>> good afternoon. welcome, this is the 12th year that we have demystifying medicine. [technical difficulties] people are experts in the little parts of the pizza pie. but they can't communicate with the people from the other part.
so we lose the big picture. what's important. what isn't? and what do we know and what do we don't know? also, the picture was taken by my grandfather, so i have a invested interest in it. okay.
how do we get to the next one? so what's aging? i try to -- when we pick out these things, i sit down and meditate, try to figure out what do i know about it? i figure many of you know much more. but is aging something like this
terrible poem by holmes, one shores shay? this is a one horse carriage that was built. the best. now, how did it end? it went to pieces all at once, all at once and nothing first, just as bubbles do when they
burst, end of the wonderful, one hoss shay. is that what aging is about? does everything just sort of give out? is there a basic behind the scenes biological phenomenon of aging? but people rarely do that.
they usually -- they may be much older these days, and everybody is getting older these days, but even as you're heal more, but when you get older lots of things happen. degenerative diseases, near shouldst system, cardiovascular system, everything.
is aging the same thing as the degenerating diseases? are the degenerating diseases the same thing as aging? this is a very important question. whether there is a common underlying pathway behind all of this.
at least these are the things i wonder about. are the degenerative diseases, whether it be alzheimer's, cardiovascular, are they increasing because the population getting older or is there another thing. more importantly, are the
experimental mechanisms which prolong life in invertebrates, mice, and maybe humans, applicable to the human being? and how can you study all this? so today we are really most fortunate in having 2 truly global experts in not only this, but the whole parameter of what
is aging. so i'm going to briefly introduce both of them to you. and then dr. hodes will be the first speaker. richard is the director of national institutes on aging. he's a widery recognized immunologist.
a physician, graduated from harvard medical schol e, trained at mass general. trained here in oncologist at the national cancer institute. he's a member of the institute of medicine. he presides over this whole arena that is encompassed by the
national institutes of aging, which covers much more as we will hear than what i prepared. i just discovered several months ago that, for example, alzheimer's disease, the major focus for it is in the national institutes of aging. and richard is the coordinator,
the director of all of that. so he's going to speak first. and then following his talk, toren finkel from the heart institute will discuss at a more reductionist level his work in relationship to mitochondriamitochondriaial metabolism, turn over of cells and the aging process itself at
a more, let's say, basic level. toren is also a physician. also graduated from harvard. and has a ph.d. in bio physics. he has been here at the nih for not too many years. but he's chief of the cardiology branch of the intramural
research program and heart institute. wait a minute! come, come, come. take your thing -- sit down. so this is our class, lila. and so this young lady is a very dear friend and most remarkable individual, aren't you?
>> well, if you say so. >> right. now, she is -- how old are you? >> 95. >> 95 years young. and how old is your sister? >> she was 100 this august, this past august. >> and how old were your
parents? >> 86. >> and what to you attribute your youthful appearance and vigor to this young age? >> i really don't know. people ask me what is my secret. i wish i had something to say. i have no idea.
i never thought of being this age. i really don't know how i got here. it just happened. >> so what do you do? what is your -- do you have an occupation? profession?
>> i retired -- i went to howard university 44 years. he retired in 1991. i was busy, in the studio since and in 20 of my husband died. now i'm the housekeeper, the one that goes to the grocery store, the cleaners, as well as doing my work in the studio.
>> lila is an accomplished artist, her work has been shown in many institutions in this area and else where. deyou of do much physical activity. >> i was not terribly athletic as a child but i did, at my height, played basketball in
high school, girl's rules were very different than those -- in those days, so as short as i was, as short as i am today. i was not very fall. but i played basketball. had somebody's elbow in my face to loosen my teeth. later i didn't do anything
special until i somehow got into a class at the hospital navy where they had a wonderful pool and they have an exercise group, which i joined and that was about the 80s. i used to go there. we had a group that exercised. one of us led the group, then
we'd swim. and i did that -- we all did that until they took down the pool. >> i think you told me, this was about 30 years, right? >> i suppose. it was sometime in the 80s that i started.
i really don't know when they took down the pool. they took down the whole building. >> but you swam 36 laps? >> i got up to 36 laps. 18 is quite -- so when i was really good i could do 36. >> do you smoke?
