Raw NGS data of Caenorhabditis Elegans (ChIP and RNA)

It has been assumed for a long time that lifespan and healthspan strongly correlate,but the two can be clearly dissociated1-6. Although life expectancy increases globally,increasing longevity is scarcely accompanied by an extended healthspan4, 7. Thus,understanding the origin of healthy behaviours in old people emerges as an importantand challenging task. Here we report a conserved epigenetic mechanism underlyinghealthy ageing. By genome-wide RNAi screening of genes regulating behaviouraldeterioration in ageing C. elegans, we identified 59 genes as potential ageing ratemodulators. Two screening hits, a neuronal epigenetic reader BAZ-2 and a neuronalhistone 3 lysine 9 methyltransferase SET-6, accelerated age-related behaviouraldeterioration in C. elegans. These modulators reduced mitochondrial functions byrepressing the expression of nuclear-encoded mitochondrial proteins, a mechanismconserved in mouse cultured neurons and human cells; deletion of these epigeneticmodulators prevented age-related deterioration in the worm's food-induced behaviour,food intake, and male virility by improving mitochondrial functions. Interestingly,ablation of Baz2b, the mouse ortholog of BAZ-2, attenuated age-dependent bodyweight gain and prevented cognitive decline in ageing mice. Furthermore, humandatabases show that the expression level of BAZ2B and EHMT1, the human orthologof SET-6, in the frontal cortex increases with age and positively correlates withAlzheimer's disease progression. Thus, our genome-wide RNAi screen in C. eleganshas unraveled conserved negative epigenetic regulators of ageing, providing insightsinto new approaches for achieving healthy ageing.