Certain manipulations of organisms will reliably extend their lifespans, manipulations such as calorie restriction or the genetic reduction of insulin and IGF-1 (insulin-like growth factor) signalling. But what is the physiological mechanism behind the extension of longevity? In the following study, the researchers wanted to know whether the upregulation of cytoprotective pathways, which occurs in calorie restriction and impaired insulin/IGF-1 signaling, merely accompanied the extension of longevity or was necessary to it. They devised an ingenious way to test this.
Induction of Cytoprotective Pathways Is Central to the Extension of Lifespan Conferred by Multiple Longevity Pathways
Many mutations that increase animal lifespan also confer stress tolerance, suggesting that cytoprotective mechanisms underpin the regulation of longevity. It has not been established, however, whether the induction of individual cytoprotective pathways is essential for lifespan extension, or merely correlated. To establish whether the regulatory pathways for the induction of cytoprotective responses are key in the extension of lifespan, we performed an RNAi screen for gene inactivations that decouple the activation of cytoprotective pathways from xenobiotic stimuli that normally induce them. The screen identified 29 genes that constitute the regulatory cascades of the unfolded protein response, oxidative stress response, and detoxification. These upstream regulatory genes are critical to stress tolerance and the extension of lifespan conferred by decreased insulin/IGF-1 signaling, disruption of mitochondrial function, or caloric restriction, but have little effect on normal longevity.
So the answer is that when these cell defense responses were disrupted, the extension of longevity normally seen in calorie restriction and the rest did no occur, meaning that these responses are essential to increased lifespan.
From the discussion section:
Stress tolerance and lifespan extension are remarkably correlated. The contradictory extension of lifespan by ostensibly deleterious conditions, and the concomitant induction of stress tolerance, suggests that lifespan extension may occur through the hormetic induction of damage-buffering cytoprotective mechanisms. […]
Lifespan poses an evolutionary conundrum, as the genetic determination of lifespan ostensibly suggests post-reproductive selection. Our data suggests that lifespan-determining genes do not specify lifespan per se, but rather the activity of damage-buffering cytoprotective pathways normally engaged only in response to stress stimuli, such as toxins.
Once again, it’s hormesis for the win. These stress responses are activated in the face of potentially damaging stimuli, such as exercise, toxins, fasting, and solar radiation. If one wants the chance to live a longer life, activation of these responses on a regular basis is the way to go.