>> never. >> no bad habits? >> i wouldn't say that. [laughter] i don't smoke. >> have you had any other health problems? >> well, i had an operation, i had a lung removed and
carcinoma. why, i have no idea. i never smoked. my father smoked cigars. i always sat behind him in the car when we drove. i sat on that side of the car. my first husband also smoked cigarettes until the children
were small, then he realized he didn't want the children to smoke so he quit. and i never did. >> so when was that, that you had your -- part of your lung removed. >> 2006. >> almost 20 years ago.
and believe me, it's hard to keep up with her when you're walking along the street. >> well, might balance is bad and i do better faster than i do slower. >> is there anything you'd like to ask the group? >> i don't know, if you'll tell
me what makes some people get older, i'd be delighted. >> maybe you have any questions that you'd like to ask lila. anybody? yes. speak up. >> [inaudible question] >> what was your diet?
>> i think i do eat -- being aware of a good diet. i was a chubby child, and from the time i was about 16, i was aware of diet. my father was a doctor. i would complain i wouldn't eat weight. he said your system doesn't
require that much food, and that was it. so i have been watching my diet or aware of my diet all these years. >> lula, do you take food supplements, like lots of vitamins? >> well, i take general vim and
here lately, i take extra vitamin b. b12 shots. they're supposed to help my balance. i don't know that it does. >> anybody else? >> many people, when they retire, feel that they kind of
not [inaudible] how active are you socially [inaudible] well. artwork is about the only thing i know. i don't get to the studio every day. i get involved in social things and as i say, i'm in charge of the house and i have to call the
plumper or whoever is needed. art is the only thing i know to do. i don't know what else i would >> lila lives in a 3 story house. her studio is both up and down and she's up and down those steps many, many times.
i have to congratulate you! it was just a month or so ago that montgomery county gave you an award for a outstanding lifetime of creativity. you were the awardee of the year! >> yes. >> that's wonderful.
well, listen, thank you so much. [applause] >> richard? >> well, it's a hard act to follow. really inspiring to all of us. i'd like to talk very broadly about a few aspects of aging. i'd like to give a broadesque
picture of the population level of what is happening to the aging globally and to this country. move from their to talk about some of the clinical issues that are related to aging and the progress we made in addressing them, and finally talk about
some of the underlying processes, biological molecular level which i hope is a real transition to what you'll hear in terms of an expert perspective on one important aspect of molecular science. to begin, this is -- i think one of the more graphic
illustrations, what's been happening to the population of the world in terms of its age demographics. so what you see plotted here is from years, from 1950 to 2050, two lines proportioned to people, percentage of the world's population that are older, over
65, or young, under 5. if you look on the left, 1950s, 1960s, there were about 3 times as many kids under 5 as people over 65. about 14, 15% to around 5%. look dramatically what's happened until we reach the current point.
the personal of young goes down, percentage of old goes up. we're approaching undoubtedly the first time in human history, there will be as many people at older age as there are younger. if you look at what is projected by 2050, that will be completely reversed.
quite apart from all the medical issues, the sociologic implications are huge. it will be a very different world. this is perhaps a back ground for understanding what a very dynamic point we're at and why it's important to understand
what aging means to us, societally, medicall, and underlying biology. the theme we'll try to under go through here is that aging is a major risk factor for most chronic diseases, and evolved hypothesis, this is because the biological process of aging
itself, multi factorial as it is, underlies some of the common risk factors for multiple diseases. you can sigh changes in immune system. dna, repair, metabolism. but the notion is that all of these changes which happen with
age might be common risk factors to disease. as we'll see, thinking has been that in addition to trying to treat or prevent individual conditions, if we can address some of these conditions which may be underlying and uncommon to multiple diseases, we may be
even more effective in trying to improve health overall. this is just a slide to show you the many, many conditions illustrated here. how age dependent they are. so there is kidney disease, stroke, congestionive heart failure, osteoporosis.
