Scientists in the US working with yeast and mice found that a gene that is responsible for regulating the activity of the genome is also called upon to repair damaged DNA and the more this happens the less it is able to look after genome integrity which then allows chronically unregulated genes to kick off the aging process in cells.
The discovery was the work of Dr David Sinclair of the Department of Pathology and Glenn Labs for Aging Research, Harvard Medical School, Boston, Massachusetts, and colleagues from other research centres in the US, and is published as a study in the 28 November issue of the journal Cell.
Scientists have known for some time ago that gene activity changes with aging, but the underlying mechanisms and what drives them is somewhat of a mystery. Research has suggested a link between DNA damage and aging: for instance UV damage and free radicals cause cells to age, but exactly how, at least in mammals, was unknown.
One clue lay in what happens in yeast. About ten years ago, Sinclair and colleagues at the Massachusetts Institute of Technology lab of Leonard Guarente discovered that the protein Sir2 stabilized the yeast genome, but when there was a break in DNA, the protein left its post and went to effect repairs, allowing genes to switch on that leave yeast sterile, a characteristic of aging.
“For ten years, this entire phenomenon in yeast was considered to be relevant only to yeast,” said Sinclair. So he, Dr Philipp Oberdoerffer, a postdoctoral scientist at his Harvard Medical School lab, and other colleagues, decided to find out what happens in mammals by using a sophisticated microarray platform to probe the mammalian version of Sir2, called SIRT1, in mouse cells.
They found that SIRT1, behaved like Sir2; it stabilized the genome by controlling the way that DNA is packaged into chromatin, the complex array of DNA, RNA and protein that makes up chromosomes inside the nuclei of cells. Like Sir2, SIRT1 keeps the genome “youthful” by stopping genes switching on and off when they shouldn’t.
The researchers found that when DNA is damaged, like Sir2 in yeast, the mammalian SIRT1 proteins are called upon to to help with repairs, and while they are “away”, genome activity shifts to patterns seen in the aging mouse brain. Sinclair and colleagues suggested similar changes happen in the rest of the body too.
For example, all cells have all the genes for making a whole organism, but each cell only needs to have “switched on” the genes that regulate the function of that cell. So a kidney cell does not need to have the liver genes switched on. SIRT1 is involved in keeping that genomic integrity coherent, it is like shrink wrapping, using chromatin to keep the unwanted genes from becoming active. When SIRT1 goes walkabout, gene expression becomes unregulated and chaotic.
“This is the first potentially fundamental, root cause of aging that we’ve found,” said Sinclair.
“The critical protein controls both which genes are off and on as well as DNA repair; it’s used for both processes, and that’s the catch,” he added, explaining that as more and more DNA damage accumulates, the busier the SIRT1 proteins become with repairs and the less chromatin maintenance they do, so disregulated gene activity becomes chronic and leads to symptoms of aging. This is what they found in aging mice: the chronically disregulated genes were linked to symptoms of aging.
The researchers also discovered that lab mice with an excess of SIRT1 showed fewer unwanted changes in gene expression and improved ability to repair DNA. Perhaps this is a way to slow down the aging process; by developing a drug that stimulates SIRT1, said the researchers. There is already evidence that the red wine ingredient resveratrol works via SIRT1, as do several other targeted drugs that are in various stages of development. Following a calorie restricted diet is also thought to slow aging and improve health via SIRT1.
They showed this by using mice genetically altered to model lymphoma. They gave them extra copies of SIRT1, or fed them the SIRT1 activator resveratrol, and found this extended their lifespan by between 24 and 46 per cent.
This study may explain how those anti-aging chemicals and processes work, but as Sinclair explained, the ultimate test will be whether they can keep the gene profile youthful.
The study also shows that where aging is concerned, yeast and mammals are remarkably similar, something Sinclair described as “pretty striking”:
“Something as simple as yeast can tell us about the mechanism of aging in mammals,” he said.
Guarente, now Novartis Professor of Biology at MIT, said:
“It is remarkable that an aging mechanism found in yeast a decade ago, in which sirtuins [SIRT1 proteins] redistribute with damage or aging, is also applicable to mammals.”
“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,” he added.
Oberdoerffer agreed, explaining that:
“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.”
“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-principle demonstration, that elements of aging can be reversed,” he added.
Other recent studies appear to support these findings, for example Chu-Xia Deng of the US National Institute of Diabetes, Digestive and Kidney Diseases, showed that mice that don’t have enough SIRT1 are more susceptible to DNA damage and cancer.
“SIRT1 Redistribution on Chromatin Promotes Genomic Stability but Alters Gene Expression during Aging.”
Philipp Oberdoerffer, Shaday Michan, Michael McVay, Raul Mostoslavsky, James Vann, Sang-Kyu Park, Andrea Hartlerode, Judith Stegmuller, Angela Hafner, Patrick Loerch, Sarah M. Wright, Kevin D. Mills, Azad Bonni, Bruce A. Yankner, Ralph Scully, Tomas A. Prolla, Frederick W. Alt, David A. Sinclair.
Cell, Vol 135, Issue 5, pp 907-918, 28 November 2008.
DOI:10.1016/j.cell.2008.10.025
Sources: Cell Press, Harvard Medical School.
Written by: Catharine Paddock, PhD