SIN3, a transcriptional corepressor has been implicated in varied functions both as transcription activator and repressor. Recent studies associated Sin3 with the macroautophagic/autophagic process as a negative regulator of Atg8 and Atg32. Though the role of SIN3 in autophagy is being explored, little is known about the overall effect of SIN3 deletion on the survival of an organism. In this study using a Caenorhabditis elegans sin-3(tm1279);him-5(e1490) strain, we demonstrate that under in vivo conditions SIN-3 differentially modulates autophagy and lifespan. We provide evidence that the enhanced autophagy and decreased lifespan observed in sin-3 deletion mutants is dependent on ROS and intracellular oxidative stress. Inability of the mutant worms to maintain redox balance along with dysregulation of enzymatic antioxidants, depletion of GSH and NADP reserves and elevation of ROS markers compromises the longevity of the worms. It is possible that the enhanced autophagic process observed in sin-3(tm1279);him-5(e1490) worms is required to compensate for oxidative stress generated in these worms. Abbreviations: cat: catalase; DCFDA: 2ʹ,7ʹ-dichlorodihydrofluoroscein diacetate; GSH: reduced glutathione; GSSG: oxidized glutathione; H₂O₂: hydrogen peroxide; HDAC: Histone deacetylase; HID: HDAC interacting domain; him-5: high incidence of males; HLH-30: Helix Loop Helix-30; HNE: 4-hydroxyl-2-noneal; LIPL: LIPase Like; MDA: malondialdehyde; NGM: nematode growth medium; PAH: paired amphipathic α-helix; PE: phosphatidylethanolamine; RFU: relative fluorescence unit; ROS: reactive oxygen species; sin-3/SIN3: yeast Switch Independent; SOD: superoxide dismutase; NADP: nicotinamide adenine dinucleotide phosphate; SQST-1: SeQueSTosome related-1; ATG: AuTophaGy related

Aging/senescence includes not just decline in lifespan but also etiologies of age associated morbidities which are inadequately understood. Extensive research has been undertaken to delineate the pathways and generate mutants with extended lifespan. However, little is known about the health status of these long lived mutants in the background of important genetic perturbations. Caenorhabditis elegans is one of the leading in vivo model organisms to study aging. Deletion of SIN-3, a transcription coregulator in C. elegans has been shown to reduce the lifespan of the mutant worms by half as compared to the wild-type and isogenic controls. The current study focuses on the effect of SIN-3 deletion on the healthspan of the worms. We find that not only are sin-3 mutants more susceptible to stress, but the overall stress intolerance and physiological decline is sex dependent. The severity of the phenotype is more pronounced in hermaphrodites as compared to the males carrying the same mutation with respect to the controls. The results further suggest that genetic perturbation along with the gender play an important role in determining the lifespan, healthspan and overall fitness of an organism.