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Importantly, nuclear-localized FOXO4-positive Leydig cells in elderly testes showed reduced expression of 3-HSD, a rate-limiting enzyme in testosterone synthesis, implying a connection between nuclear FOXO4 and age-related decline in testosterone production [1]

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The issue has been most thoroughly investigated in native Japanese where persons with a single-nucleotide polymorphism (SNP) variant allele of the ALDH2 gene were found