‘Fitness our evolutionary advantage, not longevity’

In an interview with Down To Earth, Nobel laureate Venki Ramakrishnan talks about his new book on ageing

Nobel laureate Venki Ramakrishnan’s latest book, Why We Die, covers a journey that starts in the 1800s, when British biologists Charles Darwin and Alfred Wallace proposed natural selection, and continues to this day, as researchers investigate anti-ageing compounds. But how close are we really to cheating ageing and death? Ramakrishnan, who received the 2009 Nobel prize in chemistry, says the focus of research is on staying healthy for a bigger fraction of life. He also examines the causes of ageing, the drugs being explored to slow down this deterioration, the people involved in the research and a few controversial claims. Edited excerpts:

Rohini Krishnamurthy (RK): Can science help humans defy death?

Venki Ramakrishnan (VR): Defying death is a tall order because it means that lots of systems need to be kept going. The breakdown of these systems is indeed the common cause of death. You could also die of an infectious disease or accident.

Some people feel that if you can address the underlying common causes, you could postpone death by preventing or slowing down ageing. But can we slow it down to an extent that we live well beyond our natural limit, which is about 110 years or so? Very few people live past 110, and only one person has lived past 120 [a record held by Jeanne Calment, a Frenchwoman who died in 1997 at the age of 122]. It would take some fundamental breakthroughs to go beyond that limit. I do not think it is as easy as some people claim it is.

RK: Could improvement in health infrastructure or medicines push that limit beyond 110 years?

VR: It would be very hard because there are other issues, like general frailty and tissue breakdown. For example, we have the drug semaglutide, which is being used to treat diseases that accelerate ageing, like obesity. But I do not know how much time that will buy us.

A lot of focus is on healthy ageing, which is not about extending life but staying healthy for a bigger fraction of your life, so that one does not spend two decades or so in really poor health at the end. The idea is to stay healthy so people can move around and be independent. My father, until he was about 92, used to go on eight-mile (over 12 km) walks. He cooked and did laundry by himself. At 98, he still does these chores, but finds it hard to walk now. You can see a decline between 92 and 98, even in a relatively long-lived individual. So, the question is whether you can compress that period of decline so that you are healthy for a bigger fraction of your life.

RK: Your book talks about the different factors involved in ageing—like genes and proteins—and how they interact with each other. Some funders want to hack ageing. Given the complexities of the human body, is this doable?

VR: Quite a significant amount of ageing work is funded by technology billionaires. I joke that they like the party and do not want it to end. So, they want to fund ageing research to stay healthy and perhaps live longer. But it is a misguided notion because the human body is quite complicated and is not a computer.

Billionaires talk about hacking the code and solving ageing, but biology is complicated. We do know some of the major causes of ageing. And we know they are complicated; that they are not isolated processes, and that they all interact with each other. For example, damage at a molecular level will affect function at the cellular level, and then the organismal level. And that will feed back and affect things at the molecular level. So, it is a very complicated web of interactions.

The ageing research community loves rapamycin [initially developed to suppress the immune system during organ transplantation and being explored as an anti-ageing drug]. But it has the potential to make you more prone to infections. It is not clear that you would want to give this to a healthy population. We need to do proper clinical trials to see if it is efficacious in the long run, and has minimal side effects.

And then there are other remedies that, for example, target senescent cells [cells that stop multiplying but are not dead. They then release chemicals that can trigger inflammation, a hallmark of ageing]. There is certainly a lot of very good science that suggests that we may make some big breakthroughs in ageing. And that is one of the reasons I was curious to write this book. But there is so much hype that solutions are around the corner. People who think it is going to happen anytime now, or in the next few years, may be disappointed. But I think in the long run, there may be some real breakthroughs.

RK: How many years before we see a breakthrough?

VR: Well, in science, it is very hard to define the “long run”. It took 400 years to go from Newton’s laws to satellites. But if you take penicillin, there are maybe 10 or 15 years from the discovery to use in humans. I would not want to hazard a prediction.

Is there a reason the book does not talk about gene therapy, an approach to treat or prevent disease by providing new DNA to certain cells or correcting them to slow down ageing? I do not think gene therapy is a particularly useful target at the moment for anti-ageing. None of the researchers I have talked with or any prominent leaders in the field are advocating gene therapy as a recourse for ageing.

