New Genetic Model Accurately Predicts Who's Likely to Live to 100

In 1997, Jeanne Louise Calment of France died at the age of 122, making her the oldest documented human to have ever lived. But is there something genetically unique about centenarians that enables them to age gracefully and relatively disease-free?

According to the results of a long-term study at Boston University School of Medicine, the answer is yes. People who live to be 100 years or older are rare, and only about 1 in 600,000 people in industrialized nations live that long.

As part of the New England Centenarian Study, a team of aging research specialists led by Paola Sebastiani and Tom Perls looked at 300,000 genetic markers in 800 centenarians and compared their profiles with those of random individuals. They then developed a genetic model that can compute an individual's predisposition to living a long life and found that centenarians shared a common genetic signature that could predict extreme longevity — with 77 percent accuracy. The findings represent a breakthrough in understanding how genes influence human life spans.

"Out of 100 centenarians we could correctly predict the outcome of 77 percent, while we incorrectly predicted the outcome of 23 percent," said Sebastiani. The researchers believe the 23 percent error rate can be attributed to genetic variance not yet known and included in the analysis, as well as other factors that influence longevity. "Making healthy lifestyle choices such as eating a well balanced diet or exercising regularly and avoiding exposure to tobacco plays an undisputed role in determining how each of us will age," said Andrew Sugden, international managing editor of Science.

Centenarians are a model of aging well, and 90 percent of people who reach this milestone are disability free at the average age of 93, Perls said. But he advised caution about the possibility of "testing" people to determine longevity, saying that much more study needs to be done regarding how health care providers and the research community guide individuals about what to do with the information they get. "I think a test for exceptional longevity is not quite ready for prime time," he said. "We're quite a ways from understanding what pathways governed by these genes are involved and how the integration of these genes, not just with themselves but with environmental factors, are all playing a role in this longevity puzzle."

According to Perls, future analysis of the results may shed light on how specific genes protect centenarians from common age-related diseases, such as dementia, heart disease, and cancer. "I look at the complexity of this puzzle and feel very strongly that this will not lead to treatments that will get a lot of people to become centenarians, but it could make a dent in the onset of age-related diseases like Alzheimer's," he said.

Key to long life is having two mothers but no father!

Mice produced in the laboratory from two biological mothers and without a father have been found to live significantly longer than normal mice bred from a mother and a father. These findings indicate that genetic traits inherited from the father but not the mother may play an important role in ageing and longevity.

Researchers from Saga University and Tokyo University of Agriculture, Japan, took DNA (deoxyribonucleic acid) from eggs of one day-old mice and genetically modified it so that it would behave like sperm. They then used it to fertilise eggs from adult mice, thereby producing offspring with two mothers, dubbed bi-maternal mice. Control mice were bred that were genetically identical to the bi-maternal mice except that they had been conceived conventionally using genetic material from a sperm and an egg.

Professor Tomohiro Kono, who led the study, explained the researchers' goals: 'We have known for some time that women tend to live longer than men in almost all countries worldwide, and that these sex-related differences in longevity also occur in many other mammalian species... The study may give an answer to the fundamental questions: that is, whether longevity in mammals is controlled by the [genes] of only one or both parents, and just maybe, why women are at an advantage over men with regard to the lifespan.'

Reporting in the journal Human Reproduction, the researchers compared the lifespans of 13 bi-maternal mice with those of 13 control mice. On average, the bi-maternal mice lived for 841.5 days - 186 days longer than the control mice, which averaged 655.5 days. The researchers also found that the bi-maternal mice were significantly smaller and lighter than the control mice. There were also signs that the bi-maternal mice had better immune systems than the control mice, as they had higher numbers of eosinophils (a type of white blood cell that play an important role in protecting mammals against parasites and infections) in their blood.

The researchers believe that the effects they observed may result from a genetic process called 'imprinting' whereby the activity of a gene depends on whether it is inherited from the mother or the father. They suggest that a gene called Rasgrf1, found on chromosome 9, may be responsible for the increased lifespan and smaller weight of the bi-maternal mice.

Rasgrf1 is an imprinted gene that is always turned on when it is inherited from the father and always turned off when it is inherited from the mother. The bi-maternal mice had two inactive Rasgrf1 genes as they were both inherited from female mice instead of having the usual one active Rasgrf1 gene inherited from a father and one inactive Rasgrf1 gene inherited from a mother. However, Professor Kono emphasised: 'it's not clear whether Rasgrf1 is definitively associated with mouse longevity, but it is one of the strong candidates... we cannot eliminate the possibility that other, unknown genes that rely on their paternal inheritance to function normally may be responsible.'

Professor Kay-Tee Khaw, an expert in ageing at Cambridge University, commented to the BBC: 'These are interesting findings but I think any sex differences in longevity - which in humans have changed over time and differ in different environments - may have more complex explanations than any single gene'.