DEATH

Secrets of the centenarians: Life begins at 100

07 September 2009 by Ed Yong


THIS year, the number of pensioners in the UK exceeded the number of minors for the first time in history. That's remarkable in its own right, but the real "population explosion" has been among the oldest of the old - the centenarians. In fact, this is the fastest-growing demographic in much of the developed world. In the UK, their numbers have increased by a factor of 60 since the early 20th century. And their ranks are set to swell even further, thanks to the ageing baby-boomer generation: by 2030 there will be about a million worldwide.

These trends raise social, ethical and economic dilemmas. Are medical advances artificially prolonging life with little regard for the quality of that life? Old age brings an increased risk of chronic disease, disability and dementia, and if growing numbers of elderly people become dependent on state or familial support, society faces skyrocketing costs and commitments. This is the dark cloud outside the silver lining of increasing longevity. Yet researchers who study the oldest old have made a surprising discovery that presents a less bleak vision of the future than many anticipate.

It is becoming clear that people who break through the 90-plus barrier represent a physical elite, markedly different from the elderly who typically die younger than them. Far from gaining a longer burden of disability, their extra years are often healthy ones. They have a remarkable ability to live through, delay or entirely escape a host of diseases that kill off most of their peers. Supercentenarians - people aged 110 or over - are even better examples of ageing gracefully. "As a demographic group, they basically didn't exist in the 1970s or 80s," says Craig Willcox of the Okinawa Centenarian Study in Japan. "They have some sort of genetic booster rocket and they seem to be functioning better for longer periods of time than centenarians." The average supercentenarian had freely gone about their daily life until the age of 105 or so, some five to 10 years longer even than centenarians, who are themselves the physical equivalent of people eight to 10 years their junior. This isn't just good news for the oldest old and for society in general; it also provides clues about how more of us might achieve a long and healthy old age.

One of the most comprehensive studies comes from Denmark. In 1998, Kaare Christensen at the University of Southern Denmark, in Odense, exploited the country's exemplary registries to contact every single one of the 3600 people born in 1905 who was still alive. Assessing their health over the subsequent decade, he found that the proportion of people who managed to remain independent throughout was constantly around one-third of the total: each individual risked becoming more infirm, but the unhealthiest ones passed away at earlier ages, leaving the strongest behind. In 2005, only 166 of the people in Christensen's sample were alive, but one-third of those were still entirely self-sufficient (Proceedings of the National Academy of Sciences, vol 105, p 13274). This is good news from both personal and societal perspectives, for it means that exceptional longevity does not necessarily lead to exceptional levels of disability.

Christensen's optimistic findings are echoed in studies all over the world. In the US, almost all of the 700-plus people recruited to the New England Centenarian Study (NECS) since it began in 1994 had lived independently until the age of 90, and 40 per cent of supercentenarians in the study could still look after themselves. In the UK, Carol Brayne at the University of Cambridge studied 958 people aged over 90 and found that only one-quarter of them were living in institutions or nursing homes. Likewise, research in China reveals that before their deaths, centenarians and nonagenarians spend fewer days ill and bedridden than younger elderly groups, though the end comes quickly when it finally comes.

Distinctive minds
Of course, people can live independently without being entirely healthy, and it is true that most centenarians suffer from some sort of ailment. These range from osteoarthritis - which is almost universal and often omitted from studies - to simple loneliness. Neurodegenerative diseases are common too, with around 70 to 85 per cent of centenarians suffering from some form of dementia. But dementia in this group follows a different pattern to the general population. It is more likely to be vascular dementia or rare neurodegenerative conditions such as Pick's disease or Lewy body disease.

Alzheimer's disease, the most common form of dementia, is relatively rare among centenarians yet, intriguingly, autopsies reveal that the brains of the oldest old, who had shown no outward sign of dementia, are sometimes riddled with the lesions associated with Alzheimer's disease. The basis of this resilience to Alzheimer's is largely unknown. The simple fact is that many people who become centenarians seem able to tolerate damage that would significantly harm less robust individuals, and although many suffer from dementia as death draws near, most remain mentally agile well into their nineties.

Not all of the oldest old survive by delaying illness or disability, though - many soldier through it. Jessica Evert of Ohio State University in Columbus examined the medical histories of over 400 centenarians (The Journals of Gerontology Series A, vol 58, p 232). She found that those who achieve extreme longevity tend to fall into three categories. About 40 per cent were "delayers", who avoided chronic diseases until after the age of 80. This "compression of morbidity", where chronic illness and disability are squeezed into ever-shorter periods at the end of life, is a recent trend among ageing populations. Another 40 per cent were "survivors", who suffered from chronic diseases before the age of 80 but lived longer to tell the tale. The final 20 per cent were "escapers", who hit their century with no sign of the most common chronic diseases, including heart disease, cancer, diabetes, hypertension and stroke. Intriguingly, one-third of male centenarians were in this category, compared with only 15 per cent of women (see "Two paths to 100").

So what are the secrets of a long and healthy life? Gerontologists point to four key factors: diet, exercise, "psycho-spiritual" and social, so anyone aiming for a century should not underestimate the power of lifestyle - despite the odd centenarian who proudly claims to have smoked 60 cigarettes a day for decades. Thomas Perls, who heads the NECS, believes that up to 70 per cent of longevity is due to non-genetic factors (New Scientist, 3 June 2006, p 35). Nevertheless, many people who live well into old age do tend to have another advantage: an inherited genetic pass.

Take a close relative of a centenarian and you can put good money on their chances of living a long life. Among Americans born in 1900, brothers of centenarians were 17 times as likely to reach a century as their peers, and sisters, eight times. The New England study reveals that the children of centenarians are less than one-third as likely to die of cancer as the general population, and less than one-sixth as likely to die of heart disease.

