Sci. Aging Knowl. Environ., 19 November 2003
Gene that assembles "bad cholesterol" particles influences human life span
Key Words: single-nucleotide polymorphism haplotype genotyping statistical distortion
In addition to genes for eye color and high IQ, future parents designing their children might want to include this one: a longevity promoter. New work has zeroed in on a gene that helps humans package cholesterol and controls aging. Although some experts question the generality of the paper's conclusion, the result fits with other work showing that lipid metabolism affects mortality.
Accidents and environmental factors such as smoking curb survival rates, but genetics dictates about 25% of a person's life span (see "Of Twins and Centenarians"). By identifying candidate DNA sequences and comparing the frequency of different variants in longer- and shorter-lived individuals, researchers have discovered some genes that apparently shape longevity; several such genes help handle lipids (see "Greasing Aging's Downward Slide"). But scientists have only recently begun to perform open-ended searches for sequences that extend life span.
In previous work, geneticist Annibale Puca of Elixir Pharmaceuticals (see "Joining Forces") in Cambridge, Massachusetts, and colleagues connected a region on human chromosome 4 to exceptional longevity; it contains about 50 genes (see "Hints of a 'Master Gene' for Extreme Old Age"). They wanted to narrow down this stretch to a single life-extending gene, so they sought DNA sequences that were enriched in very old populations. To do so, they compared single DNA letters that vary from person to person, called SNPs.
The team analyzed SNPs by sequencing DNA from 760 U.S. adults--half of them averaging 100 years old and half averaging 39 years old--and identified ones that cropped up more often in extremely old individuals than in the younger volunteers. The SNP that was most enriched in old people resides in a gene that encodes microsomal transfer protein (MTP), which helps assemble low density lipoprotein (LDL), the cholesterol carrier that hardens arteries. Each volunteer carried either a G or a T at the site of interest, which appears in a portion of the gene that adjusts how much of the gene's product is made; previous studies revealed that large amounts of MTP render people susceptible to cardiovascular disease. The G that was found disproportionately in the superold blunts gene activity by 50%. The researchers determined that individuals with the G are 1.4 times more likely to live to be 100 than are those with the T.
The researchers then tried to verify this benefit by repeating the analysis in a French population composed of 500 people averaging 103 years old and 500 averaging 51 years old. The same SNP was enriched in extremely old French seniors but not often enough to be statistically significant. Geneticist David Burke of the University of Michigan, Ann Arbor, says the observation indicates that MTP is not a longevity gene: The result "didn't replicate in the French. So, as my French friends are fond of saying when the discussion is at an end: 'Voil�.' " Gerontologist Nir Barzilai of Albert Einstein College of Medicine in New York City isn't troubled by the French result because the MTP SNP makes only a small contribution to the genetic factors that dictate life span, and other longevity genes undoubtedly make up for it in the French, he says. Puca and colleagues suggest that the discrepancy might be due to environmental factors, such as the French diet. Although French people eat a lot of fat in cheese and rich sauces, they aren't keeling over from cardiovascular disease, a phenomenon known as the French paradox. Garlic and wine--also staples of French cuisine--reduce MTP activity, Puca notes, so these ingredients might counteract the effects of the detrimental SNP.
Geneticist Lindsay Farrer of Boston University Medical Center says the result is exciting and that "biologically, it makes a lot of sense." Other genes involved in lipid metabolism associate with old age, and cardiovascular disease is one of the highest mortality risks. Perhaps in time, people who don't love garlic will have MTP as a longevity option for their offspring.
November 19, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150