biochemical pathway responsible for redox metabolism of methionine plays in regulating the effects of MR on lifespan and health span. Aerobic organisms have evolved methionine sulfoxide reductases to counter the oxidation of the thioether group contained in the essential amino acid methionine. Of these enzymes, methionine sulfoxide reductase A (MsrA) is ubiquitously expressed in mammalian tissues and has subcellular localization in both the cytosol and mitochondria. Loss of MsrA increases sensitivity to oxidative stress and has been associated with increased susceptibility to age-associated pathologies including metabolic dysfunction. We rationalized that limiting the available methionine with MR may place increased importance on methionine redox pathways, and that MsrA may be required to maintain available methionine for its critical uses in cellular homeostasis including protein synthesis, metabolism, and methylation. Using a genetic mutant mouse lacking MsrA, we tested the requirement for this enzyme in the effects of MR on longevity and markers of healthy aging late in life. When initiated in adulthood, we found that MR had minimal effects in males and females regardless of MsrA status. MR had minimal effect on lifespan with the exception of wild-type males where loss of MsrA slightly increased lifespan on MR. We also observed that MR drove an increase in body weight in wild-type mice only, but mice lacking MsrA tended to maintain more stable body weight throughout their lives. We also found that MR had greater benefit to males than females in terms of glucose metabolism and some functional health span assessments, but MsrA generally had minimal impact on these metrics. Frailty was also found to be unaffected by MR or MsrA in aged animals. We found that in general, MsrA was not required for the beneficial effects of MR on longevity and health span.

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Data availability

The data presented in the work are available from the corresponding author upon request.

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Acknowledgements

We would also like to acknowledge the experimental assistance of Yuhong Liu throughout this study and Dr. Jonathan Dorigatti for experimental assistance and helpful discussions. We would also like to acknowledge Jodie Cropper and Dr. Wenbo Qi for their assistance in monitoring the mice during the lifespan study. We would like to acknowledge Dr. Catherine Cheng for her assistance in analyzing the lifespan data. Health span measurements were performed by the Integrated Physiology of Aging Core at the San Antonio Nathan Shock Center (P30 AG013319) [65].

Funding

This research was funded in part by R01 AG050797, R01 AG057431, T32 AG021890 and the San Antonio Area Foundation. AS is partially supported by the Geriatric Research, Education and Clinical Center of the South Texas Veterans Health Care System. This material is the result of work supported with resources and the use of facilities at South Texas Veterans Health Care System, San Antonio, Texas.

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Authors and Affiliations

  1. Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX, 78229, USA

    Kevin M. Thyne & Adam B. Salmon

  2. Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX, 78229, USA

    Adam B. Salmon

  3. Geriatric Research Education and Clinical Center, Audie L. Murphy Hospital, South Texas Veterans Health Care System, San Antonio, TX, 78229, USA

    Adam B. Salmon

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  1. Kevin M. Thyne
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Study was formulated by ABS and KMT. Data was collected and analyzed by KMT. Figures and manuscript drafts were prepared by KMT. ABS and KMT reviewed, edited, and approved the manuscript.

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Correspondence to Adam B. Salmon.

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Thyne, K.M., Salmon, A.B. Sexually dimorphic effects of methionine sulfoxide reductase A (MsrA) on murine longevity and health span during methionine restriction. GeroScience 45, 3003–3017 (2023). https://doi.org/10.1007/s11357-023-00857-8

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