Longevity and Aging in Humans

Stanford University well good evening everyone glad to see you're all here tonight I imagine after last week's presentation on obesity many of you have been managing your weight more carefully over the last days you look great so I know that's been happening tonight you'll likely hear somewhere during the presentation that if you really restrict your counselee caloric intake you might live longer I don't know whether that's a good idea or not but you can make your judgments about that but when you begin to think about the topic of tonight which is on Aging and indirectly longevity it begins to bring together some of the issues that we have been talking about during this quarter and indeed antecedent ones lots of genetic issues you know that inherently because you look around in families and you note that some people seem to live longer than others but there has now been an increasing amount of genetic sophistication about aging as well and obviously lots of environmental factors I mentioned one nutrition being a factor of course you've heard me talk before about exercise and how important that is but where you live what the environmental factors are can play a very important role among other issues as well so tonight we're going to do a exploration into Aging it may shock you and Mays you to think that some of the most fundamental findings on Aging have actually come from the study in the worm a simple species you thought you were complex right but you'll be interested to know that worms the kind used in most studies have about 18,000 genes and you've got about 22,000 so don't feel too exuberant because there's a lot more complexity of course to that but there's been a lot learned in experimental models and tonight we have two wonderful speakers both pioneers in their own way and Bernay who will come second comes to Stanford from actually starting out in France she went to school in Paris initially did her PhD at the University of nice you might all say it's very nice if you've ever been there it is and then moved to Boston to do her postgraduate training at Harvard in a laboratory that was actually very close she probably didn't know this - the building that I was working in during that very same time she was in the enders building I suspect which is associated with the Children's Hospital where I was on the faculty as well so it took us both coming to Stanford to meet together and her research is really enormous ly exciting because it's beginning to focus on some of the fundamental issues of aging at the molecular level and addressing the interface between aging and stem cell biology which is another really important factor in this process but we're going to start tonight's session with a presentation by Tom Rando who's our second speaker we've got another duet and he approaches this process from a different perspective although he also has that big H bias by having been an undergraduate and medical student at Harvard trained on the East Coast initially and then came to UCSF where he did neurology you could see these connections right they keep coming up over and over again but we are very careful we only take the very best after they've had their pre training and then bring them to Stanford where they really excel and tom has done that and has achieved considerable national recognition for his work which is on stem cells and particularly muscle stem cells which has a lot to do with regeneration and rejuvenation he's been recognized for his pioneering work by being an NIH pioneer and this is a very prestigious award that the NIH gives each year to investigators who are really doing out-of-the-box thinking actually awarded 81 for the entire nation over the last five years and I'm happy to say that we have 15 of them here at Stanford so a pretty disproportionate chair which only affirms my comments on selectivity and so Tom will not only speak from the perspective of his research work but also in his capacity of leading the center on Aging both at the VA hospital where his primary labs are but also as the associate director of the Center for longevity here at Stanford so Tom if you could get us started okay well thank you very much Phil it's a real honor and pleasure to be here this sounds like a great forum from what we've heard very interactive and we will welcome questions along the way I will start my talk with really talking about some very general points about aging and longevity how we measure it how we define it things like that which I think will be very important and then get into some of the background on what we think aging is and finish up I hope with some some work from our own studies on aging and stem cells okay so okay so just we'll start with some definitions and again these will become clear I think there'll be some questions that will arise from these but we'll talk about longevity a lot tonight we'll talk about aging quite a bit and just as a starting point I would make this distinction that longevity is a measure something we can measure it doesn't imply a process whereas aging is the opposite aging is a process that goes on that can be studied but is related to longevity primarily by the fact that aging organism organisms ultimately die and when we measure longevity we essentially measuring how long an organism lives so I want to make one comment about population aging before I get into the discussion about how individuals or individual animals age and because we talk a lot in the society about an aging demographic and aging population and and there are a lot of interesting aspects of what makes a population old and what makes the population in one country older than another country things like this but the point the main point I want to make is that a population can age without any changes in the aging or longevity of its individuals made for example if it were the case that suddenly we had a mass immigration to the country or away from the country of young people that would just change the whole population aging structure and could lead us to be a more youthful society or more aging society and this is just a an illustration of the population distribution in this country at nineteen fifty two thousand five and then projected for 2030 and you have males on one side and females on the other side and it just shows how our population the shape of our population is changing from a more pyramidal shape to a more rectangular shape and this is primarily because of really the movement of baby boomers through the population so what was a large population of young people becomes a large population of middle-aged people and ultimately a large population of older people of course is that as that changes our population will return perhaps more to a pyramidal structure but other countries can look very very different in terms of how their population looks and whether they're a youthful Society or an aging Society okay so let's talk about human longevity or in some case we'll talk about animal longevity but I want to begin with these definitions and how do we define it how do we measure it I'll then move on to some points about what are the determinants of longevity what determines how long we live and then end with some questions about is there anything we can or should do about that okay so so how do we define it how do we measure it so when you ask a question of how long do people live or how long do mice live what are we really asking and it really depends on who's asking at what they mean because they could usually mean one of two different things if we talk about actuarial tables and how long we live it as individuals born today we're usually talking about life expectancy or the average amount of time that a person born today can be expected to live and that's determined and I'll show you this in a graph in a second by the age at which 50% of the people who are born say today are alive and that becomes the average life expectancy of that cohort of people now bike trust there's another interesting aspect of the question how long do we live in that's how long can you live and that's what would be considered the maximum lifespan and that is not something that's so easy to measure because really that's determined by how old the oldest person or oldest mouse or oldest worm ever seen is so that's a number that can change actually I heard that the the most recent oldest living person died yesterday so as a woman in Japan from a famous play Okinawa is where a lot of Surgeons of Okinawan 114 plus almost 115 died yesterday so there's a new 114 year old is the current world record holder okay so this is a graph that you're going to see a lot of curves that look something like this and it's a so-called life curve or you heard different names given to it but basically the way this presents the life curve of population of say people or mice or worms where you pick a date say 1950 and you take a hundred people and you ask how many of those hundred people are alive as a function of time since birth now with humans is always a little bit of infant mortality but in a developed society this is a very typical curve where there's very very little little death through the ages of 50 or so and then people start to fall off and then the curve trails off like that so this is the way we we plot the population and then from this we can calculate average life expectancy and we can estimate maximum life expectancy so just as I said a minute ago if we just take this curve when we ask when 50 percent of the people have died or are still alive what's that average age so here it's around 70 so this was again a typical life curve for people born around 1952 a 1940s and 1950s the average life expectancy was around 70 years old now again the maximum lifespan is somewhere out here it's hard to know exactly where that is because this hundred people is certainly not going to reflect the oldest person and is in the in the world and so that number is somewhere out here but you can get a sense of where that is from where this curve tails off so one of the things that is a common phrase is to say that we're living longer what do we mean by that do we mean that we're living longer average or does it mean that we're living longer in terms of maximum lifespan so we can we can get a sense of that by looking at these average these life curves and looking at the averages across the history history of history and across the time when humans were inhabited the Earth's we have some evidence of what the population curve looked like this is fifty thousand years ago and of course this data is is really just an estimate based on the fossil record but a life curve looked very differently fifty thousand years ago than today but that would have been at that point and then still in the Stone Age but fifteen thousand years ago in Europe to begin to be this this knee and the curve and then as we moved through time again the estimates become a little bit more accurate but Rome 1100 BC so well past the the Bronze Age and the Iron Age again getting more of an e in this curve and then up to this curve and say around 1970 so if you look then at the average life expectancy you can see there has been phenomenal and dramatic changes in average life expectancy over this over this history so at this point in fifty thousand years ago people live pretty much just long enough to propagate the species so just long enough to have offspring and the species was propagating basically just as people are coming to reproductive age and