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Mortal combat (Eat less, live long) (downtoearth,)

Squatted on a charpai just outside his one-room tenement in an obscure village called Karahal on the edges of the Chambal ravines in Madhya Pradesh, Ram Sevak Pathak exudes a Buddha-like serenity. His eyes, ears and knees might be deserting him, and his brain may now have a tenuous hold over his hand muscles, but looking at his relatively smooth skin, his upright spine, and, most remarkably, his exceptionally supple memory, no one can guess that the man is 105 years old.

What’s the secret of his long life when an average Indian man does not even cross 70? He betrays a childlike smile and replies with utter seriousness: “I believe the most important thing is to give your body the respect it deserves. If you don’t, there would be obvious consequences.” Pathak says that as much as he could, he has tried to follow a regular regimen of diet and exercise, besides abstaining from alcohol and tobacco. “Even now I do yoga in the morning,” he says with pride. “My only weakness,” he adds, “was spicy food, especially chilies, which I think did me much harm.”

In Pathak’s reckoning, having a purpose in life also plays a key role in keeping body and soul together for a long time. Pathak is a veteran Gandhian who, among other things, fought against the British rule; worked hard to unshackle the Saharias, an adivasi tribe that dwells in these parts, from the fetters of feudalism; walked thousands of miles as part of Vinoba Bhave’s Bhoodan movement; and was closely involved in the 1972 mass surrender by the Chambal dacoits. An impressive body of work, but Pathak says he owes his long years chiefly to the good wishes of the Saharias for whose good he has worked all his life. “If I am born again, I want to be born as a Saharia,” he says.

Anyone who has lived long swears by a few curious nostrums. Pathak is no different. His recommendation: quaff a litre of water first thing in the morning, but drink water only three-four hours after meal, eat less, and munch garlic with tea.


At 117, Emma Morano (top) of Italy is the world's oldest living person and credits her long life to eating eggs and singlehood, while Misao Okawa of Japan, who died in 2015 after her 115th birthday, said eating a good meal and relaxing were the key to long life
Pathak’s recipe for long life might seem plausible, and some credulous souls might even try to emulate it, but it is essentially idiosyncratic—another centenarian is very likely to prescribe an entirely different list of do’s and don’ts. For instance, Italian Emma Morano, the oldest living person at 117 years, put it down to eggs and singlehood. For Misao Okawa of Japan who died in 2015 after her 115th birthday, it was eating a good meal and relaxing. The British war veteran Henry Allingham’s formula was “cigarettes, whisky, and wild, wild women”. Zohra Sehgal, the irrepressible Indian actress and danseuse who passed away at the age of 102, declared, with her witty tongue squarely in her cheeky cheek, sex to be the elixir of her long life. Others have included happy marriage, minding one’s own business, and wine as prime suspects.

Evidently, there is no universal magic potion for a long life. As Hazel Miller, an American centenarian, told The New York Times, “there’s no secret about it. You just don’t die… The best part of being 100 is that you lived to be 100. If you can enjoy it, it’s an extra good thing.” Nevertheless, while a happy-go-lucky attitude might well be one of the secrets to a long life, it still does not explain how both life expectancy and longevity have risen appreciably over the last two centuries.

For the greater part of human history, life was, to quote 17th century British philosopher Thomas Hobbes, “poor, nasty, brutish and short.” As recently as in 1900, the average American did not get past her 47th birthday; now she can expect to cross 78 years. One reason average lifespans were so short is that many people died in infancy or childhood. Until the advent of modern public health care and medicine in the early 19th century, many children died before their fifth birthday. And among those who did survive the early attacks, very few crossed the age of 60.

Today, people are living longer than ever before. In fact, every six years, the average lifespan in the US increases by a year. In India, average life expectancy, which used to be around 42 in 1960, steadily climbed to around 48 in 1980, 58.5 in 1990, and 66.4 today.

Even more striking is the rise in number of people living beyond 100. According to the ‘UN World Population Ageing Report’ published in 2015, there were an estimated 316,600 living centenarians in the world, of which, as of now only 45 have been verified to have crossed 110, although their number is estimated at 350-400. Globally, the number of centenarians is projected to increase to 3.2 million in 2050. India is at present home to between 11,000 and 20,000 centenarians. But this number may go up to anywhere between 0.15 million and 0.6 million by the middle of this century.

