Greaves, L. | bioRxiv Science

bioRxiv2026

The Transcription Factor Sob Maintains Intestinal Stem Cell Homeostasis to Delay Ageing

Ageing is associated with physiological decline and disrupted tissue homeostasis, often driven by imbalanced stem cell activity. The Drosophila midgut serves as a powerful model for studying epithelial homeostasis and ageing as it exhibits many conserved hallmarks of regulation and deteriorating intestinal stem cell function with age. We have identified the transcription factor encoded by Sister of odd and bowl (Sob) as a conserved marker of intestinal stem/progenitor cells in homeostasis whose expression is lost with age. Premature downregulation of sob shortens lifespan while overexpression in the intestinal stem/progenitor cells is sufficient to extend lifespan, suggesting a critical role in maintaining homeostasis with age. At the cell and tissue level stem/progenitor knockdown and overexpression reveal that Sob maintains homeostasis by regulating both proliferation and lineage specification. In young guts, Sob restricts intestinal stem cell proliferation and promotes enteroendocrine differentiation while limiting excessive enterocyte differentiation. We have also found that the transcription factor Exex, the Notch pathway inhibitor Numb, and the enterocyte differentiation regulator Dawdle act downstream of Sob to regulate proliferation and differentiation. Our findings position Sob as a critical molecular switch linking stem cell dysfunction to gut ageing.

developmental biology↗

bioRxiv2018

Length-independent telomere damage drives cardiomyocyte senescence

Ageing is the biggest risk factor for cardiovascular health and is associated with increased incidence of cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age-related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post-mitotic cardiomyocytes and investigate if clearance of senescent cells attenuates age related cardiac dysfunction. During ageing, human and murine cardiomyocytes acquire a senescent-like phenotype characterised by persistent DNA damage at telomere regions that can be driven by mitochondrial dysfunction, and crucially can occur independently of cell-division and telomere length. Length-independent telomere damage in cardiomyocytes activates the classical senescence-inducing pathways, p21CIP and p16INK4a and results in a non-canonical senescence-associated secretory phenotype. Pharmacological or genetic clearance of senescent cells in mice alleviates myocardial hypertrophy and fibrosis, detrimental features of cardiac ageing, and promotes cardiomyocyte regeneration. Our data describes a mechanism by which senescence can occur and contribute to ageing in post-mitotic tissues.

cell biology↗