Sexual identity of enterocytes regulates rapamycin-mediated intestinal homeostasis and lifespan extension

Pharmacological attenuation of mTOR by rapamycin and other compounds presents a promising route for delay of ageing-related pathologies, including intestinal cancers. Here, we show that rapamycin treatment in Drosophila extends lifespan in females but not in males. Female-specific, age-related gut pathology and impaired intestinal barrier function are both markedly slowed by rapamycin treatment, mediated by increased autophagy. Upon rapamycin treatment, female intestinal enterocytes increase autophagy, via the H3/H4 histone-Bchs axis, while male enterocytes show high basal levels of autophagy that do not increase further upon rapamycin treatment. Sexual identity of enterocytes alone, determined by the expression of transformerFemale , dictates sexually dimorphic cell size, H3/H4- Bchs expression, basal rates of autophagy, fecundity, intestinal homeostasis and extension of lifespan in response to rapamycin. This study highlights that tissue sex determines regulation of metabolic processes by mTOR and the efficacy of mTOR-targeted, anti-ageing drug treatments. ### Competing Interest Statement The authors have declared no competing interest.