A lifespan-extending calorie-restricted diet reversed some of the aging effects - but, unlike the widespread changes observed in somatic organs, it had an impact only in a small number of gonad-specific genes.

As well as tackling one of the key questions of ageing - by exploring if reproductive organs age in the same way as other body organs - this research is important in the light of the trend for some women in developed countries to put off childbearing until later in life.

A research team led by Minoru Ko, MD, PhD, from the National Institute on Aging, Baltimore, USA used whole-genome DNA microarrays to study the effects of age, sex and diet on the global gene expression in mouse ovaries and testes. They found that reproductive organs age in a different way to other body tissues and, furthermore, that ovaries age in a different way from testes.

Age-related changes in gene expression occurred in gonads - as they are known to in other body tissues - but these changes tended to be in different classes of genes. Only two of the six categories of genes previously associated with aging in muscle, kidney and brain were associated with aging in the ovary; none were associated with aging in the testis. The changes seen in ovaries could be influenced by changes in the tissue composition of ovaries as females age and ovulation ceases.

The researchers also found that calorie restriction in females reduced the expression of genes involved in metabolism and follicle growth, which seems to be consistent with a popular view that the calorie restriction causes a shift in energy use away from reproduction towards general body maintenance and repair. However, male mice on the same diet did not appear to sacrifice reproductive function, suggesting an evolutionary difference between males and females when coping with a food shortage.

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The subtle effects of variation in enzyme activity may well account for conflicting results of some clinical trials, including the confusing data on the effect of vitamin supplements, he noted. In the future, the enzyme profile of research subjects will have to be taken into account in analyzing the outcome of clinical trials.

If one considers not just vitamin-dependent enzymes but all the 30,000 human proteins in the genome, "every individual would harbor approximately 250 deleterious substitutions considering only the low-frequency variants. These numbers suggest that the aggregate incidence of low-frequency variants could have a significant physiological impact," the researchers wrote in their paper.

All the more reason to poke around in one's genome, Rine said.

"If you don't give people a reason to become interested in their genome and to become comfortable with their personal genomic information, then the benefits of much of the biomedical research, which is indexed to particular genetic states, won't be embraced in a time frame that most people can benefit from," Rine said. "So, my motivation is partly scientific, partly an education project and, in some ways, a partly political project."

Marini and Rine credit Bruce Ames, a UC Berkeley professor emeritus of molecular and cell biology now on the research staff at Children's Hospital Oakland Research Institute, with the research that motivated them to look at enzyme variation. Ames found in the 1970s that many bacteria that could not produce a specific amino acid could do so if given more vitamin B6, and in recent years he has continued exploring the link between micronutrients and health.

"Looked at in one way, Bruce found that you can cure a genetic disease in bacteria by treating it with vitamins," Rine said. Because the human genome contains about 6 billion DNA base pairs, each one subject to mutation, there could be between 3 and 6 million DNA sequence differences between any two people. Given those numbers, he reasoned that, as in bacteria, "there should be people who are genetically different in terms of the amount of vitamin needed for optimal performance of their enzymes."

This touches on what Rine considers one of the key biomedical questions today. "Now that we have the complete genome sequences of all the common model organisms, including humans, it's obvious that the defining challenge of biology in the 21st century is not what the genes are, but what the variation in the genes does," he said.

Rine, Marini and their colleagues are continuing to study variation in the human MTHFR gene as well as other folate utilizing enzymes, particularly with respect to how defects in these enzymes may lead to birth defects. Rine also is taking advantage of the 1,500 students in his Biology 1A lab course to investigate variants of a second vitamin B6-dependent enzyme, cystathionine beta-synthase.

He also is investigating how enzyme cofactors like vitamins and minerals fix defective enzymes. He suspects that supplements work by acting as chaperones to stabilize the proper folding of the enzyme, which is critical to its catalytic activity. "That is a new principle that may be applicable to drug design," Rine said.

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