you can read them all. the graph shows how dramatically this increase with age. this is an accumulation of random events that happen or whether under lying biological changes that occur that are responsible for these. we'll talk about some of this.
now, interesting, i think, what's been happening in trends for longevity for aging. in this country, in comparison to the rest of the world and for subsets of our world population. this is some socioeconomy or societal commentary. what you can see here for men
and women, from 1920 to 1950, is life expectancy from the age of 50. this is how well people are doing if they make it to 50 and beyond. it's shown as a function of the rush to poorest 10% of the population.
this is really quite telling. look at men first. you can see where we were in 1920, where the richer people did better, lived longer, not only is it true now but this is through 1950 and it continues. the gap is continuing. so the socioeconomic advantage
or disadvantage of being rich or poor in this country and this is more dramatic in this country, really, than most any other part of the world, is illustrated for women it's even more dramatic so that if you see here in the last years, the poorest 10% and 20% of women, have
actually not gained. they've lost in terms of life expectancy. some of this has occurred at earlier ages, also true at older ages. the fact it's socioeconomic related indicates it's likely to be manageable, changeable, as a
result of factors that we can do something about societially. if we take a look at how this compares worldwide, this is as of 2014, the life expectancy from birth. japan has the highest at age 84. we're not first, second, not in the top ten but down here, a
poor 34th below a lot of countries who in terms of socioeconomics and other parameters of wealth and wellbeing, ought to be at a disadvantage. so this is about as much as i'll say here in this talk based on medicine, biology.
but it's a challenge to all of us to understand what's happening in this country verses the rest of the world. a lot can be dope that needs to be done. if we look at the same issue here, this is a plot saying something very similar, showing
the u.s. this is a bottom line, verses comparable country averages. that is, socioeconomically, comparable countries. in 1980, we were a little bit behind once again, this trend, disturbing as it is. the gap continues to expand.
continuing to do less well in recent years than countries of similar or even less socioeconomic development. so let's move to look at some of the causes of death. as of a couple years ago, not surprising, heart disease first. cancer, respiratory disease.
you can go down the list. i'll use this as a take off to describe some of the improvements we've made and some have been very impressive and dramatic. addressing these individual once we get through some of this clinical material we'll turn
back to ask how the biology informs what's happening and what all of you and your careers in the future will do to help do something about all of this. some of the clinical research that has been carried out at or supported by nih which has made a very big difference, i'll
illustrate here. this is our understanding of the conditions that underlie disease and also our ability to do something about it. so let's look at a few examples. this study reported a couple of years ago is one of the potentially most informative in
terms of giving us an intervention that can make a difference in life and quality of life. all of you know that high blood pressure carries a risk of premature death. it's some years ago when the first studies were done which
contrary to expectation showed if you cooled systolic blood pressure, the highest of the two numbers from 160 to 140, you had dramatic decreases in stroke and congestive heart failure and heart attacks. for years, this threshold of 140, as a target, has been what
has been behind many recommendations. in fact, there were some that suggested that for older people, maybe 140 was too low. with age much vessels might get stiffer. you might need more pressure to bump the blood and get adequate
circulation. this was tested in a study called sprint funded by nih which compared controlling plop to a level of 140 or 120. this was not a case that was going to be a placebo group where you don't treat people. it's quite unethical.
