The Dog Aging Project: Can old dogs teach us new tricks?

please join me in welcoming to the distinctive voices podium dr. Daniel promess ah thank you so much for the introduction thank you for the invitation to be here tonight it's it's really a pleasure and an honor let me start by asking a question of you how many people now or in the past have had a dog in their lives how about keep your hands up how about more than add up more than 1.2 or more dogs look that's terrific so all of you will have had this experience of seeing the dog that you love so well somehow aging faster than you and your loved ones that's one of the things that that we can't help but see around us dogs age faster than we do and in fact there's something else so here I am I don't always dress like this sometimes I dress like that and this is silver and frisbee this is actually a year and a half ago frisbee is still with us silver is no longer with us and at the time of this photo silver was ten frisbee was nine and frisbees a Weimaraner and a ten-year-old Weimaraner is pretty close to a geriatric Weimaraner frisbee as a mixed breed dog she's got a little bit of everything in her she is the ultimate all-american dog we have no idea who her great-grandparents were and she's now 11 and when I take her to the dog park people always ask if she's a year old yet they think she's still a puppy so one of the big questions is why it is that dog's age so quickly but also that among dogs some seem to be much healthier Agers than others and that's what we're going to talk about tonight so just a broad overview of what I'm going to do I'm going to talk to you a little bit about why I study Aging and eventually we'll get to why study Aging in dogs what is it that's so special about dogs and aging I'll tell you a little bit about the things that we've learned so far in our studies and then I'm going to finish up telling you about this very exciting dog agent project that we're just about to launch so first of all what do we mean by aging so on the face of it literally we see aging around us we see ourselves aging when we look in the mirror for those of us who are over 25 or 30 and we certainly see it in the older members of our family of course from a scientific perspective we want to actually measure things and there are all kinds of things that we can measure when we're thinking about aging so here for example we're looking at the world record times for marathons and what you can see is there are some little kids who actually run marathons I'm not sure that all of us would let our six year olds run a marathon the the fastest times are in our 20s and 30s and then starting around age 35 it starts going up in both women and men and it actually goes up exponentially now there are 90 year olds and even older who are running marathons they run them slowly but the fact that they can run them at all is a tremendous sign of healthy aging I think and we could also look at the speed so these are the same data showing the speed and you can see that the maximum speed for man and blue and women in red is in our 20s and 30s and there's again this steady decline now as scientists we don't usually look at things like marathons we're interested in in data that we can measure in everybody and one of the most straightforward things that we measure not just in humans but in many species is survival so what we're looking at here is a figure of the percent of or the fraction of people alive as a function of age and this is just a schematic diagram that data I made up in my computer but it illustrates the fact that there's not a lot of mortality early on and then there's a quite precipitous decline and by the age of a hundred most people have died there are a few super centenarians that actually make it even beyond 110 but they're pretty quite rare now what we don't see from this figure very easily is the actual pattern of Aging so to do that we take these data and we ask what the mortality rates are so what we're looking at here are some data from 1980 census in Canada we're looking at the probability of dying at any age as a function of that age for males and blue and females in red and this figure nicely illustrates a few things it starts out quite high so that's the the neonatal mortality that we see but then precipitously declines reaching a minimum in our early teen years there's then a big bump in our late teen years most of these deaths are due to accidental trauma and then from about age 25 or so it goes up as a straight line and it's a straight line on a special kind of scale notice that we start out one in ten thousand one in a thousand one and a hundred we're going up by a factor of ten this is a logarithmic scale so what this means this straight line is that mortality rates are increasing exponentially as we age in fact mortality rates double every eight years so remember back eight years ago things were twice as good then now I've spent most of my career since about 1994 working on fruit flies Drosophila melanogaster fruit flies are a wonderful model system we've been studying the genetics or fruit flies since the early 1900s when Thomas Hunt Morgan developed them at Rockefeller I work on Aging in fruit flies here's a mortality curve for some different populations or fruit flies looks a lot like human mortality curves starts high goes down and then goes back up interestingly the demographers call this shape a bathtub shape mortality curve which makes me think that demographers have really uncomfortable bathtubs in America so why should we study aging why should we care about it well aging is actually the number one predictor of a whole lot of diseases if you look at these various diseases the number one risk factor for these diseases is not smoking or lack of exercise or a poor diet all of those things are risk factors but biggest risk factor by far is age all of these things go up with age so the community of researchers studying aging we call that the geroscience community the geroscience community is really excited about the possibility that if we can somehow delay the onset of aging or slow the onset of aging that we can actually delay or reduce the impact of all of these many diseases so if we slow aging it will have an effect on all of these diseases the ultimate goal