While the steady rise in life expectancy can be explained as a direct outcome of better public health and modern medicine, what is puzzling is the rise in number of centenarians. To put it down to luck is of no use to scientists trying to unravel the mystery of ageing. For them, longevity has more to do with biology and less with the individual quirks of diet and behaviour. As recently as two decades ago, research on ageing was considered fringe, more the preserve of charlatans and mavericks than of respectable scientists. But now it’s part of mainstream, with governments, corporations and maverick billionaires investing millions of dollars into the quixotic quest to delay the inevitable. Scientist now cannot but confront fundamental and tough questions about the nature of life, ageing and death that not so long ago were the domain of metaphysics or science fiction. For instance, why do we age and die? Is ageing and death the logical consequence of a genetic programme writ into our DNA, or is it a mere accident? Why do some animals live longer than others? Can the body be likened to a machine that can be repaired indefinitely?

FLATTERING TO DECEIVE



Science’s quest to prolong life has a long and checkered history. Many ideas began with a bang but eventually fizzled out (see ‘Quest for immortality’,). The modern state-of-the-art ageing research came of age in the 1990s when Cynthia Kenyon, then a molecular biologist at the University of California, San Francisco, showed that mutation in a single gene could double the lifespan of a worm called Caenorhabditis elegans (C elegans). Before long, scientists had unearthed many more such genes in the genomic haystack, and all of them seemed to extend the lifespan of model organisms, such as worms, flies and mice. These early findings seduced venture capitalists into investing in the quest for the elixir of life. They set about first unravelling the hidden circuits controlled by these genes and then eventually manipulating them so as to create drugs that might simulate their life-enhancing magic.


Quest for immortality

The idea of death and immortality has intrigued religious thinkers and philosophers alike since time immemorial. All of them took physical death as inevitable as they had no easy answers to the question of why we age and die. Instead they invented the idea of the immortal soul or an afterlife in order to avoid thinking about why we die. Nevertheless, that did not stop many a maverick from dreaming up fantasies of eternal youth.

Francis Bacon in the 16th century raised the uncomfortable question of prolonging life. Why does life, he mused, which is so luxuriant in the first half, start crumbling in the second? He argued that if we can cure disease, in theory we should be able to cure ageing too.

The first person to propose a logic for death was German biologist August Weismann, who in 1890 argued that death evolved as worn-out individuals are not only valueless to the species, but they are even harmful for they take the place of those which are sound. In other words, we die out for the sake of our kids.

Weismann, however, avoided the question of why are the aged worn-out. In a lecture titled An Unsolved Problem in Biology, Peter Medawar, the British biologist and Nobel laureate, argued that we die out not because we have to make room for posterity but because nature has designed us in such a way that we become irrelevant as soon as we have passed on our genes. In other words, genes that cause age-onset diseases like cancer remain more or less underground till our bodies become unfit for reproducing. As the science writer Jonathan Weiner put it, our bodies are built to grow up fast. They are not built to last.

It was Medawar's radical view, endorsed by many scientists since, that opened up the possibility of tinkering and rearranging the genetic design in order to make old age less frail and more comfortable, even, indeed, for some to pursue the dream of immortality.


It also boosted the fortunes of a few street-smart scientists, such as David Sinclair, who, working at the Massachusetts Institute of Technology (MIT), US, in 2003, claimed that resveratrol, a chemical found in red wine, mobilised sirtuins, a class of proteins that have been shown to extend lifespan in yeasts and mice. The fact that humans too possess seven kinds of sirtuins excited anti-ageing researchers. This, incidentally, was also seen to solve the mystery of the French enjoying long and healthy lives despite their gastronomical excesses. Though many were unconvinced about the connection, Sinclair went on to found a company called Sirtris Pharmaceuticals in 2007. Buoyed by the hype, big pharma GlaxoSmithKline (GSK) bought it a year later for $720 million! Unfortunately it turned out to be a bad egg as the promising preclinical results did not translate into a single anti-ageing molecule. Five years later, the company folded up.

That some sirtuins can slow down ageing was discovered in 1995 by Leonard Guarente’s group at MIT. He dubbed them sirtuins (for silent information regulator) because of their ability to silence genes.

Sirtris Pharmaceuticals was not the only victim of over-ambition. Like the dotcom boom-and-doom story running in parallel, the anti-ageing flourish in the decade post 1995 too fizzled out as most of the potential drug candidates turned out to be damp squibs. Except for a few molecules currently in clinical trials, there is precious little to show for those (mis)adventures in the quest for longevity.


When faced with shortage of food, microscopic worms called C elegans that are found in the soil go into a samadhi. This allows them to live for four months, whereas worms in the wild do not survive beyond three weeks
Despite the early disappointments, however, longevity research is enjoying a new lease of life in the last few years, thanks to new insights into the mechanics of ageing. But more importantly, it is being shored up by a bevy of venture capitalists, such as Craig Venter’s Human Longevity Inc (HLI) based in San Diego and Google’s Calico based in San Francisco. In addition, several large-scale projects are gearing up to collect massive data sets of healthy human populations such as the 100K Wellness Project at the Institute of Systems Biology in Seattle, and the Resilience Project, a joint venture between the Icahn School of Medicine at Mount Sinai, New York, and non-profit Sage Bionetworks in Seattle.

