Sci. Aging Knowl. Environ., 16 July 2003
Foxo Ladies Squander Their Eggs
Gene might link aging with early ovarian failure in mice
Key Words: forkhead daf-2
Mice that play fast and loose with their egg supply run short later in life, according to a new study. Disrupting a single gene causes mice to spend their eggs while young, leaving them infertile. Because a related gene influences longevity in worms and the engineered mice display signs of rapid decrepitude, the authors suggest that the gene connects egg loss and premature aging in mammals. Furthermore, the mouse could model early menopause in humans.
Numerous studies have shown that an insulin-related signaling pathway affects life span in worms, flies, and mice (see "Growing Old Together" and "One for All"). Disrupting the pathway in worms stimulates a protein called DAF-16, which can help extend life. In place of DAF-16, mammals have a set of proteins called the Foxo subfamily. Previous work indicated that the three Foxo proteins influence genes involved in stress resistance and cell suicide, processes that prevent cellular damage and tumor formation. A recent study implicates defects in one of the proteins, Foxo1, in diabetes (see "Outfoxing Insulin Resistance").
Molecular biologist Ronald DePinho of the Dana-Farber Cancer Institute in Boston and colleagues wondered whether the Foxo proteins forestall age-related conditions in mammals. To probe this question, they disabled Foxo3a in mice. Female animals without operational Foxo3a produced normal litters at first, but successive litters had fewer pups. By about 15 weeks of age--prime fertility time--the mutant females could no longer bear young. The problem lay within the ovary, the scientists found. At birth, the ovary contains all the eggs the female will ever have, each one nestled within a cluster of cells called a follicle. Normally in rodents, a few follicles mature each week and release their eggs. In the mutant females, however, huge numbers of follicles matured early on, depleting the supply. The researchers concluded that Foxo3a normally suppresses follicular maturation.
The mutant mice also suffered from mild anemia and absorbed blood glucose less efficiently than their normal siblings did, a condition that indicates increased risk of diabetes. These symptoms, says DePinho, strengthen the link between Foxo3a and aging, because red blood cell function and the processes by which the body handles sugar are particularly vulnerable to the ravages of age. The mice without Foxo3a are still middle-aged, however, so no one yet knows whether they will develop more signs of accelerated aging.
"What's exciting is that [the Foxo3a defect] does seem to mimic premature ovarian failure [in humans]," a condition that brings early menopause and its accompanying symptoms to about 1% of women, says cancer geneticist Karen Arden of the Ludwig Institute for Cancer Research in San Diego, California. She calls the study "elegant" but adds that to draw conclusions about the effect of Foxo proteins on longevity, "it would be nice if these mice had some of the other hallmarks of aging." If further observations reveal such characteristics, the results should egg on researchers studying mammalian aging.
July 16, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150