is not necessarily to make people live longer but to ensure that people are healthier longer what we call health span so I've been working on these kind of questions and flies for a long time but as you know from the title I'm here to talk about dogs so I wanted to give you a little bit of history to tell you how I got from flies to dogs and it's a bit of a story about accident favoring the prepared mind and to tell you why my mind was prepared we're going to jump back in time to the Rocky and Bullwinkle show for those of you who were over 45 or so and we're going to get into appropriately mr. Peabody the dogs wayback machine and we're going to go back to Merton College which was established in twelve hundred and sixty-four so we've just celebrated at seven hundred and fiftieth anniversary this was my college at Oxford although I showed up a little bit later in 1986 and this is important because Oxford by the mid-1980s had become one of the global centers for the study of evolutionary biology so evolutionary biologists are interested in diversity and I got there I was pretty clueless undergraduate I didn't know what I wanted to do but I was suddenly surrounded by all these people who were trying to understand why the world is so diverse and how it got to be that way now I wasn't about to study this incredible breadth of diversity although some of my colleagues are tackling that rather I focused right in on trying to understand the diversity in patterns of longevity and at the time now 30 years ago I started thinking about two questions that have really shaped my entire career the first question is why is it that some individuals live longer than others all of us know people who unfortunately have died untimely deaths and if we're lucky we also know people who have lived extraordinarily long lives so this couple they're both centenarians are both over a hundred years old and they've been married for more than 80 years here are some centenarians who have all achieved records in their favorite athletic endeavors this centenarian is a marathon runner ruth Frith from australia as a shot putter and Luba Tory from the US US is a skier wonderful inspirations to all of us the second question is why we see so much variation among species so what I've put here on this graph is pictures of different organisms that are either extremely short-lived this is a so down at this end we have things like mayflies the adult stage of which lives just a day or two short-lived mice and then long-lived species on on the other end so look at this for a little bit and you should all be able to guess what the longest lived species on this figure is so tell me what's the longest live species here how many people would say the whale what about the clam four hundred years and in fact this was a discovery made by my colleague Steve Austin who's at the University of Alabama in Birmingham and um these are the same species that you enjoy in your clam chowder when you visit Boston so the next time you're eating clam chowder you might be eating a 400 year old organism and there are some wonderful stories here about naked mole rats and bats and bees which unfortunately I don't have time to tell today but one of the things that we learn from thinking about all these organisms is that some are very long-lived some are short-lived but they all age their mortality rates go up as they get older so if we think about humans and mice we can assume that aging was going on about a hundred million years ago but the Flies and the worms tell us that their common ancestor was aging 500 million years ago and the common ancestor of all of these suggests that aging dates back at least six or seven hundred million years and a couple of studies in bacteria throw it back to really the beginning of life so some people have argued that as old as life is so is aging so what causes this aging if it's so common what's actually well this gets us back to the fruit flies to figure out this answer people have gone into the lab and studied organisms like the fruit fly like the nematode worm Caenorhabditis elegans like mice and yeast and done genetics so I'm going to show you the world's simplest explanation of genetics just to quickly get through it so a geneticist might start with something that looks like for sake of argument a blue square and knock out a gene and see that that blue square becomes red suggesting that this gene or set of genes might have something to do with color or they might knock out a gene and see that that blue square changes shape suggesting that these genes are involved in a pathway that shapes morphology well about 20-25 years of very beautiful work by my geroscience colleagues working on yeast and worms and flies and mice have shown us what we can think of as the hallmarks of aging this is a figure from a paper by lopez o teen back in 2013 and there these are sort of the highlights of what caught what people think goes on as we age and I'll just illustrate a few of these so till a mere attrition every time a cell divides the genetic material in that cell divided the genic genetic material is made up of genes wrapped into chromosomes those chromosomes have ends and every time the chromosomes divide the ends get a little bit shorter now eventually they get so short that they start running into genes that are important and doing bad things to those genes so to protect themselves the chromosomes have evolved these long telomeres the telomeres getting short doesn't matter unless they get too short and then things bad things start happening to the DNA the genes we care about so as we get old the telomeres get short causing problems loss of Proteus stasis / – in order for all the thousands of proteins in our body to function appropriately they need to form into the right shape when they're stressed they deform and the cells have ways of getting rid of those deformed proteins or – or of reforming them into the right shape as we get older we lose our ability to do that stem cells our cells are constantly turning over almost all the cells in our body we have stem cells that help us regenerate new cells as we get older we lose those stem cells so we know a lot about the mechanisms that underlie aging in the lab in things like the fly and the worm and the mouse and yeast