[ RadSafe ] Researchers identify a potentially universal mechanism of aging
Ludwig Dr. Feinendegen
feinendegen at gmx.net
Thu Dec 4 11:04:17 CST 2008
Dear Roy: I very much appreciate sending this most interesting report and express my gratitude. Sincerely, Ludwig Feinendegen
-------- Original-Nachricht --------
> Datum: Fri, 28 Nov 2008 00:56:03 -0800 (PST)
> Von: ROY HERREN <royherren2005 at yahoo.com>
> An: radsafe at radlab.nl
> Betreff: [ RadSafe ] Researchers identify a potentially universal mechanism of aging
> I suspect that the below described process also comes into play with
> exposure to ionizing radiation.
> Roy Herren
> Public release date: 26-Nov-2008
> Contact: David Cameron
> david_cameron at hms.harvard.edu
> Harvard Medical School
> Researchers identify a potentially universal mechanism of aging
> BOSTON, Mass. (Nov. 26, 2008)—Like our current financial crisis, the
> aging process might also be a product excessive deregulation.
> Researchers have discovered that DNA damage decreases a cell's ability to
> regulate which genes are turned on and off in particular settings. This
> mechanism, which applies both to fungus and to us, might represent a universal
> culprit for aging.
> "This is the first potentially fundamental, root cause of aging that we've
> found," says Harvard Medical School professor of pathology David Sinclair.
> "There may very well be others, but our finding that aging in a simple
> yeast cell is directly relevant to aging in mammals comes as a surprise."
> These findings appear in the November 28 issue of the journal Cell.
> For some time, scientists have know that a group of genes called sirtuins
> are involved in the aging process. These genes, when stimulated by either
> the red-wine chemical resveratrol
> (http://web.med.harvard.edu/sites/RELEASES/html/11_1Sinclair.html) or caloric restriction
> (http://web.med.harvard.edu/sites/RELEASES/html/sinclair.html), appear to have a positive effect on
> both aging and health.
> Nearly a decade ago, Sinclair and colleagues in the Massachusetts
> Institute of Technology lab of Leonard Guarente found that a particular sirtuin in
> yeast affected the aging process in two specific ways—it helped regulate
> gene activity in cells and repair breaks in DNA. As DNA damage accumulated
> over time, however, the sirtuin became too distracted to properly regulate
> gene activity, and as a result, characteristics of aging set in.
> "For ten years, this entire phenomenon in yeast was considered to be
> relevant only to yeast," says Sinclair. "But we decided to test of this same
> process occurs in mammals."
> Philipp Oberdoerffer, a postdoctoral scientist in Sinclair's Harvard
> Medical School lab, used a sophisticated microarray platform to probe the
> mammalian version of the yeast sirtuin gene in mouse cells. The results in mice
> corroborated what Sinclair, Guarente, and colleagues had found in yeast ten
> years earlier.
> Oberdoerffer found that a primary function of sirtuin in the mammalian
> system was to oversee patterns of gene expression (which genes are switch on
> and which are switch off). While all genes are present in all cells, only a
> select few need to be active at any given time. If the wrong genes are
> switched on, this can harm the cell. (In a kidney cell, for example, all liver
> genes are present, but switched off. If these genes were to become active,
> that could damage the kidney.) As a protective measure, sirtuins guard
> genes that should be off and ensure that they remain silent. To do this, they
> help preserve the molecular packaging—called chromatin—that shrink-wraps
> these genes tight and keeps them idle.
> The problem for the cell, however, is that the sirtuin has another
> important job. When DNA is damaged by UV light or free radicals, sirtuins act as
> volunteer emergency responders. They leave their genomic guardian posts and
> aid the DNA repair mechanism at the site of damage.
> During this unguarded interval, the chromatin wrapping may start to
> unravel, and the genes that are meant to stay silent may in fact come to life.
> For the most part, sirtuins are able to return to their post and wrap the
> genes back in their packaging, before they cause permanent damage. As mice
> age, however, rates of DNA damage (typically caused by degrading
> mitochondria) increase. The authors found that this damage pulls sirtuins away from
> their posts more frequently. As a result, deregulation of gene expression
> becomes chronic. Chromatin unwraps in places where it shouldn't, as sirtuin
> guardians work overtime putting out fires around the genome, and the
> unwrapped genes never return to their silent state.
