DNA damage, mutations and aging 1

Published on July 31, 2017   32 min

Other Talks in the Series: Aging

My name is Jan Vijg, I'm from the Department of Genetics, Albert Einstein College of Medicine in New York. And this lecture will be about DNA damage and aging.
So for quite a while, we learned about aging essentially through longevity. We now know a lot of genes and also even chemical compounds that in some way control longevity in invertebrate organisms but in fact also in mice. And maybe there's even an effect in humans, there's some evidence for that. But in spite of that information that we know, we're able to collect about what controls longevity. We know still very little about the process that limits longevity and that's aging. And what you basically see in this slide it's sort of a black box. That's of course, a lot of suspicions about causes of aging, we know very little about it.
One major hypothesis about what causes aging is the idea that aging is caused by DNA damage in some way or the other.
And there's a quite extensive rationale for that. The first hypothesis about damage to DNA as a possible primary cause of aging or a driver of aging, stems from the 1950s essentially. And that also in turn driven by the Manhattan Project, where they realized the dangers, of course, of radiation. I mean originally, of course, the Manhattan project was to develop a bomb, an atomic bomb. But then after that, after Hiroshima and Nagasaki, they started to study the short term and long term effects of radiation. For example, they did extensive experiments with large numbers of rodents which they treated with different types of radiation. But in one experiment, published in 1947 by Paul Henshaw, they demonstrated it and then they gave very low levels of radiation, on a daily basis to rodents. They actually, as they said in the paper, saw virtually nothing. The type of end-of-life pathology was very similar as during the normal aging process. The only thing they said is that they don't live as long. So, what they essentially said there, is said there's a premature aging due to radiation and it was clear in those days that the radiation induced DNA damage and mutation. This is how the original idea about the somatic DNA mutation is a cause of aging, was born. Now the arguments are listed in this slide. First of all, of course, we know by now that genome maintenance or the whole set of processes that repair damage and bring back the original situation, is critical for survival. It's very, very important. A large part of our genome is doing nothing else and encoding products that are enforced in some way or the other in maintaining and repairing our genome. You can say that this goes back until the very first replicators, the origin of life. As soon as we had these tiny RNA molecules maybe surrounded by some sort of a cell wall or a membrane, then already, they were exposed to radiation and to a lot of other DNA-damaging agents or RNA-damaging agents and they had to find ways to fix that damage. So, that was really, as you can say, the original form of aging that you really have nothing more than a small piece of nucleic acid. But this whole birth of genome maintenance began to take a really long stride when it actually allowed larger and larger and larger pieces of DNA. So genomes are able to grow because of the fact that you could get rid of the DNA damage. So, in this way you can see that probably a gene like in RecA which is still a very ancient DNA repair gene. It works in humans, it works in E. coli, was actively selected in the evolution of life. Probably you can say the DNA repair system, they're sort of the first trait that are really under active evolutionary selection. Now a little bit paradoxically, the success of evolution itself in generating this large variation, large diversity of life, actually depends on the same DNA damage. And there would not be any DNA damage and no mutations as a result, and obviously, we would never be able to create a substrate for evolution to be so astonishingly successful in generating this enormous diversity of life forms. So, in a sense, you can say that while yes, on average DNA damage and mutations are bad for you as most of us know, it in fact is the basis for the big success of life. So, it's really an essential component of life. Life is really dependent on two things. One of them is DNA damage, DNA mutations and the other one is evolutionary selection. So that's why, you can actually really say that that DNA damage and mutations were always there from the very, very beginning. So, there's really no reason to assume that anything changed. Of course, the event from an unicellular to multicellular organisms, that means that you now have germ cells and you have the Soma, but you can even argue that in somatic cells, innate damage and mutations are even more readily causing all sorts of degenerative phenotypes because, in fact, life is really not interested in living long and healthy. But is interested in turnover and that's exactly what you see. Now the third part, the informational component of the genome, shows the DNA sequence information, has no backup template. That's, I think, a very practical argument and it makes sense, because when proteins are damaged, you lose proteins and you can always go back to your genome as long as you have an intact gene. But then, something is wrong with your DNA sequence information, you can either have wrong information or no information. So, that's an important argument that DNA of the genome is really of primary importance for longevity. And then finally, we now know that many have heritable defects in DNA repair or any other genome maintenance function. That's not only often fatal, so you have, is embryonically lethal, but it's also associated with disease. And not only cancer. In fact, a major set of diseases that we now know is entirely caused by mutations, heritable mutations in a DNA repair genes, is segmental progeroid syndromes. So, those are human diseases that initially, everything seems to be okay. There's good, there's normal development, but then you start to see, and very quickly, a lot of symptoms of normal aging appearing prematurely. Werner syndrome is really caused by a heritable defect in a RecQ gene, called Werner. Just probably the best known example and that is also a DNA repair gene involved in a number of important repair processes.