There is a genetic component to ageing, but in humans, it is complicated. There are multiple genes, each of which exerts an influence that causes ageing.

In simple systems, scientists have found, a single gene or a variant of a single gene in a worm can double its lifespan. But worms with this variant will not be able to survive in competition with normal worms. That means it is paying a penalty for that mutation. Yes, it can live longer, but maybe it cannot compete for food or reproduce or grow as well as the normal worms.

Evolution has selected us for fitness, which is the ability to pass on our genes. It has not selected us for living long. It is a calculated balance. If you tinker with the balance to live longer, you may have other side effects. For example, there is a gene called apolipoprotein (apoE) which has multiple variants. One of the variants is overrepresented in centenarians. The same variant also protects them against Alzheimer’s disease. The reason they are living longer and not getting Alzheimer’s may be related. Now, that same variant could make them more prone to dying of COVID-19 or of certain kinds of cancer.

Targeting genes needs research, actual data, clinical trials, and so on. Gene therapy is not something I would advocate now. What I wanted to say in the book is there is a lot of exciting research happening in many areas. And the hope is that all of this will lead to better lives in old age. Whether it leads to longer lives, I am less sure. In the meantime, there are things we can do to stay healthier.

For example, I have said in my book that a trio of things can help. One is to eat in moderation and follow a healthy, nutritious diet. The second is to exercise regularly and the third is to sleep for at least seven or eight hours a day. It also is true that each of the three helps the other. For example, if you sleep you are also less inclined to overeat and more inclined to exercise. Similarly, if you exercise, you are also likely to sleep better because you reduce stress. This trio also could help you reduce your cholesterol, blood pressure, onset of diabetes, and the like.

RK: You write about nutritional supplements being marketed as anti-ageing products without evidence. Do you see their sale being regulated?

VR: You can buy things that lengthen your telomeres on Amazon [Telomeres are DNA sequences found at the end of chromosomes, which shorten with age. Shorter telomeres have been associated with increased incidence of diseases.] None of them have gone through clinical trials or approval. So, we do not know what the evidence is, including their long-term consequences. People have tried to regulate them but it is hard because many of them are ordinary nutrients and natural compounds found in plants. It would be hard to regulate, at least in countries like the US, which have libertarian attitudes. They do not like to interfere with the market too much.

If we eat fresh fruits and vegetables, we will get a lot of vitamins and minerals, and they are present in the amounts that we have naturally evolved to deal with. Pills concentrate ingredients that are found in nature and are present in huge amounts, equivalent to eating dozens of oranges. I am not sure that we need these nutrients in large amounts for beneficial effects.

RK: The book says that some anti-ageing industries have been around for nearly two decades but we have not seen breakthrough yet. Why?

VR: It is very hard to do trials. With a disease, like COVID-19 or cancer or diabetes, you can have a potential drug candidate and you can do a clinical trial and very rapidly see if they are effective or not. For example, we can test if the cancer is growing or regressing.

With ageing, it is more difficult because it is a gradual and a slow process. And so it is very hard to do clinical trials. You can do trials in animals, but they do not necessarily translate to humans as many have failed in clinical trials. So, that is one problem.

The anti-ageing research community is trying to come up with good markers for ageing to see whether the treatment is having an effect. But to do that, you have to agree on the biomarkers and whether they represent ageing. Each person does not age in a unified way. Your liver may be ageing faster than your heart or your kidneys. So, you cannot ascribe necessarily a single number to your biological age [how old your cells are, which is different from chronological age]. This makes it complicated. However, longevity companies treating a particular disease of ageing are more likely to succeed because they at least have a target and can measure something.

RK: Should humans live longer? Have we thought of the consequences of prolonging our lifespan?

VR: If somebody came to you with a pill, and said: This will give you 10 years of extra life, and a healthy one, but you have to start taking it now and there are no or few side effects, what would you do? You would probably take it. I think that is just the reality of human nature. We do not want to die.

So, consequences for the individual and for society are different. This is a constant problem, including in terms of climate change. People drive and fly around because they want to go on a vacation. This is not good for the climate, but that is not stopping us from doing it. So, human behaviour is very complicated. We often do things that give us benefits, even if it costs society in the long run. This problem can only be solved socially with education and regulation.

This was first published in the 16-30 June, 2024 print edition of Down To Earth