Can You Reverse the Aging Process

Hi I'm Cynthia Kenyon and I'm going to be talking about genes that control aging so you all know what aging is there's an example of it in the in the slide

and for many years people thought that aging was something that just happened you just wear out like an old car but I guess in the early 1990s or so in late 1980s I started to think more and more that aging was going to turn out to be subject to active control by the genes

and the reason I thought that is because everything else that people think just sort of happens in a haphazard way in biology turns out to be regulated in a very elaborate way by the genes.

For example if you look in nature what you see is that different animals can have really different lifespans a mouse lives only two years but a canary lives 15 years in the back and only 50 years so these animals have extremely different lifespans in spite of the fact that they're about the same size and even if they're living in the same place they have very different lifespans

and the reason they have different lifespans is because they have different genes so that says right off the bat that there's something about these genes that's influencing their lifespan so the idea that I had was look if there are genes that actually control aging then if we change these genes we ought to be able to produce an animal that lives longer and then if we study the genes in more detail we'll be able to understand how aging is controlled so we didn't study this problem in people instead we studied it in my favorite little animal C elegans which is shown here for you so this is an old individual now what's C elegans is a very tiny little round worm that lives in the soil it's about the size of a comma at the end of a sentence very tiny and they're really good for studying things like studying aging because they grow old and die in just about two weeks

and we wondered could C elegans teach us anything about aging in humans because obviously we don't just we like our worms but we don't really only want to learn about the worms we really want to learn about people and higher animals mammals so the question of course is couldn't studying Aging in one of these little round worms teach us anything about humans and I thought that the chances were good than it could because idea that I had was that aging was actually going to be controlled by genes a set of genes that would be controlling aging in all animals and the reason I thought that is that many biological mechanisms that control other aspects of biology like how a muscle cell differentiates or how a gizze fertilized or how a cell divides happen in the very same way in all animals and in fact lots of genes that are important for people were first discovered in these little C elegans

okay now we were very optimistic starting out that we would be able to find genes that extend lifespan and the reason was that there already was an animal that had an altered gene that lived longer and this was a mutant that had been identified by Michael class and studied by Tom Johnson for a long time these worms lived about 30 to 50 percent longer than normal so we set out to look for long-lived mutants and amazingly we found that mutations that damage one single gene in the worm a gene whose name is Daffy to double the lifespan of the worm so here you see a diagram of the lifespans of these worms so what we did is we took a whole population of worms and we just let them age and ask how long they lived so this these here in black are normal worms here and you can see that by day 30 the end of a month they're all dead so the fraction alive what you see is over here is now 0 whereas at the same time our mutant worms

the worms that have only one gene change all the other genes are the same are almost all still alive and it's not until about twice as long until 70 days when they're all dead so it's incredible really we just changed one gene all the other genes are the same and the whole animal lives twice as long as normal and the really magical thing about these worms is that it's not that they you know get old and then just hang on they actually age more slowly than normal so here you see on a normal C elegans worm quite beautiful crawling along on its bacteria so this is a movie of these worms what you're going to see first are the normal worms here it is a normal worm

when it's about the age of a college student it's three day’s also as a young adult you can see that they're very healthy now what you see here is the mutant worm the one that's going to live twice as long when it's also a young adult and what you see is that it's very healthy that's important it's not sick when it's young now here prepare yourself because this is a little bit sad is the normal worm in just two weeks you see that now the head here is moving see the head see it move there but otherwise it's just lying there it's in the nursing home basically the old folks home you're going to see some more worms in just a second

this is worm is dead and again this one you see its head is moving but otherwise it's just lying there so these are what worms look like when they're old which is just when they're two weeks old and here is our long live me and one Jean change that's all and look at it see it looks healthy it's moving around actively and they look much younger than the worms and this is like actually looking at someone who's 90 and thinking that they're 45 that's what it's like so it's like a miracle but it isn't a miracle it's science

okay so we want to know everything we possibly can about how changing one gene can produce this miraculous appearance worm that doesn't get old on time the gene was cloned in the glob of Garry ruff can at Harvard and Garry's lab showed that the daf-2 gene encodes a hormone receptor so here I've drawn for you a cell this circle here's a cell and here we have the daf-2 receptor which is situated in the membrane of the cell with one part out in the environment and the other part inside the cell and here a hormone that is receiving here in green