but there's a really critical thing missing from all those organisms they're inbred we're highly in in highly controlled situations humans aren't like that humans are highly variable and one of the earliest most well known illustrations of that variability actually comes from Connecticut State Agricultural College now it's UConn these are students at that college in 1914 lined up in order of height and they form this nice bell-shaped curve also known as a normal distribution and all of this variation is variation that we try and eliminate when we study organisms in the lab and humans don't just vary of course in terms of body height they vary in terms of just about every single thing that we can measure including aging so for example if we go back to our marathon data this is not very variable by age it's the extreme it each age but let's look at another data set this is data from Minnesota ski marathon back in 2012 and again we can see speed declining with age but there's a lot of variability too and we think that that variability is probably due in part to genetics people who inherited good cardiovascular system or a good musculature for cross-country skiing but also do to environmental factors my guess is that this 65 year old out here probably grew up in one of the Scandinavian countries and started skiing as a kid so we can actually study the genetics of these complex variable traits so the the trait we call the phenotype is highly variable and we're going to call that variable phenotype P and there are two sources of variation to explain P genetic variation G and environmental variation E so if we go back to that variable population we can assume that this variation in height came partly from genetics this guy here probably had pretty tall parents and this short fellow had pretty short parents environmental factors and the interaction between the two so here comes the only equation that I'm going to show you tonight it's not a very complex one but it's a really powerful equation p phenotypic variation is equal to genetic variation environmental variation and the interaction between the two sometimes a gene might make a person a little bit taller in one environment but a tiny bit shorter in another environment okay so what's missing now from our lab studies well certainly variation we don't have that kind of variation in lab studies so we can learn a lot about these genes we can knock out a gene and see that it makes a worm or a mouse or fly or a mouse live longer does that gene explain why some of us live longer and healthier than others we don't know the other thing that's missing is pathophysiology the the study of what goes wrong as things get old we know a little bit about mice we don't know much of anything about flies and worms bacteria might be involved but it's really just at the beginning we know a whole lot about what goes wrong in humans and in many cases we don't have a way of studying those things in these organisms and then the final thing that's really important is that at least in my experience of working on fruit flies for about twenty years other than people working on fruit flies nobody else says oh my goodness I love fruit flops especially no one says that when they've invested their compost bucket in their kitchen so this is where I think the prepared mind came in so I I've worked at Merton college I'd studied evolution I thought about the deep evolutionary history of Aging I thought about the hallmarks of Aging I thought about the variability that we see in natural populations and I'd even studied enough math that I could follow this equation so that was where I was at in 2007 working on fruit flies and I got to tell you I love fruit flies and and then one day the latest issue of science showed up in my little mailbox at work at the time I was at the University of Georgia in the department of genetics and the cover looked like this that's a Great Dane and that's a chihuahua this was work that that the lead author was Elaine Ostrander who's renowned dog geneticist at NIH there are some other really well-known folks on here I don't have time to list them all it was a terrific team that got together to try to figure out why it is that this guy is going to grow up to look like this and not like this and and it was a phenomenal discovery they found that a single gene accounted for about 50% of the variation I'm going to show you a figure to illustrate that so this is right out of their paper the dots don't show up too well they're a little light but the so what we're looking at here is the frequency of the igf-1 gene insulin growth factor one gene in a dog we also have this gene and a particular allele or a particular type of that gene all the little dogs are fixed for this big a allele and all the big dogs have none of it or very little of it interestingly if look at wolves wolves have the original allele not the big a lil so what this means is that over and over again as breeders have artificially artificially selected for small dogs all kinds of different unrelated small dogs most of the time they've been able to do it by selecting on this big a igf-1 allele there are exceptions but about half the variation is explained by this gene so prepared mind I was thinking about aging I was thinking about size I'd studied size and not in dogs but remember whales live longer than mice elephants live longer than voles and and shrews so I had two thoughts first of all I also knew from results that would come around around the same time as well as some earlier studies that in fact in dogs it's the big dogs that are short lived so here we have lifespan as a function of weight the big dogs are short lived the little dogs are long-lived but I knew that the small species should be short lived and the big species should be long-lived so something unusual was going on here so that was one thought and the other thought was well igf-1 that's very familiar so here are just a few of a large number of papers that relate AGF one to longevity lifespan longevity even in humans aging so I put that together and I thought well I wonder if I gf1 might explain why we've got this unusual relationship in dogs so the answer is we still don't know but I realized that I had to start studying dogs that there was a really interesting set