Boston-based 99-year-old Eddie Bernstein still drives his car, cooks his own food, goes out for dinner three times a week, and uses glasses only to read small prints. He keeps his age at bay by simply smoking cigars and spending time with friends. Our very own Monohar Aich, former Mr World, still flexes his muscles on podiums, at the age of 93. His mantra is exercise. What, really, is the clue to the vitality of these nonagenarians?

The secret of youthful longevity is what gerontology, the science of ageing, has been craving for long to crack. The aim has now changed to achieving longer youthfulness rather than getting a mere ripe old age. Tithonus of Greek mythology ? whose wife mistakenly asked the god for eternal life, rather than eternal youth, for him ? had to spend a dreadful long life, instead of a happy one.

Exercise, avoidance of all sorts of tobacco and other good habits prescribed in how-to-make-life-better books do prolong life. But centenarians have never been free of vices. The oldest person on earth in the documented history, French woman Jeanne Calment, continued to puff cigars till she died at the age of 122. Many like her ate fatty foods regularly, and some were even couch potatoes. What exactly propels a very tiny percentage of humanity from 80-year-old stage to a centenarian status?

Is it in your genes?

The answer, experts now think, lies in genes. Which is why we aren’t surprised to find that there are families, very few though, that have a cluster of centenarians. Scientists around the world have been identifying so-called ‘longevity genes’.

It was in 1995 that University of California-San Francisco (UCSF) biochemist Cynthia Kenyon discovered mutations, or changes, in the principal life span-determining gene ‘daf-2’ in round worms known as Caenorhabditis elegans. The gene instructs a hormone to double the worms’ life span. By suppressing one gene scientists have even increased their life span up to six times.

That may be equivalent to humans living for 400 years, but will that work the same way in them as well? The genetic choreography that controls the development and ageing of organisms like nematodes, frogs and mice is also at work in humans, albeit in a slightly different way, say UCSF’s Kenyon and her colleagues in a paper recently published in Nature. According to them, this regulator gene, which they call ‘fountain of youth’, in combination with others, regulates the circuit that directs ageing not only in worms, but also in flies, mice and, possibly, humans.

After mutation, daf-2 exerts its influence through antimicrobial and metabolic genes, controlling cellular stress, and dampening the activity of specific life-shortening genes. Kenyon’s lab has found that daf-2 affects life span of organisms through a second gene, known as daf-16, whose function was known to control the expression of other genes.

Dr Angela Brooks-Wilson, senior scientist at the British Columbia Cancer Agency’s Genome Sciences Centre, and Dr Donald Riddle, professor of biology at the University of Missouri, have jointly done a study on the expression of daf-2 in C. elegans. They found that worms that lack fully functional daf-2 gene had significantly extended lives, twice that of the others. Daf-2 prepares a less active metabolic environment before carrying out its age-regulation duties in the worms’ early and late adulthood.

Long stint: Combodia’s oldest man Sek Yim (right), 120, and his wife Ouk, 108, sit outside their home

Kenyon’s team is now investigating how insulin and another hormone called IGF-1 influence life span at the molecular level. They hope that one day they will be able to tweak the insulin/IGF-1 systems in humans to produce many of the benefits now seen in the worms.

In an email message to KnowHOW, Thomas E. Johnson, professor of molecular behavioural genetics, Institute for Behavioural Genetics, University of Colorado, writes, “Suffice it to say that many genes affect ageing and there are many possible targets but whether there will be major ones in humans is still unclear. One major pathway that does appear to regulate aging in humans is IGF-1.”

However, Dr Thomas Perls, co-author of a study conducted at the Beth Israel Deaconess Medical Center in Boston, says in another email, “In humans, a group of genes on chromosome 4 may hold the secret to living a very long life. Genes on other chromosomes may be involved, working together with the genes on chromosome 4. The gene was predicted to be the processor of fat molecules.” Dr Gary Ruvkun of the Harvard Medical School has also found that the ageing genes in worms are the genes in humans that signal for breakdown of sugar.

Eat less, live long

In his book Beyond the 120 Year Diet : How to Double Your Vital Years, Dr Roy L. Walford embarked on a satisfying diet ? one of the keys to a healthy long life. “There’s no need for plastic surgery or obsessive exercising to escape the effects of time...,” he wrote, “... reducing calorie intake, even in old age, may be effective in improving health and life span.” Caloric restriction (CR) ? reduced calories without malnutrition ? may work by reducing concentrations of free radicals (an atom or group of atoms with one or more unpaired electrons). Those highly reactive molecules degrade biological compounds present in cells.

