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'Moonlighting' protein shown to underpin ageing in mice

1 December 2008
Appeared in BioNews 486

A team has uncovered a striking genetic phenomenon in mice that adds depth to our understanding of cellular ageing. The group, led by molecular biologist David Sinclair at Harvard Medical School in Boston, Massachusetts, US, published its study in the journal Cell last week. The research suggests that two observations associated with ageing - DNA damage and decreased control over which genes are turned on or off - might be interrelated in mammals.

In each cell, DNA is naturally exposed to harmful 'free radicals' that can cause mutations or breaks in the double helix. Protein sentinels exist that work to maintain DNA's integrity, by swiftly repairing genetic injuries before they equate to more serious problems for the cell. Over time such damage accumulates, and these protein engineers necessarily work harder to keep the status quo.

One such protein, called Sir2, was identified in yeast a decade ago. Sir2 is a protein typically involved in 'gene silencing'; specifically, it suppresses a gene that leads to sterility, thus keeping the yeast cell youthful. However Sir2 has a second occupation. When called upon, it is found 'moonlighting' at sites of DNA damage, where it carries out repairs. As DNA damage accrues, Sir2 deserts its day-job more and more frequently. The genome is kept intact, but the cell becomes sterile.

Dr Philipp Oberdoerffer, postdoctoral scientist in Sinclair's lab, summed up the dogma. 'While DNA damage exacerbates ageing, the actual cause is not the DNA damage itself but the lack of gene regulation that results'.

Professor Sinclair and colleagues sought to ascertain whether the mammalian equivalent of Sir2, called SIRT1, plays an analogous role. Looking in mouse embryonic stem cells, they report that SIRT1 also plays a part in gene silencing. Then, to mimic ageing by treating cells with the damaging chemical hydrogen peroxide, the scientists observed nine tenths of all SIRT1 relocating to DNA breaks within an hour. So could SIRT1 movement be correlated with ageing? By looking at the pattern of genes 'turned on' in old mice, they saw that many that are active in old age are the very same that are normally kept silent by SIRT1. Remarkably, by feeding mice extra SIRT1, they lived on average 25 days longer than control animals. The implication is that age-related disorders, such as dementia and diabetes, may follow from the overworking of proteins like SIRT1. 'This may be a very fundamental Achilles' heel of life', says Sinclair. 'What this paper actually implies is that aspects of aging may be reversible. It sounds crazy, but in principle it should be possible to restore the youthful set of genes, the patterns that are on and off'.

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