Tissue-specific molecular regulation of aging mechanisms with methionine restriction in mice and the potential role of methionine sulfoxide reductase

Methionine restriction (MR) has many effects on different molecular and physiological systems and pathways associated with aging. However, these outcomes have often been ambiguous across studies, suggesting the context of outcomes, including tissue type or donor sex, may have a significant impact. We have previously shown that methionine sulfoxide reductase A (MsrA) may have discrete roles on aging physiology under MR. Here, we investigated the effect of MR on putative molecular hallmarks of aging, including mitochondrial function and regulation of the intracellular signal hydrogen sulfide, across tissues and in males and females. We found that females tended to have greater changes in mitochondrial oxygen consumption than males with MR, while the effects of MsrA were context-dependent. Mitochondrial hydrogen peroxide production was decreased by MR in hepatic mitochondria from females and only slightly higher with loss of MsrA in both sexes. In contrast, mitochondrial peroxide production was increased in the kidney with MR regardless of sex or MsrA status. Hydrogen sulfide production capacity was increased only in the liver by MR independent of MsrA, though expression of regulators of hydrogen sulfide generation was changed in a tissue-dependent manner that was not altered by MsrA status. Expression of methionine sulfoxide reductases was also impacted by MR, showing changes in expression in a tissue and sex-dependent manner. These results suggest a complex interaction between tissue, sex, diet, and MsrA status.