Women live on average longer than men but have greater levels of late-life morbidity. We have uncovered a substantial sex difference in the pathology of the aging gut in Drosophila. The intestinal epithelium of the aging female undergoes major deterioration, driven by intestinal stem cell (ISC) division, while lower ISC activity in males associates with delay or absence of pathology, and better barrier function, even at old ages. Males succumb to intestinal challenges to which females are resistant, associated with fewer proliferating ISCs, suggesting a trade-off between highly active repair mechanisms and late-life pathology in females. Dietary restriction reduces gut pathology in aging females, and extends female lifespan more than male. By genetic sex reversal of a specific gut region, we induced female-like aging pathologies in males, associated with decreased lifespan, but also with a greater increase in longevity in response to dietary restriction.DOI: http://dx.doi.org/10.7554/eLife.10956.001

Highlights d Primary senescence and secondary senescence are distinct molecular endpoints d Secondary Ras-induced senescence has a composite SASP, Notch-induced signature d Notch signaling is an essential driver of secondary senescence d Notch blunts the senescence-associated secretory phenotype in secondary senescence

Graphical Abstract Highlights d A 3D polymer model for heterochromatin and lamina interactions is presented d The model captures chromatin organization in growing, senescent, and progeroid cells d The model explains the change in the chromatin contact network between cell states d The model predicts the stochasticity of lamina contacts and stability of senescence SUMMARY Lamina-associated domains (LADs) cover a large part of the human genome and are thought to play a major role in shaping the nuclear architectural landscape.Here, we perform polymer simulations, microscopy, and mass spectrometry to dissect the roles played by heterochromatin-and lamina-mediated interactions in nuclear organization. Our model explains the conventional organization of heterochromatin and euchromatin in growing cells and the pathological organization found in oncogene-induced senescence and progeria. We show that the experimentally observed changes in the locality of contacts in senescent and progeroid cells can be explained as arising due to phase transitions in the system. Within our simulations, LADs are highly stochastic, as in experiments. Our model suggests that, once established, the senescent phenotype should be metastable even if lamina-mediated interactions were reinstated. Overall, our simulations uncover a generic physical mechanism that can regulate heterochromatin segregation and LAD formation in a wide range of mammalian nuclei.