Further evidence of a genetic link comes from longevity hotspots. Okinawa in Japan is the front runner. At 58 centenarians per 100,000 people (and rising), it has the world's highest proportion in this age group - more than five times the level of some developed countries. Like other hotspots, including Sardinia and Iceland, Okinawa is a relatively isolated island community, which leads to higher levels of inbreeding and a clustering of genetic variants. While such genetic similarity usually has detrimental effects, in these hotspots it seems to have united and maintained genetic variants that predispose people to a long life.

Of course, members of isolated communities or families usually share a particular environment too, but this alone cannot explain clusters of longevity. Gerontologists have found that the influence of environmental factors such as wealth or education on lifespan fades as we age, while that of genes increases. By comparing 10,000 pairs of Scandinavian twins, Christensen found that genes only start exerting a strong influence on our lifespan after the age of 60. Before then, both identical and non-identical twins have largely independent odds of reaching a given age. Beyond 60, however, the odds of one twin reaching a given age are greatly increased if their co-twin has done so, especially if the twins are identical (Human Genetics, vol 119, p 1432).

This makes the "centenarian genome" a key resource for identifying "longevity genes", an invaluable step in understanding the physiological processes underlying long lives. Such genes have been found in abundance in other organisms - including over 70 in the worm Caenorhabditis elegans. Unfortunately, it's a different story in humans. While many candidate genes have been suggested to affect lifespan, very few have been consistently verified in multiple populations.

The centenarian genome is a key resource in identifying longevity genes
Until recently, the only exception was ApoE, and in particular a variant of this gene known as e4, which bestows carriers with a much higher than average risk of developing Alzheimer's and heart disease. Across the world, this unfortunate version of ApoE is about half as common in centenarians as in younger adults. Last year, a second promising candidate emerged - a variant of a gene called FOXO3A. At the University of Hawaii, a team led by Bradley Willcox, Craig's identical twin, found that people who carried two copies of a particular form of the gene were almost three times as likely to make it to 100 than those without the variation, and also tended to start their journey into old age with better health and lower levels of stroke, heart disease and cancer (Proceedings of the National Academy of Sciences, vol 105, p 37). "There are so many false positives in this field that FOXO3A is very exciting," says Bradley Willcox.

FOXO3A is involved in several signalling pathways that are conserved across animal species. It controls the insulin/IGF-1 pathway, which influences how our bodies process food. It also controls genes that protect cells from highly reactive oxygen radicals - molecules often thought to drive human ageing through the cumulative damage they wreak on DNA. FOXO3A could even protect against cancer by encouraging apoptosis, whereby compromised cells commit suicide. The variant of FOXO3A associated with longevity is much more prevalent in 100-year-olds even than in 95-year-olds, which clearly demonstrates the value of studying the centenarian genome.

So far the search for longevity genes in humans has been extremely difficult, but prospects brighten as genomic technologies become faster and there are more centenarians to study. Only a lucky few win the genetic lottery of longevity, but if we understand what sets them apart, we may be able to make the rest of us more like them by using lifestyle or therapeutic interventions to manipulate physiological pathways. Such medical advances will not only extend our lives, but also help us remain healthy and independent for as long as possible.

Gallery: Six famous centenarians

Two paths to 100
The two sexes fare very differently in the longevity stakes. There are far more female centenarians than male ones, but men who do make it past 100 tend to be more physically robust and mentally sharper.

The reasons behind this are unclear. It may be simply that the female body is better able to tolerate chronic illnesses and disabilities as it ages. However, natural advantage cannot be the whole story as female centenarians are more likely than their male peers to have ridden to 100 on the back of healthy lifestyles.

"For all the major health hazards, women take better care of themselves," says Craig Willcox of Okinawa International University in Japan, who works on the Okinawa Centenarian Study. "They smoke less, drink less alcohol and are less likely to die of violent causes, accidents and suicides. They also go to their physician more."

Men, meanwhile, have the double disadvantage of being both more prone to risky behaviours throughout their lives and more likely to succumb to chronic illnesses as they age. This means that men who do make it to their century must depend more on genetic trump cards to see them through.

Dying of old age
"There is one, and only one, cause of death at older ages. And that is old age." So said Leonard Hayflick, one of the most influential gerontologists of all time. But dying of old age isn't just a case of peacefully losing the will to live - it is an accumulation of diseases and injuries different to those that tend to kill people at younger ages.

For a start, the oldest old have very low rates of chronic diseases such as cancer, heart disease and stroke. The trend is particularly apparent for cancer. The odds of developing it increase sharply as people age, but they fall from the age of 84, and plummet from 90 onwards. Only 4 per cent of centenarians die of cancer, compared with 40 per cent of people that die in their fifties and sixties.

Many centenarians even manage to ward off chronic diseases after indulging in a lifetime of serious health risks. Many people in the New England Centenarian Study experienced a century free of cancer or heart disease despite smoking as many as 60 cigarettes a day for 50 years. The same story applies to people from Japan's longevity hotspot, Okinawa, where around half of the local supercentenarians had a history of smoking and one-third were regular alcohol drinkers. These people may well have genes that protect them from the dangers of carcinogens or the random mutations that crop up naturally when cells divide.

So what does kill off the oldest old? Pneumonia is the biggest culprit, with other respiratory infections, accidents and intestinal problems trailing behind. "Dying of old age involves total systems failure," says Craig Willcox of the Okinawa Centenarian Study in Japan. "Centenarians avoid age-associated diseases, but you see a lot of systemic wear and tear. Almost all of them have had some problems with cataracts, they can't hear very well and have osteoarthritis. Our most recently deceased centenarian in Okinawa caught a cold and died in her sleep."
Ed Yong is a science writer based in London