okay so what we had found was that the normal function of this hormone receptor is to speed up aging that's what this arrow means it means it promotes the aging process because when we damage the gene with a mutation the animals live long so the normal function is to speed up aging so together our findings along with the rub conflab findings demonstrate that aging is controlled in its control hormones specifically there are hormones in the world in the worm that are speeding up the aging process they're making the worm get old faster now the really cool thing about this hormone receptor is that it's similar to two hormone receptors in humans the receptors for insulin and igf-1 these are two very well-known hormones they're known to do the following insulin is known to promote the uptake of nutrients into the tissues

after a meal and igf-1 the igf-1 receptor is known to promote growth and so what our findings suggested in these little worms was that maybe these hormones had another function that nobody knew about which is to speed up aging okay remember I told you that a lot of processes that happen in these little worms happen in the same way in higher animals okay so the idea was that if these hormones are speeding up aging and worms maybe they would be speeding up aging and other animals as well and that actually turns out to be the case as I as shown here in this in this slide first over here we have the worm this is a situation in C elegans so we have the insulin and igf-1 hormones activating that's what this arrow means the receptor and when the receptor is active it blocks longevity that's what this little crossbar is it means blocks longevity so people who work on fruit flies the Tator and partridge labs made the same kind of change in the gene that encodes the fly hormone receptor for insulin and igf-1 and what they showed was that the Flies live longer that was true if you change the insulin igf-1 receptor or genes that act downstream in the pathway down here and in mice there are separate genes for the insulin receptor and the igf-1 receptor there's one gene and encodes the insulin receptor and another one for the igf-1 receptor and it turns out amazingly enough that if you change either one of these genes mice can live longer

so first of all the whole Sun burger lab showed that if you make a mutation in the igf-1 receptor in other words what you really do is a normal Mouse has two copies of the gene one from its mother and one from its father but if you make a mouse that has only one copy so it's a heterozygous Mouse it has half as much receptor and what they found was that these mice live long about 20% longer than normal they're um they're very healthy they were completely fertile and they um they had a normal metabolic rate the con lab showed that if you remove the insulin receptor specifically from the fat tissue the whole mouse live longer and these mice were very lucky if you fed them a high-fat diet they didn't get bad okay so it's really quite amazing because what this tells you is that is that the insulin igf-1 hormone system is controlling Aging

in all three of these very different kinds of animals which suggests that it was actually controlling aging during evolution in a common ancestor of these three animals and that common ancestor also gave rise to humans so it suggests the possibility that maybe these genes also control aging and us so what about higher organisms do we know anything well very recently we learned something about dogs now dogs as you know come in different sizes here's a Great Dane and here's a little chihuahua here and it turns out that small dogs live a lot longer than large dogs so large dogs like a Great Dane live only five to seven years whereas these little small guys can live up to 20 years so it's very different and what was shown very recently was that the reason that these small dogs are small is because they have a mutation in the gene that encodes igf-1 which is the hormone that we've been talking about

so that makes them small and as I say small dogs are long lips that makes them long-lived as well so this is really interesting for lots of reasons first of all these small dogs they're real animals I mean the mutants are real animals but they're laboratory animals but these small those are fully functional happy little intelligent little creatures so that's one thing you could have this low level of igf-1 and they have much lower levels of the igf-1 hormone and be very healthy but it also raises a question the question is would they have to be small to be long-lived so in other words that igf-1 gene is promoting too growth to be a big dog number one and number two a long life so can they be separated from one another or would you have to be small to be long-lived if you're a dog well there's I think the answer is you would not have to be small and I'll tell you why I think that first of all if you go back to this chart the worms that we study are not small the fruit flies if you make mutations in this gene here and there insulin igf-1 receptor the flies are small and long-lived but if you just perturb the pathway slightly just a little bit not too much then you get slides that are still long-lived but they're not small they're big and long-lived same with these mice

these mice here are not small they don't get fat but they're not particularly small and these mice here the igf-1 receptor mice the heterozygous mice are almost completely the normal size they're just a tiny bit smaller almost completely normal and yet the mice live long

okay so in all these animals it's possible to uncouple the two of them the second thing is if you think about it um when would the hormone be needed in the life of the animal to make it large of course it would be needed during childhood when it's developing into an adult when would the gene be needed for aging well maybe not until it's an adult so we did this experiment we asked when is the gene needed to control Aging in our little worms ok this was done by Andrew Dillon when he was a postdoc in the lab so the question is when does the daf-2 receptor gene affect lifespan so what we did was to turn the activity of the gene down in different times of in different of times in the animal's life and the way we did this was to subject the animals to something called RNAi

