{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T14:46:17Z","timestamp":1790606777859,"version":"4.1.0"},"reference-count":40,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,6,24]],"date-time":"2024-06-24T00:00:00Z","timestamp":1719187200000},"content-version":"vor","delay-in-days":175,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Reprod Medicine &amp; Biology"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Purpose<\/jats:title><jats:p>The average fatherhood age has been consistently increasing in developed countries. Aging has been identified as a risk factor for male infertility. However, its impact on various mechanisms remains unclear. This study focused on the KEAP1\u2013NRF2 oxidative stress response system, by investigating the relationship between the KEAP1\u2013NRF2 system and age\u2010related changes in spermatogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<jats:bold>s<\/jats:bold><\/jats:title><jats:p>For examination of age\u2010related changes, we used 10\u2010, 30\u2010, 60\u2010, and 90\u2010week\u2010old mice to compare sperm count, sperm motility, and protein expression. For assessment of Keap1 inhibition, 85\u2010week\u2010old C57BL\/6J mice were randomly assigned to the following groups: control and bardoxolone methyl (KEAP1 inhibitor). Whole\u2010exome sequencing of a Japanese cohort of patients with non\u2010obstructive azoospermia was performed for evaluating.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Sperm count decreased significantly with aging. Oxidative stress and KEAP1 expression in the testes were elevated. Inhibition of KEAP1 in aging mice significantly increased sperm count compared with that in the control group. In the human study, the frequency of a missense\u2010type SNP (rs181294188) causing changes in NFE2L2 (NRF2) activity was significantly higher in patients with non\u2010obstructive azoospermia than in healthy control group.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The KEAP1\u2013NRF2 system, an oxidative stress response system, is associated with age\u2010related spermatogenesis dysfunction.<\/jats:p><\/jats:sec>","DOI":"10.1002\/rmb2.12595","type":"journal-article","created":{"date-parts":[[2024,6,24]],"date-time":"2024-06-24T10:07:26Z","timestamp":1719223646000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["<scp>KEAP1<\/scp>\u2013<scp>NRF2<\/scp> system regulates age\u2010related spermatogenesis 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