what we didn't know if being more aggressive, pushing it further than consistent with recommendations would be a good thing or a bad thing. so this study, many of you may know, was stopped prematurely. sometimes studies get stopped prematurery for ethical reasons
because there is an adverse effect. nih consequences of treatment. it's not conscionable to go on. sometimes it's so clear prior to the scheduled end of the study that there was an advantage to controlling blood pressure down to 120 that the study had to be
stopped. you can see here, the standard treatment verses intensive treatment. over time, accumulation hazard, the risk of either dieing or having serious cardiovascular effects. there were dramatic 25 to 30% in
decreases here. so we are now at that point in terms of these studies where it's up to the research to be translated by the practice community and hotchly a potentially to save hundreds of thousands of lives and despair many of these cardiovascular and
other severe incidents. now, still interesting point whether this holds true for all or is it that older people would need a higher blood pressure? perhaps a lower boston, less maybe more falls. adverse effects. so the national institute on
aging in this case was particularly focused in as collaboration with the national heart lung and blood institute, the lead in this, to make sure that there were people recruited tin study were at an older age, and the good news was shown here without going through the
specifics, function of fitness, more fit, less fit, frail, not frail, for all of these groups, individuals, adults over 75 similarly profited from a reduced blood pressure. it was not increase in falls or adverse effect and it's only this kind oframized control
clinical trial that we can be confident of this. here is the success that now needs to be translated any practice in this country and and again, if this are questions please feel free to come up with them. otherwise we'll move along.
this is another kind of example. no secret that smoking is a serious risk for multiple diseases, cancer, lung disease, but many other conditions. and one of the great triumphs in public health in this country, the relative reduction in proportion of people that smoke.
there are many that do smoke. there is another kind of research, behavioral research that's gone on to see what approaches might be effective in helping people to reduce smoking. and this study, there were financial incentives provided.
interesting strategies. if you remained free of smoking for a period of time, you got a financial reward. in another, it was similar but you belonged to a group. if the whole group succeeded, then everyone in the group profited. so this added an
interesting component of peer or colleague pressure to it. there was another set that is called commitment here, in this case, you were given money and it got taken away from you if you failed and similarly, with a group. and without going through group
by group, all of those were effective. fewer people were willing to take the risk of being given money and having it come back. they didn't like it. they didn't participate. those who did, who were willing to participate had the best
effects of all. what you can see is by -- compared to control group, by 6 months and you have less true at 12 months, there was some success mere. modest changes. if you translate these potentially into again many tens
of thousands, hundreds of thousands, millions of people still smoking, the public health implications of a small change can be huge. and in fact if you look at many of the causes of death and disease today, a good proportion of the risk is atriable to
behavior that we can do something about. understanding what it takes to make people change their behaviors is an important part of what we do. so cognition is an interesting thing. and training.
what one can do to improve or alter cognitive function. let me illustrate one set of studies that had quite remarkable potential application. so useful field of view is a concept, not a test of vision acuity.
it's the usual field of view as a cognitive function. as you can see on a computer screen through a variety of images, the idea is to focus on a point, no change in head or eye movement. then pay attention to most central an peripheral things
that are happening. complex events going on. one can be trained to do better in these tasks. the training can be speed of processing material, it can have to do with memory, and it can be with associative or executive function.
and studies have reported that you can successfully, within a short period of time, induce changes that will for years give you better outcomes on these tests. now, i'll show you more specifics but as illustrated here, these were so effective
when applied to a task of simulated driving, that in fact this test has been used as a screen for certain motor vehicle bureaus, and training in these tests is used by certain insurance companies already as a criterion for having reduced rates.
the data are good enough, the evidence was good enough to lead to both of those outcomes. let me show you what happens in a column trial. this is remarkable. so people were trained for a relatively brief period over days and weeks.
then they were followed for automobile crashes. serious crashes. so the level 1 is the control group that didn't get such training. otherwise matched for a rot of characteristics. then the effect of memory
training, reasoning training, or speed of processing training was assessed after five years. five years after this initial behavior intervention. we can turn to the increasingly more effective, reasoning and speed of processing. if you look at the scale, where
this was measured by perspective miles or person time driving and the number of serious accidents per time, there was a 50% reduction the number of serious accidents as a result off this this is all cognitive training, teaching people how to pay attention.