I now if you don't know what that is don't worry too much about it basically all you have to know is that it's a it's a way of um inhibiting the function of any gene that you want this is how it works if you feed a worm well let me start over if you um if you introduce double-stranded RNA for a worm's gene or any

any gene into an animal or into a cell the double-stranded RNA will initiate a process that leads to the destruction of all of the mRNA messengers in the cell or lots of them anyway for that particular gene and with worms what's really cool is you can have bacteria express a worm gene in the form of double-stranded RNA and then you can feed the bacteria to the worms the bacteria go into the worms they eat bacteria go into the worms and then somehow the double-stranded RNA gets out of the bacteria and into the worms cells and it catalyzes this breakdown of messenger RNA inside the worm which essentially does the same thing as making a mutation in the gene it knocks down the activity of the gene

so we did our timing experiments in the following way we just took our worms and we grew them on bacteria normal bacteria until we wanted to turn the gene down and then we took the worms off that bacteria and put them on bacteria expressing double-stranded RNA I

I'm sorry double-stranded RNA for the gene and let them eat that bacteria so here's what we found we found that if we turn the activity of the gene down throughout life that is if we put the worms on these RNA I bacteria from the time of hatching they had a long lifespan so now here the control our normal worms that have the death to gene completely active and here is what happens if you subject the animals to this RNAi

I from the time of hatching and sure enough so there they have the gene down when they're growing up and when they're aging and they live long so what happens if we just turn it down only during adulthood look they live just as long you see so that tells us that the daf-2 gene acts during adulthood to affect lifespan because if you don't have it on when the animals an adult if you turn it down when it's an adult you don't have it on it doesn't develop correct it doesn't live correctly it lives too long okay and we did other experiments where we turn the gene down during development and then we turn it back up when it was an adult and those experiments told us the daf-2 acts exclusively during adulthood to affect lifespan okay so this gene is acting during development you know to do whatever it has to do for example promote growth in these but then at least in worms it's acting in the adult to control aging and their hints that it also is acting in mice to control Aging in the adult as well okay so basically it would be really interesting to take a tiny little dog like a chihuahua that's going to live say 15 or 20 years and give it a GF 1 when it's a puppy and let it become a big dog and then lower the igf-1 level when it's an adult and see if it lives long and I bet it would based on these experiments

ok so this is all very good for our pets but what about people click this little worm C elegans actually lead us to the Fountain of Youth and I don't have the answer for you but I can tell you that there are some interesting unpublished data floating around so keep your eyes open okay so now how do these hormones ultimately affect the rate of Aging how does a hormone coursing around through the circulation affect the aging of an animal wrinkles gray hair the nursing-home the whole shebang well our first clue came when we discovered that another gene a gene called daf-16 is required for these deaf to mutations to extend lifespan so here in this graph you can see what happens if we take away the daf-16 gene in a daf-2 mutant so in red here you see the long lifespan of the daf-2 mutant and what you see in green here is the mutant that it still has the daf-2 mutation so it should live twice as long but we took away the daf-16 gene and now you see it doesn't live long anymore so daf-16 is like a Fountain of Youth gene

it's a gene whose normal function lets you live long in fact we call it sweet 16 um for youthfulness okay so what is deaf 16 well we cloned the gene and it was also cloned in the rough can lab and it encodes a transcription factor that is it makes the protein that goes in the nucleus and binds DNA and switches genes on and off so if there ever were a regulatory protein that's it in other words there's no question that aging is subject to regulation or to control because in order for these animals to live long they have to be expressing genes at levels okay so there's definitely a control system for aging okay so what is it that the daf-16 transcription factor is controlling that lets the animals live long first of all before I go into that let me just tell you a little bit more about this the daf-2 pathway so basically I showed you before the daf-2 receptor and what

