A Genetic Control Circuit for Aging
Transcript of Part 1: A Genetic Control Circuit for Aging
00:00:14.17 So I'm going to be talking about how we came to study 00:00:18.16 genes for aging, or to ask whether there were genes for aging, 00:00:21.08 that is genes that affect aging. We started this work in the early 1990s, and at that time 00:00:27.14 people didn't think that aging was subject to any kind of control 00:00:31.28 by the genes. They thought you just wear our like an old car wears out. 00:00:35.12 There are several reasons why I thought maybe this would be wrong, 00:00:39.19 that this idea was simplistic. 00:00:41.11 One is, that if you just look around in biology, nothing just happens. 00:00:46.12 It seems like everything is regulated, everything seems to be 00:00:50.06 subject to control by the genes 00:00:51.25 and when you look at different species of animals, 00:00:54.09 you see that they can have really different lifespans. 00:00:56.22 So the reason they have different lifespans is obviously because they have different genes. 00:01:01.20 So that tells you right off the bat that genes have a lot to do with the lifespan of an animal 00:01:10.09 I had been working in the field of developmental biology, 00:01:14.28 and during the time, during the early 1980s and 1990s it had become really clear 00:01:20.17 that basic fundamental mechanisms of life are conserved evolutionarily. 00:01:26.03 I lived through this realization in the field of developmental biology 00:01:31.10 when genes that pattern the body of worms, which is what we worked on 00:01:36.10 were the same as genes that patterned the body of fruit flies and mice, 00:01:40.02 which was amazing because these animals look so different, 00:01:42.04 but there was a lot of commonality there. 00:01:44.17 The same thing was happening in other fields, 00:01:47.01 like the cell cycle is driven by the same kinds of genes in different kinds of animals. 00:01:50.27 So it seemed that something so fundamental as aging, which seems to be evolvable 00:01:56.01 in other words, there are different animals that have very different lifespans, 00:02:00.02 so evolution can definitely change the rate of aging. 00:02:03.16 So anyway, it seemed to me that there might be genes 00:02:06.11 that controlled aging, so to find those genes, if an animal has them, you can just 00:02:10.09 treat an animal with something that causes mutations and look for long lived mutants. 00:02:15.18 We didn't study this in humans, instead we studied it in our little worms, 00:02:20.22 C. elegans, which is really nice for this kind of study because it is small, and simple, 00:02:26.10 and it has a very rapid lifespan of just a few weeks. 00:02:28.21 Actually, at the time we started our experiments, 00:02:32.16 it was already known that there was a gene that affected the lifespan of C. elegans 00:02:35.29 and if you change this gene, the animals could live about 50 percent longer than normal 00:02:41.13 but there was a lot of mystery surrounding this gene, because these mutants for one thing 00:02:45.26 were not very fertile, and so evolutionary biologists thought that 00:02:51.01 it was possible that the reason they live long was that 00:02:53.21 they didn't have to channel all of their resources into reproduction, 00:02:56.21 and so they would have more to live longer. 00:02:58.22 But to me it seemed like maybe it wasn't such a simple trade-off, 00:03:02.28 maybe there really were genes that controlled aging. 00:03:04.27 And I should say one more thing, which is I was really fascinated by several things 00:03:09.11 that had been known for a long time, one was Progeria. There were human mutants 00:03:12.24 that aged much more quickly than normal, so that was really interesting to me 00:03:17.15 and the other thing was that there was a phenomenon 00:03:20.06 called the Hayflick limit, where you put cells in culture, 00:03:22.06 they would just divide several times or a few number of times, and then they would stop dividing 00:03:27.12 and it had been reported that if you took the cells from a young person or animal, 00:03:31.29 they divided more times than from an old individual, 00:03:34.20 and so there was some kind of intrinsic clock for aging. So it was such a fascinating field 00:03:38.26 and it was discarded by molecular biologists, they just though there is nothing to study, 00:03:43.24 and so we thought we would give it a try. So I then decided, 00:03:49.09 okay well I'm going to look for genes that affect aging. 00:03:50.27 We already had a lab working on C. elegans, 00:03:53.12 they were studying development, but my lab members had no interest in aging, 00:03:56.25 they thought it was a real kind of a, what's the word, a swamp, is that the word? 00:04:03.18 Anyway, not very interesting. Most people had that idea because there was nothing to study. 00:04:08.08 Among molecular biologists, the field of aging had kind of bad reputation. 00:04:13.06 So I couldn't get anyone to work on the project, and the idea was to look for long lived mutants 00:04:18.09 So I kept trying and trying, and there were these students 00:04:21.01 called rotation students who come into UCSF, where I work, UCSF 00:04:24.19 and before they join a lab to get their Ph.D. they spend their time in each of three labs. 00:04:31.14 So I tried to interest these students and they weren't interested. 00:04:34.24 But then one student named Roman Tatiana thought finally 00:04:37.11 that it was a great idea, and he decided to look for long lived mutants. 00:04:40.09 So amazingly enough he set out to look for long lived mutants and he found one 00:04:45.22 He found that mutants that reduce the activity of a gene called daf-2 double the worm's lifespan. 