Harvard research

News from the Harvard Medical School research community.
Harvard research
By Partners Harvard Medical International
Thu 29 Jan 2009 04:00 AM

News from the Harvard Medical School research community.

Aging: Researchers identify a potentially universal mechanism of aging

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 known that a group of genes called sirtuins are involved in the aging process. These genes, when stimulated by either the red wine chemical resveratrol or caloric restriction, 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 10 years, this entire phenomenon in yeast was considered to be relevant only to yeast," says Sinclair. "But we decided to test if 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 10 years earlier.

Oberdoerffer found that a primary function of sirtuin in the mammalian system was to oversee patterns of gene expression (which genes are switched on and which are switched 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 to aging phenotypes. The researchers found that a number of such unregulated 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 mice would maintain a youthful pattern gene expression into old age."

That's precisely what happened.Using mice 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%.

"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. "This should lead to new approaches to protect cells against the ravages of aging by finding drugs that can stabilise 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. Cardiovascular Medicine: Analysis of generic and brand-name cardiovascular drugs finds no evidence of brand-name superiority

In a study of trials comparing generic and brand-name drugs used to treat cardiovascular diseases, researchers at Brigham and Women's Hospital (BWH) found that brand-name drugs are not clinically superior to their generic counterparts.

After also looking at editorials written on the topic, they were surprised to find that a substantial number cautioned against widespread substitution of generic drugs for brand-name drugs in the treatment of cardiovascular disease. The findings are published in the December 3 issue of the Journal of the American Medical Association.

"Generic prescription drugs can help improve patient adherence to treatment plans by reducing spending on needed drugs. And though generics must be approved by the FDA, there is still widespread concern among physicians and patients that generic drugs are somehow inferior to brand-name drugs," said Dr Aaron Kesselheim, of the Division of Pharmacoepidemiology and Pharmacoeconomics at BWH and lead author of the study. "We found that head-to-head trials do not support this notion."

The authors performed a systematic search of studies published in healthcare-related journals between 1984 and 2008 that compared clinical outcomes of generic and brand-name drugs used to treat cardiovascular disease. They identified 47 such studies, and a meta-analysis combining the results of clinical trials demonstrated no evidence for the superiority of brand-name drugs.

In addition, the authors reviewed all relevant editorials and commentaries from the same time period and found that about half expressed a negative view of the use of generic drugs to treat cardiovascular diseases, while only about a quarter supported the practice of substituting low-cost generics for brand-name drugs.

"We were surprised that so many editorials expressed a negative view of the interchangeability of generic and brand-name drugs, contradicting the available evidence on this point," said Dr William Shrank, of the Division of Pharmacoepidemiology and Pharmacoeconomics at BWH, and one of the co-authors of the study.

"It is possible that the disconnect between the data and opinions expressed stems from physicians' personal experiences, anecdotal reports, and even popular media coverage of cases in the community," said Dr Kesselheim. He also commented that another possible explanation could be undisclosed financial relationships held by the editorialists, noting that nearly half of the trials and almost all of the editorials did not disclose funding sources or conflicts of interest.

Diabetes: Joslin researchers identify new source of insulin-producing cells - study finds pancreatic progenitors exist after birth, may offer hope in fight against diabetes

Researchers at the Joslin Diabetes Center have shown that insulin-producing pancreatic beta cells can form after birth or after injury from progenitor cells within the pancreas that were not beta cells. The finding that contradicts a widely-cited earlier study that had concluded this is not possible.

The study, published online in the Proceedings of the National Academy of Sciences Early Edition, identifies the source of the progenitor cells as being pancreatic duct cells.

"This means that there is a population of pancreatic cells that can be stimulated, either within the body or outside the body, to become new beta cells - the cells that are lacking in diabetes," said Susan Bonner-Weir, Ph.D., the study's lead researcher and a Senior Investigator at Joslin and Associate Professor of Medicine at Harvard Medical School.

The experiments, conducted in animal models, suggest a new source of beta cells for replacement therapy to treat or cure diabetes.

In type 1 diabetes, the pancreas produces little or no insulin since the insulin producing beta cells are destroyed by the body's own immune system. While transplantation of human islets from donor pancreas has been successful in getting people with type 1 diabetes off insulin treatment, this insulin independence is only successful for a few years.

"One of the problems with islet transplantation is that while the proof of principle is there, we don't have enough islets to transplant and they go through a traumatic process during isolation," said Bonner-Weir. "Many islets are not in the greatest condition after being isolated from a pancreas."

The two major obstacles to islet transplants are the need for continued use of immunosuppressive drugs to prevent both rejection and return of autoimmune destruction and the lack of a reliable source of insulin-producing islet cells.

Bonner-Weir's main research focus is the search for new sources of insulin-producing islet cells. In this study, in experiments in mice, Bonner-Weir's group used a similar lineage tracing system employed by a group from Dr Douglas Melton's lab at Harvard. That group concluded in a paper published in Nature in 2004 that after birth, new beta cells only result from division of pre-existing beta cells and that beta cells do not form from progenitor cells after birth.

"That conclusion, coming from such a well-respected group, was taken by many as fact and cast a cloud over this important research area," Bonner-Weir said. However, earlier this year a group led by Xiaobo Xu in Belgium showed that islet progenitor cells within the adult pancreas could be activated to increase the number of beta cells by the process of differentiation rather than self-duplication, but the paper did not indicate the origin of these cells. Bonner-Weir's paper complements the Belgium study by identifying the source of these cells as pancreatic duct cells.

In addition to finding that these duct cells can differentiate into insulin-producing islet cells after birth and in regeneration after injury, the study showed that they can also become new acinar cells - a finding that has potential implications for pancreatic cancer, since the origin of the cancerous cells has been disputed.

Two lineage-tracing experiments involved genetically marking the ductal cells and then following them. The first experiment, which involved 1-month-old mice, found that between 30 to 40% of islets had beta cells that had formed after birth from duct cells.

In the second experiment, conducted in adult mice, the Joslin researchers used the same regeneration model employed in the Belgian study, which is based on tying off the main pancreatic duct. Beyond the area of the tie some cells die, but others grow to regenerate the whole structure. In these adult mice, new islets and new acinar cells were again shown to have been formed from the pre-existing duct cells.

"Our data provide strong support to the concept of a shared lineage of ductal, acinar and islet cells after birth, even in the adult. This means that there is a population of cells - we don't know if it is all of the cells or just some - that can be stimulated to become new islet cells," Bonner-Weir said.

She concluded: "Our identification of a differentiated pancreatic cell type as an in vivo progenitor for all differentiated pancreatic cell types has implications for a potential, expandable source for new islets for replacement therapy for diabetes. While the ideal therapy would be to have those with diabetes regenerate their own islet cells, that is still a long way off.

This article is provided courtesy of Partners Harvard Medical International.

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