Sci. Aging Knowl. Environ., 24 October 2001
Death and Aging, Together at Last
Karen Hopkinhttp://sageke.sciencemag.org/cgi/content/full/sageke;2001/4/nf2 Like private conversations at a boisterous party, cell death and aging have seemed entirely independent. The members of each of these molecular circles--having nothing in common with those in the other clique--appeared to keep pretty much to themselves (see "More Than a Sum of Our Cells"). The pathways that control longevity and apoptosis--the dominant form of programmed cell death--just didn't seem to overlap.
Now researchers think they've discovered a missing link, a protein that participates in the life-or-death discussions taking place on both sides of the room. In two papers in the 19 October issue of Cell, Leonard Guarente of the Massachusetts Institute of Technology (MIT) and his collaborators show that Sir2, a protein that promotes longevity in yeast and worms, binds to p53, a protein that determines whether cells with mutilated DNA will undergo apoptosis. This molecular association counteracts p53's destructive tendencies, permitting cells to survive an assault by DNA-damaging agents. The findings raise the possibility that Sir2 increases life-span by keeping cells from offing themselves. And they support the theory that programmed cell death might be involved in aging.
"This is a very exciting observation," says Ron DePinho of the Dana-Farber Cancer Institute in Boston. "It points to a unified theory that links pathways involved in aging and cancer." In animals, p53-induced apoptosis eliminates injured cells, preventing them from blossoming into cancer. Foiling cancer-prone cells benefits the organism, but giving p53 free rein would promote rampant cell death--which is why animals might employ Sir2 to keep this killer protein in check: Untamed p53 might eliminate cells that an aging organism would find hard to replace.
The road to the new revelation began in the mid-1990s, when Guarente first linked the Sir family of proteins to longevity in yeast. Subsequent experiments revealed that yeast cells that lack Sir2 divide far fewer times than their wild-type counterparts do, and yeast with extra Sir2 live longer (see Kaeberlein Perspective). In Caenorhabditis elegans, extra servings of Sir2 similarly extend the organism's life-span.
In yeast cells, Sir2 clings to highly repetitive DNA sequences and thus turns off transcription of nearby genes. This talent for inactivating transcription, Guarente discovered last year, stems from Sir2's ability to remove an acetyl group from the tails of histone proteins. Like the reversible phosphorylation that regulates the activity of many cellular proteins, acetylation and deacetylation alter the structure and function of histones, the protein spools around which nuclear DNA is wrapped: Deacetylation by Sir2 allows histones to tighten their grip on DNA. The resulting packed structure restricts the access of transcription factors to DNA and shuts down local gene expression.
Mammals, too, possess a Sir2 protein. In mammalian cells, however, Sir2 does not accumulate on repetitive DNA sequences. If mammalian Sir2 isn't in a position to deacetylate histones that associate with silenced genes, what might it be doing?
Enter Wei Gu of Columbia University. In 1997, Gu and others discovered that acetylation also regulates the activity of p53. Expose cells to ionizing radiation or other DNA-damaging agents, and p53 first gets phosphorylated. This modification allows p53 to break loose from Mdm2, a protein that otherwise inhibits the tumor suppressor and targets it for destruction. Once freed, p53 becomes a substrate for enzymes that transfer acetyl groups to other cellular proteins. The addition of this chemical group activates p53, allowing it to trigger apoptosis or to delay progression through the cell cycle until the DNA damage has been repaired, depending on the extent of injury (Fig. 1).
Working with Guarente, Gu and his colleagues found that mouse Sir2 removes p53's acetyl group in cells. A second team of researchers, led by Guarente in collaboration with Robert Weinberg of the MIT/Whitehead Institute for Biomedical Research, reports that the same holds true for human Sir2. Stripped of its acetyl group, p53 can no longer activate the genes that power the cell death program--a scenario that is borne out by studies in cultured cells. In mouse and human fibroblasts, raising the concentration of Sir2 protein blocks apoptosis induced by DNA-damaging agents or oxidative stress. Boosting Sir2 activity in these cells promotes survival; eliminating it promotes death. Given Sir2's ability to retard aging in yeast and worms, the new observations suggest that p53-mediated cell suicide might contribute to aging.
"It would be fascinating if p53 turned out to be a key player in the aging process," says Bert Vogelstein, a Howard Hughes Medical Institute investigator at the Johns Hopkins Oncology Center who studies how loss of p53 activity promotes cancer. The trouble, says Vogelstein, is that no one knows what stresses encountered during normal life rouse p53 into action. It's unclear whether the wear and tear of everyday living could activate p53 enough to promote aging.
Nor does anyone yet know what the molecular collaboration between Sir2 and p53 might mean for a whole animal. These studies demonstrate that Sir2 modifies p53 in cells removed from mice or humans. Would enhancing Sir2 activity make a mammal live longer?
"It might well do the opposite," muses Judith Campisi of Lawrence Berkeley National Laboratory in California. "Overproduction of Sir2 in a mammal might shorten its life-span, because eliminating p53 causes cancer."
Guarente will soon put the theories to the test. He and his colleagues are generating mouse strains that lack Sir2 and others that carry an additional copy of the gene. If mice are anything like yeast, the animals with extra Sir2 should enjoy longer life--ideally without increased incidence of cancer. "The hope," says Guarente, "is that there's a window in which you could lower the rate of apoptosis, slow aging, and not cause cancer."
The connection between Sir2 and p53 could even lead to more effective cancer treatments. Using Sir2 or a drug that mimics its behavior to tie up p53 might allow patients to tolerate higher doses of radiation or chemotherapy by preventing normal cells from dying, suggests DePinho. Conversely, inhibiting Sir2 in tumor cells that retain functional p53 might make a cancer more susceptible to destruction by conventional therapies.
Guarente is continuing his search for other proteins that partner with Sir2. "This is the first function we've found for mammalian Sir2, but it's undoubtedly not the only one," says Guarente. "It remains to be seen which function, if any, is the most important in regulating aging."
October 24, 2001
Karen Hopkin writes about science and tries to make sense of the world in Somerville, Massachusetts. Inspired by Guarente's findings, she plans to start on a novel about molecular biology and the quest for youth: Sir2, With Love.
Science of Aging Knowledge Environment. ISSN 1539-6150