Nobel Laureate Venki Ramakrishnan explores whether we can slow ageing
The quest for an elixir of life that could stop or even turn back ageing is something that has gripped humankind for centuries.
From the search for the philosopher’s stone, a legendary alchemical substance that would grant immortality, to the increasingly wild self-experimentation by Silicon Valley’s richest tech bros, the fascination with eternal youth remains strong.
But what can the latest scientific developments offer in the way of hope for extending life and perhaps even reversing ageing?
Nobel Prize-winning structural biologist Professor Venki Ramakrishnan has published a book called Why We Die: The New Science of Ageing and the Quest for Immortality, which is shortlisted for the 2024 Royal Society Trivedi Science Book Prize.
In it, he explains the latest scientific understanding of exactly why we age and how we might prevent it. He examines cutting-edge efforts to extend lifespan, and raises profound questions around death, ageing, and how to increase our chances of living long, healthy and fulfilled lives.
“The reason I wrote the book is it’s a big existential question: why do we age and die?” says Prof Ramakrishnan, who leads a lab in the Structural Studies Division at the MRC Laboratory of Molecular Biology in Cambridge.
“I think we may be the only species that’s aware of it. And it’s influenced human thought ever since we became aware of mortality. Religions all have different views of what happens when we die, and they all view it as a transition rather than some final exit. But for most of our existence, there was nothing we could do about it. It’s only in the last 50 years that molecular biology has made huge strides in understanding what happens at the molecular level as we age, and how that build-up of damage eventually results in death.
“And while we’re at it, death itself is a slightly funny business, because while we’re alive most of our cells are dying. Millions of cells are dying all the time in all of us, and some of that is actually part of natural biology. It’s actually required. And at the same time, when we die, most of our cells are still alive. That’s why you can donate your organs and they will carry on in somebody else. And so it’s a peculiar thing, ageing and death.”
Another reason to write the book, he explains, is because while we are living longer and growing older, fertility rates are going down in developed countries like Britain, Japan, Korea and many countries in continental Europe.
“The only way you can have a stable population is really by immigration,” he says.
And an ageing population leads to questions of how to keep people healthy into old age.
“For many of the diseases of old age, really one of the big risk factors is just being old, like diabetes, cancer, heart disease, dementia. They’re all much more likely when you’re old and so there’s a real need to understand and try to do something about healthy ageing,” says Prof Ramakrishnan.
At the same time, he is concerned by quackery and the supplements business that has grown up around anti-ageing concerns.
“It has generated a huge amount of hype,” he says. “People are selling all kinds of supplements and making all sorts of claims about how we’re all going to live to be over 100 or even that we might live to be 150 very soon. I thought that it would be good for someone who didn’t have an axe to grind or anything to sell to take a hard look and just say what I think is going on.”
However, he does know of two other Nobel Prize winners taking a particular supplement because of its promising research results.
Surprising findings
The reasons why we age and die are not as simple as they may seem at first.
“I went into the book somewhat naively about evolution,” says Prof Ramakrishnan. “We all have very different lifespans. An insect like a mayfly lives only for a day, butterflies maybe a few weeks. And at the other end, you have species that live for several hundred years and so I thought that maybe this means that ageing is programmed, so each species is programmed to die after a certain period and the reason for that was to allow replacement by the next generation and then to allow evolution to progress.
“But actually, that’s a somewhat naive idea, and it turns out that evolution doesn’t really care about how long you live. Evolution has selected for a balance which optimises not lifespan, but fitness, which is your ability to pass on genes. So if you’re an animal that’s likely to be eaten very quickly or die of starvation or drought or whatever, then it doesn’t pay for evolution to select for a metabolism that will keep you healthy for a very long time because you’re not going to be around.”
He explains that it is advantageous for a mouse, which has lots of predators, to grow quickly and produce lots of offspring so it doesn’t matter if they die early. But for each species, selection has been different, and there is “a rough relation to size” and to metabolism. “The bigger you are, generally speaking, the longer-lived you are,” he says, although he admits there are exceptions.
Another general rule is, “the faster your metabolism, the shorter your lifespan”. So many long-lived animals have quite a slow metabolism.
