Science & Technology

Mortal combat

Can life be extended indefinitely? There is a renewed vigour among scientists looking for ways and means to cheat death

 
By Rakesh Kalshian
Last Updated: Friday 24 March 2017

Mortal combat

Ram Sevak Pathak of Madhya
Pradesh's Sheopur district says
a regular regimen of diet and
exercise, and abstaining from
alcohol and tobacco, have helped
him live to be 105 (Photo: Bhaskarjyoti Goswami)

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

Google's
life sciences
subsidiary Verily
has started a
project to study
healthy people

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.

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