You might know of someone, a blood relative if you’re lucky or perhaps a neighbor next door, who has lived long enough to watch the events of the past century unfold. Well-known examples of such extreme longevity include Queen Elizabeth of England and the Academy Award-winning actor George Burns. Perhaps those people, whether personally familiar or famous, took especially good care of themselves. Or did some of them pull it off even while pouring on the gravy or puffing cigarettes from an easy chair?

Either way, what those centenarians have achieved is still a rare and remarkable feat. The latest data from the U.S. Census Bureau show that, in 2010, there were fewer than two centenarians for every 10,000 people in the country. Even among older people age 70 and up, centenarians are still very few and far between. (See article on page 42 for a discussion of how longevity is shifting.)

In many cases, people who live to see 100 don’t just have longer life spans but longer “health spans,” too. They survive in part by escaping diseases that drag the rest of us down: cancer, dementia, and cardiovascular disease. Studies have found that centenarians enjoy healthy metabolic signatures and especially healthy blood lipid profiles, in comparison to your average 70- to 90-year-olds. When centenarians die at the age of 100-plus, they often seem to die quickly, with little time spent sick or suffering and fewer medical bills.

In search of clues to help more people live both longer and healthier, scientists around the world are asking a simple question: What is it exactly that makes those already celebrating their 100th birthdays — against today’s odds — so special?

Like most complex traits, the keys to longevity will be found in genes and the environment and the complicated interactions within and between the two. Research has shown that siblings of centenarians are 8 to 17 times more likely to reach 100 themselves. A study of twins born in Denmark found longevity to be moderately heritable. About 25 percent of the variation in the life span of those twins was attributed to genetic as opposed to environmental influences.

It’s now generally accepted that longevity is about 25 to 30 percent dependent on the genes we carry. By the time a person reaches the age of 65, however, the role of genetics is magnified. The likelihood that people living to retirement age will have time to really enjoy themselves is 36 percent a question about genetics, and the genetic contribution to longevity goes up from there.

Clearly the places people live and the lifestyle choices they make will always be important when it comes to living longer. There are particular places on earth where it seems pretty obvious that something very special is going on. Dan Buettner and National Geographic have traveled the world looking for those spots — frequently small, close-knit communities — where people live the longest to find out how they do it and spread the word.

Those living in their so-called Blue Zones survive to 100 at rates 10 times that of other places. The Greek island of Ikaria has been referred to as the “island where people forget to die.” The reasons are uncertain and probably many: meager and homegrown diets, a relaxed approach to scheduling, and evenings spent sipping wine with friends and neighbors before enjoying cups of antioxidant tea. This aside, genes still can and do stack the cards against some people’s chances of living to a ripe old age and in favor of others.

Nir Barzilai knows this well, after studying what he calls the Super Agers for more than 15 years as director of the Institute for Aging Research at the Albert Einstein College of Medicine of Yeshiva University in New York City. The more than 500 healthy older people of Ashkenazi Jewish descent in his Longevity Genes Project, age 95 to 112, are clearly unusual.

Take Harold Laufman, who at the age of 98 was still playing the violin, hosting a visit with his grandchildren, and working on a book called To Thrive Past 95. Then there is Lilly Port, who traveled the world at 96, jetting off to Israel, Turkey, Singapore, Indonesia, and Australia. In an online video of her 100th birthday party, you’d be forgiven for thinking she was closer to 75. But many of Barzilai’s centenarians don’t make the best plug for healthy living.

If you look at the lifestyle of our centenarians, Barzilai says, almost 50 percent of them are overweight or obese, 60 percent of the men and 30 percent of the women smoke, and almost none of them eats a vegetarian diet. One woman in the study died at the age of 110 after smoking for 95 years. “As a group, we see they haven’t done anything special with their environment.”

It’s a trend he says Jay Leno once had a field day with on The Tonight Show. Barzilai recalls Leno’s saying something like, “Scientists have found the secret of longevity. Eat as much as you want, stop exercising, and the good thing is, if you die, you don’t care.”

All laughs aside, if we could find and understand the life-extending genes and gene variants responsible for the Super Agers’ good fortune and that of other people around the world who are predisposed to longevity, then perhaps it would be possible to devise new strategies and drugs to help the rest of us live longer and better. (Let’s face it: The idyllic approach to life found on that Greek island isn’t obtainable for most.)

Teams around the world have been working to do just that, bit by bit, for years, and the idea has attracted new energy and investment lately from high-profile places. In September 2013, Google announced the launch of Calico, a company that aims to apply “moonshot thinking” to the challenges of health, well-being, and especially aging and aging-related disease.

Google’s Calico announcement was followed last spring by another, this one from Craig Venter, best known for his role in the race to sequence the first reference human genome. Now he is going after death and aging with a company called Human Longevity and plans to build the world’s largest human DNA sequencing operation in search of the answers to long life.

A group of Silicon Valley investors is also fed up with aging. They’ve launched the Palo Alto Longevity Prize, offering two $500,000 awards to the first teams that show they can reverse one sign of aging or extend life span by 50 percent in the lab.

“We spend more than $2 trillion per year on health care and do a pretty good job helping people live longer, but ultimately you still die,” says Joon Yun, a doctor and backer of the prize. “The better plan is to end health care altogether.” As the website describing the prize says, “Let’s hack the code!” and put an end to aging.

Scientists have uncovered a list of candidate longevity genes based on long-term studies of long-lived people — often along with their children, elderly siblings, or spouses — begun well before today’s era of cheap and fast whole-genome sequencing. Yet only a couple of those many genes consistently show up in independent studies in connection with what passes now for “extreme longevity,” defined as living at least to age 90.