00:04:50.15 Here you see in black, you see the lifespan of a normal worm 00:04:53.29 so by the end of 30 days, or about a month or so 00:04:56.14 all the worms are dead. But you see in red, the daf-2 mutant, 00:05:00.06 lives twice as long as normal, even more than twice as long. 00:05:02.20 The thing that was the most cool about this, was that the worms were, they didn't just go 00:05:08.21 into the nursing home and hang on, they were actually aging more slowly than normal 00:05:12.27 and I have a movie here to show you this. 00:05:14.17 What this shows you first, is a normal worm, just to orient you. 00:05:19.05 So this is a young C. elegans adult, where it is about graduate student age 00:05:24.01 it's three days in worm time, and this is the long lived mutant when it is young, 00:05:28.16 and the reason I am showing you this is that the mutant looks healthy 00:05:31.16 and active, it looks great. And in fact these mutants can be completely fertile 00:05:35.18 so there is no reproductive trade-off involved here. 00:05:39.18 Here is a normal worm where it is old. You can see that its head is moving here 00:05:46.11 but otherwise it looks like it is about to die, and it is about to die. 00:05:50.02 And now next you are going to see the long lived mutant at the exact same age 00:05:54.20 and what you'll see is that the mutant 00:05:56.22 these are some more, a dead worm here and here is a worm in the nursing home 00:06:01.02 So now what you are going to see is at the same time, the long lived mutant looks much younger 00:06:06.00 than this, and I actually tell people about this, and they end up thinking 00:06:10.10 oh it's like being 90 but looking really good when you're 90 00:06:13.18 but like a 90 year-old who is healthy. But it isn't and here is a little analogy 00:06:16.24 it's like this, suppose you are single and maybe in your 40's, 00:06:20.05 and you are dating, and you find someone who you really like 00:06:22.28 and you go on a couple of dates, and then you go with them to a restaurant 00:06:27.19 and then you are sitting there with them and they ask well how old are you 00:06:31.04 and they say, oh, I'm 80, and you go oh-my-gosh because they look 40. 00:06:34.06 That's what it is like, it's like they took two days to age as much as you normally age in one day. 00:06:41.08 So it's something that, the reason I keep emphasizing this is that people 00:06:44.15 don't realize this is not something in our experience, 00:06:48.07 we never thought this kind of thing could happen, but it did. 00:06:50.06 We just change one gene and we double the lifespan. 00:06:52.25 So I have told you that was really hard to find anyone to work on this project 00:06:55.18 well Roman, the rotation student who just made this discovery 00:06:59.14 didn't join our lab, he went to another lab 00:07:02.02 and I still couldn't get anyone to work on the project 00:07:04.18 but there were all these experiments that we wanted to do with daf-2 mutants, 00:07:07.05 so we kept asking rotation students if they wanted to work on it, and they all did, 00:07:11.21 they liked to work on it, so one after another they would come to the lab 00:07:15.13 and they would do some more experiments on the daf-2 mutant, 00:07:17.22 and finally we wrote a paper, and Nature published the paper, 00:07:21.20 and except for me, every single person on the paper was a rotation student. 00:07:25.19 The amazing thing is that not one of those rotation students joined the lab. 00:07:28.27 They all went to other labs, and it was really a long time before anyone decided that aging was a 00:07:35.15 sure enough bet for a Ph.D. thesis that they would actually come to the lab and work on it. 00:07:39.00 So what is this gene, what is this daf-2 gene? 00:07:42.14 Well the Gary Ruvkun lab cloned the gene, and they found that daf-2 encodes a hormone receptor 00:07:48.09 So that means hormones control aging, and not only that, 00:07:51.23 it is similar to receptors that we knew about, number one, the human receptor for insulin, 00:07:56.25 which is a hormone that controls nutrient uptake, 00:08:00.28 and also it was similar to a hormone called IGF-1 00:08:05.03 which controls growth, and these hormones are similar to one another 00:08:08.01 that is, it was similar to the receptor for these hormones. 00:08:10.04 Okay, so what our findings had showed was that the worm's version of the same receptor 00:08:17.02 had a third function, it also controlled aging 00:08:20.04 and we now know what that happens is when you slightly damage the daf-2 gene, 00:08:26.04 the animals sees it as a signal for danger so it 00:08:30.14 rolls out a protective stress response, and that's what makes it live longer. 00:08:34.18 But anyway the big question then of course was is this just a worm thing, 00:08:37.26 or is this also the case for higher organisms. And I'll just say really quickly 00:08:43.13 that inhibiting this gene can extend the lifespan of flies, or mice, and there's a study of 00:08:49.10 Ashkenazi Jews carried out by Nir Barzilai, and he showed that 00:08:53.11 centenarians are more likely to have reduced function of the IGF-1 receptor gene 00:08:58.09 than are Ashkenazi Jews that die earlier. So at least in this population, 00:09:02.21 this mutation in the same gene have been linked to exceptional longevity. 00:09:08.11 We also found a gene called daf-16 is needed for the long lifespan, 00:09:12.21 and humans have this gene, and it's called FOX-O 00:09:15.13 and it turns out that FOX-O variants are associated with exceptional longevity 00:09:20.04 in populations all around the world. These little stars represent a population, 00:09:23.27 showing that variants in this longevity gene are present in people who live a long time. 00:09:30.27 So I think the bottom line here is that we started because we had an idea, I had an idea, 00:09:39.03 that aging would be regulated. We were really really lucky to find the daf-2 gene, 00:09:42.29 in fact my colleagues had said to me, one of them said, "You know, I knew people who started to 00:09:48.07 work on aging and they just fell off the edge of the earth 00:09:50.19 as if the earth was flat, they just fell of the edge of the earth", 00:09:53.24 but in this case we didn't fall off the edge of the earth, we found something really really interesting 00:09:58.14 that may be conserved in humans, and actually these mutants 00:10:01.23 are resistant to lots of diseases so there are all sorts of potential here for 00:10:05.24 improving human health, but that's the story. Thank you.