Deficient autophagy in epithelial stem cells drives aging in the freshwater cnidarian <i>Hydra</i>

Abstract

<i>Hydra</i> possesses three distinct stem cell populations that continuously self-renew and prevent aging in <i>Hydra vulgaris</i> However, sexual animals from the <i>H. oligactis</i> cold-sensitive strain <i>Ho_CS</i> develop an aging phenotype upon gametogenesis induction, initiated by the loss of interstitial stem cells. Animals stop regenerating, lose their active behaviors and die within 3 months. This phenotype is not observed in the cold-resistant strain <i>Ho_CR</i> To dissect the mechanisms of <i>Hydra</i> aging, we compared the self-renewal of epithelial stem cells in these two strains and found it to be irreversibly reduced in aging <i>Ho_CS</i> but sustained in non-aging <i>Ho_CR</i> We also identified a deficient autophagy in <i>Ho_CS</i> epithelial cells, with a constitutive deficiency in autophagosome formation as detected with the mCherry-eGFP-LC3A/B autophagy sensor, an inefficient response to starvation as evidenced by the accumulation of the autophagosome cargo protein p62/SQSTM1, and a poorly inducible autophagy flux upon proteasome inhibition. In the non-aging <i>H. vulgaris</i> animals, the blockade of autophagy by knocking down <i>WIPI2</i> suffices to induce aging. This study highlights the essential role of a dynamic autophagy flux to maintain epithelial stem cell renewal and prevent aging.