what I'm showing you here in this slide is a is a summary of information that was gathered from a lot of different laboratories primarily the laboratory of Gary Ruffman but with important contributions from the riddle lab at Thomas lab our lab the Johnsons lab so what you see is that the the way the hormones affect gene expression is that they activate a highly conserved a phosphorylation cascade or a kinase cascade which ends up phosphorylate these little yellow circles here our phosphate groups attached to the daf-16 transcription factor and when this happens the daf-16 transcription factor is not able to accumulate in the nucleus but if you make mutations in daf-2 or any of these downstream genes here then the transcription factor no longer gets phosphorylated and it does accumulate in the nucleus where it regulates genes that affect lifespan

so we need to know what are those genes what are the genes that affect lifespan so nowadays there are really very good ways of asking what genes in the animal are changed under a certain condition so worms have about 20,000 genes and you can actually profile all these 25 20,000 genes using a technique called microarray analysis to find out which genes are expressed at a higher level or more active and which genes are less active in the long lived mutants

so Colleen Murphy a postdoc in the lab did that she subjected these these worms to microarray analysis what she found is that daf-2 controls the expression of many different downstream genes okay so here what this slide shows is the daf-2 receptor when it's turned down by a mutation let's say the daf-16 scription factor becomes more active so that uh para means more active and as a consequence the expression of a lot of different genes changes some go up some go down okay so that's interesting now just because a gene is more or less active doesn't mean it has anything to do with lifespan it could just be more or less active and not doing anything so we had to test that

so the way we tested this idea that these genes that were changing were doing something to lifespan was again we use this RNA AI technique so we took um we just made a list of all our genes and the top of the list we had the genes whose expression changed the most in the long-lived animal at the bottom we had the ones that change the least and we just started marching down the list testing the activity of each individual gene with RNA I so we went to the refrigerator opens it up got the bacteria out of it that were or the freezer I guess oh got the bacteria out that expressed each one of these genes whose expression changed in the long-lived animal and then we fed the long-lived mutants those bacteria and we asked okay if you knock down like this particular gene here if you knock it down if it can't go up anymore can that warm still live long and what about this one and what about this one that's what we did and what we found was that lots of different genes affected lifespan so this shows you that inhibiting the activity of many of the genes that are turned up in the long-lived daf-2 mutants shortens their lifespan okay so here what we should see what you see here in black is the long lifespan of the daf-2 mutant and here as a control in this line you see what happens if we subject these animals to RNA i 4-16 the transcription factor so now we don't have the transcription factor so they can't live long

but here what you see in color here are on the lifespan curves of lots of different populations of worms that have been subjected to RNAi i for any one of a number of those genes that were more active in the long-lived mutant and you can see that now they don't live as long so all of these genes here and more are needed for the long lifespan of the daf-2 mutant and there were some genes that were turned down and along with so we asked okay are those jeans preventing long lifespan if so what would happen if you turn them down in a normal worm so we did that and what we found is that many genes that were turned down in the daf-2 mutants also effects lifespan and what we did here is we turn them down in normal animals so here we have a control it has a normal lifespan okay and each one of these lines here corresponds to a set of normal worms with a good depth daf-2 gene in which all we've done is to turn down one of these many genes that are less active in the long live mutant and you can see that they're living longer okay so it's really interesting both the genes that are turned up and the genes that are turned down in the long-lived mutants make a difference okay so what are these genes well it turns out they do many different things some encode antioxidant proteins some of these had already been shown to be more active in the long-lived mutants by the lab of Gordon Lithgow and others and we discovered some new ones but altogether they include jeans like superoxide dismutase metallo theanine glutathione s transferases catalysis a whole variety of antioxidant proteins and as I say chain inhibiting the function of these genes shorten the lifespan of the long-lived mutant there were also genes that encode proteins called chaperones now what's a chaperone a chaperone is a protein that just like the name suggests takes care of other proteins the chaperone protein will bind to another protein physically and it will help it assume the right shape or if the protein is damaged it will actually escort it to the cells garbage can so the cell can get rid of it and make a new protein so these genes

genes encoding chaperones were more active in the long-lived animals and that made a difference because with when we turn the activity of these genes back down with RNAi I the worms didn't live as long we also found a set of genes that are part of the worms innate immunity system genes whose protein products kill microorganisms these genes were much more active in the long-lived mutants and that's very interesting because we showed before that we had shown that if you feed worms bacteria that can't divide that can't proliferate the worms live longer suggesting that they're actually dying from infections and sure enough these long lived animals the daf-2 mutants actually have more active anti bacterial genes and actually the awesome Bell on webcam Labs showed that these long lived animals are resistant to pathogenic bacteria then they were metabolic genes whose activities were changed