that's very typical for animals in the wild or for people in a relatively uncivilized situation of course as civilization evolved more and more people begin to survive these early years and more people could survive into the late years so there's been a dramatic increase in average life expectancy and this is just another way to look at this this is actually looking at the average age of individuals across historic and even some prehistoric times and you can see this dramatic increase in average life expectancy and one of the important points is that the average life expectancy doubled over many thousands of years and then doubled again over the last hundred years so even over the the history period of recorded history the increase in life span wasn't was it was increasing gradually and in the last hundred years we've had a dramatic increase in that average life expectancy to where we are today now what about maximum lifespan is that increased recently over time we really don't have a good way of knowing because we obviously have a hard time even today determining with certainty how old people are who are the very oldest old because birth records are not so accurate and now we're beginning to keep better records but it's hard to know what the maximum life span would have been during this time but you can see it clearly has not changed dramatically like the average life expectancy did and in fact even from historical records there are some fairly well-known people whose ages were roughly known so Sophocles was considered to have lived to be about 90 and Hippocrates was also considered to be a very long-lived individual between 90 and 100 and then of course the the world record holders Methuselah who lived 960 and nine years and then he died so and then this is a famous person who you you may have heard of jean coma she's actually the world record holder as far as we know the oldest person to have lived with a known birth date known tiblet she lived 122 years and their amazing story she lived in Arles in France and she died Niles and France and there she became very famous of course as she passed her 110 115 birthday and she was always surrounded by journalists so there are many wonderful anecdotes about her life and her her secrets to longevity she quit smoking in 119 maybe that was her secret she did all these great things she took up fencing in her nineties she was riding a bike a hundred so really very vibrant person and a very very witty woman even right up until the time she died there's become an interest in in so-called super centenarians and these are people who are 110 years or older and this is just looking across the world at different countries and estimating the number of people who have reached this age 110 or older and some of it again is is not very accurate data but people are looking more and more now at these populations of individuals who are centenarians and super centenarians and of course a great interest is in the families of these very long-lived individuals as phil was mentioning to try and understand what the genetics might be as well as the environmental influences that allow some people to live these very very long lives so here that's that's where we're looking at these are sort of how we measure it what actually determines how long we live so in some ways we started thinking about genetics as a determinant lifespan I was trying to think about how to how to phrase this but I think if this is the big lifespan variation and the small lifespan variation and by that I'll show you what I mean so if we talk about the difference between any one of us living what would be considered an average lifespan and a maximum lifespan we're talking perhaps a 30 to 50 percent difference over that period so living to be 75 or 80 or maybe being lucky and living and living healthy to 110 or more that's a pretty wide range in terms of number of years but a small percent difference in terms of our actual total lifespan on the other end of spectrum are the genetics that determine how long individuals in the whole animal kingdom what their life span is and then we're talking about five orders of magnitude difference between the shortest lived species and the longest lit species so you start looking at some fish and giant tortoises and blue whales if we can live up to 150 to 200 years and then down to species like mayflies live less than a day what is it that determines that vastness of lifespan difference in terms of the genetics which can be quite complicated even for some very simple organisms that is so different than what we talked about in terms of modulating lifespan in terms of living between 70 or 80 or 90 years so this is the big question about genetics and lifespan but what we'll focus on more is is the oh and just to superimpose that sort of small variation I talked about in a man it's very small across this logarithmic scale over over five orders of magnitude so of course what's most interesting to us tonight I think is to talk about this differences what is it about the environment we live in the genes that we possess that might determine our likelihood of living to an average life or a maximum lifespan for humans so as I mentioned it interesting to think about how our life curve differs in society versus in the wild and and this is really a typical life curve as I mentioned probably prehistoric humans but animals in the wild and in this case what determines the shape of this curve has a lot to do with the environment so predation starvation exposure so all the things that really lead to death in the wild create this life curve which looks very very different but if we look at this what I call longevity and captivity with us being in captivity in society but this is what also the life curve looks like for farm animals or experimental animals in the laboratory or animals in a zoo so you've eliminated all those early life threats so we can feed them we can feed ourselves we keep our young alive and then we start to see see this this a very different life curve and I think of this as having two phases so there's the drop-off phase where we're coming along nicely here and then we start to fall off here and then there's the tail of this life curve so what's what's happening here what does this have to do with in terms of biology and medicine that we can learn from what these kind of early deaths are in this some in this life curve of humans well clearly these are primarily due to age-related diseases so this is when these are from 2001 leading causes of death in the u.s. heart disease cancer stroke and so forth so these are the diseases to which we become susceptible as we age and these are the disease's for which age is the most potent risk factor and people start to die from what we would consider age-related diseases and it raises the question of how does one distinguish issues of aging from age-related diseases and this is a an important distinction and people argue about this in the field is whether aging itself is a disease but medically we certainly separate them we certainly call these diseases we don't call aging a disease and these are the causes of what leads to people to die typically in their 50s 60s 70s so what happens out here is a very interesting and different question because there's something we talk about in a lot of our courses in fact and I just came from a class we teach and graduates on aging and longevity and this is a topic that we get into some very interesting discussions about its what is dying from old age even mean because if you look at people who quote die from old age we don't really have a very good characterization biologically or medically as to what the cause of death is so and it's very different if you look at people who quote die in their sleep or or it is it's unknown why they die but they're reaching some kind of biological limit and it's interesting that when we study worms and flies and mice we measure their longevity by keeping them alive and measuring how long they live and we don't know why those animals die either for the most part so they die sometimes they also follow this fall-off this curve from from cancers and other diseases but for the most part we don't understand the biology of death from old age and and we really have to begin to understand that and grapple with that because there is something and especially across this enormous spectrum of animals and the king in the animal kingdom or many orders of magnitude difference that put this stopping point in very different places so it's an interesting biology that has really remained unpin Yin unexplored so is there anything that we can do about it about our ability to live a certain length of time are there things we should be doing we obviously talked a lot about diets diet and exercise and you'll hear more in the next lecture about things that might be very important in terms of living longer but you know here's where we start really start talking about aging instead of longevity so Shakespeare had a rather bleak view I would say of aging and we tend not to think of it as rotting and rotting but but certainly there's a decline and certainly there's a decline in function and the question is really whether there's anything we can do about that decline are there any ways we can influence our aging process and then ultimately how long we live so really the fundamental arguments in the field come down to whether we age because of our environment or we age because of our genes and I'll just touch on this briefly and and and we'll talk about this in more detail but just to introduce this in in the first case talking about extrinsic determinant so basically the idea it there is that aging as a result of exposure of our ourselves our tissues the cells in our body to environmental toxins of one kind or another things that are deal it serious to our molecules ourselves in our tissues and the analogy that I actually think is really one that is quite apt as it's like rust okay so you the humans are really evolutionarily designed to grow mature and reproduce okay but when we keep them in captivity we put them in civilization we begin to see these other features emerging as we keep people alive longer and longer or mice or flies and that what we're seeing is like a contraption we've built to do one thing but then we keep it around longer and longer and you start to see rust okay so what what is rust well rust is is iron exposed to water and oxygen and here's all the chemistry if you want to go through it and through these reactive species and you end up with rust okay so so it's an interesting chemistry but it's also an interesting biochemistry because it turns out there's not such a different thing that occurs in our very bodies so this is a diagram of a mitochondria in a cell and indeed one of the characteristic features about mitochondria is that obviously are an aqueous environment they use oxygen and the product of turning oxygen into energy is a byproduct in the presence of a lot of metal irons metals like iron and other metals that produce reactive species that are damaging to the cell so very much like rust because we live in an oxygen environment because we're a quiesce we will naturally produce as a normal byproduct of our metabolism molecules that are Dilla Terius and that actually damage our DNA our proteins and our membranes so this this whole field of so-called oxidative damage is a very very powerful theory as to why we age that in fact since we can't get out of this situation of being in