Methionine restriction delays senescence and suppresses the senescence-associated secretory phenotype in the kidney through endogenous hydrogen sulfide

ABSTRACT

Aging is a risk factor for various acute and chronic kidney injuries. Kidney aging is accompanied by the secretion of growth factors, proteases, and inflammatory cytokines, known as the senescence-associated secretory phenotype (SASP). These factors accelerate the aging process and senescence-associated changes. Delaying kidney senescence may prevent acute and chronic kidney injury. Methionine restriction (MR) was found to be an effective intervention for delaying senescence. However, the mechanism of MR remains unclear. In this study, we investigated the effect of MR on the survival rate and renal aging of C57BL/6 mice and examined the relevant mechanisms. MR increased the survival rate and decreased the levels of senescence markers in the aging kidney. Both in vivo and in vitro, MR upregulated the transsulfuration pathway to increase H₂S production, downregulated senescence markers and the SASP, and activated AMPK. The ability of MR to delay aging was reduced when AMPK was inhibited. These results suggest that MR may slow animal aging and kidney senescence through H₂S production and AMPK pathway activation.

Abbreviations: DR: diet restriction; MR: methionine restriction; SASP: senescence-associated secretory phenotype; AL: ad libitum; CKD, chronic kidney disease; AKI: acute kidney disease; TSP: transsulfuration pathway; CGL: cystathionine g-lyase; H₂S: hydrogen sulfide; AMPK: AMP-activated protein kinase; mTOR: mammalian target of rapamycin; IS: indoxyl sulfate; CC: compound C.

KEYWORDS:

• Senescence
• renal
• senescence-associated secretory phenotype
• methionine restriction
• hydrogen sulfide

Acknowledgments

This work was supported by the National Key R&D Program of China (2018YFA0108803), the Science and Technology Project of Beijing (D181100000118004), the 973 Program (2013CB530800), the Twelfth Five-Year National Key Technology Research and Development Program (2015BAI12B06 and 2013BAI09B05), and the 973 Program [2013CB530800].

Disclosure statement

No potential conflict of interest was reported by the authors.

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Funding

This work was supported by the National Key R&D Program of China [2018YFA0108803]; the Science and Technology Project of Beijing [D181100000118004]; the Twelfth Five-Year National Key Technology Research and Development Program [2015BAI12B06 and 2013BAI09B05]; the 973 Program [2013CB530800].