Genetics and Longevity

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DO YOU have immediate family members who have lived unusually long lives? The current consensus traces about 25% of the variation in human longevity to genetic factors. And genetics appears to play a progressively important role in maintaining the “healthspan,” or ongoing good health, of individuals as they age into their 80s and beyond, according to researchers at the University of Calabria in Italy.

Studies of supercentenarians (ages 110+) and semi-supercentenarians (ages 105-109), however, also found that many don’t smoke, don’t drink much alcohol, are not obese and cope well with stress, according to Genetics Home Reference.  And most are women — notably in locations with famously long-lived populations, including Okinawa (Japan) and Ikaria (Greece) — as well as Sardinia, though, exceptionally, centenarians there include a significant proportion of men.

Age-related diseases—high blood pressure, heart disease, cancer, type 2 diabetes— are less likely in people with centenarian parents, and if the diseases do appear, they occur later than in the general population. So-called longevity genes include variants associated with these age-related diseases, for example the APOE gene variants linked to greater risk of Alzheimer’s disease.

Among genetic variants, or alleles, associated with a “very long life,” for example, is the variant of the ABO gene that determines an individual’s blood will be type O —which is linked to lower risk of coronary heart disease and cancer as well as lower cholesterol levels. A variant in another gene, CDKN2B, plays a role in the cessation of cell division, called senescence, which is thought to contribute to aging.

In a study of more than 75,000 United Kingdom Biobank participants, the offspring of longer-lived parents had more of the protective alleles known to have prominent roles in cardiovascular-related pathways—specifically affecting coronary artery disease, systolic blood pressure, body mass index, cholesterol and triglyceride levels, type-1 diabetes, inflammatory bowel disease and Alzheimer’s disease.

But the single gene, most often called the longevity gene, is sirtuin 6 or SIRT6, which is responsible for repairing DNA. DNA is increasingly prone to breaks with age, which leads to gene rearrangements and mutations that are hallmarks of cancer and aging.

Among 18 rodent species, the SIRT6 gene was more prominent— and DNA repair more efficient—in beavers, which have a lifespan of about 32 years, than in mice, with a lifespan of about three years. Other cellular functions affected by genes include maintenance of regions at the ends of chromosomes, called telomeres, and protection of cells from damage caused by unstable oxygen-containing molecules, known as free radicals.

People with centenarian parents are less likely at age 70 to have age-related diseases common among older adults, according to Genetics Home Reference. On the other hand, during the first seven or eight decades, lifestyle—eating well, not drinking much, avoiding tobacco, staying physically active—is a stronger determinant of health and life span than genetics.

In locations with long-lived populations, one variable that stands out is the “ipoproteic” or low-protein diet, such as the Mediterranean diet: lots of vegetables and beans. Diet may interact with genes, creating more efficient metabolism of nutrients that not only modulates lifespan but also produces epigenetic modifications, according to the Calabrian researchers.

Dietary-restricted mice, which live longer and show a very delayed aging phenotype compared to mice fed ad libitum —eating what they want —have different expression patterns for genes related to DNA repair that is correlated with life extension.

In Sardinia, where the proportion of male centenarians is about equal to that of women, some research has linked the shorter height of men with greater longevity —although only an average of two years longer. Sardinians in general are shorter than Europeans elsewhere; and, in a study comparing local municipalities, as the average height of men declined, their longevity increased.

On the other hand, for everyone in Sardinia— one of five “blue zones,” with the world’s highest proportions of centenarians—the likelihood of living to be 100 years old is about 10-fold higher than for Americans, according to cardiologist James O’Keefe.  Attributing their longevity, not to genes, but to lifestyle, O’Keefe gives credit to more exercise on the hilly terrain, but mostly to lower stress; more time spent with friends, for both men and women; and the willingness of both sexes to talk about stress when it occurs.

—Mary Carpenter

Every Tuesday, well-being editor Mary Carpenter delivers health news you can use.