being aqueous by nature and living in oxygen lineman we will by nature experience over time the accumulation of damage from the very metabolism that we need to live okay so what about the idea that aging is is not just this exposure to the environment but is in fact genetically programmed and this that this is a theory that had been very popular for for many years has been very much challenged by evolutionary biologists but there was a initial theory of aging that we were actually programmed to die so that we had a genetic program that would post reproduction eliminate older people from the species and the argument was of an altruistic one that if we could get rid of old people there be more you know and there's limited food supply that would be for the younger people who would then reproduce and so that was a theory that that had sort of wide acceptance but but fell really in the face of evolutionary theory that that we couldn't have evolved so much to have a genetic program that forced us to age and force us to die in old age for the simple reason that through evolutionary time virtually all of the people who are alive never reached old age so if people are dying in their in their teens and 20s then there would be no way for a genetic program to evolve to hope for us to have acquired a genetic program that would be determining something that would happen to us at 50 60 70 years old so so that idea that's an altruistic idea that we have a genetic program that leads us to age and died as the reason why we age has been I would say discredited although there's there's no doubt and this is the interesting thing there is no doubt that our genetic program influences the way we age and that even single genes differences single genetic mutations can influence our aging process and this you'll hear a lot more from from an next so the question is are there experiments or experiments of nature that really allow us to understand this balance between how genes influence the aging process and how the environment influences the aging process so are there environmental influences or genetic changes that either can slow aging extend lifespan that can accelerate aging aging and shortened lifespan or that can reverse the aging process so I'll touch on these each one of these so can it be slowed can it be accelerating can it be reversed interesting idea again this you'll hear more in detail from from dr. Brunei so the idea here would be can we actually increase maximum lifespan get beyond this this magical 122 years and can we influence in any way the environment or genetics to get individuals to live longer and is there a reason to think that we can actually reach much older ages 150 200 and certainly this is a it's it's reached you know the popular imagination people really have this idea and there are groups out there looking for ways to have individuals live longer and there are people who believe that the first person who will to live 200 years is alive today he's alive today and will eventually live 200 years so that's really quite a paradigm shift I doubt it I would I would bet against that but but there people who are betting betting on that now what about instead of if we think about things that can extend our lifespan instead of thinking about things that extend our maximum lifespan what about if we just extend average lifespan so as I mentioned average lifespan in this graph is around 70 so even without necessarily changing the age at which the oldest person will be can we increase the average lifespan of people alive today and certainly that's what most biomedical science is focused on is reducing the incidence of the diseases that tend to kill us in this drop off phase so it's it's been referred to in different ways but what I'm what I'm talking about here is what has been called the rectangular ization of the life curve so it wouldn't it be interesting if in fact there is a sort of biological limit out here around 120 years and what it wouldn't be interesting if these diseases of aging heart disease and stroke if we made tremendous medical progress and then instead of having a life curve that looked like this we had one that looked like this and be very strange because we all reached a point then we would just suddenly die so unlikely to be true and then actually my feeling is that everything that we do here or will will shift this graduate so this curve will always look like this I think so we'll never reach this true rectangular ization it's also been called the compression of morbidity the idea that we have a very young life here with very little morbidity most morbidity that is experienced is out here what wouldn't be interesting at that period of morbidity morbidity could be compressed to a very very few years after the age of 120 or something like that again it's a strange concept of how society would be if in fact we all live to a very very close to the same age and then died but that's the that's the model but you know what we said what we focus on is in fact treating these diseases of aging so that we can not only extend lifespan but extend health span and that is really obviously the major goal of biomedical research isn't so much to extend the maximum lifespan but to have people live as long as possible with as little morbidity as possible so can aging be accelerated okay is is there such a thing as accelerated aging due to either a genetic or environmental influence and yeah indeed that there are single gene mutations that shortened lifespan okay not that but that that comes with a bit of a caveat because obviously one can think of mutations that it could occur that just cause a disease so showing that a gene shortens life span is not the same things that is showing accelerated aging in fact you could think of just like timing you can think of some examples of single gene mutations that lead to childhood cancers familial causes of atherosclerosis there are many many many causes of early death from single gene mutations that don't really talk about accelerated aging they don't really tell us anything about the normal process of aging but there are some that still have this caveat we have to be careful of but are are compelling and I just want to show you a couple of examples of those so these are these are these disorders called the progeria x' they're also called this segmental progeria and they're really been thought of both in humans and now in animal models for many years as possible examples of true accelerated aging and so this is a disorder called hutchinson-gilford progeria and it is a disease that occurs from a gene mutation for one protein called lamin which is in the nucleus of every cell in the body so single mutations one gene one protein part of one organelle and you get a very strange phenotype because this individual is actually 15 years old so this is a this is a disorder that starts in childhood and progresses very rapidly and the individuals show remarkable signs that are similar to what we think of as people who are quite old now is this accelerated aging that's always the question that arises in these cases because in fact if you look at all of their tissues they don't really just look like old people I mean they appear to be like old people but if you look across the kinds of diseases they get the kinds of problems they develop they're not just a compressed 70 years into 20 years so they're not quite the same thing as just an accelerated aging but they are remarkably compelling in terms of appearing to be accelerate aging and many many tissues are involved so here's another disorder called Werner syndrome and this is from a again a single gene mutation and this is a gene that encodes a protein that is involved in DNA repair okay and here this is it unlike hutchinson-gilford this is a disorder that manifests itself later in life so here's an individual and this is the same person years later and in fact she's 48 in that later picture so normal appearance at age 15 at a time when hutchinson-gilford is very very advanced but then suddenly begins to develop disappear apparent very rapid aging syndrome so again these progeria have been very powerful and there are now animal models of these mutations as well as many others that have been used to study the aging process with the thought that if we can understand how these single genes and single proteins might lead to accelerated aging maybe we could understand then how to either use these these same proteins or use these pathways to slow down the aging process so so Ken aging be reversed now there's a interesting question and and one doesn't really get into this very much in terms of the field of aging until one has some surprising results that looks like it's possible for example to take a situation we have an old tissue or an old cell and you can impose on that the characteristics of a younger cell or younger tissue and I'm going to share with you some some studies from our lab that give a hint at number one what the aging process might entail and how that might be modulated experimentally so as Phil mentioned we study stem cells and we actually study primarily stem cells in skeletal muscle and that's these are these are the cells that are responsible for maintaining your muscle they repair your muscle ones injured and these are just adult tissue specific stem cells which exist in pretty much almost every tissue in the body so they're very prominent in terms of tissues that are turned over very rapidly like the skin or the gut or the blood there are less frequent tissues that are very stable there may be some in the heart there are certainly some in the brain but across most of the tissues along the kidneys one can find this population of stem cells that maintain and repair that tissue or that organ so we're interested in in skeletal muscle and we're very interested in the process by which the stem cells in skeletal muscle maintain and repair normal tissue so this is normal skeletal muscle is a typical hearing Stanford young student might see walking across the quad its contract so this is a younger adult and then as we know with age things change with skeletal muscle and this might be actually more deconditioning than age-related changes but with age one of the most prominent changes that occur in skeletal muscle is atrophy and actually goes by the name of sarcopenia which is the age related loss of skeletal muscle and it really has a profound impact on individuals with age to the point where people lose mobility they lose the ability to stand from assert and get out of bed these very very important day-to-day functions and I think interestingly there's becoming increasing interest from the pharmaceutical interest industry of this topic because right now we really have no therapies for age-related muscle atrophy I think that the success in treating osteoporosis has really stimulated interest from the pharmaceutical companies because osteoporosis of course wasn't always a disease it was considered to be normal aging with age people lost bone mass and then suddenly we begin to do two things we began to measure it we began to treat it and then it was defined that osteoporosis at some point went from being normal aging to a disease when you cross some threshold and I think the same thing will happen with skeletal muscle it will become defined as normal aging but past some point when it leads to morbidity will be considered a disease particularly when and if therapeutics are developed so this is a feature of aging that is somewhat