ABSTRACT
Aging is one of the most critical risk factors for the development of metabolic syndromes1. Prominent metabolic diseases, namely type 2 diabetes and insulin resistance, have a strong association with endoplasmic reticulum (ER) stress2. Upon ER stress, the unfolded protein response (UPR) is activated to limit cellular damage by adapting to stress conditions and restoring ER homeostasis3,4. However, adaptive genes upregulated from the UPR tend to decrease with age5. Although stress resistance correlates with increased longevity in a variety of model organisms, the links between the UPR, ER stress resistance, and longevity remain poorly understood. Here, we show that supplementing bacteria diet with 2% glucose (high glucose diet, HGD) in post-reproductive 7-day-old (7DO) C. elegans significantly extend their lifespan in contrast to shortening the lifespan of reproductive 3-day-old (3DO) animals. The insulin-IGF receptor DAF-2 and its immediate downstream target, phosphoinositide 3-kinase (PI3K) AGE-1, were found to be critical factors in extending the lifespan of 7DO worms on HGD. The downstream transcription factor forkhead box O (FOXO) DAF-16 did not extend the lifespan of 7DO worms on HGD in contrast of its previously reported role in modulating lifespan of 3DO worms6. Furthermore, we identified that UPR activation through the highly conserved ATF-6 and PEK-1 sensors significantly extended the longevity of 7DO worms on HGD but not through the IRE-1 sensor. Our results demonstrate that HGD extends lifespan of post-reproductive worms in a UPR-dependent manner but independently of FOXO. Based on these observations, we hypothesise that HGD activates the otherwise quiescent UPR in aged worms to overcome age-related stress and to restore ER homeostasis. In contrast, young adult animals subjected to HGD leads to unresolved ER stress, conversely leading to a deleterious stress response.
