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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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It has been found, using specific knock out (KO) mice and cultures, different specific activities for IRS-1 and IRS-2, additional further complexity comes with tissue-specific roles

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