unique to scale a muscle it's kind of shrinkage of size but there are a lot of changes that occur in tissues with age that are very common and one of the features that one sees so I just use this slide to illustrate a younger male and older male this is course father and son and that if you look at the tissues of a young person in response to injury say a wound those tissues heal very very quickly very effectively and completely whereas the same kind of injury in an older individual even a healthy older individual will heal more slowly less effectively and usually with some component of a scar tissue so if you have a skin wound and a young person they'll heal without almost any evidence of a scar and the older people get the more of a scars form so there's less of a regenerative capacity in tissues as we age and this is true in skin this is true in gut this is true in bone every tissue that we know of where people have looked carefully at the wound response it's less effective at as we age so this is just an illustration of experiment from from our lab just illustrating that point of impaired tissue regeneration with age so these are from the mouse this is a young mouse this is an old mouse so be equivalent to say a 70 year old human and a very old mouse say equivalent to a haha year-old human and what we're looking at here is muscle that has been injured and is in the process of repairing so each one of these structures is a newly formed muscle cell that will fill in and in between here is some connective tissue that would if not removed would form a scar but this is a few days into after the injury into the repair and this is still being recovering still recovering so this tissue will recover completely normally but if you look at the same kind of injury and a 24 month old mouse you see fewer and smaller of these muscle cells and much more of this connective tissue and at 32 months it's even more dramatic so when this is finally recovered you'll see some normal muscle but there'll be a lot of scar tissue formed okay so this is just an illustration if you looked across tissues with this kind of traumatic injury in the body you'd see the same kind of age-related decline in the regenerative capacity so one of our first questions was do we lose this regenerative capacity because we run out of stem cells and the answer was an unequivocal no we have plenty of stem cells in this mouse has plenty of stem cells even at this advanced age but they just don't seem to be responding as well or behaving as well as the stump stem cells from the young animal so we've studied in detail what's wrong with the stem cells in these old animals can we begin to understand biochemically can begin to understand molecularly why the cells that are there seem to be responding poorly to this stimulus of an injury and we've done that in some detail and we've worked out some molecular pathways that are essential for stem cell function in the young and that are impaired we see them to be impaired as these mice get older so our first question was well if we understand an important pathway for stem cell function and young and we can mimic that in the old can we kind of wake up these stem cells that are there but not functioning in the old animal so this is another experiment in which we've we've done this that exact type of type of intervention so here we're looking at a small injury so this is normal skeletal muscle these are these fully mature large muscle we call them fibers and here's an area of injury this is a few days after the injury and this is in an old mouse so you see a few new muscle fibers being formed but a lot of this against scar tissue in its place so this is a wound that will not heal very well and is healing very slowly but if at the time of injury in another old mouse we produce the same injury but we do we introduce an activator of one of these molecular pathways called the notch signaling pathway we see very very healthy normal regeneration like we would see in a young mouse okay so one molecule one pathway and we can stimulate the stem cells in this old animal to now behave like young stem cells so in a sense we've restored the youthful regenerative capacity in this area of this mouse so this was this was a profound result to us we this really made us start to think what is it that is wrong with an aging individual in terms of the stem cells they have in their tissues and the responses of those stem cells and could yes yes okay so the question was you know do we understand by the by the rust analogy what's wrong with the tissue and is it possible that I think you're saying can we modify the environment and so that the tissue the muscle repairs itself is that we okay all right so the question again is if we can we intervene if we understand what the age-related decline is due to biochemically say can we intervene at different times so that we can keep the youthful behavior you know alive and well as opposed to seeing that function decline can we introduce into the animal or into the into the tissue something that will allow it to maintain that youthful phenotype I tuned up okay so keep it here so I'm going to show you an experiment that speaks to that question and the answer is that that's exactly what we're seeking is to understand molecular li why things change and then can we can we reverse that or if we if we've already gotten to an old animal can we reverse it or in an aging animal can we stop it so so our question from from from this experiment was was really along the lines of what you're asking is if it takes just one pathway to be activated to take a an old tissue and make it look like a young tissue what would happen yes how do we do it so the way we do it is so all of the stem cells that are sitting this tissue have a receptor for what's called a receptor what's called the notch pathway so what we introduce is just when we produce the injury we just inject an activator of that receptor those LC that molecule we've introduced activates the notch pathway and it wakes them up and in fact we had previously shown that the problem in the old animal was that the cells the stem cells that have this receptor are just not getting a signal to activate that pathway so we gave them the signal okay so and we're trying to figure out why they don't get the signal but we gave them the signal and then they behaved like normally or they behave like young cells yes the population do more physical therapy or something with that so the question was can an older population for example undergo physical activity to help with this process we don't know that the that physical activity enhances muscle repair but there's no doubt that physical activity even in older individuals can slow the progression progression of muscle loss okay so what in one case muscle loss is just this atrophy that occurs here we're talking about something's really an injury that has to be repaired so we don't know where their exercise enhances the ability of an injured tissue to repair but we certainly know that exercise maintains healthier muscles for longer period of time yes okay it comes from surrounding cells that's so with the question is where does the signal normally come from so in the young animal well I don't have the another picture but if this were a young animal which it looks like and we had produced an injury right here the signal comes actually from these cells that are uninjured around it okay so there's a lot of this that the normal signal that goes to the stem cell that comes from the adjacent normal tissue and for some reason in the old animal that signal is not being produced or secreted so we experimentally introduced it here and basically by that simple technique restored this youthful property so our question in a general sense would give good so we introduced this molecule one time with one injection so that we don't see any detriment really exhibited in careful in detail but if we look at this response recovery looks normal now we think that if we continue to introduce this signal repeatedly it would lead to an adverse effect because normally in a regenerative response that signal comes on they get shut off again so we tried to mimic that by doing a single injection at the time of the injury yes it is PRP oh so is that part of is that is that stimulating stem cell activity actually so the question is does PRP enhance stem cell function actually I don't we've never you know approach that I'm not sure that there's any reason to think it would have this kind of effect but I'm not sure okay so when we when we saw this result again our thinking was we have to understand what it is about the environment of these stem cells that is keeping them from activating normally so we have some ideas there are signals missing but they're there in a sense they're dormant so there they're capable of normal function if given the right signal so the question was can we change the environment the whole environment without doing an injection of this one molecule can we enchant change the whole environment of the old muscle stem cells so that they now these cells now reacted as if there are in a young environment so we did then a very strange experiment and this is called a para biotic pairing so in this case we can take two animals and surgically connect them to the point where they become essentially like conjoined twins so what happens is they get surgically connected just at the skin and they develop spontaneously vascular connections between them so we don't do any vascular surgery we just connect them at this under the skin they spontaneously develop these connections and within a couple of weeks they have a single shared circulatory system okay so the tissues of one animal are being bathed by the blood partially from the other animal okay so we did these kind of control experiments which we call isochronic the same age where we paired to young animals together or to old animals together but of course the the interesting experiment or the so-called heterochronic pairs young and old a young animal - an old animal paired so we did this and we then kept these mice and we've done this many times we kept this as mice together for two months first time we did this and then we injured the muscle of the old animal we asked what happens then when you have an old tissue that has now been bathed in the circulating environment this young animal for a couple of months what happens to the to the regenerative capacity of that tissue so if we look at the isochronic pairs here is normal muscle here's an area of injury that's in the process of repairing you see a lot of these new muscle fibers being formed just like an unpaired young animal if we look at the old isochronic pairs two old animals pair together here's the uninjured muscle looking normal and here's the area of injury we see a little bit of new muscle formation a lot of scar tissue being formed but if we look at the hetero chronic animals the old pair we see really what looks like normal regeneration from a young animal so uninjured muscle here and a lot of very very healthy regeneration going on in this in this otherwise older now older mouse so this was again a kind of extension of that previous experiment but what we found was that this was true across many tissues so if we looked at regeneration and liver it was enhanced in the old animal fur looked at neurogenesis in the brain it was enhanced if we looked at hematopoiesis in the blood it was enhanced so clearly this was not something that was limited