of questions we could address with dogs the problem was I had no veterinary training I had dogs but I didn't know how to work with them I needed a veterinarian at the time I was at the University of Georgia which has a vet school and so I made some phone calls and someone said you need to talk to dr. creepy so I made friends with dr. creepy and formed the dog aging project so the dog ate the goal of the dog aging project is to study the genetic and environmental determinants of healthy aging in companion dogs we're not talking about dogs and colonies we're talking about the dogs that all of us loved who raised our hands that have we've raised in our own homes so why dogs what's special about dogs well first of all unlike the worms and mice and flies in yeast that I told you about dogs have tremendous variation at multiple levels so incredible morphological variation and in many ways not just in size but also in coat color and fur type and face shape all kinds of morphological variation they have behavioral variation so I don't know if any of you so they they love to jump any of you have seen dogs jumping they love to dig all kinds of variation so they also have genetic variation and that variation has actually turned out to be very useful for studying diseases like cancer cancer is actually as I'll tell you about in a minute cancer is actually very common in dogs so these are golden retrievers and this was a study done by a researcher at the Broad Institute at MIT in Boston Cambridge chuffed in Lindblad tow and they were they were interested in whether they could find genetic risk factors for two very common cancers in Golden Retrievers b-cell lymphoma which hits about 6% and hemangioma which hits about 20% what we're looking at here is called a Manhattan plot each one of these points and they're actually hundreds of thousands of points but we can't see them all because they're all smushed together each point represents a test of a hypothesis the hypothesis is where the question is is this marker in the genome – in the genome correlated with whether the dog had cancer or not and we have thousands and thousands of markers in the genome and for each one we asked is it correlated and what you can see is when the point is above a certain line that represents significance it becomes considered correlated and you can see there are a whole bunch of markers at this point on chromosome 5 so we've lined up the 39 chromosomes 38 actually they didn't include the sex chromosome so dogs have 39 chromosomes and you can see on chromosome 5 that this one gene there's a lot of correlation with cancer risk oh sorry and it turns out that this gene is associated with effects on expression of immunity genes so the important message here is that dogs are highly variable morphologically behaviorally genetically highly variable and we can use that genetic variation to find genes associated with disease they're also highly environmentally variable so here for example is a plot of the incidence of heartworm in dogs the country and you can see there are regions where it's quite high and regions like the Midwest and the northwest where it's quite low we think that's because the vector the insect vector of the parasite is common here and rare here so it's not anything that people are doing we're doing our best to try and protect our dogs from heartburn and there's also a great deal of other kinds of variations so there are rich dogs this is a dog right here and it's dog house and there are poor dogs now whether that's related to health and aging and dogs we don't know yet but that's a question we want to ask there are healthy dogs and not so healthy guys there are a lot of dogs and this is important for those of us who want to study dogs so they're about 70 million dogs in the u.s. in about 40 million households and the view of dogs has changed a lot over time so for those of us who are in our 50s or 60s we certainly remember the the popular dog when we were kids was Snoopy and where did Snoopy sleep outside so who's the popular cartoon dog today Brian and not only does Brian sleep inside Brian sits on the couch Brian drinks martinis our view of dogs has really changed but this is really important so let me get serious here so these are data collected by an organization that monitors dogs and veterinarians and other animals as well and here is how people viewed their pet in 2011 almost 70 percent consider their dog a family member not quite 30 percent as a pet and very few people consider it property and in fact the highest category of people who consider the dog property is little kids who don't really yet have a concept of of how a nonhuman animal fits into the household dynamic people care about their dogs the way they care about their children and in fact any studies we do need to recognize that that the the ethical bar for the kinds of things we do with dogs is very high and like little kids dogs can't give consent so we need to be really careful with with what we do so should we work with dogs well let's get back to our our sort of checklist here so how about dogs well yep highly variable genetic variation environmental variation they have pathophysiology they have diagnosis and treatment and finally of course Pete lots of people say oh my goodness I love dogs so we've started working on dogs already and I'm gonna tell you a little bit about what we've accomplished so far what we've learned in terms of what they died from the effects of inbreeding the effects of spaying and neutering I'm going to tell you about a pilot study that we've started in Seattle with a drug to see if we can actually improve healthy aging and dogs and then finally I'll talk to you about the dog aging project and what comes next so first of all what what do dogs die of well to ask this question Kate creevy and I approached the veterinary medical database so for many many decades any time that any animal dog horse cat bird lizard was brought into any of the 30 odd Veterinary Teaching Hospitals in North America in the US and Canada a record of that animal in its diagnosis was sent to Purdue University where they entered it into the veterinary medical database so we obtained data on a almost 200 American Kennel Club breeds we have about 8,000 diagnostic codes we have over 