Scientists have pinpointed the start of aging and discovered it is not a slow series of random events. Two Northwestern University scientists have identified a molecular switch in the transparent roundworm C. elegans, that abruptly begins cell aging just as the animal reaches reproductive maturity.

A genetic switch starts the aging process by turning off the cell's ability to respond to stress. Responding to stress would otherwise protect a cell by keeping essential proteins folded as well as functioning. The switch is thrown by germline [sperm and egg] stem cells in early adulthood, after reproduction begins.

While the studies were conducted in worms, the genetic switch and other components identified by scientists as part of aging, are conserved in all animals — including humans. And as C. elegans has a biochemical environment similar to our own, it is a popular animal model for human disease and for human aging.

Knowing more about how the quality control system works in cells could help researchers unravel how cells are capable of providing their own "quality of life" and may help us delay those diseases related to aging.

"Wouldn't it be better for society if people could be healthy and productive for a longer period of 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." 

Richard Morimoto PhD, the Bill and Gayle Cook Professor of Molecular Biosciences, director of the Rice Institute for Biomedical Research, Weinberg College of Arts and Sciences, Northwestern University.

The study, built on a decade of research, is published in the journal Molecular Cell. Johnathan Labbadia PhD, is a postdoctoral fellow in Morimoto's lab and first author of the paper.

Almost all individuals of C. elegans are female hermaphrodites, with a small minority, around one in a thousand, being true males. They have an average lifespan of around 2–3 weeks, and begin to decline eight hours into their adulthood. Richard Morimoto and Johnathan Labbadia's work has identified that the animal's germline stem cells control when cell switches get thrown to shut down all of an animal's protective mechanisms against cell stress.

In all animals, including humans, the heat shock response is essential for keeping proteins correctly folded thus protecting cell health. Aging is a decline in that quality control, which is why Morimoto and Labbadia specifically targeted heat shock response for study.

Morimoto and Labbadia identified a genetic switch between two major tissues which determines the future of a species: 1) the germline or sex cells and 2) the soma or body tissues such as muscle cells and neurons.

Once the germline has completed its job and 1) produced eggs and sperm needed to create the next generation, it 2) sends a signal to cell tissues to turn off protective mechanisms and begin the decline of the adult.

"C. elegans has shown us that aging is not a continuum of various events, which a lot of people thought," Morimoto explains. "In a system where we can actually do the experiments, we discovered a switch that is very precise for aging," he added. "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 genetic and biochemical approaches, Morimoto and Labbadia found the protective heat shock response declines steeply over a four-hour period in early worm adulthood, precisely at the onset of their reproductive maturity. The animals appear normal in behavior, but scientists can see molecular changes indicating the decline of protein quality control.

In one experiment, researchers blocked the germline from sending the signal to turn off cellular quality control, and found the somatic tissues remained robust and stress resistant.

Morimoto: "This was fascinating to see. We had, in a sense, a super stress-resistant animal that is robust against all kinds of cell stress and protein damage. This genetic switch gives us a target for future research."

Abstract Highlights
•Stress responses are rapidly repressed at the onset of egg laying in C. elegans
•Transcriptional repression at stress response genes is due to increased H3K27me3
•Reduced jmjd-3.1 expression underlies increased H3K27me3 at stress response genes
•Repression of stress responses is regulated by germline stem cells

Summary
The heat shock response (HSR) is essential for proteostasis and cellular health. In metazoans, aging is associated with a decline in quality control, thus increasing the risk for protein conformational disease. Here, we show that in C. elegans, the HSR declines precipitously over a 4 hr period in early adulthood coincident with the onset of reproductive maturity. Repression of the HSR occurs 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 results in a repressed chromatin state that interferes with HSF-1 binding and suppresses transcription initiation in response to stress. The removal of germline stem cells preserves jmjd-3.1 expression, suppresses the accumulation of H3K27me3 at stress gene loci, and maintains the HSR. These findings suggest that competing requirements of the germline and soma dictate organismal stress resistance as animals begin reproduction.

The title of the paper is "Repression of the Heat Shock Response Is a Programmed Event at the Onset of Reproduction."

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