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Modulating p38 MAPK signaling by proteostasis mechanisms supports tissue integrity during growth and aging.

ABSTRACT: The conserved p38 MAPK family is activated by phosphorylation during stress responses and inactivated by phosphatases. C. elegans PMK-1 p38 MAPK initiates innate immune responses and blocks development when hyperactivated. Here we show that PMK-1 signaling is enhanced during early aging by modulating the stoichiometry of non-phospho-PMK-1 to promote tissue integrity and longevity. Loss of pmk-1 function accelerates progressive declines in neuronal integrity and lysosome function compromising longevity which has both cell autonomous and cell non-autonomous contributions. CED-3 caspase cleavage limits phosphorylated PMK-1. Enhancing p38 signaling with caspase cleavage-resistant PMK-1 protects lysosomal and neuronal integrity extending a youthful phase. PMK-1 works through a complex transcriptional program to regulate lysosome formation. During early aging, the absolute phospho-p38 amount is maintained but the reservoir of non-phospho-p38 diminishes to enhance signaling without hyperactivation. Our findings show that modulating the stoichiometry of non-phospho-p38 dynamically supports tissue-homeostasis during aging without hyper-activation of stress response.

SUBMITTER: Yuan W

PROVIDER: S-EPMC10382525 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Modulating p38 MAPK signaling by proteostasis mechanisms supports tissue integrity during growth and aging.

Yuan Wang W Weaver Yi M YM Earnest Svetlana S Taylor Clinton A CA Cobb Melanie H MH Weaver Benjamin P BP

Nature communications 20230728 1

The conserved p38 MAPK family is activated by phosphorylation during stress responses and inactivated by phosphatases. C. elegans PMK-1 p38 MAPK initiates innate immune responses and blocks development when hyperactivated. Here we show that PMK-1 signaling is enhanced during early aging by modulating the stoichiometry of non-phospho-PMK-1 to promote tissue integrity and longevity. Loss of pmk-1 function accelerates progressive declines in neuronal integrity and lysosome function compromising lon ...[more]

PMID: 37507441

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Project description:IntroductionAge-related decline in testosterone is associated with Leydig cell aging with impaired testosterone synthesis in aging. Obesity accelerates the age-related decline in testosterone. However, the mechanisms underlying the Leydig cell aging and the effects of obesity on Leydig cell aging remain unclear.MethodNatural aging mice and diet-induced obese mice were used to assess the process of testicular Leydig cell senescence with age or obesity. Bioinformatic analysis of the young and aged human testes was used to explore key genes related Leydig cell aging. Leydig cell-specific p38 MAPK knockout (p38LCKO) mice were used to further analyze the roles of p38 MAPK in Leydig cell aging. The levels of testosterone and steroidogenic enzymes, activity of p38 MAPK, aging status of Leydig cells, and oxidative stress and inflammation of testes or Leydig cells were detected by ELISA, immunoblotting, immunofluorescence, and senescence-associated β-galactosidase (SA-β-Gal) staining analysis, respectively.ResultThe serum testosterone level was significantly reduced in aged mice compared with young mice. In the testis of aged mice, the reduced mRNA and protein levels of LHCGR, SRB1, StAR, CYP11A1, and CYP17A1 and the elevated oxidative stress and inflammation were observed. KEGG analysis showed that MAPK pathway was changed in aged Leydig cells, and immunoblotting displayed that p38 MAPK was activated in aged Leydig cells. The intensity of SA-β-Gal staining on Leydig cells and the number of p21-postive Leydig cells in aged mice were more than those of young mice. Similar to aged mice, the testosterone-related indexes decreased, and the age-related indexes increased in the testicular Leydig cells of high fat diet (HFD) mice. Aged p38LCKO mice had higher levels of testosterone and steroidogenic enzymes than those of age-matched wild-type (WT) littermates, with reduced the intensity of SA-β-Gal staining and the expression of p21 protein.ConclusionOur study suggested that obesity was an important risk factor for Leydig cell aging. p38 MAPK was involved in Leydig cell aging induced by age and obesity. The inhibition of p38 MAPK could delay Leydig cell aging and alleviate decline in testosterone.

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Modulating p38 MAPK signaling by proteostasis mechanisms supports tissue integrity during growth and aging.

Publications

Modulating p38 MAPK signaling by proteostasis mechanisms supports tissue integrity during growth and aging.

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