Reduced systemic autophagy by simultaneous loss of ATG4B, ATG4C and ATG4D leads to accelerated aging in mice

Abstract

Autophagy is a housekeeping catabolic process crucial for maintaining cell, tissue and organism functions. Through the years, the study of animal models with tissue-specific inactivation of autophagy essential genes has allowed us to understand its protective roles in the context of multiple human diseases, including cancer and neurodegeneration. However, due to the essential nature of autophagy, the effects of its systemic inhibition in mammals have not been explored in detail. Here, we report the generation of ATG4A-only mice, simultaneously deficient for three of the four mammalian ATG4 proteases (ATG4B, ATG4C and ATG4D). Through extensive characterization of ATG4A-only cells, which show a severe (albeit not complete) deficiency in autophagic activity, we define the specific roles of ATG4A protease towards ATG8 proteins (its physiological substrates), shedding some light into the evolutionarily-acquired complexity of mammalian ATG4-ATG8 system. Moreover, we show that the profound whole-body autophagy deficiency of ATG4A-only mice not only impacts the function of multiple tissues, but also leads to the development of an accelerated aging phenotype, characterized by the accumulation of genetic damage, systemic senescence, and premature death. Thus, through the analysis of ATG4A-only mice and other murine models deficient for ATG4 proteases, we do not only provide new insights on how autophagy maintains cell, tissue, and organismal homeostasis, but also show for the first time that the degree of autophagic competency ultimately emerges as a critical determinant of organismal longevity.