7 January 2002. P53 misregulation and cancer have become almost synonymous
in the scientist's imagination. Mutations in this prominent tumor suppressor
gene have been found in the majority of human cancers, and downregulating the
protein increases tumor incidence in animal models. P53 can halt cell division
and induce DNA repair in response to stress and trigger cell death if the cell
is beyond repair. One would think, then, that upregulating this protective protein
could treat cancers, and therapies to that effect are being developed. The only
trouble, according to a report in last Thursday's Nature10, is that too much
p53 may accelerate aging.
Larry Donehauer of the Baylor College of Medicine in Houston, Texas, and colleagues at several other institutions report that they have, by mistake, created a mutant mouse that overproduces p53. The reason for the overproduction appears to be that one of the two alleles is considerably shortened and induces its normal counterpart to overproduce the protein. As expected, these mice are more resistant to tumors, but rather than living longer, their life spans were only about 80 percent that of their wildtype littermates. This surprising finding is accompanied by numerous signs of early aging, including osteoporosis, generalized organ atrophy, and diminished stress tolerance.
"The influence of p53 on life span may result from a delicate balance between its antitumour and pro-ageing effects, such that too little p53 increases mortality from cancer whereas too much p53 increases mortality," write Gerardo Ferbeyre of Universite de Montreal in Canada and Scott Lowe of Coldspring Harbor Laboratory in New York in an accompanying News and Views article. They add, "The results raise the disturbing possibility that the DNA-damaging drugs used to treat cancer in young people might prompt p53 into action and accelerate age-related disorders later on."
. . . And of Coenzyme Q
A molecule that is better known in conjunction with aging is coenzyme Q (Q). The enzyme, from both endogenous and dietary sources, is an important player in maintaining the proton gradient across the mitochondrial membrane that drives ATP synthesis. One of the byproducts of this movement of charged particles is the production of reactive oxygen species (ROSs), free radicals that have been linked to aging in general and the destruction of cells in particular. In the current issue of Science, Paula Larsen and Catherine Clarke of the University of California, Los Angeles, show that removing Q from the diet of normal nematodes (Caenorhabditis elegans) dramatically extends their life spans.
The study extends work showing that dietary Q could rescue worms genetically altered to block the production of endogenous Q, allowing them to develop normally and live longer. The researchers wanted to avoid interfering with normal larval development, which depends on Q, in order to isolate the effects of reduced Q on adult aging. They found that wildtype nematodes fed a Q-less diet beginning in adulthood lived approximately 60 percent longer.
The data support a model whereby a mitochondrial membrane protein gradient deprived of dietary Q, relying solely on endogenous sources, will produce fewer ROSs. This in turn could help slow aging. Larsen and Clarke also show that they can further extend the life of several nematode mutants (clk-1, daf-2, daf-12, daf-16), which already live longer than wildtype nematodes. They authors suggest that this additive effect on longevity may result from reduced ROS production combined with increased breakdown of ROS.
"I think the article is very interesting," said nematode aging expert Cynthia Kenyon of the University of California, San Francisco. "It will also be interesting to learn how, at the molecular level, this extension of lifespan occurs." An accompanying News and Views article discusses how the paper points to interactions in the mitochondrion between Q and the insulin signaling pathway.-Hakon Heimer.
Reference:Tyner S et al. P53 mutant mice that display early ageing-associated phenotypes. Nature 2002 Jan 3;415:46-51. Abstract
Ferbeyre G, Lowe SW. The price of tumour suppression? Nature 2002 Jan 3;415:26-7. Abstract
Larsen PL, Clarke CF. Extension of life span in Caenorhabditis elegans by a diet lacking coenzyme Q. Science 2002 Jan 4;295:120-3. Abstract
Tatar M, Rand DM. Dietary advice on Q. Science. 4 Jan 2002;295. Abstract