{"id":5594,"date":"2015-08-13T10:18:27","date_gmt":"2015-08-13T10:18:27","guid":{"rendered":"http:\/\/revoscience.com\/en\/?p=5594"},"modified":"2015-08-13T10:18:27","modified_gmt":"2015-08-13T10:18:27","slug":"a-single-germline-stem-cell-switch-may-be-anti-aging-drug-target","status":"publish","type":"post","link":"https:\/\/www.revoscience.com\/en\/a-single-germline-stem-cell-switch-may-be-anti-aging-drug-target\/","title":{"rendered":"A Single Germline Stem Cell \u201cSwitch\u201d May be Anti-Aging Drug Target"},"content":{"rendered":"
\"CrawlingCelegans\"<\/a>
Crawling C. elegans hermaphrodite worm (Credit: Bob Goldstein, Wikimedia Commons)<\/figcaption><\/figure>\n

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\u00a0Molecular Cell<\/em>\u00a0by a Northwestern University team.<\/span><\/p>\n

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.<\/span><\/p>\n

But importantly, when germline stem cells are removed, that aging doesn\u2019t occur. And as this genetic switch is apparently conserved in all animals, a unique anti-aging drug target for humans may have been found.<\/span><\/p>\n

\u201cPerhaps the most important aspect\u2026is the demonstration that the switch for aging is indeed just that: a switch that occurs very early,\u201d lead author Richard Morimoto, M.D., director of Northwestern\u2019s Rice Institute for Biomedical Research, told\u00a0Drug Discovery & Development<\/em>. \u201cThis could mean that if something similar occurs in humans, we could flip the switch back on to restore robustness.\u201d<\/span><\/p>\n

Harvard Stem Cell Institute geneticist Keith Blackwell, M.D., Ph.D., told\u00a0Drug Discovery & Development<\/em>: \u201cWhat 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.\u201d Blackwell was uninvolved in the new study. \u201cAt some level, this paradigm is likely to be applicable to humans, whether through maintaining stem cell function, or tissue robustness. \u00a0The 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.\u201d<\/span><\/p>\n

Anat Ben-Zvi, Ph.D., a Ben Gurion University life scientist, was also uninvolved in the new study. She told\u00a0Drug Discovery & Development<\/em>\u00a0she agreed that, if key elements of the pathway downstream of the \u201cswitch\u201d are found conserved from worm to human \u201cwe might be able to, in the long run, activate cells\u2019 ability to combat protein misfolding diseases with a systemic drug.\u201d<\/span><\/p>\n

The new paper<\/strong><\/span><\/p>\n

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\u2019s lab discovered that germline stem cells\u2014which produce eggs and sperm\u2014control the initial genetic switch responsible for this loss.<\/span><\/p>\n

They discovered this while examining worms\u2019 heat shock response, which is necessary to maintain the proper protein folding that drives cells. Morimoto\u2019s 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.<\/span><\/p>\n

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\u2019 adult somatic cells remained robust, stress-resistant.<\/span><\/p>\n

Blackwell told\u00a0Drug Discovery & Development<\/em>\u00a0the idea that stress responses \u201ccollapse\u2019 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. \u00a0I 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.\u201d<\/span><\/p>\n

Given that, Blackwell said, he was surprised by the study\u2019s 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.<\/span><\/p>\n

He was also surprised the response could be restored by simply removing germ-line stem cells.<\/span><\/p>\n

\u201cIn people as well,\u201d Blackwell said, \u201cthe levels of stress defense genes change with age. \u00a0While humans are infinitely more complicated than C. elegans, the new research holds forth a model whereby a specific regulatory mechanism can restore `youthful\u2019 stress defenses.\u201d<\/span><\/p>\n

The mechanism<\/strong><\/span><\/p>\n

\"Richard<\/a>
Richard Morimoto, M.D., Ph.D., University of Chicago<\/figcaption><\/figure>\n

Morimoto told\u00a0Drug Discovery & Development<\/em>\u00a0his paper demonstrates that \u201ccell 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.\u00a0 The consequence: a rapid, coordinated inhibition of stress survival mechanisms.\u201d<\/span><\/p>\n

In showing this, Morimoto said, his group \u201cdiscovered 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.\u201d<\/span><\/p>\n

His group is analyzing whether this pathway is the same in males and females. As to human relevance: \u201cOur work was directed to the question of `when does aging begin?\u2019\u00a0 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.\u00a0 The timing of decline may not be as abrupt. Other free-living animals are sufficiently mature upon birth that they can survive.\u00a0 Humans and other primates require a period of time when they must be fed and nurtured until they can survive independently.\u201d \u00a0\u00a0<\/span><\/p>\n

So human systems may be \u201coptimized 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.\u201d<\/span><\/p>\n

