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There has been a lot of hoopla about a recent study that looked at the genes of people who live to a ripe old age. If you haven’t heard about the Boston University genetic study of centenarians, you must be living in a cave. The story was all over the internet, highlighted on the evening news, and displayed prominently in print media. However, the real gems in this study have not been covered by the media, probably because “the meat” of the story could not be dumbed-down enough to pass editorial review. So, dear readers, let us give it a try.


The Genome-Wide Association Study

BU scientists Paola Sebastiani, a geneticist, Thomas Perls, a geriatrician and scientist, and their colleagues took advantage of a relatively new technique called Genome-Wide Association Study (GWAS). GWAS involves looking at the genomes of a large number of individuals in a group and plotting the relative frequency of each gene in that population.

By looking at the genomes of specific populations, one gets a “signature” of its genetic makeup. For example, a recent study looking at the genetic makeup of Ashkenazi (European origin) and Sephardic (Mediterranean) Jews found that their respective genetic signatures were statistically closer to each other than to the signatures of the non-Jewish populations of Europe and the Mediterranean countries. None of the individual genes have been determined, only their relative contribution to the “signature”. Think of it as pattern recognition of a familiar composer’s work that helps you recognize the composer even though you have not heard the musical composition before. Similarly, in clinical practice, it is often more fruitful to make a diagnosis based on pattern recognition of signs and symptoms rather than analyzing each individual sign/symptom to construct a differential diagnosis.

It is generally accepted that long life is the result of the combined influence of environmental factors (lifestyle choices) and genetic factors. Extensive research has shown that lifestyle choices determine longevity up to about age 85. In order to break through the 85-year barrier, you have to pick your parents wisely.

To explore the genetic contribution to exceptional longevity, the researchers of the longevity study looked at the genetic patterns of 1,055 centenarians and 1,267 controls. They looked at about 290,000 single nucleotide polymorphisms (SNPs). SNPs are single point variations in the basic genetic code. For example, adenine is mutated into guanine. A small genetic difference, such as an A to G mutation, is the genetic basis for many common human variations that we are all aware of—differences in hair color, eye color, skin color, allergies, susceptibility to diseases, and even behavior to some yet unknown degree. The researchers selected 150 of the SNPs that are known to be Longevity Associated Variants (LAV) for further analysis of their association with Extreme Longevity (EL).

The findings were intriguing.

  • As a group, the 150 LAVs predicted Exceptional Longevity with an astounding 77% accuracy. There is good reason to believe that as more oldsters are added to the sample, accuracy will be even higher.
  • Contrary to common sense expectations, only 5 SNPs out of the 150 Longevity Associated Variant SNPs (LAV) were associated with diseases known to be related to unhealthy aging: cardiovascular disease, hypertension, stroke, diabetes, pulmonary disease, macular degeneration, dementia, and cancer.
  • The researchers arrayed the LAVs in clusters. Each cluster has its own unique set of longevity associated variants as well as its own association with disease and longevity.
  • More than 75% of the subjects in clusters C1 – C4 were 106 years of age or older. Forty-six percent of the subjects in these clusters were super-centenarians (age > 110 years). The average age of death for clusters 1 – 4 is 106 -107, with the oldest individual dying at age 119 (!).
  • These data suggest that Exceptional Longevity may be the result of an enrichment of LAVs that counter the effect of disease-risk alleles (genes) and contribute to the compression of morbidity and/or disability to just the last few years of a very long life.

This study is exciting, but it is important to understand that the results are quite preliminary. For instance, cluster C19 is composed of 30 centenarians who lack almost all of the LAVs. Although the Exceptional Longevity of these subjects may be the result of good health behaviors, they could just as well have been the result of chance. Alternatively, they could have been the result of as yet unidentified genetic variants that were not represented in the 290,000 SNP array used to cull out the 150 LAV. In other words, there may be many more genetic modifiers of Extreme Longevity yet to be discovered.

Whole genome sequencing is becoming less and less costly, and it is now feasible to sequence the whole genome of vast numbers of individuals in populations. This almost inevitably will uncover a vastly richer and more nuanced picture of what allows some people stay healthy into extreme old age.


A bit of advice about genome testing

Before you run out and get your genome tested for those 150 longevity variants, be forewarned: You may possess the profile of longevity-associated clusters 1-4, but your path to advanced old age is not guaranteed. You must first clear the “getting to 85 hurdle”—and that is critically dependent on your lifestyle. If you smoke or drink excessively, or if you are overweight or a couch potato, you haven’t made your contribution to healthy aging.


Some musical parting words (from the Sporting Life in Porgy and Bess):

Methus’lah lived nine hundred years,
But who calls dat livin’
When no gal will give in
To no man what’s nine hundred years

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.