But what is so special about the new insights and approaches that are making venture capitalists gamble their millions when previous attempts to replicate research on animal models in humans have mostly come to naught?

A NEW LEASE OF LIFE

The science of ageing has been revised in recent years. Earlier, it was like the proverbial Indian elephant—it was described and understood differently depending on how each scientist looked at it. Now the approach is a bit like solving a jigsaw puzzle by putting together different pieces representing various approaches such as nutrition, genetics, and the new fashionable analytical tool called big data. The aim is to slow down ageing using an ensemble of tricks and devices so that the torments of old age are packed into a short span at the end of life. The idea is to make people live longer by ridding the autumn of their lives of dreaded afflictions like cancer, heart disease, dementia and diabetes.


But how does one prolong life without having to go through the seemingly unavoidable physical and mental suffering? And any attempt to solve this dilemma will have to necessarily confront the fundamental question of what is ageing.

Scientists are all agreed that ageing is much like the Gordian knot. Unravelling it seems like an impossible task. The neatest and time-honoured solution is to cut it with the sharp and lucid knife of death. But that’s of no use to those trying to defy death. The trouble is that unlike the development trajectories of specific organs like the heart or the skin, ageing does not follow a well-scripted plot that unfolds consistently over time. In an article titled ‘The New Biology of Ageing’ published in the November 2009 edition of the Philosophical Transactions of the Royal Society B, geneticist Linda Partridge of University College London, described ageing as “an unregulated side effect of the failure of natural selection to maintain function at the later ages that few individuals reach in nature.”

Illuminating, but it still leaves in the dark the question of why we age and die. Truth be told, no one knows why some species live longer than others; or why the Grim Reaper is partial to some within the same species; or why within the same body some parts wear down faster than others (see ‘Elixir of life’,).

Nonetheless, an emerging view suggests that ageing, and its apotheosis death, is probably like an elaborate dish whose recipe is hidden deep inside the labyrinth of life. In the absence of an open sesame, scientists suspect the ingredients of that recipe could be a random assortment of the several genetic and cellular processes implicated in the logic of life and decay.



Elixir of life

Even though immortality was an exclusive privilege of the gods (in Christianity, even humans were immortal, created as they were in the image of god, but they lost it after Adam and Eve tasted the Forbidden Fruit), it did not deter cultures across the world from concocting all kinds of elixirs and panaceas in order to defy or deceive death forever.

The quest for immortality may appear antithetical to the spirit of modern science, but it didn't deter its apologists (who by the way always happened to be men) from dreaming and theorising about it. Francis Bacon wrote a book of recipes that allegedly prolonged life. French philosopher Rene Descartes longed for it as he entered the autumn of his life. Marquis de Condorcet, a luminary of the Enlightenment, prophesied a day when "the duration between the birth of man and his decay will have no assignable limit".

While that day is yet to come, the scientific imagination has been busy conjuring up fanciful theories about the causes of ageing and how to get around them. The Russian biologist and Nobelist Ellie Metchnikoff proposed in 1914 that we die of the poison made by the bacteria in our guts.

Even more outlandish, Charles-douard Brown-Squard, a neurologist at Harvard, allegedly injected lots of men, including himself, with fluids from the testicles of dogs and pigs to restore youth (women, presumably, never aged or their ageing was of little consequence). And then there was Austrian doctor Eugene Steinach, who in the 1920s did vasectomies to make men feel and look younger. The idea became such a fad that even wise old men like Freud and W B Yeats fell prey to it.

These early flights of fancy bit the dust soon. However, one idea that endured till the end of last century was the rate of living hypothesis, according to which animals that expend more energy tend to age faster. In 1954, Denham Harman at Berkeley University, California, proposed that lifespan was limited by free radicals, small molecules with an unpaired electron that can potentially damage a cell. Denham's free radicals explained how burning more calories could make you age faster and hence made the hypothesis more plausible. However, as happens in science so often, the rate of living hypothesis went out of favour as subsequent evidence on more species contradicted it.
According to this new thinking, ageing is not a disease but rather an ensemble of several as yet indefinite age-related diseases. This runs counter to the traditional approach that focused only on one age-related disease such as cancer or Alzheimer’s at a time in order to develop a drug against it. Nir Barzilai, director of the Institute for Aging Research at the Albert Einstein College of Medicine, New York, argues that if we don’t stave off ageing, “all we can hope for is to exchange one disease with another” that come with ageing. Empirical evidence suggests that by targeting one or the other disease, we can get a reprieve of three years at best.

