Longevity gene mutation discovered

Researchers have discovered the first gene that may play a direct role in longevity by protecting against some of the most important diseases of ageing, such as heart disease, diabetes and stroke.

The study was carried out in a long-lived group of Ashkenazi jews, who are often the subject of genetics studies as they have been a close-knit community over many generations and as a result have a remarkably homogeneous genetic make-up. This makes it easier to look for individual genetic mutations that have an impact on a particular trait.

"Individuals with exceptional longevity have a lower incidence and/or significant delay in the onset of age-related disease,"​ said the researchers, led by Nir Barzilai of the Albert Einstein College of Medicine of Yeshiva University in the USA.

Barzilai's team wanted to see whether their family members may inherit biological factors that modulate ageing processes and disease susceptibility. They recruited 213 long-lived Ashkenazi subjects - with an average age of 98 - and 216 of their children. An age-matched group of Ashkenazi jews, and a similar cohort from the large-scale Framingham epidemiological study, were used as controls.

The researchers found that high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particle sizes were significantly higher in the long-lived subjects compared with both control groups (P= 0.001). A high level of HDL is thought to exert a protective effect against cardiovascular disease, while LDL has the opposite effect.

The subjects children also showed the same tendency on particle size, but it was not observed in the control groups. Interestingly, there was no correlation between the overall plasma levels of HDL and LDL, as well as two other particles thought to have an effect on cardiovascular health (apolipoprotein A1 and B).

HDL and LDL particle sizes were significantly larger in offspring and controls without hypertension or cardiovascular disease, (p=0 .001 and p=0.008, respectively).

W genotype​

The gene mutation that seemed to herald these changes was found to be that coding for CETP (cholesterol ester transfer protein), which is involved with the movement of cholesterol from between plasma and tissues.

Among the men in the study, the long-lived subjects and their offspring had a 2.9-fold increase of the mutation - known as the W genotype - while for women the increase was 1.5 fold compared with controls (p<0.001 for both). Subjects with the VV genotype had increased lipoprotein sizes and lower serum CETP concentrations.

"This is the first gene to be associated with longevity,"​ said Barzilai, although he suggested that many other genes are likely to be involved, as only about a quarter of the long-lived people that he has studied have the CETP mutation.

The rationale behind the protective effect has also not been established. One theory is that the size of the LDL particles in some way inhibits the process that leads to the build-up of atherosclerotic plaques in blood vessels. And it is always possible that there is no direct relationship between the gene and longevity, and it is merely a marker.

Pfizer is among a number of companies that are already developing drugs to affect the activity of CETP, and has a lead compound - CP-529,414 - in Phase II clinical trials.