One gene that has turned up again and again across long-lived populations and studies is known as FOXO3. FOXO3 has been described as a gene that can flip the longevity switch, although it isn’t exactly clear how. The gene also has a role to play in cancer and in antioxidant pathways that help manage stress at the cellular level.

But the most high profile of the bona fide longevity genes has to be APOE. One variant, APOE4, is the most significant known genetic risk factor for Alzheimer’s disease. APOE2, on the other hand, is at the top of the list of gene variants associated with long life.

Yun Freudenberg-Hua of the Litwin-Zucker Research Center for the Study of Alzheimer’s Disease and Memory Disorders at the Feinstein Institute for Medical Research in Manhasset, New York, describes it as two sides of the same coin. People who don’t carry the disease risk variant for APOE may have the protective variant instead. In addition to its role in Alzheimer’s disease risk, APOE is also connected to the risk of cardiovascular disease and plays a role in the transport of cholesterol and lipoproteins.

When it comes to living longer, metabolism and healthy lipid profiles in particular appear to be an important part of the equation in many cases. In Barzilai’s relatively homogeneous group of Ashkenazi Jews, those who live for a long time also often carry a beneficial version of a gene called CETP, which is tied to higher concentrations of the “good” HDL cholesterol, the kind one can get by consuming plenty of olive oil.

A new study of exomes — the full sequence of protein-coding genes in the genome — of people representing three long-lived families uncovered another new longevity gene candidate. That gene, known as APOB, works together with APOE to transport cholesterol. Timothy Cash, of the Spanish National Cancer Research Centre in Madrid and the first author of the study, says that while they are still working to pin down the function of the APOB mutation they’ve found, known mutations in the gene lead to hypercholesterolemia — very high cholesterol — and an early heart attack death. Other versions of the gene can produce the opposite: exceptionally low circulating levels of cholesterol.

For P. Eline Slagboom of the Netherlands Consortium for Healthy Ageing and the Leiden Longevity Study, which includes more than 400 long-lived families, much of what is now known about the genetics of longevity seems to point in one direction.

“What is especially striking in long-lived families is that their metabolism is so healthy,” she says. “They can have the same food intake pattern and weight and BMI, and yet they do something different with their nutrition or metabolic health.”

While there may be something uniquely favorable about the metabolic makeup of centenarians, they surely don’t have a perfect, disease-free genome. Freudenberg-Hua and a team including Barzilai recently sequenced the complete genomes of 44 of the Ashkenazi Jewish centenarians Barzilai has been studying for so many years. They turned up 130 relatively rare coding variants in those genomes that have been identified as pathogenic, or likely to cause disease, including mutations known to influence cardiomyopathies, arrhythmias, cancers, degenerative diseases, and more.

Perhaps most surprising, Freudenberg-Hua says, was one individual who was found to carry two APOE4 alleles, a combination that should make a diagnosis of Alzheimer’s by age 80 almost certain. At the age of 97, however, the individual in question had no sign of dementia.

The Leiden Longevity Study in the Netherlands has turned up a similar pattern. The study participants who are older than 90 carry just as many risk alleles for cardiovascular disease, cancer, and type 2 diabetes as do younger people in the general population.

In other words, the centenarians aren’t growing old because they hit the jackpot and came up with a genome that is free of trouble spots. Instead, some other combination of genes, working together with the environment, must counteract the detrimental effects of the disease variants they do carry.

Barzilai suggests that his centenarians and others may be protected from disease because their bodies age at a slower rate. Perhaps those people who look a decade or more younger than their years really are at that biological level. After all, aging is the No. 1 risk factor for all age-related diseases, such as cancer, diabetes, Alzheimer’s, and cardiovascular disease.

While high cholesterol might up the risk of cardiovascular disease three fold, Barzilai notes, aging multiplies that risk by something closer to 1,000. More importantly, aging increases the odds of developing essentially all of the major common diseases concurrently.

“When we look at this relationship, we say unless you prevent aging, there is no way to make a real impact [on health],” Barzilai says. The way he sees it, by treating diseases one by one — a heart attack, for example — all you do is trade one condition for another. While someone might get past that cardiovascular event, down the road he’ll turn up with another disease and then another, because “you never changed the rates of aging.”

As the complete genomes of all these well-studied centenarians start to come in and yield more answers, what if Barzilai, Calico, Human Longevity, and all the rest get their way? Imagine, for a moment, what might happen if it were possible to slow aging itself? Some think aging should be reclassified as a disease, if only to encourage the search for and approval of drugs designed primarily to fight against time.

Curing aging is surely not simple, and not everyone thinks it’s very likely. Aging, after all, is really a fact of life.

“I look at aging as a biologic process unique to each individual,” says Eric Topol, a cardiologist, the director of Scripps Translational Science Institute, and a member of Genome’s board of advisors. With the Wellderly Study, Topol is busy sequencing the genomes of 1,400 people who have lived to the age of 85 with a clean bill of health. “I don’t see aging as a disease, no. But when one ages, the process makes people more susceptible to a variety of late-onset conditions. Some are preventable or actionable, and in the future I think they’ll be far better managed. I don’t believe it will be easy to control aging with drugs or to change the aging process. It would be wonderful, but I think it’s far-reaching.”

For now, you can do plenty to live a longer and healthier life without taking an anti-aging pill or moving to Ikaria. In addition to the usual advice to eat right and exercise, it also pays to have the right attitude.

“When I started working with centenarians, I thought we’d find they survived so long in part because they were mean and ornery,” Barzilai says. Instead, he has found them to be outgoing, optimistic, and easygoing. They value laughter, express their emotions, and have a large social network.

In fact, says Freudenberg-Hua, who is a geriatric psychiatrist and a geneticist, there is general consensus that a positive attitude toward life really pays when it comes to longevity.

So, go ahead, call up a friend, laugh, and enjoy yourself. You might just buy yourself some time.