The hypothesis sounds persuasive but how does one delay ageing, considering we only have a glimmering of its mysterious and complex persona. That is the billion-dollar question. Buoyed by recent discoveries about the cellular and genetic underpinnings of ageing, scientists are optimistic about developing drugs capable of delaying ageing in humans.

Eat less, live long

Arnab Mukhopadhyay, who heads the molecular ageing lab at the National Institute of Immunology (NII) in Delhi, is fascinated by the puzzle of ageing. “I was drawn to this subject after I learnt that some plants have phenomenally long lives. In fact, a species of tree called the bristlecone pine, which grows in the arid regions of the US, is more than 5,000 years old,” he says. But his model organism for ageing is the far less glamorous C elegans, the same round worm whose mutants had made Kenyon a celebrity. A mere 1 mm long, these microscopic creatures live in soil and feed on bacteria. They are mostly hermaphrodites. But they have another fascinating trait that has made them the darling of gerontologists. If there is less food or more competitors vying for it, the young worms go into a samadhi, as it were, thereby putting their growth into a coma. This state of being is called dauer (German for “enduring”) and it allows them to live for as long as four months whereas worms in the wild do not survive beyond three weeks.

Kenyon’s mutant worms, produced by disabling a single gene called daf-2, could live twice as long as its normal parents. Besides, the worms also looked healthy till their death. Her work raised the possibility that the longevity of the dauer is not simply a consequence of its arrested growth, that there were other ways of instigating it. Many researchers have replicated Kenyon’s feat since, and some have even created mutants that live 10 times longer.



The bristlecone pine tree, which grows in the arid regions of the US, is more than 5,000 years old. Scientists are looking for clues to understand why some plants and animals have a substantially longer lifespan
But the trouble with genetic therapy is that genes don’t work alone; they work as a corps. Often one gene is responsible for many assignments, but, equally often, many genes may contribute to a single function. For instance, C elegans’ life is doubled by knocking out a gene that is triggered by the worm version of the human hormone insulin or Insulin Growth Factor-1 (IGF-1). Intriguingly, evolution has conserved this genetic algorithm, albeit in altered forms, in different species like yeast, fruit flies and mice. In fact, silencing daf-2 gene does prolong life in these animals too. But the real challenge before ageing researchers is whether it is possible to delay ageing in humans by manipulating similar pathways.

Turns out that we do possess a gene called FOXO, which, like the C elegans’ longevity gene, is involved in the production of insulin hormone in humans. Interestingly, studies have found that mutants of a particular version of FOXO lengthen life in Okinawan and Ashkenazi Jewish centenarians. Two copies of FOXO double your chances of living long while three copies would treble your odds of crossing 100.

Many scientists believe that pathways involved in the production of insulin are the key to the secrets of ageing. Indeed, many animal studies have demonstrated a correlation between low IGF-1 levels and long and healthy life. This might be true in humans too as Barzilai has found that Ashkenazi Jews over 90 with low IGF levels have higher odds of living longer.

Like Mukhopadhyay, Ullas Kolthur-Seetharam, a molecular biologist at the Tata Institute of Fundamental Research, Mumbai, too is keen on decoding ageing. His handmaiden in this quest is sirtuins that regulate, among other things, the balance between metabolism and energy. Sirtuins and the genes controlling them, are found across the animal kingdom. Of the seven sirtuins possessed by mammals, at least three are known to delay ageing in yeast and fruit flies.

Kolthur-Seetharam and his colleagues also demonstrated the role of sirtuins in retarding ageing but in their case the trigger was a low-calorie diet. “The body’s metabolism maintains a delicate balance between feast and famine cycles. Any aberration in this balance can impact ageing,” he explains. Turns out eating fewer calories than normal once or twice a week does activate sirtuins.

Studies have shown that restricting diets in yeasts, roundworms, fruit flies, mice (even in monkeys, though it is disputed) delays ageing. But the big question is if it would work for humans too? Though the jury is still out, it’s already become a fad with some people, mostly rich, to eat less in the hope of looking younger. Anti-ageing pioneers like Kenyon have already incorporated the findings on animal models in her lifestyle. To quote from one of her interviews, “No desserts. No sweets. No potatoes. No rice. No bread. No pasta. When I say ‘no,’ I mean ‘no, or not much’,” she notes. “Instead, eat green vegetables. Eat the fruits that aren’t the sweet fruits, like melon. Bananas? Bananas are a little sweet. Meat? Meat, yes, of course. Avocados. All vegetables. Nuts. Fish. Chicken. That’s what I eat. Cheese. Eggs. And one glass of red wine a day.”

