Faster, higher - and for a lot longer

Anyone over 40 with a well-lit bathroom can see evidence of decay in the mirror every morning. It is probably a good thing people can't peer inside their own bodies, where various types of cells are deteriorating in ways that make wrinkles and grey hairs seem benign.

Consider the bones. Twenty per cent of the skeleton gets replaced every day. Stem cells are a key part of the repair crew, but scientists recently have discovered that as we grow older, they start churning out fat cells instead of bone-building cells, says Gustavo Duque, a Canadian researcher based at the University of Sydney in Australia. The result? Bone gets replaced by fat.

As well, our limited supply of muscle cells starts dying when we are in our 40s. Not that you could tell by looking at the startling physique of Dara Torres, the 41-year-old American swimmer who will be competing in the Olympics that begin in Beijing on Friday.

And she's a well-muscled baby compared with Japanese dressage rider Hiroshi Hoketsu, 67, or Canadian show jumper Ian Miller, 61. Canadian fencer Luan Jujie, 50, will be competing in her fourth Olympics and French cyclist Jeannie Longo-Ciprelli will be taking part in her eighth Games at 49.

But even age-defying Olympians, as strong or as fast as they are today, will get smaller and slower as they continue to age. If they live to be 80, they too will lose 40 per cent of their muscle mass.

Their teeth will soften, their ears will get waxier and the lenses in their eyes will yellow, letting in less light. Their blood vessels will harden and their heart walls will thicken and be less efficient at pumping blood. Their brains will shrink, their lungs will stiffen and so will their joints. Nerve impulses will travel more slowly through their bodies.

It's not pleasant to think about, but every cell type, every body part, has its own story of decline and decrepitude. Researchers such as Dr. Duque are piecing together how we fall apart in the hope of finding ways to keep our bodies functioning well for longer.

Canada's population is aging, and it is estimated that by 2025, one in five Canadians will be over the age of 65, compared with one in eight in 2000. While life expectancy has gone up, the number of years people live without disabilities has not increased to the same extent. The Canadian Institutes of Health Research says this means that a growing number of seniors face the combined effects of physical decline and medical problems, including chronic disease.

Figuring out a way to stop aging - or at least slow it down - is the modern version of Spanish explorer Ponce de Leon's quest for the fountain of youth. If researchers succeed, they could offer people the chance not only to live longer, but also to extend the healthy, active, even Olympian prime of their lives.

But many in the field caution that we are still far from finding the fountain - if it exists - and that any drug or elixir that would keep people looking and feeling young might carry a heavy cost.

WHAT IS AGING, EXACTLY?

Grey hairs are often one the first outward signs of aging. The pigment cells that colour hair last only a few years. Eventually replacements run out and grey hairs proliferate. The skin on the bottom of the feet thickens over time and the nerves that transmit information grow less sensitive. This makes it harder for elderly people to keep their balance and is one of the reasons they fall more frequently.

But is the same thing happening from the top of our heads to the soles of our feet as we age? Do memories fail for the same reason that hips and knees give out? Does skin wrinkle for the same reason hangovers seem to hurt more?

"We know what happens when we age. We get wrinkled, weaker, sicker, slower," says John Sedivy, a Canadian cell biologist based at Brown University in Providence, R.I. "But we don't know exactly how this happens - what exactly is it that happens to our cells, organs and systems," he says.

Some researchers argue that aging is a simple matter of wear and tear. The average human lifespan has extended beyond 30 years only in the past couple of centuries. Different body parts are bound to break down in different ways now that we are regularly living past 80, half a century more than our hunter-gatherer ancestors. This damage is why age is a major risk factor in heart disease, cancer, diabetes and Alzheimer's.

But others argue that aging is not the result of random breakdowns and failures but involves general processes common to many different cell types. More than 50 theories have been proposed, says Judith Campisi, senior staff scientist at the Ernest Orlando Lawrence Berkeley National Laboratory, a U.S. government lab operated by the University of California.

Some hold that aging is driven by hormones or the accumulation of genetic mutations over time. Another major hypothesis blames oxidative stress. Free radicals, produced when our cells burn oxygen, can damage cells and their genetic material the same way rust damages a car.

