Combined loss of ATG4B, ATG4C and ATG4D impairs systemic autophagy and triggers accelerated aging in mice

Autophagy is an essential catabolic pathway that safeguards cellular and tissue homeostasis, yet the systemic consequences of its impairment in mammals remain poorly defined because complete autophagy ablation is embryonic or perinatal lethal. Here, we generate ATG4A-only mice, a model in which ATG4A is the sole remaining ATG4 protease due to combined ATG4B/C/D deletion. Through comprehensive biochemical and cellular analyses, we delineate the in vivo substrate specificity of ATG4A and demonstrate that it sustains only minimal ATG8 priming, uncovering a previously unrecognized functional asymmetry within the mammalian ATG4-ATG8 system. ATG4A-only mice exhibit a profound but incomplete whole-body autophagy deficiency that disrupts multiple organ systems and triggers a premature aging syndrome marked by increased DNA damage, systemic senescence, metabolic dysfunction, and dramatically shortened lifespan. Integrating these findings with comparisons to additional ATG4-deficient models, we show that organismal longevity scales with residual autophagic competence. Together, our work reveals how graded reductions in autophagy integrity influence tissue fitness and aging, establishing autophagic capacity as a key determinant of mammalian lifespan.