Study backs theory that accumulating mutations of ’quiet’ genes foster aging

A theory that suggests the aging process might be safely slowed by targeting genes that are quiet early but threaten damage later in life has gotten a boost from new findings from the University of Illinois at Urbana-Champaign.

The researchers don’t promote such tinkering in their paper, which appears online this week in advance of publication by the Proceedings of the National Academy of Sciences. Rather they detail their tests, based on models of mathematical prediction, of the two leading evolutionary theories of aging on the reproductive success of 100 different genotypes of fruit flies (Drosophila melanogaster) across various age groups.

The results suggest that more needs to be learned about which genes do what and when in the aging process so that artificial manipulation does not cause evolutionary damage in future generations, said Kimberly A. Hughes, an animal biologist in the Program in Ecology and Evolutionary Biology at Illinois.

The study provides the strongest support yet for the theory of mutation accumulation (MA), Hughes said. The theory, which has been difficult for scientists to test, proposes that aging is the result of an accumulation of mutations of genes that are kept in check by reproductive-oriented selection processes early in life and only are active later on.

Examples are genes associated with Huntington’s disease and forms of cancer that strike late in life. Such mutations exist in prime reproductive years but only have noticeable effects late in life. In old age, when reproduction is not an organism’s primary function, accumulating mutations are no longer checked by selection, increasing the risk of disease.

The other, more widely accepted theory of antagonistic pleiotrophy (AP) says that aging occurs when genes that offer help during the reproductive years — those that produce estrogen, for example — take on harmful roles later in life. Selection under AP theory favors the early life effects because these lead to the production of offspring but does not oppose the deleterious effects in late life, Hughes said.

Building on her theoretical study of age-related inbreeding depression and genetic variability (PNAS, June 1996) while a doctoral student at the University of Chicago, Hughes and colleagues raised fruit flies to test the effect of delayed mutations.

The new study found that the deleterious effects of mutations on reproduction rose dramatically with age during the reproductive years in both genotypes — homozygous (those with many identical genes, or inbreeding) and heterozygous (those having a variety of genes present). Reproductive success declined more rapidly, however, in the homozygous lines, as predicted by the MA theory.

“This study allowed us to detect certain kinds of genetic effects called dominance variance that are predicted to increase with age only under the MA theory,” Hughes said. “The power to detect these effects is critical to tests of evolutionary aging theories, because an age-related increase appears to be a unique prediction of the MA theory, while other kinds of genetic effects can increase under either model.”

While the study shows support for the MA theory, the scenario under the antagonistic pleiotrophy theory is not discounted. “They are not mutually exclusive,Ó Hughes said. “They can both be happening. Both kinds of genes can be accumulating.Ó

If geneticists try to remove bad late-in-life effects of a gene that has a positive role early in life, then its overall function could be negatively altered in future generations, Hughes said. Manipulating genes with no early life benefits to negate their deleterious late life effects, she said, might not cause negative evolutionary changes in the future.

The authors of the paper are Hughes, postdoctoral researcher Jenny M. Drnevich and doctoral student Rose M. Reynolds, all of Illinois, and former postdoctoral associate Julie A. Alipaz, who now is at Harvard University.

The National Science Foundation, National Institutes of Health and the School of Integrative Biology at Illinois funded the research.