Longevity Gene GWAS

Life span has increased greatly in the last 200 years. But many of the extra years are not lived while in good health. It is been estimated that in modern society only 75 to 80% of life is spent in good health. But there are populations in which older people remain in good health throughout old age. There have been various types of studies to find out whether there is a genetic component to longevity, that is, a longevity gene. Estimates are that approximately 25% of life span variation is due to genetics.

Human genomeA Recent Longevity Gene Study

Despite all this interest, until a recent study there had been only one longevity gene candidate that was found associated with longevity. The present study (1) did a meta-analysis of Genetic-Wide Association Studies (GWAS) for longevity in the older European population. This study found one additional longevity gene (gene associated with longevity).

The researchers felt that this additional longevity gene works by reducing the risk of dying from stroke. They also found it to be associated with lower blood pressure in middle-aged Europeans. These two associations make it very likely that this longevity gene is associated with either sodium or potassium control in the cell. However, the researchers did no studies on the function of the gene.

The longevity gene that this study discovered was not the same gene as the gene that was discussed in the post about the Sardinian centenarians. The report about the Sardinian gene was published in January of this year, and was discovered by a targeted genetic study, not by a GWAS. That report showed that in older Sardinians there was a high percentage of a gene variant that slowed sodium reabsorption.

Too Many Variables

Because the present study involved the general European population, there was a greater mixture of genes and environmental factors than in the Sardinians. This greater mixture makes it very difficult to find genes that contribute to longevity. If there are multiple biochemical pathways with potential longevity genes that are affected by environmental factors, there will be too many variables to account for.

Each potential longevity gene interacts with environmental factors to determine longevity. Because there are so many variants of each of these genes, it would be expected that any particular variant associated with longevity would be rare. This means that none would stand out in a GWAS. More targeted genetic studies in more uniform populations, such as was done in the Sardinian study, are more likely to find genes associated with longevity.

Sardinian Study

In the Sardinian study the Sardinians were relatively uniform in their genetics, having little contribution from genes outside of Sardinia. This genetic isolation has been for several centuries, if not longer. So there has been less chance for a mixture of genes and their variants. The genes that would contribute to longevity would not be as varied, and it would be easier to find contributing variants.

Also the Sardinian study was done in families living as herders in a mountainous area, providing a greater environmental uniformity. Since their physical activity and diet were more uniform than in the general European population, these well known environmental factors would have less influence on differences in longevity.

Approaches other than a Genome-Wide Association Study (GWAS) are needed to find genes associated with longevity. A GWAS involves screening many thousands of genes. A more focused study on some of the areas where there are a great number of centenarians or older individuals, and where there has been little genetic mixture and environmental variation will be more likely to find other genes associated with healthy longevity.

Other Approaches

Because of the high prevalence of hypertension, cardiovascular disease and strokes in old age, and the reduction in function they cause, the genes associated with these diseases would be the best early choices to target in studies looking for longevity genes. As discussed here, many of the genes involved in hypertension are variants involving potassium channels, sodium channels, and calcium channels. In addition to these genes, gene variants in sodium and potassium transporter proteins, and sodium potassium ATPase pump proteins would be good genes to examine.

One of the Blue Zones, made popular by Dan Buettner, would be a good place to start targeted longevity gene studies. Sardinia was one of the Blue Zone areas, and it made possible discovery of a sodium reabsorption gene that may have contributed to the longevity of Sardinians. And some of the other Blue Zones, as well as Sardinia, may provide good populations in which to study these genes.
1. Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age. Deelen J, Beekman M, Uh HW, Broer L, Ayers KL, Tan Q, Kamatani Y, et al. Hum Mol Genet. 2014 Aug 15;23(16):4420-32. doi: 10.1093/hmg/ddu139. Epub 2014 Mar 31.