to muscle and clearly this phenomenon of stem cell aging we think is related to an age-related suppression of stem cell activity that is relieved in the setting of these heterochronic parabolic pairs count there's no free lunch so the young animal had to give up something and indeed if we look at the regenerative response in the young pairs at his header chronic parabolic pairs regeneration in every case was impaired okay so what we really focused on now is looking at the age-related changes that occur in the blood and in tissues that we think are actually suppressing stem cell function with age and are being either diluted or relieved by these hetero chronic parabolic pairings so we're beginning to get to this idea that there are these age-related changes in protein levels some go up some go down that are actually regulating stem cell function generically across many many tissues but these are these are inbred strains of mice so the question is are the mice genetic the mice a genetically identical okay sorry so the question was pairing too much obviously if we pair two mice that are not genetically identical we have problems with you know rejection we'd have to deal with that these are genetically identical mice so yes okay excellent question so the question was have we disconnected these mice and looked for the loss of these these effects in fact we have and interestingly the effects last for quite a long time meaning if we've kept them together for two months and we disconnect them two weeks later and even a month later we can see some declining but lingering effects so it's not an instantaneous loss of this effect when we disconnect them but there's some memory we think there's some actually reprogramming of the stem cells that that has a lasting effect and takes some time to wear off yes so the question is how how profound is the negative effect on the on the younger animal and how long does it did it last so we haven't done and how long does it last after the disconnection we haven't done too many disconnection experiments so I don't have too much information on the time course but we certainly have looked at the impaired regenerative response in the young animal of these heterochronic pairs and depending on the tissue we look at a little bit depends on how you measure it the the effect is profound if we look at the effect on new neuron formation in the brain the effect is really quite dramatic okay it's less dramatic in the skeletal muscle stem cell compartment so it depends a little bit on the tissue but the the effect is you know again I think is quite profound in places and particularly tissues where the age-related normal age-related changes are quite dramatic yes okay so that's the question is is this effect seen in blood transfusion so to Mike's to my knowledge no one's ever looked and we wouldn't we look to see if anyone's looked a lot of blood is not coated for age so it's hard to find out if that's true remember these animals are connected 24/7 for two months so so we pretty would I often get asked that question if did we do this by a blood transfusion and we never did it because I never thought it would work but it turns out our collaborator a Tony Y score a faculty member here actually his graduate student Salviati did an experiment after having done this header chronic para biases and looking at neurogenesis so enhanced neurogenesis and the old animals suppress neurogenesis in the young and all he took blood from old animals and did a series of transfusions and saw a similar we saw less of a profound effect but saw the same direction effect a suppression of neurogenesis from blood transfusions now he did quite a few of them over short period times that wouldn't again be analogous to what we see what might be occurring in humans from a single transfusion but it's an interesting idea that what an effective transfusion might be might be more than just the blood itself okay so so really this this gets to us this fundamental question I think of is aging reversible and this is a painting of the Fountain of Youth youth by Lucas Grenache the elder from the Weimar Republic in the 16th century and this is a painting in which he has that for some reasons all women being carted in on the left I don't know why and oh is that it maybe that's right and it's of course they're coming in from this very bleak landscape okay where everything is stark and harsh being examined by some physicians they enter the Fountain of Youth and they emerge as nubile young women and their clothes and they enjoy all the all the fruits of youth romance and sex and good food and all the great so so this is his idea of the Fountain of Youth and and you know for us the question is are we beginning to understand something about aging that is in fact reversible and we don't know what the total consequences of reversing this phenotype is we don't really understand the mechanism yet but clearly from the point of view of just asking can you have old tissues restored to youthful capacity the answer seems to be yes now I can imagine that if one did this chronically many things would happen that would be untoward and undesirable but for these kind of the way I see this thinking therapeutically is not to reverse aging or to revert or to stop aging but actually to help with repair of injuries in older individuals so can we take a bone fracture and help it heal more rapidly and more effectively in an older individual a very limited treatment in terms of time in terms of space I think perhaps it's possible you get away with that without having the untoward effects of stimulating stem cells and older people which I think one of the greatest risks would be the development of cancer so you know we want to stimulate cells at a very specific time in a very specific place and see if we could get away with that to enhance tissue repair without having negative consequences yes so the question is how does our research relate to telomere research in aging I mean it's an excellent question so in in the field of aging of course the issue of telomeres is as cells divide over and over telomeres shorten and ultimately there's a potential for the cells to be able to to lose their ability to divide so they undergo that they die or they stop dividing because their telomeres shorten we don't we haven't actually looked at telomere length in these in these cells but they they don't as far as we know Express this enzyme called telomerase which you would need to restore telomere length so if that were the mechanism by which this we're working these cells we think would have to express this enzyme so that the old cells which have shorter telomeres would then be able to have you know longer and quote younger telomeres we don't think that's happening okay so we we don't think this is related to a mere biology but it bets a good question phil was just mentioning the idea that endurance athletes appear to have longer telomeres are you get so that you would I mean I just know the phenomenon and I don't know if anybody knows the mechanism of that yeah right so there's so the question is are they so again the comment is with endurance athletes appearing to have sustained longer telomeres than they are then they're not say control athletes or control individuals and the question is whether this is because through endurance training they're just not shortening their telomeres as fast or they're actually expressing telomerase and lengthening the tumors so either way it seems like a good thing even if we don't understand the mechanism yes I'll turn that over Phil actually I have been you know to my knowledge okay I I don't know I mean I think we as far as I know there's no reason to think that athletic ability is limited by telomeres that that I'm aware of so I would I would predict the answer will be no but I'm speaking more for speculation than from knowledge okay so so this is where we are in terms of thinking about this kind of intersection interesting between biology of Aging and the biology of stem cells I think they come together very interesting lis here with potentially kind of a therapeutic angle that if we begin to understand what makes a stem cell age its environment and how we can change that environment to enhance the function of stem cells we think well we'll learn some basic biology and also potentially have some therapeutic window there so just I joined we're now with just some food for thought that as I was putting this together that I think are interesting questions to think about both from a biological point of view and from a societal point of view is that if we could extend lifespan should we this obviously is it is a philosophical question I think is an important question for society answer should we be investing in research to extend lifespan I think most people agree that research to extend health span is a good thing but is it worth it as a society should we be having people striving to live longer maximally as opposed to live healthier for the amount of time we have what are the societal implications of this rectangular ization of the life curve I mean if we really can start doing this if we really could start taking care of the diseases of aging what would that mean for society as we have now where people retire in their 60s and they what if they could live to be 120 and quite healthy what would they do for the next sixty years of their life how would we change how it society to deal with that and then I know you talked about this last time is that what are the cultural trigger your the current trends cultural otherwise that may actually be actually leading us to lose some of this great Bennett that we benefit we've obtained in the last hundred years in the extension of average life expectancy I mean it clearly the obesity epidemic is actually threatening to have for the first time in hundred years to have us actually have a shorter average life expectancy from all of the advances we've made it doesn't mean it's going to continue just because we made these progress so far so this is this is my group from my lab just want to thank them for all their everything we've done is their hard work and their creativity and I'll just stop there and take any other questions before I turn it over to Anne thank you very much all right so good evening everyone it's a real pleasure to be here tonight to speak about the topic of interest tonight which are the mechanisms of aging and longevity and to pursue in the theme that Tom already introduced and spoke about so as you can see on this drawing from Leonardo da Vinci there are obvious differences outward differences between the young adult and an old adult and those outward differences are also accompanied with a decline in a number of physiological functions that affect a number of different tissues and organs in the body and for example if we take the brain as an example there is a decline as early as in the 20s and 30s this slow but progressive decline in a number of cognitive functions including working memory short term long term memory speed of processing although you can notice that verbal knowledge stays pretty constant but it's probably due because of the fact that people get exposed to much more words as they get older now this decline in a number of physiological functions in a number of tissues including the brain is also accompanied by the increasing onset strikingly of a wide range wide spectrum of age-related disease so you can see as human get older this striking increase of diseases such as