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Crawling C. elegans hermaphrodite worm (Credit: Bob Goldstein, Wikimedia Commons)Aging is not gradual in the C. elegans roundworm. It begins suddenly at reproductive maturity (or roundworm puberty), according to a provocative new study in Molecular Cell by a Northwestern University team.

At this time of worm adolescence, a single genetic switch, flipped in germline stem cells, turns off critical cell stress response mechanisms that keep key proteins folded and functional. Aging begins there, and progresses rapidly.

But importantly, when germline stem cells are removed, that aging doesn’t occur. And as this genetic switch is apparently conserved in all animals, a unique anti-aging drug target for humans may have been found.

“Perhaps the most important aspect…is the demonstration that the switch for aging is indeed just that: a switch that occurs very early,” lead author Richard Morimoto, M.D., director of Northwestern’s Rice Institute for Biomedical Research, told Drug Discovery & Development. “This could mean that if something similar occurs in humans, we could flip the switch back on to restore robustness.”

Harvard Stem Cell Institute geneticist Keith Blackwell, M.D., Ph.D., told Drug Discovery & Development: “What is surprising to me is that, with respect to the response to heat in this simple organism, this loss of responsiveness can be traced to failure to clear a single repressive chromatin modification, and that the response can be restored by fixing this.” Blackwell was uninvolved in the new study. “At some level, this paradigm is likely to be applicable to humans, whether through maintaining stem cell function, or tissue robustness.  The specifics are likely to be different and more complex, but this paper indicates such problems can be solved, and gives an idea of where to look.”

Anat Ben-Zvi, Ph.D., a Ben Gurion University life scientist, was also uninvolved in the new study. She told Drug Discovery & Development she agreed that, if key elements of the pathway downstream of the “switch” are found conserved from worm to human “we might be able to, in the long run, activate cells’ ability to combat protein misfolding diseases with a systemic drug.”

The new paper

In C. elegans, aging begins eight hours into reproductive maturity. It has been known that, at around that point, cells begin losing precious stress protection mechanisms. Morimoto’s lab discovered that germline stem cells—which produce eggs and sperm—control the initial genetic switch responsible for this loss.

They discovered this while examining worms’ heat shock response, which is necessary to maintain the proper protein folding that drives cells. Morimoto’s team saw the unmistakable collapse of the normal heat shock response shortly after the start of worm adolescence; shortly after egg laying. The heat shock response devolved dramatically, the team found, after measuring protein quality control and other signs of cellular stress.

Knowing that egg laying itself could not trigger the sudden decline, as mutants sans eggs or sperm are unchanged, they removed the stem cells. The worms’ adult somatic cells remained robust, stress-resistant.

Blackwell told Drug Discovery & Development the idea that stress responses “collapse’ with age has been developed in recent years by the Morimoto lab and others, but it has not been clear how and why this occurs. By collapse, I mean that the ability of the organism to adapt to challenges declines and is largely lost.  I would have expected that the answer would be along the lines of regulatory entropy; that this ability is simply lost because its maintenance could be complicated/difficult, and not selected for during evolution, in addition to the possibility that devoting resources in this direction might be deleterious to reproduction.”

Given that, Blackwell said, he was surprised by the study’s finding that the loss of stress protection responsiveness in C. elegans is a result of failure to clear a single repressive chromatin modification, which interferes with a heat shock factor (HSF-1) binding event, which in turn suppresses transcription initiation in response to stress.

He was also surprised the response could be restored by simply removing germ-line stem cells.

“In people as well,” Blackwell said, “the levels of stress defense genes change with age.  While humans are infinitely more complicated than C. elegans, the new research holds forth a model whereby a specific regulatory mechanism can restore `youthful’ stress defenses.”

The mechanism

Morimoto told Drug Discovery & Development his paper demonstrates that “cell stress responses essential for stress survival and organismal robustness are rapidly repressed in early adulthood of C. elegans as part of a genetically programmed event controlled by germline stem cells at the onset of reproductive maturity. The molecular mechanism is particularly intriguing, as it involves a signal from germline stem cells that decreases expression of a specific demethylase enzyme, resulting in elevated levels of a repressive class of histones targeted to the genes for cell stress responses.  The consequence: a rapid, coordinated inhibition of stress survival mechanisms.”

