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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Appearances
and so if even one of those cells became cancerous and triggered a cancer then the animal would die so you would think those animals would be more likely to get cancer instead it's a mouse that's more likely to get cancer that has to do with the fact that you know all these repair mechanisms don't work as well in a mouse because evolution doesn't care how long a mouse that a mouse should live that long
But anyway, so it turns out that there's a DNA response repair mechanism. One of the genes involved is called P53 or TP53. And this is involved in sensing DNA damage and triggering repair mechanisms. And it turns out that elephants have something like 20 copies of this gene.
So they're much more efficient at detecting cells where there's been some problem with the DNA and destroying them so they don't become cancerous. And people have looked at whales, and whales also seem to have alternative repair pathways that presumably prevent them from getting cancer. That is the way that evolution has dealt with the cancer problem.
And yeah, that's right. It's not exactly a cure, but it does give you some understanding. And it also shows you the relationship between aging and cancer. It turns out many of the... things that cause aging, like telomere shortening, these are the ends of our chromosome, get a little shorter each time the cell divides.
And when they reach a critical stage, the cell stops dividing and goes into a state called senescence, and then it's eventually destroyed. And you would ask, why would it do that? Why not? And if you were to let cells have the ability to proliferate indefinitely, then if that cell became cancerous, it would be a cancer risk.
And so this idea that you destroy that ability to divide forever in most of our cells and restrict it to just a few cells, like our stem cells, that's probably evolved as a cancer prevention mechanism. And that, again, is because you don't want to get cancer before you have a chance to reproduce.
And once you've reproduced, okay, the consequences that you age, that's okay because you've passed on your genes. That's the evolutionary game.
No, there are many different aspects to aging, and they happen from the molecular level all the way to the level of tissues where cells talk to each other. So just to give you an example, we could start with DNA. which encodes proteins and so on. And DNA damage is one of the primary causes of aging. And of course, we have extensive repair mechanisms, but the DNA repair mechanisms themselves
can break down with aging. So it's a kind of auto catalytic or accelerating phenomenon that DNA damage becomes increasing with age. But that's a cause of aging. And then the proteins that are made using genetic information They often, the quality of those proteins goes down with age. Our ability to recycle proteins that are defective also goes down with age.
So there's all those levels at what I call the protein level. And then this also affects organelles like our mitochondria, which are our organelles in our cell that are responsible for energy production. Of course, some of you may be interested that mitochondria actually were bacteria that were swallowed up by an ancestral cell of ours.
And the two somehow managed to live in a symbiotic state ever since. But mitochondria now control a lot of the health of the cell, including a lot of metabolic pathways. And so if mitochondria become dysfunctional, that's another cause of aging. or the lysosome, another organelle which is responsible for removing the junk in our body.
So all of these proteins that accumulate that are defective or entire organelles that are defective are taken to the lysosome and recycled, basically degraded and recycled. But that process called autophagy can also decline with age. And then cells themselves can decline. So I pointed out that when cells are stressed, when they sense damage, they go into a state called senescence.
These cells can't divide, but they, in turn, they secrete inflammatory molecules. And early on in life, that has a purpose because this senescent cell is saying to the immune system and other repair cells that, look, I'm damaged. This site around me is probably damaged. Maybe there's a virus attack. And so come here and repair the damage.
And so in the process, they repair the damage and the senescent cell is destroyed. But as we get older, the ability to destroy the senescent cells has also declined. And of course, more and more senescent cells are formed because other processes stop working and more cells go into senescence. So you get this buildup of senescent cells and inflammation. So that's another problem.
And then stem cells, which are the cells which are responsible for regenerating tissues. So they have to do two things. They have to regenerate themselves, and they also have to regenerate the tissue that they are sort of in charge of. Early stem cells can make any kind of tissue. So in an early embryo, you have what are called pluripotent stem cells. These cells can make anything.
But later stem cells, later in development, they specialize. So some stem cells can only make skin and hair. Others can only make cells of the nervous system. Of course, there are many different types, but still a subset. Others can only make cells of the blood, and that includes the entire immune system and our red blood cells. So these stem cells themselves
decline with age because many of them go into senescence. And so you get a depletion of stem cells. And the quality of the remaining stem cells is also not as diverse and not as good because they're often descended from a few clones which don't have necessarily the optimal properties. So that's another cause of aging. And that leads to tissue loss.
For example, a common problem with aging is loss of muscle and frailty. So you can see that at every level there's an effect, but each level is not independent. They all interact with each other. And so there's this complicated web of things happening at different levels of complexity.
Yeah, it does. People have made a lot of progress. For example, I mentioned senescent cells. So amazingly, people have been able to target senescent cells using some particular biomarkers, things characteristic of senescent cells. And when they destroy senescent cells in, say, mice, aging mice, the symptoms of aging improve in those mice. And so that's one way.
that one of the more exciting and more challenging ways to deal with aging is to reprogram cells. So you take cells and you reprogram them so they go slightly backwards in development. So effectively they become like stem cells. So you're reactivating stem cells for different types of tissues.
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