Pan-tissue Transcriptome Analysis Reveals Sex-dimorphic Human Aging

ABSTRACT Complex diseases often exhibit sex-dimorphism in morbidity and prognosis, many of which are age-related. However, the underlying mechanisms of the sex-dimorphic aging remain foggy, with limited studies across multiple tissues. We systematically analyzed ∼17,000 transcriptomes from 35 human tissues to quantitatively evaluate the individual and combined contributions of sex and age to transcriptomic variations. We discovered extensive sex-dimorphisms during aging with distinct patterns of change in gene expression and alternative splicing (AS). Intriguingly, the sex-biased age-associated AS events have a stronger association with Alzheimer’s disease in males, and are regulated by several sex-biased splicing factors that are controlled by sex hormones. Breakpoint analysis showed sex-dimorphic aging rates, with males having a larger and earlier transcriptome change, which were significantly associated with decline of sex hormones. Collectively, this study uncovered an essential role of sex during aging at the molecular and multi-tissue levels, providing new insight into sex-dimorphic regulatory patterns.