There's a reason some people don't look as old as they actually are

It's hard not to think, "Wow, they really look old for their age."

The idea that time wears on the body in a predictable way - and that for some people the process is accelerated or slowed - seems obvious. But is it true?

Do we have a bodily timekeeper? Where might it reside? Can we tell whether it's in sync with the calendar?

These questions are central to the mystery of aging, our one-way ride on the arrow of time. They're also important to understanding chronic diseases - the heart attack, stroke, cancer and dementia that grow more likely the older we get. The newest strategy to prevent disease, in fact, is to find ways to slow aging.

"There is such a thing as 'biological age,' and it is distinct from chronological age," said Steve Horvath, a professor of human genetics at UCLA. "There is a huge debate about how to measure it. But everybody would agree 'biological age' should be a better predictor of how long you live than chronological age."

Brian K. Kennedy, who heads the Buck Institute for Research on Aging, in Marin County, Calif., goes a step further.

"I'm a firm believer that there is a 'biological age,' that it is different for different people, and that it can be manipulated," he said. "At least it can be manipulated in animals, and I think we will be able to manipulate it in humans, too."

The idea that biological age is measurable and predictive only recently moved out of the mouse lab into human epidemiology.

A study published last year looked at roughly 1,000 New Zealanders who have been followed by researchers since their birth in the city of Dunedin in 1972 and 1973. The group is periodically given tests of organs (heart, lungs, liver, kidneys, immune system, etc.) whose function slowly begins to decline starting about age 30. The results are used to calculate "biological age."

(The researchers employed a formula developed from a sample of 9,400 Americans aged 30 to 75. Biological age describes how a person's measured physiological profile compares to that of the average person of the same age in the population.)

In the Dunedin study, biological age was calculated for each person when the group was 26, 32 and 38 years old. Because the calculation was done repeatedly over a dozen years, the researchers were also able to estimate a "pace of aging" for each person.

The results were startling. Even though all subjects had a chronological age of 38, their biological ages ranged from 28 to 61. There was a similarly wide range in the pace of aging. A few people showed virtually no aging over 12 years, a few showed three years of biological aging per year lived, and the rest fell in between.

Cognitive and physical function tracked biological age.

People with higher biological age did less well on tests of balance, fine motor skill, grip strength and abstract reasoning. The blood vessels in their retinas - a view into the blood vessels in the brain - looked older. When a panel of college students estimated the age of these Dunedin individuals based on a photograph, those with advanced biological age were judged older. The conclusion was that people who were "biologically old" for their age showed it in many ways - with weaker muscles, slower thinking, narrower arteries and a careworn appearance.

"Our data suggest that aging is a systemic process - that you see an accumulating loss of integrity across many systems of human physiology," said Daniel W. Belsky, an epidemiologist at Duke University who was lead author of the study in the Proceedings of the National Academy of Sciences.

Although few people in the Dunedin group had an age-related chronic disease, research suggests that the biologically old among them will soon start getting sick.

A study last year found that people in their 70s whose biological age is five years greater than their chronological age have a 20 percent higher risk of dying over six years than people whose biological and chronological ages are the same. A study of Danish twins in their 80s found that when a pair has different biological ages, the "older" one was twice as likely to die over the ensuing eight years as the "younger" one.

Biological age appears to be real and able to predict the future, at least to some extent. But what is driving it?

Cell division

For a while it looked like the answer was: "Telomeres."

Telomeres are tails of extra DNA on the end of our chromosomes. The end of the tail gets docked each time a cell divides because the duplicating machinery can't copy the last few DNA "letters" at a chromosome's ends. Some cells have an enzyme that restores telomeres, but in many cells the telomeres shorten over time until the cell loses the ability to divide. It then becomes senescent. Not only may it function poorly, it may also secrete substances that pollute the neighborhood, causing inflammation that leads to disease.

The notion that telomere wear was the engine of aging had many adherents - until research revealed the story was much more complicated.

It is true that short telomeres are associated with a higher risk for heart disease, diabetes, some cancers and poor immune function. Life stress also appears to shorten telomeres, which may partly explain high disease prevalence in the poor.

However, people with a rare mutation that keeps telomeres long are more, not less, susceptible to some cancers, such as melanoma. The reason may be that their cells divide more times, increasing the chance of malignant mutation in ones that are especially vulnerable, such as cells in the skin. Furthermore, many mammals (including mice and rats) have short lives and die with long telomeres; the latter don't assure longevity.

"There's been 20 years of research, and the field has learned that telomere shortening plays a role in aging. But it is not the fundamental cause of aging," Horvath, the genetics professor, said. "We can debate how important it is."

A newer and more informative measure is known as the epigenetic clock. It keeps track of age-related changes in molecules, called methyl groups, that attach to the outside of our strands of DNA, like barnacles on a rope dangling off a dock. "DNA methylation" plays a part in regulating genes; its exact role is still being worked out.

