ATG4B Overexpression Increases Life Span in Flies
Researchers here show that increased expression of the autophagy regulator gene ATG4B improves health and extends life in flies, most likely via improved autophagy - though other mechanisms are involved, as is usually the case. Expression of the human version of ATG4B declines with age, and in humans long-lived individuals tend towards higher levels of expression. Autophagy is a maintenance process that clears out damaged proteins and structures.
A great deal of evidence points to the value of autophagy to long-term health, and to cellular stress responses in general, though the effect on life span in long-lived species seems to be much less impressive than is the case in short-lived species. In principle, more efficient clearance of damage leads to better cell and tissue function, but it is possible that cell maintance in long-lived species has already evolved to be much more efficient than is the case in short-lived species, leaving less room for benefits to be achieved via this sort of intervention.
Autophagy plays important but complex roles in aging, affecting health and longevity. We found that, in the general population, the levels of ATG4B and ATG4D decreased 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 overexpressing Atg4b (a homolog of human ATG4D) in Drosophila, and found that, indeed, Atg4b overexpression increased resistance to oxidative stress, desiccation stress and fitness as measured by climbing ability. The overexpression induced since mid-life increased lifespan.
Transcriptome analysis of Drosophila subjected to desiccation stress revealed that Atg4b overexpression increased stress response pathways. In addition, overexpression of ATG4B delayed cellular senescence, and improved cell proliferation. These results suggest that ATG4B have contributed to a slowdown in cellular senescence, and in Drosophila, Atg4b overexpression may have led to improved healthspan and lifespan by promoting a stronger stress response. Overall, our study suggests that ATG4D and ATG4B have the potential to become targets for health and lifespan interventions.