Kenyon, however, would not recommend it to others, because the claimed benefits are still unproven. Nonetheless, many have taken to so-called sirtfoods after a fashion. Moderation is advised as studies have shown that extreme restriction can cause side effects like fatigue and low libido. As Woody Allen quipped once, “you can live to 100 if you give up all the things that make you want to live to be 100.”

EASTER ISLAND'S MAGICAL RESTORATIVE

Another gene that is involved in regulation of lifespan is the gene that produces a protein called TOR, which stands for “target of rapamycin”. Rapamycin is an antifungal compound that was first isolated by an Indian émigré biochemist Suren Sehgal from bacteria native to Easter Island in the Pacific, the remotest inhabited island on the planet. The chemical was named after the island’s local name, Rapa Nui. Rapamycin is one of the many chemical weapons microbes use against one another. Penicillin is an example of an antibacterial compound produced by a fungus.

Rapamycin was initially developed as an antifungal agent. However, ever since it was discovered that it had a strong inhibitive effect on the immune system, it has been used more commonly as an agent to prevent rejection in organ transplants. But there was more to this Eastern Island import. In 2006, scientists discovered that inhibiting TOR with rapamycin extends lifespan in multiple species, from yeast to mouse, presumably by shifting metabolism away from growth towards maintenance. Experimental feeding of rapamycin to 6oo-day-old mice increased their lifespan by about 10 per cent.

As of now, thousands of clinical trials on rapamycin are on, and, ironically, several companies have been formed around refining inhibitors of TOR since rapamycin is unsuitable for long-term use. So far this troika—insulin-signalling genes, sirtuins and rapamycin—represents state-of-the-art research into the basic biology of ageing, and many scientists believe that the first anti-ageing drug will come out of this bootstrap strategy. That said, some scientists have chosen to take a more practical and innovative approach to the problem.

THE DEVIL LIES IN EVER FINER DETAILS

Three years ago, Delhi-based Institute of Genomics and Integrative Biology (IGIB) put out an ad saying they were looking for centenarians. However, they were not motivated by the desire to understand ageing. They were after a big prize. In 2006, XPRIZE, a non-profit based in Culver City, California, and funded by companies like Google and Deloitte announced the Archon Genomics XPRIZE offering $10 million to the first team that could rapidly and accurately sequence 100 100-plus humans at a cost of $10,000 or less per genome. Sequencing the genomes of the 100-plus presents a unique opportunity to identify those “rare genes” that protect against disease, while giving researchers valuable clues to health and longevity.

IGIB managed to collect the genomes of 100 90-plus people and also fully sequenced the genome of 30. But unfortunately for them, in 2013 the prize sponsors suddenly decided to cancel the prize, as, to quote from their website, “the competition was not incentivizing the technological changes for which it was intended,” and that today “companies can do this for less than $5,000 per genome, in a few days or less—and are moving quickly towards the goals we set for the prize.”


Cynthia Kenyon (top), a molecular biologist at the University of California in the 1990s, showed that mutation in a single gene could double the lifespan of microscopic worms called C elegans. Aubrey de Grey, a maverick British gerontologist and Chief Science Officer of SENS Research Foundation based in Cambridge, believes it is possible to stretch life indefinitely by applying a bouquet of
Meanwhile, there are many institutes in the world that have sequenced genomes of centenarians and have tried to find the genetic key to long life. In 2014, a group at Stanford University, US, compared the genomes of 17 supercentenarians with those of 4,300 “regular” people recorded earlier in a US National Institutes of Health study. The study was geared towards finding a single gene or group of genes responsible for a particular trait—in this case longevity—similar to genes which have been found to cause disease or confer immunity. But they have had no luck.

Nevertheless, the fact that supercentenarians have average rates of cancer and heart disease, and that their behaviour with respect to smoking, alcohol, exercise and diet appears no different from ordinary people, suggests that longevity is more a genetic than a lifestyle thing. Furthermore, as noted in the article, the parents, siblings and children of the centenarians have also lived well beyond average.

On cue, a year later another Stanford study published some very interesting research in PLoS Genetics about regions of the human genome that appear to be associated with extreme longevity. One, a gene called APOE, is associated with the development of Alzheimer’s disease. It’s been previously implicated in longevity.

Craig Venter, who was the first to map the human genome, however believes that the sample used by Stanford University study was too small to come to any plausible conclusion. So he has set up a company called Human Longevity Inc (HLI) with the ambitious objective of sequencing a million genomes. Venter believes that understanding variation will come from sequencing not hundreds but at least a million genomes. In addition to collecting whole genomes of individuals, his company intends to gather many other kinds of data such as the levels of chemicals in a person’s body, or the genomes of all the microbes found in our body. This big data, it is hoped, will eventually throw up viable strategies for healthier ageing.

