Aging is a global concern that brings formidable socioeconomic and healthcare challenges. It is characterized as accumulation of deleterious changes in organelles, cells and tissues with expanding age that collectively responsible for the risk of several age associated diseases. In the last decade, various studies have shown evidences towards the utilization of plant derived molecules against aging and various neurological diseases. Here we report the identification of the polymethoxyflavone, 5-demethylnobiletin (DN) as a natural compound with anti-aging potential. We have utilized Caenorhabditis elegans as the model system to study anti-aging effects of DN in vivo (life span, lipofuscin accumulation, oxidative stress resistance, ROS levels lipid levels, pharyngeal pumping, reproductive span and total brood size) and pathway involved in underlying mechanism. DN is isolated from gum exudates of Gardenia lucida, which is known to possess rich anti-oxidant activity. We show that external administration of DN extends the lifespan and oxidative stress tolerance against artificial ROS inducer juglone, in a dose dependent manner. The studies revealed that lifespan extension is arbitrated through decreased levels of ROS (DCF-DA method), lipid levels (Nile red staining) and intestinal lipofuscin levels in both young adult and aged worms upon low dose administration of DN. Additionally, DN also reduces the pharyngeal pumping and enhances the reproductive span of worms. The interaction of DN with genes required for lifespan extension is deciphered by studying effect of DN on gene mutants and gene expression of these genes. DN activates dietary restriction (DR) pathway in nematodes mediated by
pha-4,
sir-2.1,
skn-1 and
eat-2 genes. We also show that DR induced lifespan requires the activation of autophagy genes viz.
bec-1,
unc-51 and
lgg-1. This induction of both processes is fully required for lifespan extension in the worm. Moreover, mutant analysis is further validated by gene reporter assay (DA2123, LGG-1::GFP; SM481, PHA-4::GFP and LD1, SKN-1::GFP) and qPCR studies of relevant genes. Altogether, DN can enhance the lifespan of C. elegans via DR pathway which also requires the induction of autophagy mechanism.