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Cited by 48Sperm and Testicular FunctionHormonal and reproductive studiesTelomeres, Telomerase, and Senescence

Involvement of p38 MAPK in Leydig cell aging and age-related decline in testosterone

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Luo, Dandan, Qi, Xiangyu, Xu, Xiaoqin, Yang, Leilei, Yu, Chunxiao, Guan, Qingbo·2023·Frontiers in Endocrinology
DOI 10.3389/fendo.2023.1088249PMC PMC10025507
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Abstract

Introduction: Age-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. Method: Natural 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. Result: The 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. Conclusion: Our 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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  • Leydig-cell steroidogenesis is sensitive to aging, metabolic dysfunction, inflammatory stress, and changes in the testicular niche.

    “Experimental and translational evidence also indicates that Leydig-cell steroidogenesis is sensitive to aging, metabolic dysfunction, inflammatory stress, and changes in the testicular niche [13,14].”

    From Vitamin D Supplementation, Total Testosterone, and Androgen Bioavailability Markers in Adult Men: A Systematic Review and Meta-Analysis of Randomized Controlled Trials (2026) · cites this paper as [14]

    The Results report reduced Leydig-cell steroidogenic proteins in aged and high-fat-diet mice, while the Discussion links obesity-associated oxidative stress and inflammation to Leydig-cell aging. The paper also observes changes in testicular tissue, including interstitial lipid deposition, but does not establish changes in the testicular niche as a distinct influence on steroidogenesis. Page numbers are unavailable in our copy. (LLM, conf=0.82)

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  • Modern mechanistic literature on Leydig-cell aging and metabolic dysfunction supports the biological plausibility of endocrine vulnerability, but it also indicates that testosterone decline is multifactorial and unlikely to be reversed by a single micronutrient intervention in unselected populations.

    “Modern mechanistic literature on Leydig-cell aging and metabolic dysfunction supports the biological plausibility of endocrine vulnerability, but it also indicates that testosterone decline is multifactorial and unlikely to be reversed by a single micronutrient intervention in unselected populations [13,14].”

    From Vitamin D Supplementation, Total Testosterone, and Androgen Bioavailability Markers in Adult Men: A Systematic Review and Meta-Analysis of Randomized Controlled Trials (2026) · cites this paper as [14]

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Cited by

Sorted by citations

Authors
Luo, D., Qi, X., Xu, X., Yang, L., Yu, C., & Guan, Q.
Affiliations
Shandong University (CN)
Corresponding author
  • Yu, Chunxiao
  • Guan, Qingbo
ORCID
Venue
Frontiers in Endocrinology
Publisher
Frontiers Media SA
Published
2023-03-06
Volume
14
Pages
1088249-1088249
ISSN
1664-2392 (ISSN-L)
DOI
10.3389/fendo.2023.1088249
PMC
PMC10025507
OpenAlex
W4323316741
Cited by
48
References
6
Citations by year
2026: 18 · 2025: 17 · 2024: 12 · 2023: 1
FWCI
10.72
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Endocrinology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Keywords
p38 MAPK, obesity, testicular steroidogenesis, steroidogenic enzymes, oxidative stress, inflammation, senescence-associated β-galactosidase, p21, high-fat diet
MeSH terms
Aged, Aging, Animals, Humans, Inflammation, Leydig Cells, Male, Testis, Testosterone, Cellular Senescence, p38 Mitogen-Activated Protein Kinases, Mice

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