Autophagy plays important but complex roles in aging, affecting health and longevity. We found that, in the general population, the levels ofATG4BandATG4Ddecreased during aging, yet they are upregulated in centenarians, suggesting that overexpression of ATG4 members could be positive for healthspan and lifespan. We therefore analyzed the effect of overexpressingAtg4b(a homolog of humanATG4D) inDrosophila, and found that, indeed,Atg4boverexpression increased resistance to oxidative stress, desiccation stress and fitness as measured by climbing ability. The overexpression induced since mid-life increased lifespan. Transcriptome analysis ofDrosophilasubjected to desiccation stress revealed thatAtg4boverexpression increased stress response pathways. In addition, overexpression ofATG4Bdelayed cellular senescence, and improved cell proliferation. These results suggest thatATG4Bhave contributed to a slowdown in cellular senescence, and inDrosophila,Atg4boverexpression may have led to improved healthspan and lifespan by promoting a stronger stress response. Overall, our study suggests thatATG4DandATG4Bhave the potential to become targets for health and lifespan interventions.