Researchers here present a fairly compelling case that the characteristic decline in the protective heat shock response with age is an evolved program. Compelling but not airtight: one could still argue that the rapid transition from effective to less effective observed in nematode worms is, along with other changes that occur at the same time, a response to rising levels of cellular damage rather than something that will occur regardless of circumstances. It is not too hard to envisage further studies that might add evidence to either side of the argument, and I will be very interested to see the outcome of similar investigations in mammals, but for now the primary point of interest is to see if the signaling that causes this decline can be usefully interfered with. The expectation is that increased levels of heat shock activity should result in more active maintenance and damage repair in cellular machinery, leading to slower aging and longer healthspan, and thus there is some interest in the research community in finding potential approaches to achieve this end.
Knowing more about how the quality control system works in cells could help researchers one day figure out how to provide humans with a better cellular quality of life and therefore delay degenerative diseases related to aging, such as neurodegenerative diseases. "Wouldn't it be better for society if people could be healthy and productive for a longer period during their lifetime? I am very interested in keeping the quality control systems optimal as long as we can, and now we have a target. Our findings suggest there should be a way to turn this genetic switch back on and protect our aging cells by increasing their ability to resist stress."
A genetic switch starts the aging process by turning off cell stress responses that protect the cell by keeping important proteins folded and functional. In C. elegans, the decline begins eight hours into adulthood - all the switches get thrown to shut off an animal's cell stress protective mechanisms. Researchers found it is the germline stem cells responsible for making eggs and sperm that control the switch. In animals, including C. elegans and humans, the heat shock response is essential for proper protein folding and cellular health. Aging is associated with a decline in quality control, so researchers looked specifically at the heat shock response in the life of C. elegans. "We saw a dramatic collapse of the protective heat shock response beginning in early adulthood." Once the germline has completed its job and produced eggs and sperm - necessary for the next generation of animals - it sends a signal to cell tissues to turn off protective mechanisms, starting the decline of the adult animal. "All these stress pathways that insure robustness of tissue function are essential for life, so it was unexpected that a genetic switch is literally thrown eight hours into adulthood, leading to the simultaneous repression of the heat shock response and other cell stress responses."
Using a combination of genetic and biochemical approaches, researchers found the protective heat shock response declines steeply over a four-hour period in early adulthood, precisely at the onset of reproductive maturity. Repression of the heat shock response occurred due to an increase in H3K27me3 marks at stress gene loci, the timing of which is determined by reduced expression of the H3K27 demethylase jmjd-3.1. This resulted in a repressed chromatin state that interfered with HSF-1 binding and suppresses transcription initiation in response to stress. The animals still appeared normal in behavior, but the scientists could see molecular changes and the decline of protein quality control. In one experiment, the researchers blocked the germline from sending the signal to turn off cellular quality control. They found the somatic tissues remained robust and stress resistant in the adult animals.