heart disease cancer stroke can FEMA type 2 diabetes' neurodegenerative diseases such as Alzheimer's Parkinson's etc so an important question at this stage is is aging itself a regulated process and could maybe understanding Aging in of itself help us understand a common mechanism behind all these age-related diseases and help us identify maybe new avenues to treat and prevent those disease instead of treating them one by one finding the root cause or the root mechanism behind all those diseases now for the longest time aging was actually thought to not be a regulated process - just as Tom was mentioning we just wear and tear or the resting of the organisms but actually this view has changed and it is really now thought by experiments seminal experiments in the last decades also that aging is actually a very regulated process and that it can be regulated by a combination of genetic and environmental factors and for example studies in twins in human have indicated that the contribution of genetic factors can be as much as 25 to 30 percent to human longevity so in the next slides couple of slides I'm going to present examples of how genes and how the environment can regulate aging and obviously an interesting aspect is also how what happens at the interface between genetic and environmental factors and how gene products can really integrate environmental changes to in the end affect lifespan an indication that aging and longevity are regulated by genes came as tom was already mentioning from observation genetic studies in human with families like this family here which is an American family reported in Utah where both parents were centenarians and eight out of their 10 children were also sent own ions are living more than 95 years old studies in families like that by the group of tampers have revealed regions in the human genome on human chromosomes that are associated with this exceptional longevity being sent and ions so there are for example regions on chromosome 4 that are in human that are associated with exceptional longevity but so far those studies haven't been able to zoom in and pinpoint the specific genes that are on those chromosomal regions that are responsible for this exceptional longevity in human and what really made a breakthrough a key breakthrough in the world of aging to identify the specific genes that were important for regulating lifespan was studies in a very tiny one millimetre worm called sinner abilities elegant so it's a little tiny worms that lives in the soil and experiments by the group of Cynthia Kenyon at UCSF back in 1993 identified worm mutants that could live two to three times longer than wild-type normal worms and not only could those mutant worms live longer but they were also more useful as far as were more concerned so they were more active they had less wrinkles so they kept their it's not that their decline period was extended it was really their youthful period of life that was extended both the mean and maximal lifespan and it turned out that those were mutants that can live two to three times longer had a mutation in one single gene a gene that encode the receptor for insulin now this was revolutionary as well because people had already a hard time and realizing that aging could be regulated by genes but let alone a single genie wood it was thought to be very complex and maybe that 10 or hundreds genes would be needed to affect lifespan but here that when he said that at least in a worm mutating a single gene was enough to extend the youthful period of the worm by two to threefold now this mutation in the insulin receptor that extends lifespan in a worm is not turns out not to be an idiosyncrasy of this tiny round worm in the soil and it actually turned out by further experiments done in the fly Drosophila in mice and now even in human centenarians now that we knew the gene it's easier to go back in those exceptional centenarians and they also some of them turn out to have the same similar mutation in this insulin receptor and indicating that this incident mutation that lower the activity of the insulin receptor in a conserved manner from worms to human have this ability to extend longevity or to be associated at least in human with extension of longevity now how does that work how does at the molecular level in the cell how does reduction of activity of a receptor the insulin receptor how does that add well normally insulin is a circulating hormone that for example gets circulated in the blood when we eat a meal and this hormone will bind to receptors that are present at the outer surface of the cells that contains this receptor and what this trigger is a cascade of event signaling event which culminates in what's called the phosphorylation which just means the modification of a family of proteins in the cells called the fo'c'sle transcription factors and it modifies them and it prevents them from acting normally those factors would be acting to regulate a lot of genes in the cells and in this case if they cannot no longer act and those are conditions that are associated with aging now in those worm that live very long or in those mice or flies or even human that have lowered mutation in the insulin receptor or if one has lower amount of circulating insulin this whole pathway is no longer set in motion and what that means is that this factor that was normally kept inactive now becomes active it can go into the nucleus and it can activate many many genes and those genes form a program of the program that is important in the cell to detoxify those reactive oxygen species that Tom talked about and to repair a number to have to enhance the repair process of the cells and those are conditions that are associated with longevity yeah so there is less receptor in this case if there is absolutely this is a oversimplification if there is absolutely no receptor this is really bad and there is actually no organism that gets alive because it's lethal so it's a it's the mutation is a that's why it's a reduction in function it's not a total loss of function yeah so the question was is it was there no receptor at all and in fact those worms steal all those humans still have a receptor just less active than the normal one so those dude or Otto's receptor active right from the birth from birth and indeed they are active from right from birth but then they play a slightly different function during development actually very important for the growth of an organism and it's actually why it's really needed to have them but then as one becomes an adult there are no not as beneficial anymore and they actually turn up what's good for growth during development turn up to be detrimental for an adult aging alright in the past couple of years it has become clear that again in human this pathway that I just talked about is really conserved and what was discovered in the tiny worms has hold true now for human that live actually 2,000 times longer we live 2,000 times longer than those miniature worms that live like 15 days also and yet similar in papers that were just published if one has a specific type of those FOXO molecule that are downstream of this insulin pathway one is more likely actually to or has more risk or if you prefer like more chances to live longer and if one so those those mutations are actually quite common and nowadays one can even like find out if one has this type of Foxhall in their genome like this type of mutation that type of mutation or that type of mutation those are the different possibilities and if one has that type that's associated with just regular lifespan one left 70 to 80 years f1 has those type of mutation in that specific gene this is associated with possibility can increase chances of being centenarians or even a super centenarians so this indicates that discovery made in a worm as actually but like revealed like this is published like last year in 2009 so it's taken a while to go from the worm to human but it is indicating that there is conservation in the pathway that can regulate lifespan and that studying model organism can have a huge impact in our understanding of what are the genes that regulate lifespan in human so this was four genes now what about the environment in this so obviously there are lots of ways in which the environment can be detrimental for lifespan for example smoking is detrimental for lifespan pollution etc but there is one environmental intervention that's extremely beneficial for lifespan and Tom already alluded to it and also here and it's called dietary restriction so dietary restriction is defined as restriction in food intake without malnutrition so supplemented in vitamins and minerals for example and you can see here in experiments done in mice by Richard one drugs that restricting food intake by 25 to even in this case 60% extends both the meal and surprisingly in fact the maximal lifespan of those organisms and dietary restriction is not only working in mice to extend drastically by 60 to 80% mice lifespan it's actually an intervention that can extend lifespan in virtually all species that have been tested so far so people have done experimental spiders on trout on dogs on the model organism that we use in the lab yeast worm fly and mice even on primates this seems to be working and they are actually now human who self-report to perform dietary restriction and they self-report to have health benefits we don't know about that longevity yes but health benefits that are associated with increased anonymity now dietary restriction extends lifespan but interestingly it also delays a number of age-related traits and age-related diseases so again it's not something that just prolong misery and just extends the decline periods of life it has been shown to decrease the risks of cancer in both mice and human and it also has been shown interestingly to slow the decline in learning and memory part of this decline that I showed you in in human that occurs it also occurs in mice and in rodents and you can slow that decline by applying dietary restriction and here is just to show that in the presence of dietary restriction a region in the brain called the hippocampus that's really key for the formation and the storage of memories is really preserved whereas in a usual diet you can see that there is a lot of already death and degeneration in that area so dietary restriction has this amazing impact in all animal kingdom including primates and probably human to prolong lifespan and prolong health span there is an evolutionary theory of why would that be that dietary restriction is so potent at extending lifespan in such a conserved manner and the edge volitional retiree goes as follows that in times of food scarcity dietary restriction this mechanism food scarcity would extend lifespan such that the individual can allocate the little energy that they have to the maintenance of the youthfulness so that they can reproduce but on me later on when better times become available and reproduction the survival of the youth is more ensured that's just a theory but that may be explaining why it has such a pervasive impact on lifespan in so many different species so because of this amazing ability of dietary restriction to extend lifespan and health span one can ask a key question which are what are the molecular mechanisms by which dietary restriction or caloric restriction can extend lifespan and if we understand those mechanisms can we harness the benefits of caloric restriction without necessarily having to perform caloric restriction which