Dr. Campisi sees the causes of aging fitting into two broad categories. The first involves damage and would include changes to the DNA carried in our chromosomes or their protective tips, known as telomeres. The second involves evolutionary trade-offs. Many important biological processes that help individuals survive and pass their genes to the next generation have downsides that aren't apparent until we get old.

Testosterone, for example, is key to the male sex drive and helps to maintain muscle mass and strength. But as men age, testosterone can cause the prostate gland to swell and make it harder for them to empty their bladders. They produce a weak, hesitant stream or have to get up more at night. It is price men pay for the many benefits of testosterone, Dr. Campisi says.

She and Dr. Sedivy are pioneers in a hot area in aging research that involves both damage to cells and an evolutionary trade-off. They are studying senescent cells, the rusted-out cars on the landscape of the human body.

CELL POLLUTION

Senescent cells have stopped working but don't die. They hang around and gum up the works, possibly leaking pollutants that make it harder for others cells to do their jobs properly, including repairing damaged tissue.

In the early 1960s, American biologist Leonard Hayflick discovered that human cells are hard-wired to divide only 50 to 80 times before they senesce. But it is only relatively recently that researchers have been able to detect senescent cells in aging mammals, including humans.

Now, a growing number of researchers are studying the role they play in aging in the bone, skin and other parts of the body where replacement cells are urgently required to keep the body healthy.

Senescent cells are part of the complicated explanation for why bone is replaced by fat as we age, Dr. Duque says. In the immune system, senescent cells help to explain why older people are more vulnerable to infectious diseases. They also build up in the skin and may contribute to wrinkles. Dr. Sedivy and his colleagues found that in elderly baboons, up to 15 per cent of the skin cells are senescent.

There is also good evidence that senescent cells pump out inflammatory proteins that can contribute to cardiovascular disease, says Richard Faragher at the University of Brighton in Britain. He has looked at the role senescent cells play in Werner's syndrome, a rare genetic disorder marked by signs of accelerated aging. People with Werner's go grey very young and develop cataracts, osteoporosis and other illnesses associated with advancing years. On average, they die at the age of 47, usually from cancer or hardening of the arteries.

Senescent cells may help to explain why patients with Werner's look so elderly in their 40s. There is evidence that they accumulate them far faster than healthy individuals, Dr. Faragher says. But what causes cells to senesce? At the University of Guelph, Dean Betts and his colleagues are studying a gene - p66Shc - that may play a major role.

Genetically engineered mice that lack the gene live 30 per cent longer than average. The Guelph team is now studying how it works in human skin cells. Dr. Betts dreams of finding a way to stop cells from becoming senescent, to slow down or reverse the aging process, or to perhaps find new therapies for age-related illnesses. "There is a possibility that you could develop a drug that could target this gene," he says.

It sounds simple, but Dr. Betts knows that it isn't. Senescence evolved for a reason: It protects the body against tumours. Cells senesce when they get a cancer-causing mutation or when their DNA is damaged. It is a good thing that they stop dividing, otherwise they might start the out-of-control growth that turns into a tumour. So what would you choose? Looking and feeling young when you are old - or avoiding cancer?

STARVING TO LIFE

It is so much easier to play with genes in laboratory animals such as mice, fruit flies or C. elegans, a worm that is the workhorse of aging research. Scientists have been able to dramatically increase the life-spans of all these creatures by altering single genes, often without an increased incidence of cancer.

Trying something similar in humans is far too risky, but finding a diet or a drug that would affect how a gene such as p66Shc works is a more viable option.

Diet has been shown to affect aging. Scientists have been able to reliably extend the life of mice and other mammals in the lab by giving them 30 per cent fewer calories than usual. The theory is that eating a meagre diet triggers a mechanism for surviving famine. Their bodies stop using energy on reproduction and instead devote more resources to maintaining tissue. The result is a longer, healthier life.

Living a long but hungry life is not an appealing prospect for many people. But what if you could trick the body into acting as though it wasn't getting enough food? Enzymes known as sirtuins appear to play a key role in the famine reflex, and Harvard University researcher David Sinclair has found that they are can be activated by drugs, including resveratrol, a substance found in red wine. Alas, it seems you can't stay young by drinking more. The amounts of resveratrol in wine are too small to kick-start the famine reflex.

