The Pursuit of Longevity

JEANNE CALMENT, A FRENCH WOMAN, LIVED in a place called Arles and that was also where the famous artist Vincent Van Gogh spent a year towards the end of his life. Van Gogh died young at the age of 37. Calment was more for­tunate. She went on to become the oldest human being ever and by the time of her death in 1997, she was 122 years old. She was so old that she remembered seeing Van Gogh as a teenager. She rode a bicycle even at the age of 100. She ate a lot of chocolate and being a smoker did not affect her longevity. In fact, she was very healthy almost until the very end, even though this was a time before antibiotics or any of the miracles of modern medicine that has increased life spans enormously over the last century.

In his just published book Why We Die: The New Science of Ageing and The Quest For Immortality (Hachette; 320 pages; ₹699), the Nobel laureate Venki Ramakrishnan, mentions Calment’s story to explore the ques­tion of how long can human beings realistically expect to extend their lives. At another point in his work, he brings in an interesting category of people called supercentenarians. He quotes a study in which it was found that the number of centenar­ians, or those who became 100, were increasing among human beings but they were still different from super­centenarians, or those who lived to be over 110. For one, not many centenarians reached the age of 105 (semi-supercentenarians) or 110. About 40 per cent of centenarians also had age-related diseases before they turned 80. But it was differ­ent for the supercentenarians, like Calment, who were healthy almost their entire lives. It was only towards the very end that their bodies began to deteriorate. Would studying them hold the key to making lives longer for everyone? Not really as of now.

In a Zoom interview, Ramakrishnan says, “This is a very odd finding that these people who are 110-plus live extraordinarily healthy lives and then they have a rapid decline. Many of them live quite independent lives even. Nobody knows why. Some compo­nent has to be genetic and people are studying their genomes and trying to find out what it is that gives them these healthy, long lives. Another could be their particular life history. But even if you find out about them, it’s not clear how you would translate that to the general population. First of all, it may be some combination of genes, and it may be different. It may not be one common set of genes for all supercentenarians, they may have different combinations. So it’s a very complex problem. But they do live to be very healthy until almost near the end.”

THIS IS IN keeping with the book’s premise that there is really no single silver bullet to make humans live beyond a point. Ramakrishnan is a structural biologist. Born in India in 1952, he studied in the US and then moved to the United Kingdom where, in Cambridge, he is with the MRC Laboratory of Molecular Biology. In 2009, he won the Nobel prize for breakthroughs in the study of ribosomes, which he describes in the book as “a giant, ancient molecular machine that consists of almost half a million atoms”. They exist in cells and their key function is to make proteins that the human body uses for most of its upkeep and functioning. One of the most im­portant functions of genes, the embed­ded codes by which life is governed, is the making of proteins. Proteins carry out chemical reactions essential for life, allow cells to communicate with each other, allow nerves to send signals, make antibodies against diseases, enable cells to make other molecules like hormones, fat, carbohydrates and vitamins. Proteins are therefore directly related to how humans age. Ramakrish­nan felt himself qualified to write Why We Die because his field of research is al­lied to the subject by way of proteins. He had earlier written a book on ribosomes called Gene Machine: The Race to Decipher the Secrets of the Ribosome. So, when he was contemplating his next work, the subject presented itself. He says, “This is a big existential topic. You know, the whole question of aging and dying has been something humans have wondered about for a long time. At the same time, in most of our history, there wasn’t anything you could do about it. But it looks as if the science of aging is advancing quite significantly in the last 40 or 50 years. At the same time, there’s also an enormous amount of hype in the field. I thought somebody who’s not actually working in the area but is in a closely related area—I’m a molecu­lar biologist and my field is the process of protein synthesis that is central to many of the processes of aging—who doesn’t have a vested interest or any particular agenda, if I took a look at it, it might be an interesting way to write about the field.”

We age because of not one single reason and most of it is happening at the cellular level. For instance, DNA is supposed to be the blueprint that regu­lates the process but blueprint implies rigidity whereas the DNA is flexible in its programming. It is the central hub that regulates the cell’s programme but using a striking metaphor, he writes that the cell itself is “more like a democ­racy than a dictatorship”. Conditions within it and its environment decide which part of the DNA is used and when. The programme is not fixed and it is also not capable of running forever because DNA changes and deteriorates with time. In the book, many of these scientific processes are explained for a lay reader. Take cells that detect DNA damage and initiate a response against it. It can be senescence where cells go into a state where they cannot divide. Sometimes they even commit suicide. A protein called p53 plays a key role in repair. This protein has a connection to cancer because over half of all cancers have a mutation in p53. Some studies have shown that humans who have a better ability to do DNA repair live longer. Ramakrishnan says, “Aging has multiple causes. One is a breakdown in the programme of the cell due to accu­mulated damage. The cell has elaborate mechanisms to repair damage and to clear away defective components, and if those break down then you ac­celerate the process.”