80,000 dogs over a 20-year period that died in the hospital we know their breed we know their age we know their sex whether they're male or female spayed or neutered or entire so in the vet clinic they're actually four sexes entire females and spayed females entire males and neutered males we know all the things that they were diagnosed with and so working with the veterinary clinicians we were able to assign a cause of death to each dog in the data set other than those where we just know that it was euthanized we've been able to ask a lot of exciting questions with these data so getting back to the variation any veterinarian will tell you that some dogs are long-lived some dogs are short-lived some dogs are at risk of cancer some of other causes we were able to actually in form the veterinary veterinarian community about the really rare dogs that they might see only once a year or once every other year we had hundreds of those and so we could tell them what would happen I'm going to tell you just show you to illustrate some of the more common dogs that you would be familiar with so let's start with this Bulldog this is a brachycephalic dog brachycephalic dogs are the flat faced dogs as opposed to the the Dolokhov cephalic long those dogs many of you probably know that the brachiocephalic dogs are a risk of dying of respiratory disease like the Bulldog our little friend that Chihuahua here actually has a relatively high risk of heart problems this is a Chesapeake Bay Retriever retrievers have a very high risk of cancer especially of lymphoma and then finally this is a shar-pei and this is interesting Shar Peis have a high risk of gastrointestinal disease and interestingly shar-peis have a low risk of cancer and we're actually starting to study this because I have a colleague at the University of Rochester Vera Garber Nova who's worked on the naked mole-rat I showed you a picture of that beautiful little rodent earlier the naked mole rat kind of looks like a sausage with teeth and what's really interesting about the naked mole rat is that they don't get cancer and they live for 30 years in their the size of a mouse they have extremely high levels of something called hyaluronic acid so in fact when you put their cells into culture the cells don't adhere and they secrete this gummy substance hyaluronic acid the shar-pei the the coat there's a wrinkly coat is caused by high levels of hyaluronic and there are certain kinds of cancer that these guys just never get so dr. Korba nova and i are working together to try and figure out if if there's a connection there but the point I want to make here is that there's a ton of variation in what it not just in how long dogs live but in what they die of and we can figure out the genetic basis of that coming back to our story about longevity and the fact that large breed dogs are shorter lived in small breed dogs we were able to collect enough data to actually construct mortality curves and here working in collaboration with a colleague in the United Kingdom Dan O'Neill we have some data so here we're looking at mortality as a function of age and I just want to point out the red curve here is the large breed dogs and what you see is for most of their life the large breed dogs have a higher hazard or a higher mortality than the small breed dogs or the medium breed dogs but look at this and this is a new finding that we haven't even published yet the large breed dogs seem to be protected early in life and that might make sense if most of these early age deaths are due to trauma due to two accidents dogs being hit by cars the large breed dogs can run faster and a large breed dog that is actually hit is more likely to survive with just a broken limb rather than a catastrophic accident so we're now trying to explore this in in more detail the other thing that we're really interested in is actually comparing dogs and humans so as I'll stress later on we're studying dogs because we can learn a lot about dogs but also because dogs can teach us a lot about us so here are a couple of examples where the age dynamic in humans and dogs looks pretty similar so for example we're looking at here is the proportion on the y-axis is the proportion of individuals that died at that age of a particular cause so of people who died unfortunately young in their 40s about 30 to 40 percent of them died of cancer and late in life cancer risk continues to go up but the proportion of people who died of cancer and their 90s is actually really low they tend to die of other things like Alzheimer's disease cardiovascular disease similarly in dogs cancer rates go up and then the proportion of dogs dying of cancer goes down same with death due to toxins either poisoning or drug overdose relatively high early and then late in life quite rare just like dogs but there are some things that are really different and for reasons we don't yet know so cardiovascular disease is the single greatest cause of death in older people in dogs it's relatively age independent and relatively low if we can figure out how dogs do that that could be a tremendous boon to health span in humans let's focus in a little bit on the cancer story so there are some cancers that are relatively rare like heart cancers melanoma is actually relatively rare in people and in dogs and then blood cancers are unfortunately quite common in dogs as well as in people there are some diseases that some cancers that are quite common in people like respiratory cancer lung cancer but relatively rare in dogs again we don't know why but we're certainly going to try and and figure out why one of the things that the geroscience communities really become very interested in is the problem of comorbidity or multiple chronic conditions as we get older the number of chronic conditions that we carry around with us goes up and the causal arrows go in both directions so age leads to an increase in the number of chronic conditions we're carrying around but here what you're looking at is life expectancy as the function of the number of chronic conditions from age 67 so a 67 year old with no chronic conditions can expect to live to a pretty good age of 90 a 67 year old with 10 or more chronic conditions is unlikely to make it past 70 or 72 so why is that well the dog actually might be a