Mortal combat

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 chillies, which I think did me much harm."

In Pathak's reckoning, having a purpose in life also plays a vital 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 a meal, eat less, and munch garlic with tea.

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 the 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 figure 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 the 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 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? Are 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?

Science's quest to prolong life has a long and checkered history. Many ideas began with a bang but eventually fizzled out. 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.

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.

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 for Systems Biology in Seattle, and the Resilience Project, a joint venture between the Icahn School of Medicine at Mount Sinai, New York, and nonprofit 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?

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 confront the fundamental question of what is ageing.

Scientists have 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.

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.