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

Thyne, Kevin M.; Salmon, Adam B.

doi:10.1007/s11357-023-00857-8

Cited by 4 publications

(5 citation statements)

References 63 publications

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“…Not all mouse studies of low methionine resulted in longer life though. A recent study using the same diets as previous mouse studies but an inbred (C57BL/6) background found no significant lengthening of life and only marginal impacts on health or frailty ( Thyne and Salmon, 2023 ). Notably, this was the only study in which mice on a low methionine weighed more, not less, than controls.…”

Section: A Brief History Of Dietary Restrictionmentioning

confidence: 87%

Amino acid restriction, aging, and longevity: an update

Austad,

Smith,

Hoffman

2024

Front. Aging

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Various so-called dietary restriction paradigms have shown promise for extending health and life. All such paradigms rely on ad libitum (hereafter ad lib) feeding, something virtually never employed in animals whose long-term health we value, either as a control or, except for food restriction itself, for both control and treatment arms of the experiment. Even though the mechanism(s) remain only vaguely understood, compared to ad lib-fed animals a host of dietary manipulations, including calorie restriction, low protein, methionine, branched-chain amino acids, and even low isoleucine have demonstrable health benefits in laboratory species in a standard laboratory environment. The remaining challenge is to determine whether these health benefits remain in more realistic environments and how they interact with other health enhancing treatments such as exercise or emerging geroprotective drugs. Here we review the current state of the field of amino acid restriction on longevity of animal models and evaluate its translational potential.

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Section: A Brief History Of Dietary Restrictionmentioning

confidence: 87%

Amino acid restriction, aging, and longevity: an update

Austad,

Smith,

Hoffman

2024

Front. Aging

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“…We have described all husbandry conditions, the genetic mutant MsrA KO mouse, and diets used in this study in our previous publications 19 , 20 , 39 . All mice were maintained in the C57Bl/6J background and MR diets used were control diet (CD) (0.86% Met, TestDiet 578F w/0.86% MET – 5SFD) or MR (0.15% Met, 0% Cys, Test Diet 96D2, modified TestDiet 58B0).…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Our group has explored the potential role that methionine sulfoxide reductase A (MsrA), a regulator of methionine oxidation/reduction (redox), may play in the molecular and physiological effects of MR 19 , 20 . The chemical structure of methionine is easily oxidized to methionine sulfoxide which has been shown to modify protein structure and function 21 – 25 .…”

Section: Introductionmentioning

confidence: 99%

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Sulfur Amino Acid Restriction alters mitochondrial function depending on tissue, sex, and Methionine sulfoxide reductase A (MsrA) status.

Thyne,

Camones,

Salmon

2023

Preprint

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Methionine restriction (MR) has been shown to affect mitochondrial function including altering oxygen consumption, reactive oxygen species (ROS) generation, Complex expression, and oxidative damage. The sulfur-containing amino acid methionine can become oxidized forming methionine sulfoxide which can lead to changes in protein function and signaling. Methionine sulfoxide reductases are endogenous enzymes capable of reducing methionine sulfoxide, with Methionine sulfoxide reductase A (MsrA) being ubiquitously expressed in mammals. Here we investigated if the effects of MR on mitochondrial function required functional MsrA in the liver and kidney which are the major tissues involved in sulfur biochemistry and both highly express MsrA. Moreover, MsrA is endogenously found in the mitochondria thereby providing potential mechanisms linking diet to mitochondrial phenotype. We found sex-specific changes in oxygen consumption of isolated mitochondria and females showed changes with MR in a tissue-dependent manner – increased in liver and decreased in kidney. Loss of MsrA increased or decreased oxygen consumption depending on the tissue and which portion of the electron transport chain was being tested. In general, males had few changes in either tissue regardless of MR or MsrA status. Hydrogen peroxide production was increased in the kidney with MR regardless of sex or MsrA status. However, in the liver, production was increased by MR in females and only slightly higher with loss of MsrA in both sexes. Mitochondrial Complex expression was found to be largely unchanged in either tissue suggesting these effects are driven by regulatory mechanisms and not by changes in expression. Together these results suggest that sex and MsrA status do impact the mitochondrial effects of MR in a tissue-specific manner.

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“…However, it is possible that IMR might not extend lifespan despite its effects on IGF-1. For example, a recent study found that feeding adult mice (7–12 months old) a methionine-restricted diet (containing 0.15% methionine) failed to extend their overall survival 24 . A possible explanation for this finding might be that continuous MR at a level of 0.15% methionine does not alter IGF-1 levels sufficiently in adult animals to produce robust longevity benefits.…”

Section: Introductionmentioning

confidence: 99%

Intermittent Methionine Restriction Reduces Marrow Fat Accumulation and Preserves More Bone Mass than Continuous Methionine Restriction

Johnson,

Plummer,

Horowitz

2024

AgingBio

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Continuous methionine restriction (MR) is one of only a few dietary interventions known to dramatically extend mammalian healthspan. For example, continuously methionine-restricted rodents show less age-related pathology and are up to 45% longer-lived than controls. Intriguingly, MR is feasible for humans, andanumberofstudieshavesuggestedthatmethionine-restrictedindividualsmayreceivesimilarhealthspan benefits as rodents. However, long-term adherence to a continuously methionine-restricted diet is likely to be challenging (or even undesirable) for many individuals. To address this, we previously developed an intermittent version of MR (IMR) and demonstrated that it confers nearly identical metabolic health benefits to mice as the continuous intervention, despite having a relatively short interventional period (i.e., only three days per week). We also observed that female mice undergoing IMR show a more pronounced amelioration of diet-induced dysglycemia than continuously methionine-restricted counterparts, while male mice undergoing IMR retain more lean body mass as compared with continuously methionine-restricted controls. Prompted by such findings, we sought to determine other ways in which IMR might compare favorably with continuous MR. While it is known that continuous MR has deleterious effects on bone in mice, including loss of both trabecular and cortical bone, we considered that mice undergoing IMR might retain more bone mass. Here, we report that, as compared with continuous MR, IMR results in a preservation of both trabecular and cortical bone, as well as a dramatic reduction in the accumulation of marrow fat. Consistent with such findings, mechanical testing revealed that the bones of intermittently methionine-restricted mice are significantly stronger than those of mice subjected to the continuous intervention. Finally, static histomorphometric analyses suggest that IMR likely results in more bone mass than that produced by continuous MR, primarily by increasing the number of osteoblasts. Together, our results demonstrate that the more practicable intermittent form of MR not only confers similar metabolic health benefits to the continuous intervention but does so without markedly deleterious effects on either the amount or strength of bone. These data provide further support for the use of IMR in humans.

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

Cited by 4 publications

References 63 publications

Amino acid restriction, aging, and longevity: an update

Amino acid restriction, aging, and longevity: an update

Sulfur Amino Acid Restriction alters mitochondrial function depending on tissue, sex, and Methionine sulfoxide reductase A (MsrA) status.

Intermittent Methionine Restriction Reduces Marrow Fat Accumulation and Preserves More Bone Mass than Continuous Methionine Restriction

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