Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers Identify a Potentially Universal Mechanism of Aging

01.12.2008
Researchers have uncovered what may be a universal cause of aging, one that applies to both single cell organisms such as yeast and multicellular organisms, including mammals.

This is the first time that such an evolutionarily conserved aging mechanism has been identified between such diverse organisms. The mechanism probably dates back more than one billion years. The study shows how DNA damage eventually leads to a breakdown in the cell’s ability to properly regulate which genes are switched on and off in particular settings.

RELEVANCE
Researchers have known that damage to our DNA is central to the aging process. They have also known that overall, genome-wide patterns of gene expression, which are hard-wired in early development, break down over time. This study connects these two phenomena, explains how they accelerate aging, and demonstrates their universality. It also introduces hypotheses on how this process might be reversed.
PRINCIPAL INVESTIGATOR
David Sinclair, Ph.D., Professor of Pathology, Co-director of the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School

http://pathology.hms.harvard.edu/sinclair.htm

JOURNAL
Cell
FUNDING
National Institutes of Health, National Space Biomedical Research Institute (NSBRI) and the Glenn Foundation for Medical Research

Newswise — 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.

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.

David Cameron | Newswise Science News
Further information:
http://www.hms.harvard.edu

Further reports about: Aging Chromatin DNA DNA damage DNA repair Diabetes Disease Eye Genetics Max Planck Institute Medical aging process immune

More articles from Health and Medicine:

nachricht Researchers image atomic structure of important immune regulator
11.12.2018 | Brigham and Women's Hospital

nachricht Potential seen for tailoring treatment for acute myeloid leukemia
10.12.2018 | University of Washington Health Sciences/UW Medicine

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Researchers develop method to transfer entire 2D circuits to any smooth surface

What if a sensor sensing a thing could be part of the thing itself? Rice University engineers believe they have a two-dimensional solution to do just that.

Rice engineers led by materials scientists Pulickel Ajayan and Jun Lou have developed a method to make atom-flat sensors that seamlessly integrate with devices...

Im Focus: Three components on one chip

Scientists at the University of Stuttgart and the Karlsruhe Institute of Technology (KIT) succeed in important further development on the way to quantum Computers.

Quantum computers one day should be able to solve certain computing problems much faster than a classical computer. One of the most promising approaches is...

Im Focus: Substitute for rare earth metal oxides

New Project SNAPSTER: Novel luminescent materials by encapsulating phosphorescent metal clusters with organic liquid crystals

Nowadays energy conversion in lighting and optoelectronic devices requires the use of rare earth oxides.

Im Focus: A bit of a stretch... material that thickens as it's pulled

Scientists have discovered the first synthetic material that becomes thicker - at the molecular level - as it is stretched.

Researchers led by Dr Devesh Mistry from the University of Leeds discovered a new non-porous material that has unique and inherent "auxetic" stretching...

Im Focus: The force of the vacuum

Scientists from the Theory Department of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science (CFEL) in Hamburg have shown through theoretical calculations and computer simulations that the force between electrons and lattice distortions in an atomically thin two-dimensional superconductor can be controlled with virtual photons. This could aid the development of new superconductors for energy-saving devices and many other technical applications.

The vacuum is not empty. It may sound like magic to laypeople but it has occupied physicists since the birth of quantum mechanics.

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

New Plastics Economy Investor Forum - Meeting Point for Innovations

10.12.2018 | Event News

EGU 2019 meeting: Media registration now open

06.12.2018 | Event News

Expert Panel on the Future of HPC in Engineering

03.12.2018 | Event News

 
Latest News

Some brain tumors may respond to immunotherapy, new study suggests

11.12.2018 | Studies and Analyses

Researchers image atomic structure of important immune regulator

11.12.2018 | Health and Medicine

Physicists edge closer to controlling chemical reactions

11.12.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>