> In fact, many of these haplessly activated genes are directly linked with
> aging phenotypes. The researchers found that a number of such unregulated
> mouse genes were persistently active in older mice.
> "We then began wondering what would happen if we put more of the sirtuin
> back into the mice," says Oberdoerffer. "Our hypothesis was that with more
> sirtuins, DNA repair would be more efficient, and the mouse would maintain a
> youthful pattern gene expression into old age."
> That's precisely what happened. Using a mouse genetically altered to model
> lymphoma, Oberdoerffer administered extra copies of the sirtuin gene, or
> fed them the sirtuin activator resveratrol, which in turn extended their
> mean lifespan by 24 to 46 percent.
> "It is remarkable that an aging mechanism found in yeast a decade ago, in
> which sirtuins redistribute with damage or aging, is also applicable to
> mammals," says Leonard Guarente, Novartis Professor of Biology at MIT, who is
> not an author on the paper. "This should lead to new approaches to protect
> cells against the ravages of aging by finding drugs that can stabilize this
> redistribution of sirtuins over time."
> Both Sinclair and Oberdoerffer agree with Guarente's sentiment that these
> findings may have therapeutic relevance.
> "According to this specific mechanism, while DNA damage exacerbates aging,
> the actual cause is not the DNA damage itself but the lack of gene
> regulation that results," says Oberdoerffer. "Lots of research has shown that this
> particular process of regulating gene activity, otherwise known as
> epigenetics, can be reversed—unlike actual mutations in DNA. We see here,
> through a proof-of-principal demonstration, that elements of aging can be
> Recent findings by Chu-Xia Deng of the National Institute of Diabetes,
> Digestive and Kidney Diseases, has also found that mice that lack sirtuin are
> susceptible to DNA damage and cancer, reinforcing Sinclair's and
> Oberdoerffer's data.
> This research was funded by the National Institutes of Health, and the
> Glenn Foundation for Medical Research. David Sinclair is a consultant to
> Genocea, Shaklee and Sirtris, a GSK company developing sirtuin based drugs.
> Written by David Cameron
> Full citation:
> Cell, November 28, 2008 Volume 135, Issue 6
> "SIRT1 Redistribution on Chromatin Promotes Genome Stability but Alters
> Gene Expression during Aging"
> Philipp Oberdoerffer(1), Shaday Michan(1), Michael McVay(1), Raul
> Mostoslavsky(2), James Vann(3), Sang-Kyu Park(3), Andrea Hartlerode(4), Judith
> Stegmuller(1,7), Angela Hafner(1), Patrick Loerch(1), Sarah M. Wright(5), Kevin
> D. Mills(5), Azad Bonni(1), Bruce A. Yankner(1), Ralph Scully(4), Tomas A.
> Prolla(3), Frederick W. Alt(6), and David A. Sinclair(1)
> 1-Department of Pathology and Glenn Labs for Aging Research, Harvard
> Medical School, Boston, MA
> 2-Massachusetts General Hospital Cancer Center, Boston, MA
> 3-University of Wisconsin, Department of Genetics and Medical Genetics,
> Madison, WI
> 4-Beth Israel Deaconess Medical Center, Boston, MA
> 5-The Jackson Laboratory, Bar Harbor, ME
> 6-Howard Hughes Medical Institute, Children's Hospital Boston, Immune
> Disease Institute, and Department of Genetics, Harvard Medical School, Boston,
> 7-Present address: Max Planck Institute for Experimental Medicine, 37075
> Gottingen, Germany
> Harvard Medical School http://hms.harvard.edu has more than 7,500
> full-time faculty working in 11 academic departments located at the School's Boston
> campus or in one of 47 hospital-based clinical departments at 18
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> include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital,
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> Institute, Forsyth Institute, Harvard Pilgrim Health Care, Hebrew SeniorLife,
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> Institute, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital,
> McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute,
> Spaulding Rehabilitation Hospital, and VA Boston Healthcare System.
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