Morimoto noted the work is relevant to that of famed molecular biologist Cynthia Kenyon, who repeatedly extended worm lifespan. \u201cOf course this is linked to the foundational discoveries of Kenyon.\u00a0 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.\u201d Moriomoto\u2019s new paper \u201cis mostly about the down-regulation of HSF-1 in early adulthood, suggesting DAF-2 could be delaying the genetic switch we found.\u201d\u00a0<\/span><\/p>\n

The history<\/strong><\/span><\/p>\n

Ben-Zvi said that, with her, Morimoto\u2019s group previously showed that proteostasis\u2014the proper formation and balance of protein levels\u2014collapses\u00a0early<\/span><\/a>\u00a0in worm adulthood. More\u00a0recent<\/span><\/a>\u00a0work by Ben-Zvi\u2019s group \u201cdemonstrated 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.\u201d<\/span><\/p>\n

In the new paper, Morimoto\u2019s team \u201cextend this observation to other stress responses, suggesting there is a global change in animals\u2019 response to stress at reproduction onset.\u201d The team \u201cthen 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\u2019 ability to respond to stress after reproduction onset.\u201d\u00a0<\/span><\/p>\n

Ben-Zvi said Morimoto\u2019s crew has shown the change in\u00a0H3K27me3 is \u201cassociated 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.\u201d<\/span><\/p>\n

Ben-Zvi added that \u201cgermline arrest, previously shown to extend\u00a0lifespan<\/span><\/a>\u00a0and rescue heat shock response\u00a0collapse<\/span><\/a>, reduces the accumulation of \u00a0H3K27me3 marks, and restores promoter accessibility in accord with changes in jnjd-3.1 levels.\u201d All this demonstrates, \u201cfor the first time, that signals from the reproductive system modulate the chromatin of somatic cells, and modulate cells\u2019 ability to respond to stress.\u201d\u00a0<\/span><\/p>\n

The new paper is \u201can elegant mechanistic demonstration of how cell non-autonomous signals from one tissue can alter the response of another.\u201d \u00a0\u00a0<\/span><\/p>\n

From C. elegans to the clinic?<\/strong><\/span><\/p>\n

Ben-Zvi believes it all both does and doesn\u2019t have human ramifications. \u201cYes, because many protein miscoding diseases are associated with aging,\u201d she told\u00a0Drug Discovery & Development<\/em>. \u201cWe previously showed that signals from the reproductive system can modulate aggregation in a polyQ model of Huntington\u2019s disease. A regulated signal suggests that the organism is capable of an effective damage removal, but shut it down in adulthood.\u201d\u00a0<\/span><\/p>\n

But, she said, \u201cthere is currently no clear demonstration the reproductive system sends such signals in human,\u201d if there is support for such a notion. \u201cThe germline effect on aging is conserved in flies.\u201d<\/span><\/p>\n

Ben-Zvi concluded there are \u201cmany 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?\u201d<\/span><\/p>\n

\n

Source: dddmag<\/p>\n","protected":false},"excerpt":{"rendered":"

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\u00a0Molecular Cell\u00a0by 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 […]<\/p>\n","protected":false},"author":6,"featured_media":5596,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[17],"tags":[],"class_list":["post-5594","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-research"],"featured_image_urls":{"full":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2015\/08\/morimoto.jpg",128,179,false],"thumbnail":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2015\/08\/morimoto-128x150.jpg",128,150,true],"medium":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2015\/08\/morimoto.jpg",128,179,false],"medium_large":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2015\/08\/morimoto.jpg",128,179,false],"large":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2015\/08\/morimoto.jpg",128,179,false],"1536x1536":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2015\/08\/morimoto.jpg",128,179,false],"2048x2048":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2015\/08\/morimoto.jpg",128,179,false],"ultp_layout_landscape_large":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2015\/08\/morimoto.jpg",128,179,false],"ultp_layout_landscape":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2015\/08\/morimoto.jpg",128,179,false],"ultp_layout_portrait":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2015\/08\/morimoto.jpg",128,179,false],"ultp_layout_square":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2015\/08\/morimoto.jpg",128,179,false],"newspaper-x-single-post":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2015\/08\/morimoto.jpg",128,179,false],"newspaper-x-recent-post-big":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2015\/08\/morimoto.jpg",128,179,false],"newspaper-x-recent-post-list-image":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2015\/08\/morimoto.jpg",46,65,false],"web-stories-poster-portrait":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2015\/08\/morimoto.jpg",128,179,false],"web-stories-publisher-logo":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2015\/08\/morimoto.jpg",69,96,false],"web-stories-thumbnail":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2015\/08\/morimoto.jpg",128,179,false]},"author_info":{"info":["Amrita Tuladhar"]},"category_info":"Research<\/a>","tag_info":"Research","comment_count":"0","_links":{"self":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/posts\/5594","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/users\/6"}],"replies":[{"embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/comments?post=5594"}],"version-history":[{"count":0,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/posts\/5594\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/media\/5596"}],"wp:attachment":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/media?parent=5594"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/categories?post=5594"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/tags?post=5594"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}