Experiments on yeast, worms, and mammals have all revealed that cutting calories extends life span, but how it occurs is largely unknown. In the past, CR was thought to be a passive mechanism; fewer calories reduced metabolism and the oxidative stresses that came with it. In the mid-1990s, Dr Leonard P. Guarente at the Massachusetts Institute of Technology discovered a family of specialised agents ? coined ‘silencing genes’ ? that influence the life span of yeast cells. Later, as he genetically engineered an extra copy of those genes in round worms and yeast cells, they lived longer.

Establishing the link between diet and longevity, they found that the so-called sir-2 gene got activated when food intake and metabolism were reduced in tandem. Two recent studies, one of them reported in Science by Dr David Sinclair at the Harvard Medical School, and the other published in Nature by Guarente, have uncovered a gene called SIRT1 which links ageing to diet. A study, published on May this year in PLoS Biology, also supports this correlation.

So should people starve to live longer? Prof. Judith Campisi, Buck Institute, California, writes in an email message, “Caloric restriction does about 30-40 per cent life-lengthening job in mice and rats. It is still not clear why, but it may reduce oxidative damage and/or improve repair processes.”

Genes and free radical

Dr Stephen L. Helfand, professor of genetics and developmental biology, University of Connecticut Health Centre, doesn’t entirely support this view. “Genetic manipulation or CR ? the two are probably inseparable,” he says. “It is likely that there will be genetic manipulations that cause calorie restriction.” Dr Linda Partridge at the University College London has also found that the idea that animals live longer if they eat less is not correct ? at least not in fruit flies Drosophila melanogaster. For these insects, it is the type of food and not just the quantity that controls their longevity.

Many of the age-related diseases involve oxidative damage. The free radical theory of ageing holds that chemicals with unpaired electrons attack the body’s molecules and cause the decline of organs over time. The genetic theory of ageing may agree with the free radical theory. As Helfand says, “Genetics may set the ability to respond to free radicals ? damage or repair. Gene impacts do not necessarily mean programmed events ? they may simply mean the predisposition to respond to various insults.”

The results of a mouse study underscore the potential of antioxidants as a weapon to stop the ageing clock. Prof. Peter S. Rabinovitch of the University of Washington have engineered mice to produce higher-than-normal amounts of the enzyme catalase. Within cells, catalase removes hydrogen peroxide, a waste product of metabolism that could otherwise lead to damaging oxygen free radicals. In a paper published in Science, Rabinovitch and his colleagues have reported that animals with higher levels of catalase in their mitochondria ? the cell’s energy-producing units ? lived 20 per cent longer on average than control animals did. “It shows the significance of free radicals, and of reactive oxygen species in particular, in the ageing process,” says Rabinovitch.

“Anti-oxidants are probably a good strategy for postponing ageing, although they need to be balanced. Genes control antioxidant defenses, repair pathways and the rate of damage by metabolism,” says Campisi. So can an unchanging catalase activity in mitochondria ensure our immortality? “Of course not,” she adds, “mutant mice with in creased mitochondrial catalase did not live forever.”

‘The pill will act like calorie restriction, and slow ageing, and tackle age-related diseases’

— Dr Leonard P. Guarente

Enter anti-ageing pill

Is an anti-ageing drug a feasible proposition? It may sound like the pseudoscientific method adopted by the French scientist Charles-Edouard Brown-Sequard in 1889. He prepared an injection containing crushed dog testicles for youthful immortality. Today’s hope for anti-ageing tonics are probably much more well-grounded.

Experts are hopeful about making an anti-ageing pill. Kenyon and Guarente have been nurturing their dream of treating age-related diseases and slowing down the process of ageing. Their joint initiative, Elixir pharmaceuticals, Cambridge, Massachusetts, is pushing hard to at least add 10 to 30 years to a person’s life. They intend to work by tapping a small number of genes are known to that control life span. Says Guarente, “It may take 10 years. It will act like calorie restriction, and slow ageing, and tackle age-related diseases.” Guarente and his colleagues will soon manipulate two specific age-regulating systems led by daf-2 and sir-2 genes. “By 2010-15,” he writes in an e-mail to KnowHOW, “we’ll begin human trials for the proposed anti-ageing drug.”

Confusing tips

In their book Successful Aging, John Wallis Md Rowe and Robert L. Kahn write, “The topic of aging is durably encapsulated in a layer of myths in our society.” Till such time as the magic clue to ageing is discovered, people will cite this or that agent responsible for it. A restrained lifestyle or a vibrant family will always be cited as contributory factors along with, of course, the genes. But will anyone follow the tips of Bernstein, the grand old man from Boston, who, when asked about his secret, quipped, “Don’t get married”?