US scientists studying the genes of a large group of centenarians found 150 unique DNA sequences predicted exceptional longevity with 77 per cent accuracy, and showed that 19 clusters of the sequences or “genetic signatures” had strong links with different age-related diseases: but perhaps most remarkably they found that these genetic signatures predicted longevity more strongly than the absence of disease-related variants. They hope their findings will be useful for developing better prevention and screening tools and personalized medicine.

The researchers also cautioned that the discovery that genes play such a strong part in exceptional longevity does not mean lifestyle factors such as following a healthy diet and exercising are ineffective; they still play an important role in helping humans live to a healthy old age, they stressed.

Drs Paola Sebastiani, a professor of biostatistics at the Boston University (BU) School of Public Health and Thomas Perls, associate professor of medicine at the BU School of Medicine and a geriatrician at Boston Medical Center, led the study, which is published in the 1 July online issue of Science.

While healthy aging appears to be influenced by environment and family history, it would appear from this study that genetic variants have a strong and complex influence on exceptional longevity.

As a first step, the researchers conducted a genome-wide association study in 1,055 centenarians and 1,267 controls. Centenarians are considered a model of healthy aging because they tend not to get many of the diseases of aging until they are well into the mid 90s.

From the genome data the researchers built a model based on 150 single-nucleotide polymorphisms (SNPs: unique sequences of DNA from inside or between genes).

Using the 150 SNP model the team found they could predict exceptional longevity (living to late 90s or more) with 77 per cent accuracy in a separate, independent group of centenarians and controls.

They also noted that 45 per cent of the oldest centenarians (110 years old or more), had the highest proportion of longevity- linked SNPs.

In a second analysis the researchers showed there were strong links between 19 clusters of SNPs, which they termed “genetic signatures”, and the prevalence and onset of age-related diseases like dementia, high blood pressure and cardiovascular disease, in 90 per cent of the centenarians.

Although these genetic signatures had varying predictive value the team said they may help identify key subgroups of healthy aging.

Perls, who is founder and director of the New England Centenarian Study, told the press that the discovery of these genetic signatures is an important step towards the development of personalized and predictive medicine that takes into account the genetic make up of the patient.

“This analytic method may prove to be generally useful in prevention and screening of numerous diseases, as well as the tailored uses of medications,” he added.

Sebastiani said that the method they used to arrive at the 150 SNPs for their model could be applied to other complex genetic traits like Alzheimer’s and Parkinson’s, diabetes and cardiovascular diseases.

” It reinvigorates the potential high utility of collecting and analyzing such data,” she said.

As well as looking at which SNPs were linked to longevity, the team tried to find out if the absence of disease-related variants also made a difference.

They found that regardless of how many disease-related variants each centenarian had compared to controls, they made little difference to the predictive value of the longevity-linked SNPs, suggesting that having longevity genes had a stronger influence on how long they lived compared to the absence of disease-related variants.

This is an astonishing finding, because if confirmed by other studies, it suggests, as the authors themselves noted, that:

“Predicting disease risk using disease-associated variants may be inaccurate and potentially misleading, without more information about other genetic variants that could attenuate such risk.”

In conclusion the researchers wrote that their findings suggest exceptional longevity may be:

“The result of an enrichment of longevity-associated variants that counter the effect of disease-associated variants and contribute to the compression of morbidity and/or disability towards the end of these very long lives.”

They said further studies are now needed to help us better understand how and why these variants, both individually and together, influence exceptional longevity.

But they added a note of caution for those who use this study as a reason to give up following a healthy lifestyle. They noted that the 77 per cent predictive accuracy of the 150 SNP model is not perfect, and while it may help improve our knowledge of the genes behind longevity:

“Its limitations confirm that environmental factors (eg lifestyle) also contribute in important ways to the ability of humans to survive to very old ages.”

The researchers also cautioned that their model has only been shown to work with the groups in the study: it would have to be tested with a wider population before it could be used in a clinical setting.

“Genetic Signatures of Exceptional Longevity in Humans.”
Paola Sebastiani, Nadia Solovieff, Annibale Puca, Stephen W. Hartley, Efthymia Melista, Stacy Andersen, Daniel A. Dworkis, Jemma B. Wilk, Richard H. Myers, Martin H. Steinberg, Monty Montano, Clinton T. Baldwin, and Thomas T. Perls
Science, Published online 1 July 2010
DOI: 10.1126/science.1190532