Another reason for aging is because of manufacturing defects and quality control. He compares it to house­hold items that become useless. They can either arrive damaged. Or the damage could be done while it is being used, or it could just rust away with time. There are items which are not damaged but are not used anymore and these can add up and need to be cleared for the house to be inhabitable. It is the same with human cells and proteins. How they do it efficiently has conse­quences for increasing longevity or vice versa. There is, for instance, a molecule called ubiquitin, that the cell tags to a protein that it feels is defective or unwanted. The book adds, “Eventually researchers discovered a huge molecular machine called the proteasome, which acts as a giant garbage disposal. When a ubiquitin-tagged protein is fed into the protea­some, it gets chopped up into pieces that can be recycled.” Defects in the proteasome or ubiquitin tagging system leads to cellular debris hanging around. One more cause of aging is proteasome ac­tivity declining with age.

Despite increasing knowledge about how aging works and discoveries, like stem cells and promising medi­cines, Ramakrishnan thinks there is a limit. “There’s no law that it cannot be extended. Just like there’s no law that we cannot colonise Mars. Colonising Mars in a hostile environment with no atmosphere is just in the realm of fan­tasy today. But it doesn’t mean it’ll never happen. I just don’t think that with cur­rent knowledge we’re going to extend maximum lifespans. We would need a number of breakthroughs to happen before that and not least we would need to know how to stop aging of the brain. That’s not a solved problem.” It hasn’t stopped all kinds of ventures for immortality, some bordering on the absurd. There is a small industry of cryonics where people freeze their dead bodies for a fee in the hope that science will have advanced far enough in the future to revive them.

Ramakrishnan touches on the social fallouts of research into solving aging and it is not necessarily good. People retire in the 60s based on current life spans but if they start living longer without being simultaneously healthier, there will be a lot of old people who will need to be supported by the rest of society. Another consequence will be inequity. Medical advances typically go to the rich first and any increase in longevity based on expensive treat­ments will leave out the poor. It could lead to two classes—those who live longer with good health and the rest.

HE SAYS, “THERE’S a huge dispar­ity in longevity already today. For example, there is disparity between rich and poor countries in life expec­tancy, but even within rich countries the bottom 10 per cent live 15 years or so less than the top 10 per cent. That’s a big difference. If you look at the healthy years, it’s even bigger. So, the poor are not only living shorter lives, but they’re living unhealthier lives. Now if you have very fancy treatments, you could create a class of extremely rich people who are all living to be 90, a 100 and so on. And then others, you know who are starting to become sickly at 60 or 70. These are social issues that people need to be aware of.”

He compares the pursuit of longev­ity to technology that led to social media and artificial intelligence. They were unleashed by Silicon Valley entrepreneurs without thinking of unintended consequences that range from election tampering to intrusion of privacy to crime. He argues that the same should not happen to anti-aging research. Many of those tech billionaires are now investing heavily into anti-aging and expect it to be solved. He says, “They don’t under­stand the complexities of biology. It’s not like writing a programme to allow quick cash transfers. They think longevity research is always great. They need to consider what it will do to dispar­ity in society. How it would change the nature of societies if everybody started living longer. These people have not thought through the social consequences of it. Many of the serious anti-aging researchers are not about extending lifespan, they’re more about im­proving health in old age. I think that’s a very good goal because if we’re all going to live longer anyway, we should try to be healthy and independent.”

The biggest takeaway Ramakrish­nan gives in the book is actually some­thing that all of us know. That you don’t need to chase a magic pill, instead anti-aging is available right within you by simply focusing on your own diet, exercise and sleep. That is what research into aging also indicates. A healthy lifestyle directly affects the fac­tors the make us live longer and health­ier, like improving insulin sensitivity, muscle mass, mitochondrial function, blood pressure, reducing stress and the risk of dementia. Having a purpose in life and community contributes. All this will not only make you live longer in the future but even your present bet­ter. As he writes, “These remedies cur­rently work better than any anti-aging medicine on the market, cost nothing, and have no side-effects. While we wait for the vast gerontology enterprise to solve the problem of death, we can enjoy life in all its beauty.”