One of the more intriguing findings to emerge from study of the relationship between stress response mechanisms in cellular metabolism and the pace of degenerative aging is that evolution has not optimized for life span. Many aspects of metabolism can be adjusted in small ways - in mice, worms, flies, and so forth - in order to modestly slow aging. Yet these small changes are well within the bounds of what one would expect evolution to have already produced. Why didn't that happen? A long life and lasting health are just not high in the list of important pressures on evolutionary selection, it seems. Thus we have autophagy, an important collection of cellular maintenance mechanisms that run suboptimally in near every species. Make autophagy somewhat more efficient, up to a point, and health and life span improve.
The increasing number of people living with age-related diseases underscores the importance of ageing research to improve healthspan. Two well-studied evolutionary conserved interventions that extend lifespan and improve health are dietary restriction and down-regulation of nutrient sensing pathways, such as glucose sensing by insulin and amino acid sensing by the target-of-rapamycin signalling pathway. One common characteristic of these anti-ageing interventions is an increase in autophagy, a cellular pathway that degrades damaged proteins and organelles to supply essential building blocks and energy.
To help provide a more direct link between autophagy and healthy ageing, we fine-tuned overexpression of Atg1 kinase, which is critical for autophagy induction, and measured its effect on longevity in the fruit fly Drosophila. Interestingly, we observed that a moderate increase in autophagy is beneficial in extending healthy lifespan, whereas strong autophagy up-regulation is detrimental and leads to progressive lipid loss and decreased lifespan. Moderate and stronger Atg1 overexpression displayed opposing transcriptional profiles of mitochondrial genes, being upregulated in long-lived and down-regulated in short-lived Atg1 over-expressing animals. Overall, we provide a detailed description of the phenotypes associated with varying degrees of autophagy up-regulation in vivo, demonstrating that autophagy enhancement delays ageing only when applied in moderation.