so for example there are some genes that whose normal function is to make proteins that transport fat around the animal from place to place and these genes were less active in the long lived animals and when we made the genes less active in normal worms they live longer and that's interesting because genes that transport fat or whose protein products transport fat around the animal have been implicated in the ability of people to live to be a hundred people who live to be a hundred called centenarians and it turns out that a lot of centenarians seem to have mutations in genes whose function is to transport fat around the body and the mutations cause the genes to be less active just like these long-lived worms

so there may be a link between this part of the worm pathway and centenarians that was discovered by new NIR Barzilai and other people okay other labs also using different techniques identify individual genes that are controlled by deaf - and deaf 16 and again they found that that when they inhibited their activities in many cases they effected the lifespan of the animal

okay so now let's look at the big picture here what we've seen is that these two genes daf-2 and daf-16 together control a wide variety of subordinate genes lots of them see all these genes here not just one but many okay so it's pretty neat it's actually kind of like a regulatory circuit or a little a little cassette in which you know these controlled genes up here say you know dance and all these genes down here say okay I will so it's kind of like an orchestra where here we have the flutes and the violins and the cellos and the French horns and so forth each doing something differ but all doing every everybody doing it at the same time and actually I should point I didn't really make emphasize this but it's important when you change any one of these genes you get an effect on lifespan

that is not as big as the effect that you get when you change daf-16 or daf-2 suggesting that they act in a cumulative or additive way to produce these huge effects on lifespan I just wanted to point out that daf-16 FOXO the transcription factor is actually a really important regulator of lifespan you can get CL against to live long as I said by changing the def to pathway the hormone insulin igf-1 hormone pathway but you can also get them to live long by changing other genes you can get them to live long if you overexpress the gene encoding a protein called heat shock factor which is a stress response protein that protects worms from heat worms and other anoles from heat another stress response protein called jun kinase or a histone deacetylase protein called sir2 overexpressing any of these proteins in the worm extends lifespan and interestingly in each case the lifespan extension requires daf-16 fox

oh ok so while the drawing that I just showed you has you know daf-16 and daf-2 up at the top and then it branches down at the bottom maybe it's more like a network where you have lots of inputs one from def - one from sir - one from Jun kinase and so forth into daf-16 which is like a node in a regulatory circuit in a way and then you have another bifurcation where you regulate all the downstream genes okay so daf-16 is a key regular regulator what so what does it all mean why should insulin and igf-1 which are essential hormones why should inhibiting them extend lifespan insulin and igf-1 are very important and they're very good for you if you don't have them you die if you're a worm if you're a mouse if you're a dog if you're a poor person anybody everybody dies so they're very important because I promote growth and food storage so again why would inhibiting their activities on extend lifespan

well I think this is the way to think about it I think what happens is that when you lower the level of insulin or igf-1 you actually shift the metabolism of the animal from one that favors growth and storage of food and things like that to one that favors maintenance so low insulin igf-1 signaling or high heat shock factor or high June kinase or high soar to activity promotes cell maintenance and kind of resistance to stress and actually these long lived animals are very resistant to lots of environmental stresses this was shown by Tom Johnson's lab first by Pam Larson's lab actually a long time ago and more recently also to other stresses by Gordon lift gas lab but basically they're resistant to heat to UV to hydrogen peroxide to para quite all sorts of things and it may be that the same proteins that make them resistant to these environmental insults also allow them to be resistant to the toxic products that build build-up say from reactive oxygen species generated by the mitochondria during normal lifespan so there may be a connection between the resistance that an animal has to environmental stress and its ability to live long and like I said some of those downstream genes