really good model to get at the genetic and environmental factors that underlie that so here our dog data females in red males in blue the number of conditions diagnosed in these dogs as a function of their diseases and what I want to jump to here is obesity many people who I meet tell me that obesity and dogs is not a problem they have an obese dog and it's doing just fine and often the people who are telling me that are also people who have weight problems themselves challenges for them managing their weight and in fact we know from epidemiological studies that there's a correlation between human body mass index and dog condition we know that this is an epidemic in our society obesity and diabetes dogs don't get the kind of type 2 diabetes that we get but they certainly suffer from obesity and we see that it leads to other comorbidities so this is a really important issue we want to study and it might help us to understand more about human aging and obesity so what about in treating well there's actually a lot of variation within purebred dogs so this is just a list of a whole bunch of purebred dogs from highly inbred ones like Scottish deerhounds and Bernese Mountain Dogs to relatively out bred ones like golden retrievers and laboratory retrievers and Weimer honours homozygosity is high in some breeds and quite low in other breeds it's very hetero zygosity it's quite quite low are there consequences to that well the first thing too that we wanted to look at was whether there was a relationship between the most out bred dogs the months the lovable months so we looked at lifespan in mixed breed dogs versus these purebred dogs as a function of size and here's what we found so you can see life expectancy versus weight and for all the different weight categories what you can see is that the yellow mixed breed dogs live about a year longer on average than the purebred dogs so if you want to maximize the probability and of course it's just a probability of having a long live dog in your life you want to get a 20 pound month of course we get dogs for all kinds of different reasons and the best reason to get a dog is not simply that it's going to be around for a long time the right dog for each of us is different the other thing we see here is that again as in other studies lifespan goes down with body size now what about spaying and neutering this is obviously a controversial topic and I'll tell you that those of us in the community don't all agree some of my colleagues think that spaying and neutering leads at least in spaying and females leads to shorter lifespan some people say longer lifespan let's see what our data have to say well the question actually goes back to my evolutionary training so back in 1992 the young inventor Dueck in Holland developed what they call the why model to ask about trade-offs between reproduction and survival there's a question that we in the field have been thinking about for many decades so the idea is that resources come into an organism I eat and I use those resources either for reproduction or for growth cellular maintenance survival repair and I have an option for different strategies now it's not that I have an individual choice but different species have evolved different strategies there's the strategy of breeding a lot and not surviving so much we might think of Pacific salmon that put a lot of energy into spawning climbing up those incredible waterfalls rep reducing and then they all die and on the other hand organisms that put an enormous amount of effort into growth and maintenance and survival and might only maybe only a few in their lifetime over a relatively short period us so in fact in evolutionary biology we often think that there's nothing new Under the Sun and all the good ideas harken back to Darwin so in fact I was I was actually reading the Origin of Species and I stumbled across this quote which just kind of bowled me over Darwin in the Origin of Species quoting goodto of all people which he probably read in the original German because they did that back then said in order to spend on one side nature's forced to economize on the other side pretty amazing so in fact we have a lot of studies that support this idea so here's some data from my friend and colleague Mark Taylor who's at Brown University showing that when you knock out the germ cells in a fly so it's sterile either in females or in males you get this increased lifespan so knock out reproduction and flies longer lived there are a whole bunch of studies and flies that have shown this in many different ways well we even have some data from people that suggest it might be true so KJ men who actually was a postdoc with mark tater now back in Korea published a paper in 2012 looking at historical Korean populations hundreds of years ago comparing life expectancy of eunuchs for which there was really good data with the general population and what you can see here is eunuch males live longer than the general population now this was a very well-cared-for population and so it's hard to know whether what what really was going on so what about dogs well in our data set of a hundred eighty thousand dogs in a study that a very talented graduate student in my lab and now a postdoc in Steve Austin's lab published she found that the dogs that were sterilized both males shown in blue here and females lived about a year longer than the intact dogs that are shown in red this is just a survivorship curve but Jessica had the insight that with our data we could ask not only whether they live longer but why they live longer what they were dying of is it that they were just dying of the same things but at a later age or dying of different things and the results kind of stunned us so what we're looking at here is the relative risk after being spayed or neutered of dying it's so if the bar is to the right of the line it means the risk goes up if the bar is to the left of the line the risk goes down and the height of each bar is the frequency of that cause in the population so the largest bar here the highest bar is the aplasia or cancer because that's the most common cause dogs so immune mediated autoimmune diseases and neoplasia or cancer go up in dogs that are sterilized it doesn't mean that they don't live as long it's just that they