Nobel-winning biologist on the most promising ways to stop ageing

Good to see and he is able to be independent in his approach.  All good.  

Biologically, it looks promising for two things.  It should be possible to clean out old cells somehow with some form of treatment agency that may already exist.  After all, we did have the mythalogical elixer and that sure sounds like something that does just that.

The other is it may well be possible to restore teleormide integrety.

Both these can powerfully extend our lives.  Is this goji berry tea?

Real life extention in this manner may well give us three centuries.  Wanting more would then be an issue as return to the other side may well become compelling.  just when are you done?

Nobel-winning biologist on the most promising ways to stop ageing

Efforts to extend our lifespan continue and many look promising, but success will have unintended consequences, says Nobel prizewinner Venki Ramakrishnan

By Graham Lawton

18 March 2024

https://www.newscientist.com/article/mg26134830-900-nobel-winning-biologist-on-the-most-promising-ways-to-stop-ageing/?

Ula Šveikauskaitė

ANTI-AGEING is big business. From books encouraging diets such as intermittent fasting to cosmetic creams to combat wrinkles, a multibillion-dollar industry has been built on promises to make us live longer and look younger. But how close are we really to extending our lifespan in a way that gives us extra years of healthy life?

Nobel prizewinner Venki Ramakrishnan, a molecular biologist and former president of the UK’s Royal Society, is the latest to tackle this question. He has spent 25 years studying the ribosome, which is where our cells make proteins using the information encoded in our genes, at the MRC Laboratory of Molecular Biology in Cambridge, UK.

In his latest book, Why We Die: The new science of ageing and the quest for immortality, he goes on a journey around the cutting-edge biology of human ageing and asks whether it will be possible to extend our lifespan in the near future.

He talks to New Scientist about the recent breakthroughs in our knowledge of what causes ageing, how close we are to creating therapeutics to combat it, and the potential consequences if we succeed.

Graham Lawton: What inspired you to take a break from a hugely successful career researching how cells make proteins to write a book about ageing?

Venki Ramakrishnan: Two things. One is that the translation of genetic code into proteins affects almost every biological process, and it turns out to be central to many aspects of ageing.

The other reason is that we have worried about ageing and death ever since we became humans. For most of our existence as a species, there was very little we could do about it. But because of the tremendous advances in biology over the past few decades, we now have tools and a level of knowledge to think about what causes ageing and what we could do to either ameliorate it or postpone it.

At the same time, there’s a huge amount of hype in this field. I thought that, as a molecular biologist who understands the broad field while not being in it, who doesn’t have an agenda or any companies involved in ageing, I was perfectly positioned to take a very hard look at what’s going on and ask: what are some of the real things we know about ageing and what are the prospects for the future?

Do you think we fully understand the main causes of ageing?

No. Ageing occurs at every level, from the molecular to the cellular to the organs and the entire body, and it has multiple causes that are highly interconnected. Cause at one level can influence cause at a more basic level and vice versa. If some entirely new aspect of ageing were to come about, I don’t think the researchers would quibble.

But we understand it enough to start thinking about interventions?

Yes, I think that’s a fair comment. The idea is that a cell doesn’t want to spend too many resources trying to prevent ageing because it comes at a cost, and it’s not worth it if you’re going to die anyway, such as by starving or being eaten by a predator. Our life expectancy has doubled over the past 150 years, so we encounter all these diseases of ageing that, in the past, very few of us would have encountered. As we start to understand the biological basis, people are trying to intervene.

What do you see as the most promising avenues for interventions against ageing?

One very exciting area is stem cell regeneration and cellular reprogramming. Stem cells and regenerative medicine are already established areas with a lot of promise and some people are segueing into anti-ageing research. The idea is to reprogram cells so that you can perhaps reverse them back to an earlier stage so they’re capable of regeneration. But it’s early days.

How close are we to gaining extra years of healthy life?

What other approaches are there?

Everybody agrees DNA damage is a fundamental cause of ageing, but so far [work on] DNA repair, and therapeutics targeted at that, has been mostly to address cancer rather than ageing.

But there are people working on telomere loss. Telomeres are the ends of our DNA strands. When you replicate DNA [during cell division], you start losing the ends. If you kept losing the ends, you would start going into the part of the chromosome that codes for important information.

There’s an enzyme, telomerase, that adds telomere sequences every time there’s a replication, but it turns out we shut off telomerase in most of our cells, except for certain cells that have to live for a very long time, like stem cells. Many of our cells, like our skin cells and hair cells, have often lost telomerase, and so the question is, could you reactivate telomerase and regenerate these tissues? There are people who are studying that and there’s some initial promise. I would say [reactivating telomerase] is probably most likely to help with diseases where you have telomere loss, and only after that will we know whether it’s a general thing against ageing.