A similar big data venture but with much sharper focus called the 100K Wellness Project will target supercentenarians, newborns, children with congenital disorders, and old adults suffering from diseases like dementia, Parkinson’s and heart-related ailments. They will start with a sample of 100 and steadily increase it to 100,000. The idea is to collect all kinds of data—clinical, diagnostic and genetic—and follow the subjects over a period of time. Ultimately, the hope is that parsing this humongous data will reveal insights into how healthy people become ill, and how some lucky people escape the agonies of ageing despite portents to the contrary.

In 2008, cardiologist Eric Topol of San Diego’s Scripps Translational Science Institute had launched the “Wellderly” project to understand how some people remain exceptionally healthy as they grow old, say, people with enduringly youthful eyesight, hair, heart or hearing. If we can solve the puzzle of how some people cheat the torments of old age, it could become the basis for developing drugs that could mimic those tricks and take suffering out of old age, not to mention drastically bring down healthcare costs.

But that silver bullet remains a fantasy. The results of the study came out in April 2015, but, alas, they revealed no secrets. Nevertheless, the study has inspired a couple of similar endeavours—Google’s life sciences subsidiary Verily has started a project to study healthy people while the Resilience Project, led by Icahn School of Medicine at Mount Sinai, “aims to discover hidden factors that protect people from disease.” Any old “resilient” person who has led a disease-free life can sign up as a “hero” for the project.

Some scientists say there are reasons to believe the gene hunt is misguided. In 2013, Yaniv Erlich, who is associated with the New York Genome Center, and his colleagues created a family tree of 13 million people dating back to the 15th century, including their dates of birth and death. Erlich found that longevity “is one of the lowest heritable traits”.

Other researchers believe that the genome you inherit at birth may be less important to ageing well than epigenetics, or the way chemical groups glom onto DNA in response to environment and life experiences. The result of epigenetic changes that occur during life can turn genes up or down, off or on, and influence diseases.

Luigi Ferrucci, director of Baltimore Longitudinal Study of Aging, the world’s longest-running study of human ageing, believes that the secret lies in the tango between environment and genes. Instead of trying to mine many hundreds or thousands of genomes, Ferrucci will pick 100 people and then collect blood cells at regular intervals so epigenetic changes can be tracked over time. Everybody will also undergo a battery of tests and probes to measure how the body changes with age and life experience.



THE YAYATI EFFECT

Injecting young blood into the old is another exciting experiment that might throw up new insights into ageing. Several studies in the past decade have shown that when infused with young blood, older organs, such as the liver and muscles, get rejuvenated. In one interesting experiment, researchers found that the brains of older mice injected with younger blood produced more neurons.

However, what angels trigger this blessed change is still not clear. Some scientists believe that comparing the language of cells (from the very young to the very old might) give us clues about why most old brains turn ramshackle while some rare lucky ones keep greying along in good health as if mocking time. In fact, in yet another provocative experiment, Stanford University scientists discovered that young human plasma revitalised old mice brains whereas old ones left them cold. Inspired by this finding, they set up a company called Alkahest that is currently carrying out the same experiment on 20 Alzheimer’s patients to see if their brains light up too. Luckily for them, they do not have to go through the painstaking task of proving it’s safe because the US Food and Drug Administration has endorsed plasma transfusion.

CRUCIAL TELOMERES

One of the more popular theories of ageing posits that it is an outcome of the body’s diminishing ability to repair its worn-out parts. As the DNA, the chief repair mechanic, gets rusty and error-prone, all sorts of blemishes scar it. Many scientists believe that the tapering of telomeres is by far the most damaging. Telomeres are tiny crowns at the head of each of our 46 chromosomes. They are often likened to plastic caps at the tip of shoelaces. Like them, they protect the DNA strands from fraying, thus allowing cells to reproduce smoothly. However, every time a cell divides, the telomeres shrink. After about 50-70 divisions, the cell simply ages and dies, which is a kind of precursor to our own senescence and eventual death. No surprise then that relatively more prolific cells, such as skin and lung cells, age faster because their telomeres taper off more rapidly. Studies have also shown that telomere span is affected by our lifestyle choices—what we eat, how we sleep, what we think, and so on.