Richard Morimoto, M.D., Ph.D., University of ChicagoIn showing this, Morimoto said, his group “discovered that enhancing this demethylase (jmjd3.1), which is conserved to humans, prevents this decline in stress resilience, and results in animals both robust and long-lived.”

His group is analyzing whether this pathway is the same in males and females. As to human relevance: “Our work was directed to the question of `when does aging begin?’  The demonstration that the decline can be placed at eight hours into adulthood, at the moment of reproductive maturity, could have similar relevance and implications for humans.  The timing of decline may not be as abrupt. Other free-living animals are sufficiently mature upon birth that they can survive.  Humans and other primates require a period of time when they must be fed and nurtured until they can survive independently.”   

So human systems may be “optimized at the onset of reproductive maturity, and if our observations with C. elegans extend to other animals--that there is a signal from the germline stem cells to shut down our cell stress responses--the decline may simply not be as rapid, and could occur over years, not hours.”

Morimoto noted the work is relevant to that of famed molecular biologist Cynthia Kenyon, who repeatedly extended worm lifespan. “Of course this is linked to the foundational discoveries of Kenyon.  We showed in 2004 the stress response transcription factor HSF-1 is essential for insulin-signaling regulated longevity by down regulation of the gene DAF-2, which was discovered by Kenyon.” Moriomoto’s new paper “is mostly about the down-regulation of HSF-1 in early adulthood, suggesting DAF-2 could be delaying the genetic switch we found.” 

The history

Ben-Zvi said that, with her, Morimoto’s group previously showed that proteostasis—the proper formation and balance of protein levels—collapses early in worm adulthood. More recent work by Ben-Zvi’s group “demonstrated that changes in the heat shock response activation occur as early as 12 hours after animals reach adulthood, and are reversed by signals from the reproductive system.”

In the new paper, Morimoto’s team “extend this observation to other stress responses, suggesting there is a global change in animals’ response to stress at reproduction onset.” The team “then focus on the heat shock response, and examine the regulation of the heat shock response factor early in adulthood. They demonstrate that HSF1-promoter accessibility sharply declines on the second day of adulthood. This is strongly associated with sharply increased levels of H3K27me3 marks at the promoters of heat shock genes, a hallmark of transcriptional repression [that results in dysfunctional protein production]. This demonstrates, for the first time, that the repression of the heat shock response is regulated, and that epigenetic changes modulate the animals’ ability to respond to stress after reproduction onset.” 

Ben-Zvi said Morimoto’s crew has shown the change in H3K27me3 is “associated with reduced expression of the demethylase, jmjd-3.1. The reduced stress response activation (heat shock and other stress responses) is associated with jmjd-3.1 levels, and its levels are regulated at the onset of the collapse.”

Ben-Zvi added that “germline arrest, previously shown to extend lifespan and rescue heat shock response collapse, reduces the accumulation of  H3K27me3 marks, and restores promoter accessibility in accord with changes in jnjd-3.1 levels.” All this demonstrates, “for the first time, that signals from the reproductive system modulate the chromatin of somatic cells, and modulate cells’ ability to respond to stress.” 

The new paper is “an elegant mechanistic demonstration of how cell non-autonomous signals from one tissue can alter the response of another.”   

From C. elegans to the clinic?

Ben-Zvi believes it all both does and doesn’t have human ramifications. “Yes, because many protein miscoding diseases are associated with aging,” she told Drug Discovery & Development. “We previously showed that signals from the reproductive system can modulate aggregation in a polyQ model of Huntington’s disease. A regulated signal suggests that the organism is capable of an effective damage removal, but shut it down in adulthood.” 

But, she said, “there is currently no clear demonstration the reproductive system sends such signals in human,” if there is support for such a notion. “The germline effect on aging is conserved in flies.”

Ben-Zvi concluded there are “many open questions. Is the signal and receptor conserved? Can we find such epigenetic changes in human? There are indications for chromatin remodeling, but there is need to examine the timing. The most important question is: once modified, can the chromatin repressive state be reversed?” 

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