A person's methylation pattern is partly inherited and can be altered by lifestyle and environmental exposures. DNA damage, telomere shortening and cell senescence also change methylation patterns. But the biggest driver is the passage of time.

The most accurate epigenetic clock looks at 353 methylation sites out of millions on our chromosomes. Of those, 193 gain methylation with age and 160 lose it. The clock considers both gains and losses.

People with HIV infection or Down syndrome - conditions that put them at risk for early heart disease and dementia - have older-than-expected epigenetic ages. On the other hand, people who live to be 100 have epigenetic ages that are nine years younger, on average, than their actual age. Interestingly, their children also have younger-than-expected epigenetic ages, which suggests they're aging more slowly, too. (Research suggests that about 25 percent of longevity is determined by genes.)

DNA methylation appears to be a true biological clock, turned on at birth and not stopping until death. Whether it's the engine of aging is another question.

"In my opinion, there is a fundamental aging process - the true root cause of aging," Horvath said. "We are currently designing a large human study that will test to what extent epigenetic changes underlie this process."

Whatever the answer, it's clear that aging slowly, avoiding disease and living a long time are intertwined phenomena.

For example, centenarians not only have retarded biological ages, they're also more likely to carry specific gene variations (called single nucleotide polymorphisms, or SNPs) that protect against disease. A study published last year found five regions in the human genome where such SNPs reside.

In one region, certain SNPs lowered the risk for Alzheimer's disease, high cholesterol and pancreatic cancer. In a second, the SNPs protected against heart disease and diabetes. In a third, they made lung cancer, pancreatic cancer, heart disease and rheumatoid arthritis less likely.

In the end, a person who avoids fatal diseases is likely to grow old and have a body that seems younger than it is, even at age 100. It's hard to know what causes what.

Repairing DNA damage

The fact that we don't yet know the fundamental drivers of aging may be irrelevant. That's because we already know enough about how aging happens in organs, cells and molecules to tinker with it.

For a cell to remain youthful, it has to maintain the ability to detect and repair DNA damage, keep up its energy production, dispose of its garbage, send out the right chemical messages, stay attached to other cells and do lots of other things.

In recent decades, scientists have identified genes, enzymes, metabolic pathways and signaling molecules that control those activities. Stimulating or blocking them, with the goal of lengthening life, especially healthy life, can now begin.

Nearly all the experiments so far have been in laboratory organisms ranging from yeast to monkeys. The experiments often require drastic steps (such as knocking out genes, killing cells with antibodies, sewing animals together) that are impossible in human beings. The hope is to find behaviors or drugs that accomplish the same thing as those experiments have.

The easiest way to extend life in many organisms couldn't be more low-tech. It's controlled starvation: limiting the intake of food, but not to the point of malnutrition.

Caloric restriction invokes myriad physiological responses. It makes organisms more resistant to stress and toxins, more sensitive to glucose and insulin, and in mice it helps prevent heart attack, diabetes, stroke, dementia and Parkinson's disease. Simply limiting components of the diet (such as protein), or even specific amino acids, lengthens life in some organisms.

Many interventions now or soon to be in human trials seek to mimic those effects. And caloric restriction itself is being tried.

Researchers last year reported on a two-year study in which 218 non-obese people ages 21 to 51 were randomly assigned either to eat as they wanted or to reduce their caloric intake by 25 percent. People in the caloric-restriction group cut their calories by 12 percent over the two years (more the first year than the second), and lost 10 percent of their weight. Metabolic rate, blood pressure, cholesterol, insulin resistance and a marker of inflammation all moved in healthful directions. But the study was too small and short to measure longevity or incidence of disease. Its purpose was mostly to show that such experiments are feasible and safe.

The list of anti-aging compounds - verified in yeast, nematodes, flies, fish and mammals - now moving into human trials is growing.

An immunosuppressive drug called rapamycin down-regulates an enzyme called mTOR; the drug extends the life of rats by 30 percent. A widely used diabetes drug, metformin, which extends life in mice, will soon be tested in non-diabetic elderly people. Researchers want to learn whether it prevents or delays ailments such as cancer, stroke and dementia. Resveratrol, a compound in grapes and blueberries, and some other natural substances are being studied for their epigenetic effects on chromosomes.

Your biological age

So when might any of this be coming to your doctor's office?

"We try not to share information with patients that is not of use to them," said Belsky, the lead author of the New Zealand study. Measurements of biological age aren't valid enough "for them to be clinically useful."

Will there be a time when they're part of the medical exam? "Absolutely."

Kennedy, of the Buck Institute, feels similarly about drugs to slow aging.

He foresees a time when patients meet with a physician at age 50 for an assessment that includes blood and gene tests, personal and family history, and talk about diet, habits and behavior. It may result in a prescription.

"Some drugs will work in some people," he said. "They will certainly work better if people are choosing healthy lifestyles."