Venki Ramakrishnan
speaker
313 appearances
2 recordings
2 series
first heard Sep 2024
last heard 25 Apr
Venki Ramakrishnan’s voice in public audio — every appearance, attributed to the second.
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And then they have to be replaced by stem cells. And also those tissues can't be any other kind of cell, okay? So cellular reprogramming would be taking one of these final tissue cells, like a skin cell or an epithelial cell from your gut, and programming it to go backwards in that development process. And that means changing which genes it's expressing.
And what's amazing is that it, and this is why Yamanaka won the Nobel Prize, is that it only takes four factors to to take a final cell all the way back to that early pluripotent cell, which could create any type of cell, okay? The downside is that if you do that, you often end up getting cancers.
If you start developing those cells in a tissue culture, they often will develop tumor-like growths and so on. So I think, you know, That's both a promising and a challenging approach. And it's the one thing that actually reverses the process. And one reason that I am perhaps somewhat optimistic is, remember Dolly the Sheep? I do. Dolly the Sheep was cloned from something like a skin cell, okay?
And It was a sick sheep and it had all sorts of problems. It had shorter telomeres than normal, and it died at about half the age of a normal sheep. And everybody went, aha, that's because you started with an adult cell, which is already old and damaged. And then you tried to grow a new animal out of it. And so of course you haven't reset the clock.
Well, it turns out Dolly was only one of a cohort. There were other sheep like Dorothy and Daisy and Debbie. They gave them all D names for some reason. Anyway, it turns out most of these sheep were normal. Of course, you have to realize that the frequency of success in a cloning experiment is very small. most of those experiments fail and don't grow into adult animals.
But of the ones that actually made it into adult animals, a number of them had normal lifespan and apparently normal health. So at least in those cases, and of course there was ruthless selection involved because as I said, most of these embryos failed to take. But nevertheless, it is possible, at least in theory, to reset the aging clock, just as we naturally do every generation.
And that involved wiping out the signals, the programs of which genes are expressed, back to an early embryonic state. And that program is different from, the skin cell makes only a subset of genes, that we have. And it's a different subset from a brain cell or a heart cell or a blood cell. But you could take it all the way back.
that you need tissue regeneration. And it turns out that, and you need to recycle bad products. You need a number of things that have to happen that become dysfunctional as we get older. And it turns out one of the things that allow us to be healthier in old age is caloric restriction. Again, there's a big debate about that because they're always comparing
animal that gets just the bare number of calories it needs to live without starving. The animal is not losing weight and becoming lethargic. It's getting the bare minimum, though, to live. And they're comparing that with Animals that can eat all they want, an ad libitum diet. And there's always a difference.
Now, some people have argued, including Leonard Hayflick, who was the first person to discover that cells can only divide a certain number of times, which eventually was explained by telomere loss and so on. But that guy died, by the way, Leonard Hayflick died in his 90s, only about a month or two ago. Anyway, he was a skeptic.
He said, all this shows is that an all-you-can-eat diet is bad for you. Because in the wild, you never have all you can eat. This is a problem of a plentiful food supply, civilized society. But nevertheless, caloric restriction makes a difference, and it does affect a number of pathways. And people have found out that there are drugs that can inhibit some of these pathways.
And those drugs will often have some of the benefits of caloric restriction, maybe many of the benefits of caloric restriction. One of them called rapamycin was discovered in this very odd way. It has a fascinating history, how it was discovered. But it inhibits a major pathway called the TOR pathway. but which is also restricted by caloric restriction, inhibited by caloric restriction.
And so when they tried to give rapamycin to older animals, those older animals did seem to have improved health and improved symptoms and also lived a bit longer. So it's become a darling of the aging, some of the aging research community. But rapamycin is also the reason that it was known as a drug was because it's immunosuppressant.
It's given to transplant recipients to prevent organ rejections. And you wouldn't want to take an immunosuppressant all your life. I mean, if you're an organ recipient, you would, because otherwise you'd die, you'd reject your organ. But the equation's different if you're normally healthy. Why would you want to risk infection? And then it has all sorts of other side effects.
So the aging, some of the rapamycin advocates would argue that, well, maybe there's a dose at which it has the benefits without the side effects. Or maybe we can find compounds similar to rapamycin that don't have the side effects but have the benefits. So that's an ongoing research field. And I would say that's a valid field.
So the other thing is exercise. The other thing is exercise. And exercise, it turns out... helps to repair and renew the body. In fact, It's involved in regeneration of mitochondria, regeneration of muscle. So it has a huge number of benefits. And the last leg of this trio is sleep. So we think of sleep as something that maybe mammals do or animals with a brain or eyes do.
It turns out sleep is highly conserved, even very simple organism sleep, even things like single-celled animals sleep. have a daily fluctuation in the genes they express, which is the equivalent of sleep. And sleep would normally, you would have selected against it because you're vulnerable when you're asleep.
And the fact that we all sleep and need to sleep means it's performing an essential function in life. There's a fascinating book called Why We Sleep by Matthew Walker. And, you know, he goes into a lot of this detail. It turns out during sleep, we're doing a lot of maintenance and repair, both of our nervous system, but also of our cells. And sleep is essential for healthy aging.
And so this trio, I would say, is a great place for us. You don't have to restrict your calories to the absolute minimum you need, but As long as you avoid bad food and being overweight, and especially obesity is a real problem with all sorts of things, including aging and cancer.
So if you can avoid that, eat moderately and eat healthily and exercise regularly and sleep, that's a great way in which we can take control. And these might have been longstanding pieces of advice, but what's different now is we understand the molecular basis for why they're actually working. So we know that they do actually work.
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