RRC ID 70850
Author Lu YX, Regan JC, Eßer J, Drews LF, Weinseis T, Stinn J, Hahn O, Miller RA, Grönke S, Partridge L.
Title A TORC1-histone axis regulates chromatin organisation and non-canonical induction of autophagy to ameliorate ageing.
Journal Elife
Abstract Age-related changes to histone levels are seen in many species. However, it is unclear whether changes to histone expression could be exploited to ameliorate the effects of ageing in multicellular organisms. Here we show that inhibition of mTORC1 by the lifespan-extending drug rapamycin increases expression of histones H3 and H4 post-transcriptionally through eIF3-mediated translation. Elevated expression of H3/H4 in intestinal enterocytes in Drosophila alters chromatin organisation, induces intestinal autophagy through transcriptional regulation, and prevents age-related decline in the intestine. Importantly, it also mediates rapamycin-induced longevity and intestinal health. Histones H3/H4 regulate expression of an autophagy cargo adaptor Bchs (WDFY3 in mammals), increased expression of which in enterocytes mediates increased H3/H4-dependent healthy longevity. In mice, rapamycin treatment increases expression of histone proteins and Wdfy3 transcription, and alters chromatin organisation in the small intestine, suggesting that the mTORC1-histone axis is at least partially conserved in mammals and may offer new targets for anti-ageing interventions.
Volume 10
Published 2021-5-14
DOI 10.7554/eLife.62233
PII 62233
PMID 33988501
PMC PMC8186904
MeSH Aging / drug effects* Aging / metabolism Animals Autophagy* Chromatin / metabolism Drosophila melanogaster Eukaryotic Initiation Factor-3 / metabolism Female Gene Expression Regulation Histones / genetics Histones / metabolism* Intestines Mechanistic Target of Rapamycin Complex 1 / genetics Mechanistic Target of Rapamycin Complex 1 / metabolism* Mice Sirolimus / pharmacology
IF 7.08
Drosophila DGRC#104863