Dr. Sinclair is working on two more potent drugs now being tested in clinical trials. He co-founded Sirtris, a company bought this year by GlaxoSmithKline for $720-million (U.S.). Its product SRT501 (now being tested in patients with Type 2 diabetes) may be put on the market as a natural compound, which means it would not require approval from the U.S. Food and Drug Administration.

Many people, including members of the Life Extension Movement, already take a wide array of antioxidants, hormones and other supplements in the hope of slowing the aging process. But there is no proof that they work.

And even if scientists did succeed in finding a way to mimic the anti-aging effects of a low-calorie diet, it probably wouldn't be an option for people who want to have children. Starving animals don't have babies.

TRIMMING THE FAT

Given the enormous difficulty and perhaps impossibility of switching off or slowing down the general aging process, many scientists are looking for ways to prevent the more damaging aspects of aging in specific organs or parts.

Dr. Duque and his colleagues in Sydney are looking at ways to prevent accelerated bone loss in old age by coaxing stem cells to keep producing bone-building cells instead of fat. It might even be possible to get fat cells to change back to bone, he says. Vitamin D, the sunshine vitamin, may help. In mice that have been genetically altered to age more quickly, Vitamin D converts fat back into bone in the bone marrow.

But it is not only our bones that shrink. Cheryl Grady, a senior scientist at the Rotman Research Institute at Baycrest in Toronto, says she can tell a 20-year-old from an 80-year-old by looking at magnetic resonance imaging scans of their brains. "The older brain looks somewhat shrunken. It is called 'atrophy,' " she says.

The process is variable, but brain shrinkage can start when people hit their 60s. It isn't clear what causes it. Researchers used to believe that we lost a lot of brain cells, but there is now evidence that isn't the case, Dr. Grady says. It may be the connections between cells that are diminished.

As we age, we don't remember the events in our lives in as much detail. But age doesn't affect what researchers call semantic memory, which Dr. Grady describes as what we know about the world, including the meaning of words and concepts, and making associations.

One experiment found that people in their 80s use more parts of their brains in a memory test than younger adults do. Perhaps their brains are able to work in different ways to compensate for changes that come with age. "I don't think it is just a bad-news story," Dr. Grady says. "There are things about the brain that show it is quite adaptable."

There is also evidence physical exercise, keeping mentally active and eating well can help the aging brain. Dr. Grady is hopeful that in the next 10 years it will become clearer what kinds of regimes keep shrinking brains working well.

At the University of Calgary, Russ Hepple is trying to figure out what kind of exercise can prevent the loss of muscle cells. The associate professor in kinesiology and medicine has found that jogging on a treadmill was beneficial to rats in the equivalent of their 60s, but it didn't help to conserve muscle performance and mass as their entered the equivalent of their 80s.

"Their muscles actually looked no better and in some ways they looked worse," he says. "It was a bit of a downer." He is planning to explore whether weight training might be more helpful.

Adults basically have the same number of muscle cells they had when they were 5, Dr. Hepple says. Those cells start to die when we are in our 40s, and those that remain don't work as well as they once did. But most people don't notice a loss of strength or speed until their late 50s or 60s, when the damage appears to accelerate.

Dr. Hepple, who is 42, hasn't noticed any changes. "It's probably starting now," he says glumly. "But as long as you are active, you probably aren't going to lose much until you are 50ish."

His knowledge of what happens to our muscles as we age is one of the reasons he will be rooting for Ms. Torres, the freestyle swimmer still breaking records at 41: "She is carrying the torch."

But scientists such as Dr. Hepple are providing insight into what even the healthiest elderly people are up against: In their own way, all seniors are as heroic as aging Olympians.

Anne McIlroy is The Globe and Mail's science reporter.

RESOURCE/SOURCE: http://www.theglobeandmail.com/servlet/ArticleNews/freeheadlines/LAC/20080802/COVER02/science/?pageRequested=4 on Saturday, August 2, 2008.