A TORC1/histone axis regulates chromatin organization and non-canonical induction of autophagy to ameliorate ageing

Modulation of histone levels is commonly seen during ageing in many species. However, any role for histone levels in longevity of multicellular organisms remains undiscovered. Here we show that inhibition of mTORC1 by rapamycin post-transcriptionally increases expression of histone proteins H3 and H4 in Drosophila intestine. Expression of H3/H4 in enterocytes alters chromatin organization, induces intestinal autophagy through transcriptional regulation, and prevents age-related structural and functional decline in the intestine. Increased H3/H4 expression in enterocytes is essential for rapamycin-dependent longevity and intestinal health. Histones H3/H4 regulate expression of a selective autophagy cargo adaptor Bchs (ALFY in mammals), increased expression of which in enterocytes is necessary and sufficient for increased H3/H4-dependent healthy longevity. In mice, rapamycin treatment increases expression of histone proteins and ALFY transcript, and alters chromatin organisation in small intestine, suggesting the mTORC1-histone axis is at least partially conserved in mammals and may offer new targets for anti-ageing interventions. RNA-seq in rapamycin-treated and control guts in wild type D. melanogaster at the age of 10 days, 30 days and 50 days. Three biological replicates and 25 guts per replicate.