The other “surprise” is that ageing is not just down to wear and tear.
“Species live such different lifespans, and we’re all made of the same material: DNA, lipids and proteins. We repair all the wear and tear constantly, otherwise we wouldn’t live very long. And it’s those processes that are different in different species and so there’s a number of ways to understand what actually breaks down,” he says.
The real reason we age
Ageing appears to be related to the number of senescent cells we have in our body. A senescent cell is one that has aged and stopped dividing, but has not died. They can accumulate in tissues throughout the body and release harmful substances that can cause inflammation and damage to nearby healthy cells.
Prof Ramakrishnan explains: “Our DNA accumulates changes and damage that lead to ageing; this is called telomere shortening, and that results in cells becoming senescent, which is, they no longer function properly, and they can’t divide, and instead, they secrete inflammatory compounds. Early in life, that’s beneficial, because it’s a response to stress like an infection or a wound, and it’s signalling that I’m damaged, and so I’m not going to continue to divide, because that will just create more problems, and instead signalling the immune system to come and repair the damage. But as we get older, those cells break down and become senescent at much greater frequency, and at the same time, the ability of our immune system to clear them is also worse.”
Latest research
Anti-ageing research looks at how this process can be slowed down. It turns out there are several contenders for treatments that may hold back the years for patients.
“Once cells become senescent, it’s very hard to turn them back,” he says.
But one field of ageing research has emerged called senolytics, which explores how to kill senescent cells so they don’t continue to cause inflammation and problems.
“That has shown very promising results in animals,” says Prof Ramakrishnan. “The question is, can you do it safely? There are a number of clinical trials which are using cell analytics to see if they can help with human conditions.”
Drug treatments
One area of research that is proving promising is an immunosuppressant drug that mimics some of the effects of restricting calorie intake, which is known to have an impact on lifespan.
“People found that restricting the number of calories an animal consumes makes it resemble a younger animal in many ways and improves many of the symptoms of ageing,” says Prof Ramakrishnan.
“Caloric restriction affects a number of pathways, but some of those pathways can be inhibited by drugs, and some of those drugs have effects that are similar to caloric restriction – maybe not identical, but similar, and one of them is rapamycin. But of course, rapamycin is also an immunosuppressive drug.
“It’s given to transplant recipients to prevent rejection of transplanted organs by their immune system. And of course, if you suppress your immune system, you’re more prone to infections. If you get hurt, you won’t be able to heal your wounds very easily. It has a number of other side effects. So it’s not a great idea to give rapamycin without proper trials. And of course, the people who advocate rapamycin suggest that maybe you can adjust a dose so you have the benefit without the side effects. Or that you can find compounds similar to rapamycin, maybe modifications of rapamycin, which have the benefits without the side effects. So these are all things that people are working on.”
These drugs are the most promising in terms of a treatment that could more easily be rolled out to the general population, he believes.
He says: “I think if I had to bet on the short term, it would be these drugs that mimic caloric restriction or drugs that destroy senescent cells – these senolytics, I think those are the two that are scalable. You can take them as a pill and if they work, they could be useful to a large population. I think those are also much further along in terms of being attempted, at least, to trial in humans”.
Young blood
After some early promising experiments with mice, it appeared that blood transfusions from younger to older animals could confer anti-ageing benefits. Famously, multimillionaire tech exec Bryan Johnson began having blood plasma transfusions from his son in the hope that he could begin to age backwards.
“I believe he tried that for a while and felt it didn’t have the intended effect. So he stopped. He was getting blood from his son, and then he’s also donating blood to his dad. So there was a three-way transmission,” says Prof Ramakrishnan.
“It did work in mice. But initially the mice were physically connected. So it wasn’t clear whether the young mouse had better organs for cleaning up the blood, and it was simply doing a kind of cleaning exercise, or whether they were actually other factors. So then they gave mice, which were not connected, transfusions with the young blood or old blood, and one of the experiments suggested that the old blood added more harm to the young mouse than the young blood had benefits for the old mouse.
“What’s not controversial is that there’s differences in young and old blood. So people are looking at factors in young blood that are beneficial. That’s an ongoing area of research, but as a life extension thing, I don’t think it’s going to be very useful right away. However, I think the research on which factors are producing benefits that could lead to some very interesting outcomes.”