Another approach involving DNA damage we are hearing more about is senolytics. What is this?

When you have DNA damage or you have extreme telomere loss, the cell can go to two outcomes. One is [cell] suicide, a phenomenon called apoptosis. The other is to go into a “senescent” state where it stops dividing and is no longer functional in the usual sense. But it turns out these senescent cells aren’t just quietly sitting there – they’re secreting inflammatory molecules. These are triggers for the immune system to come and do repairs.

If you accumulate senescent cells, you get inflammation, and if you specifically kill senescent cells, you can alleviate many of the symptoms of ageing that are a result of inflammation. That field is called senolytics, and it seems to be promising.

How does your own specialist area, protein synthesis, tie into ageing?

When you make proteins, they usually fold up into their normal shape and do their thing, but as they age, proteins can unfold. When they unfold, they expose the inside amino acids, which are sort of sticky. And so these proteins tend to aggregate. They’re bad for the cell, so the cell has lots of ways of trying to deal with unfolded proteins.

What you want to do is shut down protein synthesis. It’s a bit like if you have a traffic jam, you want to stop new cars from entering. And that’s what a protein called TOR does. Whenever there’s stress, TOR will shut down protein synthesis, and this seems to have an effect on ageing because it also turns on degradation and recycling pathways. These metabolic pathways indirectly slow down ageing.

This provides a biological explanation for the long-standing observation that if you calorically restrict animals, providing them with just enough calories to survive, they tend to live longer. Now, of course, nobody likes caloric restriction. Even mice. As soon as you stop caloric restriction, they start gorging on food. I think it might be easier to take a pill that has the same effect, and I joke that this is a “get out of kale free card”. But actually, we’re nowhere near.

That is a recurring theme in your book, a reticence to extrapolate from basic science to applications in people.

I just know from much more clear-cut areas how long it takes to go from a basic finding to something that’s actually useful. Even in the best cases it takes 10 or 20 years. When you take a much more multifactorial and ill-defined process like ageing, this idea that we’re going to solve it tomorrow is highly optimistic.

The anti-ageing field is also being highly distorted by the injection of huge amounts – billions and billions of dollars – of private capital. A lot of it is driven by tech billionaires. They’re mostly middle-aged men and they’ve got everything in the world. They can buy anything they want. Except youth.

Younger people may approach life with an openness that is lost with age

If we can eventually intervene in ageing, do you think people will want to?

I do believe if someday somebody comes up with a pill and says it’ll keep you healthier for 10 years longer with no side effects, who wouldn’t want to take it? I think we have to be prepared for a potential future where it might be possible, though I’m sceptical that it’s around the corner.

But I’m also optimistic that eventually there may be breakthroughs that will help us overcome some of these barriers. Then we’ll be in a situation where maybe we’ll all be living quite a bit longer. I just don’t think it will happen in my lifetime or even to anybody born today.

What do you think the consequences will be if we start living longer?

If we all start living longer and we reproduce at the same rate, then the population will start exploding. You’d have what I think of as a stagnant society. People say, “oh, but if we had 200 years to live, we would have five different careers”. This is wishful thinking. I think most of our innovation happens when we’re young. You look at great scientific discoveries, even great works of literature: all were done when people were relatively young. Why is that?

I think part of it is that when we’re young, we approach life with a freshness and an openness. We’re willing to challenge existing ideas and dogma. And that gives us a sort of creativity that we start losing as we age. So it’s not simply a question of staying healthy. I’m reasonably healthy, but I don’t think I’m nearly as creative as I was when I was 40.

I think this is a serious problem, especially if you look at social trends. For example, civil rights or women’s rights or LGBTQ+ rights. Social changes are often driven by young people. People talk about older people: maybe they’re not quite as sharp, but they have more wisdom. I’m sceptical about that too. Often, older groups are driven by conservatism born of nostalgia. I don’t think that’s necessarily wisdom.

We already live twice as long [on average] now as we did 150 years ago. Are people today really more creative or more prolific than Mozart or Beethoven or Charles Darwin or Isaac Newton? I don’t think so.

There are much more pressing issues than slowing ageing. Where would you redirect our efforts?

As someone who grew up in India, I do think this mania to live longer is a First World problem, and I think there are so many more important problems: infectious diseases, chronic diseases, malnutrition, food security, climate change. Those are all much more pressing problems than living 20 years longer.

I do think we should aim to live healthily for as long as we can. But we’ve got to accept our mortality as just part of the grand scheme of things. It is very hard, and I think we’re deeply evolved to avoid death. It goes against our natural instinct, so it’s hard work to accept it gracefully.