Sci. Aging Knowl. Environ., 12 October 2005
Aging eggs might starve to death
The ovaries are cradles of life, but they are also chambers of death. Droves of egg cells commit suicide there during a woman's life. The cells might off themselves because they run out of food, according to a new study. The work could inspire new treatments for age-related infertility.
Female mammals are born with a limited supply of eggs. Over time these cells die, eventually triggering infertility--at least according to conventional wisdom. Last year, reproductive biologist Jonathan Tilly of Harvard Medical School in Boston and colleagues roiled the field by suggesting that adult mice can produce fresh eggs. However, that conclusion remains controversial (see Hoyer Perspective). Studies of mice that lack an enzyme called caspase-2 imply that the protein helps foster programmed egg death, or apoptosis: The rodents carry a surplus of eggs. But researchers don't understand what makes cells choose death in the first place. Some work indicates that food scarcity is to blame. Molecular biologist Sally Kornbluth of Duke University Medical Center in Durham, North Carolina, tested whether nutrition controls egg apoptosis through caspase-2.
The researchers turned to frog eggs, which are easier to study than mammalian eggs because they are larger and more abundant. They removed the eggs' contents, which can carry out the first steps of embryonic development. With the right coaxing, the contents replicate many events of egg apoptosis, including increased activity of a different member of the caspase family, the cell-killer caspase-3. But its activity remained low if the researchers added a cellular food called glucose-6-phosphate or its final metabolic product NADPH. Both of these molecules presumably signal that the cell has food aplenty. Exposing the extracts to a compound that blocks breakdown of glucose-6-phosphate sped up caspase-3 activation. The same compound spurred frog eggs to commit suicide. Together, those results suggest that going hungry can goad an egg to kill itself.
To find out how, the team focused on caspase-2, which helps supervise apoptosis, according to some studies. To work, caspase-2 enzymes must stick together, and the researchers found that NADPH and glucose-6-phosphate hinder this association. Further experiments showed that the two metabolic molecules spur another protein to affix a phosphate group to the caspase-2 site that allows it to hook onto its collaborators. Overall, the findings suggest that food scarcity sparks apoptosis by unleashing caspase-2 activity, says Kornbluth. Nutrient availability could fall in older cells for two reasons, she says. Most of the egg's glucose-6-phosphate comes from digestion of yolk, which could become scarce over time. Or the enzymes that help break down glucose-6-phosphate could falter with age.
Tilly praises the work for identifying a mechanism that could contribute to egg death. However, he cautions against extrapolating from amphibians to mammals. Frog eggs can run low on nutrients because they are outside the mother's body, he notes. Mammal eggs, by contrast, receive continual nurturing from neighboring cells that replenish their food supply. Researchers need to confirm whether keeping eggs well-fed reduces the ovaries' grim toll.
October 12, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150