Researchers identify a potentially universal mechanism of aging
A team of researchers from the New South Wales Centre for Overweight and Obesity has determined that children and young teenagers who spend more than two hours a day in front of computers or televisions are significantly less likely to be fit. The researchers, led by the University of Sydney’s Dr Louise Hardy, surveyed 2,750
Full Post: Warning on too much TV for kids
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.
New evidence may explain why it is that we lose not only our youthful looks, but also our youthful pattern of gene activity with age. A report in the November 26th issue of the journal Cell, a Cell Press publication, reveals that a protein perhaps best known for its role in the life-extending benefits of
Full Post: Researchers provide new evidence that aging can be slowed
Two previously identified pathways associated with aging in mice are connected, say researchers at the Stanford University School of Medicine. The finding reinforces what researchers have recently begun to suspect: that the age-related degeneration of tissues, organs and, yes, even facial skin with which we all struggle is an active, deliberate process rather than a
Full Post: Researchers find link between two aging pathways in mice
Aging yeast cells accumulate damage over time, but they do so by following a pattern laid down earlier in their life by diet as well as the genes that control metabolism and the dynamics of cell structures such as mitochondria, the power plants of cells. These research findings, presented at the American Society for Cell
Full Post: Both theories about human cellular aging supported by new research
The DNA in our cells is constantly under assault from oxygen, the sun’s radiation and environmental stresses. Most of the time, our cells can repair the damage before it gets copied into a permanent mutation that could lead to cancer. Adding a wrinkle to our understanding of how cancers begin, scientists have found that cells
Full Post: Researchers reveal a new aspect of tumor development
If you have had a hard day at work, you may change your eating habits, perhaps favoring comfort food, but you don’t suddenly develop the ability to eat the plate and cutlery. A new paper, published in this week’s issue of PLoS Biology, describes an evolutionary mechanism in yeast that allows cells to respond to
Full Post: Prion switching in response to environmental stress