Longevity is in the Genes

Although it is generally accepted that environmental factors play a greater role in determining a person's lifespan than the genetic makeup, several "longevity genes" have been discovered in the past few years, suggesting certain genotypes are strongly associated with longevity in some populations. (Proc Biol Sci 2008 June 07; Epub ahead of print)

"We know from studies of caloric restriction models in animals that environment is really important, but we decided to look at a group of centenarians for genetic clues," reported Dr. Nir Barzilai at a plenary lecture entitled "Why did Moses live to be 120?"

Barzilai and colleagues from the Albert Einstein College of Medicine, New York, US, asked whether healthy centenarians have a characteristic genotype and phenotype that protects them from the metabolic syndrome and a decline in the endocrine axis (i.e. Sex hormones and growth hormone).

The researches recruited a genetically homogeneous population of 450 unrelated Ashkenazi Jews with exceptional longevity (95-108 years of age) and 400 offspring of these subjects.

"Of course, we had no matching control group for the centenarians, but we assumed that offspring of centenarians are also enriched with longevity genotypes and phenotypes. The study of offspring permits comparisons with age - and gender-matched controls," explained Barzilai.

There were no vegetarians or former athletes among the centenarians; some reported they were obese in their 50s and 60s, and many were former or even current smokers. "This is a really unique group of individuals who reached very old age despite unhealthy lifestyle and are still healthy and active," e remarked.

The investigators assessed the subjects' clinical, metabolic and endocrine phenotype, looking at their general health status, lipoprotein profile, insulin and insulin growth factor 1 (IGF-1) and thyroid stimulating hormone.

"We found that the offspring of centenarians were less likely to have age-related diseases such as hypertension, diabetes, MI and stroke, than matched controls, which might be expected," reported Barzilai. "Moreover, the prevalence of these diseases among the centenarians was also lower than in the control group, which was the age of their children."

The result showed that centenarians have a unique lipoprotein profile (high HDL and less small dense LDL) that is inherited by their offspring. The researchers then used several methods to detect single nucleotide polymorphisms in genes associated with this phenotype to discover new mutations.

"We identified three genotypes that monotonically increase between age 60 to 108 years in unrelated individuals and are over-expressed by two or three fold in the oldest old group," he said. These include cholesterol ester transfer protein (CETP), apolipoprotein c-3 and adiponectin.

According to Barzilai, all these genotypes were validated by the least one additional study and were associated with clinically significant phenotypes. "Each genotype was associated with more than one outcome. For example, CETP VV genotype was linked to improved cognitive function in centenarians and their offspring," he noted.

The study also demonstrated the role of IGF-1 receptor mutation and telomere length in exceptional longevity and good health.

"These genotypes may play a role in conferring survival to exceptionally old age (individuals) by providing protection from the metabolic syndrome and other endocrine manifestations of aging. Hopefully, our studies will lead to a drug that can prevent the chronic debilitating age-related disease," Barzilai suggested.