die later but they die with these diseases the intact dogs tend to die earlier with infectious disease and trauma there's a lot of variation all of you will have stories about dogs that don't fit that pattern so it's just averages we're talking about of course an important exception for cancer is that we know and have known for a long time that any female that spayed before the age of 1 will not get mammary cancer which is a common cancer in female dogs so cancers appear to go up in spayed females but spaying is pretty as protective of that one cause of cancer so sterilized higher risk of cancer and autoimmune disease intact higher risk of trauma and infectious disease so the last study I want to tell you about before I tell you about what's next has to do with our interest in the question of whether we can actually increase health span so there are many studies that have been done over the years showing that when you knock out a gene in a fly or a worm or a yeast cell or even a mouse you can make it live longer more recently people have started giving drugs to these organisms and showing that they can increase both health span and lifespan the most widely accepted one in terms of the quality of the data is probably a drug called rapamycin rapamycin is called rapamycin because it was found in soil from Rapa Nui or Easter Island and it's produced by bacteria it's commonly used in people who have undergone a transplant whether a an organ transplant or a bone marrow transplant rapamycin at high doses helps them prevent rejection and low doses whether given two mice in 20 months or as early as nine months it makes them live longer it does something else though if you give it to mice for just 10 weeks and there are two studies published by my colleague Peter rabinovich at the University of Washington it improves heart function left ventricular heart function in mice it actually makes the mouse the heart of an old Mouse look more like the heart of a young Mouse so this is Matt cabe reline my colleague and friend at the University of Washington that's Dobby and Chloe his dogs and Matt has been working for many years on rapamycin among many other things he's a leader in the field of aging research and when we started talking about dogs he thought well maybe we can try this in dogs to see if it could improve heart function so rapamycin had already been given to dogs and other cancer trials without severe adverse effects so we designed effectively a pilot study or a phase 1 study placebo-controlled double-blind study someone asked me why do it double blind the dogs don't know what they're getting but we we didn't want the owners to know either large-breed middle-aged dogs so over 40 pounds a 10-week treatment and here the focus was on safety the first thing we wanted to make sure was that there were no serious adverse side-effects and at age zero at at time zero weeks and time 11 weeks for these middle-aged dogs they got echocardiograms so let me show you the mouse data so there are three variables that have been studied and I I'm not going to go into what they are now but they're all measures of left ventricular function how good the heart is at pumping blood ejection fraction fractional shortening and eita a ratio and these three things are all better when they're higher so what we see in the mice the control mice over the period of the study went down for ejection fraction they went down for fractional shortening and they went down from eda ratio and the my son wrap-up all went up it was significant it was published in aging cell in 2013 so what about the dogs well we saw an increase in ejection fraction we saw an increase in fractional shortening and we saw an increase in NIDA a ratio this is very exciting now this is a phase one study very small sample size this statistical analysis is based on about 25 dogs so this is not the answer we don't know yet that short or medium or long term treatment with rapamycin will improve heart function especially where you know we're interested in dogs like Dobermans where where heart function is a big issue for them but it does suggest that we might be on to something important and we're certainly excited to move forward so what do we know now well we know that dogs share our homes they share our environment they age just like we do in many ways and they have a health care system that is second only to us and they have a genome sequenced we can identify the genetic basis of many diseases and dogs and importantly we know a lot about their environment because there are you know there in our environment I mentioned Peter rabinovich who did the heart study I have another colleague at University Washington Peter Rabinowitz and Peter Rabinowitz is very interested in the possibility possibility that dogs could be sentinels if we experience an environmental risk factor when we are 10 years old and it affects how we age we won't know for 40 50 60 years if it affects how a dog ages we'll know in 5 or 10 years and we can then drill down and find out whether that's a risk factor for us so what should we do next well the next big step is the dog aging project a national study of Aging in dogs and this is not a really original idea we're standing on the shoulders of many giants I'm going to tell you about just a few of them the biggest giant of all is probably the people who came up with a Framingham Heart Study in 1948 it's still going we are now in there enrolling grandchildren of the initial participants we have learned so much about human health from this longitudinal study the idea is not just to study someone from bring them into the clinic and measure things and then never see them again we track them year after year we track their kids and their grandkids this is a longitudinal study and we have learned so much well times have changed we're now in the era of big data how many of you have heard that term big data about having so so with modern molecular biology we can now measure very easily thousands tens of thousands hundreds of thousands of measures in a single individual genes the sequences each of us have 3 billion base pairs we can measure all those base pairs for about a thousand bucks the the 20,000 genes and how much they're expressed all the molecules circulating in our body the metabolites