I told you about do both they make the animals resistant to environmental stress and to aging okay so that way to think about it is you can shift the physiology from one that is favors growth to one that favors stress a stress resistance in maintenance okay and then there are lots of different ways I think to accomplish this shift by lowering insulin igf-1 levels by activating surtout he Chuck factor lots of ways okay so what are the implications for this well the implication again as I said is that at long a longevity regulatory module exists so this is a regulatory module for lifespan this is a little set of gene interactions that's built into the cell that allows the animal to live longer which is we didn't have to you know introduce something from Mars to get these animals to live longer

we just briefly perturbed genes that they already have and because they're connected to one another in this way functionally we get this big effect on lifespan so this actually brings up an interesting question which is how could this regulatory module evolve how could that come around in evolution well it could be that there's an advantage for the worms to get old so they have you know genes that allow them to get old for example maybe it prevents an older animal from competing with its progeny which in the case of the worm has the exact same genes because C elegans is a hermaphrodite so it reproduces by self fertilization so that's one possibility but there's another possibility and in order for me to explain this other possibility to you I have to tell you a little more about the lifespan

or sorry I have to tell you a little more about the life cycle of C elegans and I'll do that here in this slide now what you see up here is the egg this is um sail against hatches from an egg and then it grows up to be an adult and it goes to these four different stages called l1 l2 l3 and l4 and then it becomes an adult now that's what it does if there's a lot of food but if you take a c elegans egg and you put it in an environment where there's not a lot of food and where the animals are all crowded together what happens is the animals don't grow up instead of becoming normal Ltd's here they actually are sorry Noah l2 animals here they become l2 d animals here and then they enter a state called dour

now what's a dour dour is a German word that means enduring and this is a kind of it's like a hibernation kind of state except it's not really hibernation it's it's also like sort of like a bacterial sport anyway these animals can move around but they don't eat and they don't grow and they don't reproduce they're arrested you're sort of suspended in and if you then give them food again they exit from this dour stage and then they grow up and become el fours okay so I should also tell you the only time an animal can become a dower is before puberty

puberty is when the reproductive system matures and that happens at this time so if you take an adult animal and you restrict its food it doesn't become a dower only at this time right here okay so what does this have to do with the evolution of Aging well let me just tell you this if you turn the daf-2 gene off instead of just down we turn it down we got these animals that live long but if you turn it off what happens is the worms hatch if you turn it completely off it's likely that they die but if you turn it down really far what happens is that they hatch from an egg here and then they um they grow up to become Dowers they don't grow up they become Dowers

okay and they just stay there they never grow up so that means that you need the normal function of the daf-2 gene to grow to be an adult now remember I told you that we found out from doing timing experiments the Deaf 2x during the adult to affect aging of course it acts during development to affect the Dower because it has to has to be on at this time in order for the animals not to become a dower that is to be able to grow up to become an adult you have to have the gene on it this time and then we showed like I told you that you have to have it on again and the adult to age normally okay but the daf-2 gene is doing two things during development it's preventing the animal from becoming a dower and during the adult it's preventing the animal from living longer than it would otherwise live

okay so we know already that a lot of the same genes that are whose expression is changed in the long-lived adults that allows the worms to live long that those same genes have a different expression in the Dower their turn either up or down same as the adult in the dour and ours also are resistant to all sorts of stresses like if you take a dower and you heat it up doesn't die if you put hydrogen peroxide or paraquat on it if the daivi shine UV on it

it doesn't die so they're very stress resistant just like the long-lived adults okay so it's possible that this lifespan module that I've been telling you about didn't evolve to control the lifespan of the adult maybe instead it evolved along with other dour specific functions to allow the Dower to live for a long time so think about this if what this means the fact that the animal can go into dower is very beneficial for it because it means that um if food is limiting it doesn't have children that will all die it just stops in waits for conditions to improve and then it grows up and has children so it's obviously very advantageous for a worm to be able to become a dower you can see that there's great survival benefit and that would be selected for during evolution but once you have the regulatory system up and running

okay so that it can extend lifespan of the dowered hours can live a very long time well there it is it exists so it seems like it's possible then to elicit at least part of this program in the adult so the animals can live long now I should say the long-lived adults they're not Dowers they're very active they eat unlike a dower they can be completely fertile unlike a dower so they don't they're not completely Dowers just like little dogs aren't ours they're normal little animals

okay but I think that the same you know like I said the same regulatory module that can allow the animal to become to live long can also be used to protect it in fact it would be interesting to study mammals when they're hibernating to see if they have low levels of insulin igf-1 activity or high levels of daf-16 activity that would be very interesting

