23 January 2003 17:00 GMT

by Sabine Louët

Studies on people who have passed their hundredth birthday are revealing the role that genetics plays in age-related disease. Many age-related diseases result from inflammatory processes, and centenarians enjoy unusually low inflammatory profiles, says Italian immunologist, Claudio Franceschi.

Franceschi, professor of immunology at the University of Bologna, Italy, says that his work on centenarians has revealed a genetic link between a mechanism for chronic inflammation and aging. "People are prone to develop inflammation on a genetic basis," he said.

Franceschi discovered that centenarians present low levels of the pro-inflammatory cytokine interleukin 6 (IL-6) and high levels of the anti-inflammatory cytokine IL-10. High levels of IL-6, which is produced in muscles and bones, is related to loss of muscle mass and power with age. Such status translates into frailty and disability and the occurrence of diseases such as osteoporosis.

"There is a balance between pro- and anti-inflammatory compounds [that is] genetically controlled," Franceschi told delegates at last month's Biochemical Society meeting held at Imperial College in London. People with certain genes that trigger an imbalance between a pro- and an anti-inflammatory cytokine are more likely to suffer from chronic inflammation related to ageing, he says.

Although 25% to 30% of longevity is due to a genetic background, says Efstathios Gonos, director of research specialised in ageing at the National Hellenic Research Foundation in Athens, "It is extremely unlikely that there is a single gene causing longevity."

The genetic make up of centenarians can thus provide a useful tool in the investigation of age-related diseases. Indeed, Franceschi brands centenarians "extreme phenotypes" that comprise all the genetic elements necessary to avoid age-related diseases. Conversely, high IL-6 levels can be considered as a genetic marker for morbidity and mortality in the elderly.

This does not come as a surprise to researcher of age-related diseases Jonathan Powell, from Unilever Research in the UK. Pro-inflammatory cytokine IL-6 is not only linked to the immune system. It is also a major metabolic regulator found in primitive organisms such as tubeworms and starfish, which have no immune system. "IL-6 has acquired some other functionality as we have evolved. But those old metabolic functions are still there in us," said Powell.

"As more and more and more of these associations are found, we'll have a better idea of the predictive value of those genotypes," he said. Genetic markers could then, one day, help in identifying subjects at higher risk, and of a new preventative medicine. "Inflammation does not describe all of ageing but it has a significant component, " said Powell.

"Major age-related diseases all share an inflammatory pathogenesis," said Franceschi. Different diseases such as arthritis and Alzheimer's disease share the same inflammatory mechanism, he adds. People treated with anti-inflammatory compounds for arthritis have a lower risk of getting Alzheimer's.

The finding of a genetic susceptibility to age-related disease also fits with an evolutionary perspective. Centenarians present low levels of pro-inflammatory cytokine IL-6, which protects them from age-related inflammatory diseases. According to Franceschi, showing a strong inflammatory response is an advantage before the age of 50 but it is detrimental in later life when the reproduction-driven force of evolution decreases. "From an evolutionary perspective, the objective is not to live long but to be fit enough to reproduce", agreed Gonos.

In addition, Franceschi has identified a difference in cytokine levels between men and women. He believes that genetics plays a greater role in protecting men from inflammatory disease than protecting women, because women have more protective hormones. "Women are less prone to having high inflammatory status because it is detrimental for bearing children," he said.

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