Reproductive period and epigenetic modifications of the oxidative phosphorylation pathway in the human prefrontal cortex.
PURPOSE: Human females have a unique duration of post-reproductive longevity, during which sex-specific mechanisms ma influence later-life mechanisms of neuronal resilience and vulnerability. The maintenance of energy metabolism, through the oxidative phosphorylation (OXPHOS) apparatus, is essential for brain health. Given the known association between reproductive period (years from menarche to menopause) and cognitive aging, we examined the hypothesis that cumulative estrogen exposure across the lifetime may be associated with differential methylation of genes in the OXPHOS pathway.
METHODS: Using DNA methylation patterns in the post-mortem dorsolateral prefrontal cortex (DLPFC) of 426 women prospectively followed until death in the Religious Orders Study and Rush Memory and Aging Project, we examined the relationship between reproductive period (subtracting age at menarche from age at menopause) and DNA methylation of a published set of autosomal OXPHOS genes previously implicated in stroke susceptibility. We then performed an unsupervised analysis of methylation levels across the Hallmark pathways from the Molecular Signatures Database.
RESULTS: We observed a strong association between reproductive period and DNA methylation status across OXPHOS CpGs. We replicated this association between reproductive period and DNA methylation in a much larger set of OXPHOS genes in our unsupervised analysis. Here, reproductive period also showed associations with methylation in genes related to E2F, MYC and MTORC1 signaling, fatty acid metabolism and DNA repair.
CONCLUSION: This study provides evidence from both a supervised and unsupervised analyses, that lifetime cumulative endogenous steroid exposures may play a role in maintenance of post-menopausal cellular balance, including in brain tissue.
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|PubMed Central ID||
P50 AG016574 / AG / NIA NIH HHS / United States
RF1 AG036042 / AG / NIA NIH HHS / United States
R01 AG036042 / AG / NIA NIH HHS / United States
RF1 AG015819 / AG / NIA NIH HHS / United States
K12 HD051959 / HD / NICHD NIH HHS / United States
R01 AG032990 / AG / NIA NIH HHS / United States
K25 AG041906 / AG / NIA NIH HHS / United States
U01 ES017155 / ES / NIEHS NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
RC2 AG036547 / AG / NIA NIH HHS / United States
R01 AG036836 / AG / NIA NIH HHS / United States