[ RadSafe ] mechanism of aging - Molecular Clocks

[HOWARD.LONG at comcast.net]

Regulation (as with Congress-forced loans to poor borrowers), not deregulation (as with local bank market control) may disrupt aging, like banking. 

A mediator of radiation effect on aging (apparently beneficial,  0.5 + cSv/yr supplement, - Cameron) may be deamidation.

See Molecular Clocks: Deamidation of Aspariginyl and Glutaminyl Residues in Peptides and Proteins - Noah E. Robinson and Arthur B. Robinson, 
Althouse Press ISBN 1-59087-250-0 

Also, www.oism.org. 

Howard Long
-------------- Original message -------------- 
From: ROY HERREN <royherren2005 at yahoo.com> 

> 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 
> 617-432-0441 
> 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 reversed." 
> 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, MA 
> 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 Harvard-affiliated 
> teaching hospitals and research institutes. Those affiliates include Beth Israel 
> Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Health 
> Alliance, Children's Hospital Boston, Dana-Farber Cancer Institute, Forsyth 
> Institute, Harvard Pilgrim Health Care, Hebrew SeniorLife, Joslin Diabetes 
> Center, Judge Baker Children's Center, Immune Disease 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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