Telomeres are tiny crowns at the head of each of our 46 chromosomes. However, every time a cell divides, the telomeres shrink, which is a kind of precursor to our own senescence and eventual death. Curiously, evolution has given us an enzyme called telomerase that can restore the shrinking telomere. If there is a way of bestowing this anti-ageing enzyme on the unlucky cells, ageing could be reversed
Curiously, evolution has given us an enzyme called telomerase that can restore the shrinking telomere. The trouble is it is found largely in stem cells, germ cells (sperms and eggs), not to mention cancer cells, which is what makes cancer so fatal. The rest of the cells contain only infinitesimal traces of it. So if there is a way of bestowing this anti-ageing enzyme on the unlucky cells, ageing could be reversed in theory. That said, one has to find the right balance between too much and too little telomerase, for both extremes can turn a cell cancerous. This explains why there are still no human clinical trials of telomerase, though it has been shown to increase longevity in mice.

But when have laws deterred the mavericks and daredevils? In 2015, Elizabeth Parrish, the 44-year-old CEO of Seattle-based firm Bioviva, claimed she had become the first human to be injected with telomerase in obvious defiance of both law and the risk of cancer. The procedure was done in Colombia to bypass US laws. She claims she feels rejuvenated. In fact, her claims were reportedly “independently” verified by two non-profits. But scientists doubt if her experiment followed scientific rigour, let aside the fact that scientists still do not agree if lengthening telomeres delays ageing.

The buzz around telomeres has not diminished nevertheless. In the US, you can now even buy kits to measure the length of your telomeres to know how fast or slowly you are ageing! Scientists inform us that birds living in cities are ageing before time because of premature shortening of their telomeres. Hype notwithstanding, many scientists are confident that they will find a compound that makes telomerase in the next few years.

The poster boy of immortality dream

It seems there is no single master key that will open the door to a long, healthy life. Most anti-ageing researchers would be content with extending life by say 20-30 years through drugs like resveratrol or by manipulating longevity genes. But a few maverick champions nurse dreams of immortality. Aubrey de Grey, a maverick British gerontologist and Chief Science Officer of SENS Research Foundation based in Cambridge, and also arguably the most high-profile salesman of the anti-ageing ideology, believes it is possible to stretch life indefinitely by applying a bouquet of “rejuvenation technologies” such as stem cell therapy and calorie restriction. He even has gobbledygook name for his formula: Strategies for Engineered Negligible Senescence (SENS). His belief in immortality is so doctrinaire that he has even decided to freeze his dead body just in case it becomes possible to revive the dead in the future.

Those of course are the Icarian dreams of a man possessed. In fact, many mainstream scientists frown upon his salesman-like spiel and chutzpah. In 2005, 28 gerontologists wrote a paper damning his approach, claiming he was living in the “realm of fantasy”. But what about the more modest claims of life-extension in recent years? Do they hold real promise of delaying ageing in humans or are they also mere fantasies?

The busting of the first anti-ageing boom did disillusion a lot of scientists and venture capitalists. But many are hopeful that the anti-ageing expedition 2.0 will not meet the same fate. In the near term, they believe, we can expect at least a few drugs emerging from rapamycin and insulin-signalling trials.

One of the nagging problems with ageing research is that designing clinical trials for the old is not an easy task. Besides, they cost a lot. On top of that, scientists still do not have reliable surrogate markers to know if some intervention has delayed ageing or not. Some scientists want to break this bind by simply abandoning the idea of looking for fingerprints of delayed ageing. They argue if a drug or any other intervention results in less inflammation, or less cholesterol, or sharper memory, how does it matter if it was because of delayed ageing or not.

Elysium Health, a startup set up by MIT’s Guarente, reflects this alternative strategy. A few months ago, it launched a blue-coloured called Basis. The makers don’t make any claims that the pill will postpone ageing. But the pill contains a chemical compound that is believed to have effects similar to that of fasting, an intervention that has demonstrably made mice to live longer.

Guarente believes that proving that drugs that delay ageing in animals would also do so in humans would take many years. So he decided to package his research on animals in the form of over-the-counter nutraceuticals, which are exempt from clinical trials in the US.

Lastly, while the work on animal models might appear impressive and promising, what would eventually count is whether it can be replicated in humans. Last month, for the first time researchers at the Salk Institute for Biological Studies in La Jolla, California, slowed down the biological clock in mice by 30 per cent by reprogramming a few critical genes known to reset the clock to zero during fertilisation. While tampering with these genes is very unlikely in humans (as we don’t know how else such tampering may interfere with other features of development), scientists hope to develop a drug that simulates the rejuvenating genes. However, they caution not before the next decade.