okay so it could have evolved to permit survival in response to environmental conditions of the Dower but once it's already up and running the same system is there so it will automatically influence aging of the adult and this also leads me to suggest that changes in either the regulators like daf-16 or deaf to or surtout or heat shock factor these other regulators or on the downstream genes like the chaperones and other may be responsible for increasing lifespan during evolution so in other words maybe the bat lives a lot longer than the mouse because bats have either lower less active regulators or more active regulators or less or more active downstream genes ok the next question I want to ask is a very interesting one having to do with hormones the question is could some kind of environmental signal affect the activity of the staff to pathway now one thing about hormones is that the cool thing about them is that they don't have to be there all the time there can be a hormone can be present under some circumstances but not others so for example the hormone testosterone is present in a developing XY human embryo and that's why the XY embryo develops into a male but is not present in the xx embryo so that's an example of a hormone being present under some conditions but not others

so is it possible that there are some kind of environmental conditions that affect the activity of the staff to pathway so that you could slow down aging yeah I should I should just note that all the changes that we've made so far are changes where we actually reach in and change the gene itself we make a mutation in the gene but what I'm trying to suggest here is that maybe it would possible to change the activity of the pathway by changing something in the environment

ok so the first obvious idea is caloric restriction so um this is a rat picture of a rat and if you normal rat lives about three years here but if you calorically restrict about that is if you give it less food than it wants to eat it will live a lot longer and not only that it stays disease resistant they don't get cancer or a lot of other age-related diseases it's kind of magical it's really neat and so you would think that the insulin igf-1 pathway would mediate the response to caloric restriction because when you eat food excuse me when you eat food your insulin levels rise and so I just told you that if you keep the insulin level down and igf-1 levels down you live longer at least in these animals so it's a nice model to think that if you when you don't eat enough you lower the level of these hormone pathways the activity of these pathways and as a consequence you live longer it's a very pleasing idea and it seems like it's probably right it's not really clear actually yet whether it's true in the worm it may be and it may not be there's some conflict now maybe under some conditions and not others but it is pretty clear that caloric restriction that the response to caloric restriction is mediated at least in part by the insulin igf-1 pathway in yeast

yeast actually also have a little insulin igf-1 pathway they don't have the actual hormones but they have some of the genes that are downstream of the receptor one called a KT here if you change this gene the yeast actually they're small they're tiny little yeast and they live long and it turns out that that pathway the group of Brian Kennedy and others showed that pathway is required for the response to caloric restriction in fruit flies the partridge lab show that the same thing is probably true and in mice there's some really cool experiments recently from the barky lab

now I didn't tell you this already but the hormone igf-1 is produced under the control of another hormone growth hormone so growth hormone which is made by the pituitary gland stimulates the release of igf-1 and mice that lack the receptor for growth hormone are also long-lived and what Aundre bartkey showed was really interesting

he showed that if you took these long live mice but don't have growth hormone receptor and you calorically restrict them they don't live any longer and it's pretty cool you take a normal Mouse and a long-lived growth hormone receptor mutant Mouse one is already living long the growth hormone receptor mutant Mouse and that Mouse it's tissues are very sensitive to insulin already when you calorically restrict this Mouse the mutant Mouse it doesn't live any longer and it doesn't become any more insulin sensitive but when you calorically restrict the normal Mouse it becomes just as insulin sensitive as the mutant mouse and it lives just as long as the mutant mouse

okay so it kind of turns into the mutant mouse in that physiological sense although it's not a mutant it's just a hungry Mouse the cool thing is both lose weight in fact these growth hormone receptor mice are just a little bit on the chubby side to begin with but they lose weight so um so it looks as though these growth hormone receptor mutants are actually reaping the benefits of caloric restriction without going hungry

so okay now I've got to the most important part of my talk which is to acknowledge the people that did the work that I talked about now this list of names these are people that did the work in both Part one and Part two of my lecture series but the work I just talked about was done by first it was started by Raymond tapped young Raymond was a rotation student who came to my lab and discovered the daf-2 mutants were long lived and I was so happy because it was extremely hard to get anyone at the time to come and study aging people generally thought that aging was something that just happened and there was nothing to study

so I was very lucky that he came to the lab Colleen Murphy did the work on the UM the lifespan regulatory module that I talked about she did the microarray analysis and she showed that some genes were turned up in along with mutants and others down and that made a big difference Andy Dillard did the timing experiments I talked about showing that the daf-2 gene and daf-16 also act exclusively in the adult to affect aging and quail in over here kWe show cloned the daf-16 gene and showed that the protein that is encoded by the daf-16 gene is a transcription factor that regulates gene expression

okay see you in part two

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