actually is like this like 40% to 60% reduction is actually very hard to do that would be the equivalent of 1200 calories per day which is very hard to make it compatible with an active lifestyle for example so can we understand how it works harness the benefits of it maybe mimic it by some let's say drugs and at least mimic some aspects of it so here is the question now so this is rephrase it Mona can we understand how what's this black box here and how dietary restriction divers way of doing dietary restriction how do they extend longevity yeah or is it if you are very thin when you're young and extend your life or think when your own it doesn't yeah so the question is those dietary restriction have the same impact no matter when it started in life and the answer is no but it does always have an impact but it's not the the percentage X life span extension that it has is lower and lower as much as shorter and shorter the dietary restriction time is done so if dietary restriction is started in young organism this will have a huge impact on its lifespan if it started at midlife let's say it will still work and still extend lifespan but by a shorter percentage and etc so it's still like you know if one is thinking about it there is it it will still be beneficial to start it but the the impact will will probably be low lower yeah so one way by which one can connect the dots between what I said at the beginning about genes that regulate lifespan and environment this amazing environmental intervention to extend lifespan is a possible simple linear relationship which goes as follow if one diet does caloric restriction or dietary restriction it's like eating less and as I said insulin is this hormone that one get like get when one eats a meal so if one eats lower amount of food one will probably have less circulating insulin and in fact that's the case rodents and humans that have that on caloric restriction have lowered amount of circulating insulin therefore this pathway that I was telling you about is going to be less active it's going to be sort of like those mutant that have a reduction in function in their activity so it's mimicking those insulin mutants that I talked about that means that their transcription factor that foxhole is going to be mostly active and in the nucleus which is good it's going to trigger all those genes that are repair detoxification genes and stress resistance type of genes and that may lead to longevity yeah yes so this is a very good question so in diabetes you may have all heard that people who have type 1 diabetes don't have anymore of those cells that produce the insulin they destroy them so they cannot produce the insulin any longer and in type 2 diabetes it's slightly different people start getting resistance they have actually increased the amount of insulin circulating probably as a compensatory mechanism but it's not being resistance to insulin so certainly tweaking this pathway too much in the other direction like lowering this pathway too much are completely can be very detrimental again like this can be too complete death and in some cases diabetes but I think here the interesting part about those worms and I think this is something to think about like one can think about of these pathways okay let's just lowering it right enough to be in the right window not too much then it's death or diabetes one can also think about it in that way but adding on top of that the layer of regulative 'ti meaning that in what happens in diabetes is that this pathway is mis regulated so it's aikido firing too high or firing too low those worms are those human that have lowered their pathway for longevity they have lower of it but it's still nicely regulatable so when insulin common goes after a meal it's still like doing its job like those waves of going in and out pretty pretty well so in fact I think it's not teased out this is a very good question and I think a lot of researchers are working on those questions right now and the idea would be that the exact amount of activity is important but also the regulative 'ti the plasticity of it is also very important yeah wait itself so for example if you had dietary restriction and you reduced your body weight that's one way of doing it but from the thermodynamic point of view if you increased your activity and achieve that same way does that have an effect so the question is whether it's the weight or if it's if it's the intake of calories and if it's the weight one could imagine that you could achieve the same effect by eating the same amount but increasing your exercise report and I'm sad to report that it is the intake that seems to matter and if animals are being exercised they have a set amount of food and they have exercised to the point that they have the same weight as the animals that our dietary restricted they display health benefits of this but this does not extend a maximal lifespan whereas dietary restriction extends their maximal lifespan it's not understood why some people think that exercise has some detrimental effect as well that when summed up lead to naught but it's an interesting point to contrast exercise and dietary restriction in that aspect exactly I'll take the drug that mimics caloric restriction and your couch potato now I'm not advocating that identify the game within the sea either God Fitness boxer 3 how was that so this was his so the question is how is the how was so identified so so was identified by many groups in many different ways but the first characterization in the worms was by doing they had those mutant of the insulin receptor that lived very long two to three times longer and they wanted to know what was mediating that so they did a screen for genes that when mutated could revert back the lifespan from very long to back to normal and by doing that the one gene that came over and over and over and over the only gene that came up was Fox oh so that's how it was identified genetically and then molecular Li a lot of experiments went to characterize the molecule for what it was meaning a nuclear transcription factor yeah yeah so the question is what is the percentage of centenarians that have the mutation in fo'c'sle so it's limited so which still goes back to the questions that there are probably many genes in the centenarian in in different centenarians have probably mutations in different pathway so it's considered that the folks who mutation accounted for 2% of the variation that they could see in there like a small percentage of the centenarians now as you could notice it's it's a whole pathway so it's insulin there's all these molecules in between folk so there's actually different foxes and I didn't talk about that then there are the target genes so I think when all is said and done it will be interested interesting to see what's the percentage of certain ions that have a mutation in that whole pathway but fo'c'sle fo'c'sle in and of itself it's actually relative so um the question is can you vary the regimen basically so that you for example low glycemic index and and lower the insulin and still have this extension of lifespan to my knowledge people are trying to do those experiments for example do the mice with the Atkins diets or like those kinds of different diets and then see in the end what happens but the results to my knowledge the results are not known based on the research I would imagine that everything that well not everything but it depends I guess but things that will decrease the insulin levels I think should will turn out to be relatively beneficial at least in terms of health span or mean lifespan maximum lifespan might be another story and in this case it might be really that it's the number of calories period hmm all right so that's one possibility we have time yeah so is it the only one though I mean is it does everything revolves around insulin as much as I would love that because we work a lot on this it doesn't seem that the insulin FOXO pathway is the only way by which dietary restriction acts to extend lifespan and in fact this is an experiment in worms it's a genetic experiment but what you can see in that experiment is that worm that live long because they have a mutation in the insulin receptor in blue here they can live even longer when they are put in the caloric restriction rich in the dietary restriction regimen so if the only thing that dietary restriction was doing was to reduce to act on the insulin pathway then it wouldn't be additive unto the mutation that already mimics that so what that meant to a lot people those seminal experiments what they meant was that yeah insulin reducing insulin is good for extending lifespan and reducing insulin is probably one of the way by which they arrest dietary restriction extends lifespan but it's probably not the only way and there's probably other way in which one can extend lifespan downstream of the entire restriction so what is it so in our lab we had this candidate approach we had this hypothesis that maybe there would be another system to sense calories in addition to insulin which is a very hormonal way of sensing food right you eat a meal boom you have insulin and these senses that you've eaten a meal maybe there would be a more in fact ancient way that cells would sense really in a very ancient evolutionary speaking in a very ancient manner could sense calories or amount of nutrients that there is and in fact there is such a molecule in the cell that's a very ancient meaning it exists already in organisms that don't even have insulin like yeast for example and it's present from yeast that don't have insulin to human which do have insulin so it's oh it's a protein that can sense energy in a different way what is it it's called a MP activated protein kinase or a MP kinase and what's interesting about this molecule to molecule in the cell is that it can sense a wide range of stimuli and it turns out that a lot of those stimuli are associated with dietary restriction low glucose low energy amounts low leptin it's a hormone that's produced by fat to low low fat content interestingly it's also activated by other types of stimuli like exercise as well as by two anti-diabetic drugs fen Foreman and metformin that don't acts with the insulin pathway drugs that act in another way than the insulin for the Arabic diabetic patients how does it sense all this those are wide range of stimuli and I said it is very ancient molecule that can sense count calories in another way than this insulin hormone well it does that because it can exquisitely sense the amount of a MP the ratio in cells between a MP and ATP and ATP is energy this is a molecule that contains a lot of energy and that will provide energy for most of the functions in the cells that require energy energy EMP is the precursor of ATP so it's like low energy so each time in the cell in the cells that the ratio between low energy to high energy increases this molecules gets activated because it can directly bind a MP so it's really a molecule it's a protein kinase it can sense low energy very directly in every single cell in the body and this MP can is was well known it's as I said its present even in yeast it's very well known to regulate very important process in the body such as lipid metabolism and protein synthesis but a key question is does this fuel gay go in the cells this counting calorie molecule can it mediate the longevity effect of the hetero structure so how did we do that well we used this little worm this nematode one-millimeter soil worms and Arbutus