the microbiome all the microbes in our body we now think that the number of microbes in our body is equal to the number of cells in our body we used to think it was ten times as much but the latest says may be equal we're talking trillions of cells that's what I mean by Big Data so whether you like President Obama or not and I don't care about a year and a half ago at the 2015 State of the Union address to January he did something amazing he convinced every member of Congress to get up and applaud him whether you like him or not that doesn't happen very often didn't happen very often to Bush what he did was he announced the precision medicine initiative the idea was to track a million people and measure everything we can about their genetics their health and their environment and to do it for a long time and we will learn so much about why people get sick why some why drugs work in some people and not in others how environment affects us it's going to cost a lot of money year one which is now underway is 215 million dollars it's going to be a multi billion dollar effort it's kind of a moonshot but when we say moonshot in my mind we think maybe it's gonna work maybe it's not it's gonna work we're gonna learn a ton of stuff but it's going to take billions of dollars and it's going to take a long time and in fact it's not the only study so in the UK the hundred thousand genomes project is already underway in Seattle Lee hood at the Institute for systems biology has started started the hundred thousand wellness project with a hundred pioneers who have had their genome sequenced of course we want to get to these little guys again we're gonna stand on the shoulders of some real giants at the Morris Animal Foundation and rod Paige a vet who's at Colorado Colorado State they've already started a study 3,000 dogs all golden retrievers started in their first year life the idea is to follow these 3,000 golden retrievers focus on cancer about half of all golden retrievers are going to get cancer sometime in their life so that makes a lot of sense they started this in 2012 they have reached their enrollment goals last year and they are just rocking and rolling it's going to take a long time to really get answers because they started with young dogs but they're going to get some great answers so resting on the shoulders of all those giants our challenge is to figure out genes and environment and G by Ian how all of those affect health and morbidity and mortality in these guys of course as a general scientist I know that there's a critical piece of the equation not here that's age the way that age affects all these things really is a black box I told you about the hallmarks right we know a lot but in natural populations like us and like dogs this is really still a black box and just to complicate matters the black box is affected by the genes and the environment and the G by E so how do we figure all of this out that's our challenge if we can figure it out we will have incredible advances in the our ability to diagnose predict treat and ultimately prevent disease and dogs so our big data 21st century phenotyping is going to be combined with a study of 10,000 dogs all around the country in your houses we're going to include a longitudinal study like the Framingham study and the golden retriever study but also a cross-sectional study where we start with old dogs so we can get going right away asking scientific questions we're going to look at clinical and demographic studies electronic medical records all that high-throughput molecular biology that I mentioned activity we're going to monitor what dogs do using doggie fitbit's in real-time mobile health we're going to use cell phone technology we're going to look at environmental factors social environment as well as the abiotic environment and we're going to do a large-scale intervention study importantly we believe in open source science and citizen science what does this mean this means that all of our data will be publicly available for scientists anywhere in the world to access and ask questions there are 10 of us on this project we don't have a monopoly on all the good scientific questions so it's important to share the data but we also want to bring all of you citizen scientists into the fold so you can go to a website and see what we're finding and how we found it how we discovered it so I already told you about these benefits but the people benefit too for obvious reasons the veterinarian's benefit the scientists benefit pet owners are going to benefit if we can have figure out how to improve health span healthy aging in dogs and the general public is going to benefit from what we learn from dogs that could affect that could help us to improve healthy aging in humans as well citizen science aspect so I want to sum up with a quote that appropriately comes from the National Academies tech futures initiative seed ideas are hypotheses that are once timely plausible and so far-reaching and audacious that they connect with a general public notion of importance they start with concrete first steps and I want to argue today that our concrete first step is the dog aging project all dogs can teach us new tricks we're now writing a program project grant so the National Institute of Aging asked me if I would write a large-scale study program project grant to do this study and we're also looking elsewhere for funds because this is kind of a big project and we're going to need some big funds but I think if we're successful we can accomplish a huge amount if you're interested in keeping track on our progress you're welcome to go to dog aging project com if you'd like to enroll to request that your in your dog and be enrolled in our long-term study or in our rap a study we haven't yet started those studies but we'll have you on file it goes without saying that I'm one of many people and these are just a few of the many people who have been helping with this project I just want to give a shout out to Kate creevy our lead veterinarian on the project without whom this would not be possible she's just moved to Texas A&M vet school where she starts next week and finally I want to thank all of you for your attention

Leave a Reply

Your email address will not be published. Required fields are marked *