Regenerative medicine
An area of research that is currently making big strides is cellular reprogramming. “That’s a very challenging but also very exciting area,” says Prof Ramakrishnan.
“This is part of a very broad deal called regenerative medicine, where you can induce the ability to regenerate tissue that normally would not be replaced. For example, heart muscle isn’t replaced very often, but if you have damaged heart muscle and you were able to restore heart muscle, that would be a big deal.
“One thing close to my heart is cartilage. If you’re able to restore cartilage in our joints, we might be able to help with osteoarthritis. As we get older, joint pain is a very common symptom. Or if you’re a man and, like me, you’d like more hair on your head… that would be a billion dollar market right there. So that’s a very general field of what’s called regenerative medicine. And I think anti-ageing is just a special case of that.
“Normally, cells develop one way. That is, they start from a fertilised egg and gradually become more and more specialised and, in the end, you have these specialised stem cells which are responsible for generating all the tissues, but the final tissue cells can’t go backwards and become stem cells again. The older we get, the number of our stem cells declines, and even the quality of the stem cells declines. And so we’re less able to regenerate tissue. That’s why if I fall off my bicycle and bruise my knee, it takes me ten times as long as my grandson to heal if he fell off his bike.”
He explains that an experiment on frogs by Cambridge biologist John Gurdon showed it was possible to clone an animal by taking an adult cell and “tricking it into becoming almost like a fertilised egg to produce an entire new frog”.
Since then, Shinya Yamanaka, a Japanese stem cell researcher and a Nobel Prize Laureate, has since found that, when activated, skin cells from mice could be reprogrammed to immature stem cells which, in turn, can grow into different types of cells within the body.
“He showed you could take four factors and introduce them into any fully adult cell, and it could go backwards in development and become like an early stem cell that could then make any kind of tissue,” says Prof Ramakrishnan. This potentially could be used to reverse signs and symptoms of ageing.
“This is not a method that’s going to be very easily adaptable to humans,” he explains, “but it’s a very exciting area.”
However, any treatment would involve a complicated procedure and would not be like “popping a pill”. And it may come with a risk of cancer.
It is, nonetheless, “one of the few things that actually has a promise of not just slowing down ageing but actually potentially reversing some of it,” he says.
Are there any anti-aging supplements worth taking?
Prof Ramakrishnan says: “There are some people who are advocates of a supplement called precursors of NAD. Now, NAD is a compound that we synthesise from vitamin B3 and it’s a very essential compound because it’s required in lots of chemical reactions.
“The idea behind this is that as we age, our ability to make this compound declines, and so there’s a kind of non-optimal level of this compound. So there are supplements you can take that are precursors of the compound. That is to say, the body can use that supplement as a starting block from which to make the NAD.
“If you give them to older mice, they seem to have some benefits, but the question of how much they benefit humans, and what happens if you give it over a very long time, I think, needs some work.”
Although he doesn’t take the supplement himself, Prof Ramakrishnan says: “I actually know two Nobel Laureates, including one in Cambridge, who take it.”
What does he recommend to slow down ageing? The simple answer is the trio of good sleep, good diet and exercise.
“This is what I say in the book is probably the most effective way to stay reasonably healthy in old age,” he explains.
“I would suggest both aerobic exercise for cardiovascular benefit, but also load bearing exercise like resistance exercise for strength to prevent muscle loss, which is a problem as we get older, and that has a benefit also of other things. For example, stress is a problem and accelerates ageing. And these things will also improve your stress level.
“I do take medicine. For example, these things are also effective against cholesterol and high blood pressure. And yet my indicators kept creeping up, and so eventually I started taking blood pressure medicine and statins.
“You could argue that those are anti-aging medicines because they’re keeping me healthy in old age and make me less likely to die of a stroke or a heart attack.
“I also take half a vitamin pill a day. I probably don’t need it. It’s just that when I travel I don’t necessarily eat well. So, psychologically, it gives me some confidence.”
The winner of the Royal Society Trivedi Science Book Prize will be announced on 24 October.