Besides, our current understanding of disease is based more on clinical reading and less on biology. And for the dream of longevity to become reality, some scientists believe the onion of biology will be have to peeled to get to the core of diseases and ageing. That’s a Herculean task because no one knows how many layers need to be peeled before the secret is revealed, if it does get revealed at all. It may take decades, even a century. The aborted hype over the first expedition should serve as a cautionary tale for the new anti-ageing apologists. Realists like Barzilai caution against the rhetoric of De Grey and are sceptical about extending life beyond 120, whereas the dreamers, which include optimists like De Grey and Venter, believe ageing can be deferred indefinitely. According to British biologist and science writer Colin Tudge, it’s quite possible that in a few years scientists might be able to correct some very basic mistakes in the genome, mistakes that cause diseases like Down syndrome, but to stave off ageing by editing the genetic programme “requires a different order of knowledge, and it would be hubristic indeed to attempt such a thing in the next few decades.”

THE PRICE OF LONGEVITY

The hubris of scientific grandstanding is one thing, but many accuse the merchants of immortality of a more dangerous arrogance—that of ignoring ethical and philosophical concerns that come with the project of life extension. They are asking inconvenient questions that cannot be brushed under the existential carpet. Like would not costly longevity drugs further widen the life-expectancy gap between the poor and the rich; or if more and more people lived relatively unravaged beyond 100, what would happen to the precariously poised balance between economy, population, insurance, employment, resources, family dynamics and healthcare cost, among other things. In a nutshell, it would spell a radical restructuring of society.


Just like the unending Penrose stairs, some researchers believe that the search for immortality is also illusive
In a debate titled “Are lifespans long enough” conducted by the website www.intelligencesquaredus.org in February this year, Ian Ground, who teaches philosophy at Newcastle University, UK, believed that the world will probably become worse. A society dominated by grandfathers and mothers will most likely become status quoist and kill innovation, as, Ground argued, all of us tend to become conservative with age.

The implications for the individual would be even more momentous. In response to the plea that people will have more time to discover the world, Ground cautioned against glorifying curiosity for curiosity’s sake. As he told in an interview to the Men’s Health magazine in 2012, “what we aren’t envisaging is just becoming knowledge-acquiring machines for the rest of our lives. We need feelings and relationships, not just work.”

Then there is the fear of boredom, which the late 19th century French poet Charles Baudelaire eloquently described as:

even uglier and fouler than the rest,
although the least flamboyant of the lot;
this beast would gladly undermine the earth
and swallow all creation in a yawn

In his 2007 book How to Live Forever or Die Trying, British journalist Bryan Appleyard embroiders the importance of ennui further. Mocking the immortalists’ naiveté, he argues that personality or the self cannot be stretched or reinvented indefinitely even if life could be. Czech composer Leos Janacek’s opera The Makropulos Affair further massages Appleyard’s point. As the story goes, Elina Makropulos, the protagonist, extends her life by 300 years—thanks to a magic potion. After three centuries elapse, she has the option of taking the elixir again but chooses to die instead as she is bored to death.



The Myth of Sisyphus
The absurdity of existence that repeats itself ad infinitum was the topic of Albert Camus' essay The Myth of Sisyphus
Or take the tragic figure of Tithonus from the Greek myths. Smitten with him, Eos, the goddess of spring, asked Zeus to make him immortal. But, alas, an endless life does not mean youth eternal. So the poor boy was condemned to grow old forever with all the suffering and pain that comes with it. Indeed, even as more of us celebrate our diamond jubilees, it is sobering to remind ourselves that we are all destined to be Tithonuses.

Some argue that a longer life would give us the luxury of living the unlived life, the promise of a life better than the lived one. A tempting and persuasive thought, but one whose futility was deduced logically through the concept of eternal return. Drilled into popular imagination by German philosopher Friedrich Nietzsche but harking back to ancient India and Greece, this ingenious hypothesis states all life is recurring and will continue to do so infinitely across infinite time or space. In short, the desire for a new existence is an illusion. T S Elliot echoed this famously in his Four Quartets:

Time present and time past
Are both perhaps present in time future
And time future contained in time past

French philosopher Albert Camus too dwelled on the idea in his essay The Myth of Sisyphus, in which the tragic figure of Sisyphus is condemned to push a boulder uphill forever, an act illustrating the absurdity of existence that repeats itself ad infinitum. The only way out of this conundrum, Camus reckoned, is to “imagine Sisyphus happy”.

No one was more sceptical of extending life than Michel de Montaigne, the 16th century French dilettante philosopher. Even though his library was full of medical texts on how to live a healthy and long life, he was not convinced if the price paid was worth the effort. For him, “we are born to grow old, to grow weak, to be sick, in spite of all medicine. . . We must learn to endure what we cannot avoid.”

But the last word on the subject must go to the irrepressible Irish wit George Bernard Shaw, who in his preface to the play, The Doctor’s Dilemma, wrote: “use your health, even to the point of wearing it out. That is what it is for. Spend all you have before you die; and do not outlive yourself. Do not try to live forever. You will not succeed.”

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Answer  1-A, 2 -C, 3-B