In this work, we examine the relationship between stress resistance and aging. We find that resistance to multiple types of stress peaks during early adulthood and then declines with age. To dissect the underlying mechanisms, we use C. elegans transcriptional reporter strains that measure the activation of different stress responses including: the heat shock response, mitochondrial unfolded protein response, endoplasmic reticulum unfolded protein response, hypoxia response, SKN-1-mediated oxidative stress response, and the DAF-16-mediated stress response. We find that the decline in stress resistance with age is at least partially due to a decreased ability to activate protective mechanisms in response to stress. In contrast, we find that any baseline increase in stress caused by the advancing age is too mild to detectably upregulate any of the stress response pathways. Further exploration of how worms respond to stress with increasing age revealed that the ability to mount a hormetic response to heat stress is also lost with increasing age. Overall, this work demonstrates that resistance to all types of stress declines with age. Based on our data, we speculate that the decrease in stress resistance with advancing age results from a genetically-programmed inactivation of stress response pathways, not accumulation of damage.
On the basis of multiple experiments demonstrating that high resistance to stress is associated with long lifespan, it has been proposed that stress resistance is a key determinant of longevity. However, the extent to which high resistance to stress is necessary or sufficient for long life is currently unclear. In this work, we use a genetic approach to disrupt different stress response pathways and examine the resulting effect on the longevity of the long-lived insulin-like growth factor 1 (IGF1) receptor mutant daf-2. Although mutation of the heat shock factor gene hsf-1, deletion of sod genes, deletion of the p38 MAPK kinase gene pmk-1, or deletion of the transcription factor gene egl-27 all resulted in decreased resistance to at least one form of stress and decreased lifespan, the magnitude of change in stress resistance did not correspond to the magnitude of change in lifespan. In addition, we found that deletion of the glycerol-3-phosphate dehydrogenase genes gpdh-1 and gpdh-2 or deletion of the DAF-16 cofactor gene nhl-1 also results in decreased resistance to at least one form of stress but increases lifespan. Overall, our results suggest that while increased stress resistance is associated with longevity, stress resistance, and lifespan can be experimentally dissociated.
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