elegans and we devised a method of dietary restriction calorie restriction in the words so the normal yarn plays they crawl around and eat bacteria and what we did is that we put them on their plates and then at some point we either give them all their food like we would do for human or mice or we gave them a third or well how far we restricted their food access so when we did that the worms eat less and see that here and importantly like in any organism the worm that eat less they live longer both in terms of mean and maximum lifespan they eat less they live longer and they are a MP not surprisingly they eat less they have less energy so they are a MP to ATP ratio increases because and that's telling the animal look you know I have low energy my MP is high my ATP is Rho so that means that probably this ampk nice gets activated well is it important so for this we can use a mutant in these little worms that doesn't have NPK knees anymore well type normal worms they live longer if you restrict their food mutants that don't have NPK knees can no longer live longer in response to this dietary restriction presented in another way you can see that wild-type worms fed replete at libitum they live a certain amount fifteen days if you restrict their life their their food they live longer and then boom they're died or starve so they live longer here for dietary restriction and they starve the mutant it doesn't matter like they don't have this energy sensing mechanism anymore it doesn't matter what you do to them they have this flat lifespan they can no longer sense the dietary restriction now that our lifespan is one measure but you know again who cares if one makes the worm live long but the worm is really like and you just say basically make it like not enjoy life so in fact we measured the what we thought was it's only a murderer of worm what we think about warm youthfulness that we murdered its activity so its ability to have rapid movement in the plate and be relatively happier this we hope and what we found was that during aging there is a very striking decline in activity in worm activity gets slower and slower as expected this is slowed down this slowing of the worm is reverted by dietary restriction again this amazing intervention to slow down aging and again the presence of a MP kinase this energy sensing molecule is necessary not only for the lifespan but also for the health span of these little worms so what that tell us is that one way by which dietary restriction extends lifespan and health span it's not just by acting on a hormone that circulates in the organism it's also acting in every single cell by acting on this molecule that can really sense how much energy there is to promote longevity and to some extent Fitness now yeah under 20 calorie I'm a sugar man yeah so the question is like in those little package they tell you like how many calories there is in there and where does that come from I think it comes from a lot of measurements that have been done we're like the calorimetry type of experiments where they merger exactly how much slip lipid a sugar or protein counts in terms of calories and then they see where the food is composed with and then so I think it's relatively trustable with some words on the label now the type so I guess like is your question getting at which type of like is sugar lipid proteins would they all need to be decree like can we just decrease sugar for example and defined in terms of proteins and lipids or do we have to decrease certain types of calories like say coming from fat or coming from sugar it's not completely clear yet a hundred percent but it seems that based on studies in model organisms that in fact proteins matter a lot in flies for example so amino acid are very important to restrict so you know like those Atkins diet for example would not be recommended for extending lifespan because it seems that one needs to restrict amino acid and that's very important in the ability to extend lifespan now in mammals the type of calories that the type of you know whether it's proteins in the diet lipids in the diet or sugar in the diet it's not clear it seems to actually in mammals if anything just due to the total amount of calories and so far in the experiments that have been done it doesn't seem to matter at all where the calories come from but I think this is an important question that that has yet to be solved yes oh can we use a can we use a formula to calculate that people who are doing the self-reported calorie restriction are called some of them are in a group called cronies CR o ni e s and the cronies have a website where they explain and the head of the cronies society is this person poor McLovin where he has made no calculation of what it represents for a man or for women which is it's different actually and based on the level of activity based on the age what is the amount of calories that is required that that would be required on how to calculate that so this website is actually quite useful if someone wants to implement those kinds of far yeah yeah so the question is how does restriction of calories affect women's ability to reproduce so that's a very good question as well obviously it's like what tom was saying there is no free lunch meaning that well in that case there is no no free lunch in the sense that basically when one restricts calories this has a negative impact on fertility especially female fertility so females that restrict their calories during the reproductive time have either inability to be fatter or less ability to be fertile now they all paradox not paradoxically but because they extend their lifespan they were all they will still extend a reproductive time also so there is a lower fertility at each point but the fertility part is extended and as I was mentioning to the question that was asked calorie consumption can also be started later in life so one could imagine starting the caloric restriction regimen if one wanted to extend their lifespan past the reproductive time yeah so the question was would you do we don't want to do extreme calorie restriction on a child and that's true too because again it would have a very negative impact on growth and then growth would be stunted and so one wouldn't want to do that but because of this ability to start in mother organisms as well as in human calorie restriction later in life and still have very important benefits it's still possible to imagine windows of time whereby one would do that that are past those critical periods yeah yeah in the back so the question is can we do the caloric restriction in different at different times do it then stop doing it then and then is the effect cumulative the people haven't done like so like good like design like this but they're starting to do that and it does seem that the effect is cumulative in the sense that the longer you do it it doesn't really matter exactly when but the overall time is what matters in terms of the lifespan yeah so the yeah so the question is does it make you live longer does it make you feel that you're living longer because of the life seems very long actually do people feel good by doing that so there are two different camps on this the first camp the clooney's society by head by poor micro Finn he will-he raves about it he says that he's been able to play chess tournament and he feels really energetic actually the mice that are placed on Carrick restriction and the primates they are there are less lethargic like they go like they seem to be relatively active so that's the optimistic camp and then there was this experiment that was done in biosphere 1 like you know where they they were the biodome and in fact essentially the people that went in there because they actually screwed up their like crops the first year they actually essentially what color across stricted in there so they had like really good blood parameters when they came out of this biosphere biodome experience there are papers on that they had really good by blood markers and probably they have beneficial impact on lifespan but psychologically they were followed by I mean maybe was also the confinement but like the the restriction on food and some people had really marked very negative psychological impact so some people fear that calorie restriction has a very very negative on human psychological impact so those are the two camps right now yes with increased lifespan especially in response to dietary restriction as we hear it with health benefits especially for diseases such as stroke cancer or all sorts of diseases and actually yes so for all the models so far that have been tested of disease dietary restriction has a very positive impact on those those models yeah yeah yeah so the question is about and I guess like we probably the I'll address this question by probably just wrapping up and then maybe we can open the final discussion to the the thing so I was going to talk about specific mechanism but I'm just going to those are more like the things that we do in our lab and actually I put reviews on the web so you can see exactly all those specific mechanisms I guess I was being ambitious here so I'll alright so to address your question about drugs you know and coming back to the end can we mimic those so all the parts that you have missed cotton code you can find on those reviews on the web and there are more details about the mechanism but you've seen the main point which is that this EMT kinase can this be important and they are actually activators of mpk means in this French clinic yup those drugs and Foreman and metformin and they can extend indeed lifespan at least in rodent model and there are also other molecules such as the reservoir all present in red wine activate such he one another molecule but also a MP kinase has some impact at least in obese model for rodent and then finally another molecule that's also in the same pathway as a MP kinase called rapamycin just shown this year a very fresh result showing that even in midlife started in midlife has a very significant impact it seems more but it started at midlife of my is very interesting increasing lifespan so yeah they are potential drugs that can potentially mimic dietary restriction can they be used can they be safe can they be combined to extend even further the lifespan those are all very interesting questions so with that I guess I will just close by thanking people in my lab and thanking you guys for being a terrific questions and now that's great well that was fantastic here's the see our society if you want to look it up it's right there it looks interesting but maybe if you want to drink wine I think you have to have quite a lot in order to have the effect I'm so go do that but do it after you get home so I would say this has been a fascinating discussion and interesting to me personally because my mother is celebrating her 90th birthday today so I don't know whether that's a good or a bad thing for her it's a good thing but we'll see if more years of me may not be a good thing but with that thank you all for being here and thank you and Tom for more please visit us at stanford.edu

Channel: Stanford

Views: 103,111

Rating: 4.7345133 out of 5

Keywords: human health, medicine, science, biology, gerontology, aging, longevity, life expectancy, span, environment, age related disease, evolutionary theory, stem cell, genes, curve, intrinsic, extrinsic, progeria, tissue, muscle, regeneration, isochronic, heter

Id: hFH44xCdTcc

Length: 110min 2sec (6602 seconds)

Published: Thu Jul 15 2010