obviously has generalized from computer training to a task such as this, and undoubtedly to other facts of life. we'll come back to other measures and diseases and conditions progressively now. but among them is going to be the issue of age related
cognitive decline and even risk of dementia, alzheimer's disease, and the very same people who have been involved in this treatment are involved to see not only is this preventing accidents but improving cognition and maintaining reserve and decreasing the risk
of progressing to dementia. we'll get to that. preventing diabetes, one of the leading cause of morbidity and death. combined with other conditions having a huge impact on quality of life, opcost to medical care. this is a study completed some
years ago which was intended to compare the effects of either life style intervention, which meant exercise and diet, relatively modest. met forman, an oral hypoglycemic, used to treat people with diabetes, or placebo.
and the idea here was to treat people that didn't have diabetes but they were at high risk as a result of chemical testing, weight, their profile of risk factors. to look at the effect of these interventions on the risk of developing diabetes over time.
so what you can see here is particularly to emphasize the effective treatment but also the difference in effect as a result of or corlative with age. so for the 25 to 44 years, young adults, about 50% reduction in who cases of december with either treatment.
metaphorem or life style. by 45-59, the metformin, a little less effective. life still effective. this is the usual glucose tolerance test. it's the principal criterion. look what happens to over 60 year olds.
for this parameter, metformin hot so effective. life style, more effective than any other group. more than 70% reduction in diabetes. so i think probably in contrast to what was expected, you can name your prediction here.
can't teach an old dog new tricks. people at advanced age have a more difficult time making a change. the result was if anything the opposite. at the older age interventions that began after 60 had a
dramatic effect in preventing if we're looking for this kind of evidence that modest changes in life style can make a difference, if we get people to adapt and comply, this is another striking example. another case where trial had to be terminated.
it was incoachen able to go on, it was so effective. subsequently, five, ten years later it's shown that some of the positive effects in avoiding disease in these groups persist. so i'd like to spend a few minutes talking about one of the diseases that is highly
associated with aging, to many in the population has become one of the most feared of diseases. alzheimer's disease, dimensiona. the loss of memory, cognitive function, the inability to identify objects, to think and reason. forgetting loved ones, the
impact this has is huge. and i might stop and ask, how many of you have had a personal experience, family member, friend, loved one, somebody with alzheimer's disease? by show of hands? yeah. me, too.
clearly these days, a majority of people. it's estimated that something over 5 million people in the country are effected today, something like 50 million effected worldwide. when the disease was named or identified in 1906 by professor
alzheimer's, who cared for a woman named august in germany for five years until her death and looked at her brain, she having presented with many stops that i described, this is what he saw and what we see today. at the gross level compared to a normal brain, the effected brain
has lost a vote of volume of gray and white matter, the cellular material, the synapses. so the solid material has shrunk leading to an increase of spaces between the brain occupied by fluid. grossly, the lesions which were identified by professor
alzheimer's, tangles, intracellular abnormal fibers, the fibers that are the tracks that help to transport nutrients through the cell. leading to disruption of cells and cell function. extra cellular deposits of senile plaques, have similar
effects on the brain. these remain the diagnostic criteria of alzheimer's disease which could be detected only after death because one couldn't sample boys from the brain with any justifiability. but here is what's changed tin last few years.
begins to change the story as you'll see, give a new kind of hope for making an impact on this disease, which has been resistant to date. so what has been developed are dyes, when injected in a human subject as well as animals, will specifically pinned to a. beta
or tau. a. beta makes up the plaque, tau, makes up the tangle. this is a normal individual. for someone with dementia, the concentration of dye across the brain, you can see dramatic increases in both amyloid and tau in the brain of people
effected. now, just to point out that it's not such a simple story. there is a subset of people cognitively normal who also have these changes. i'll show you in a moment why this is important to our understanding of the disease,
how long it takes to progress, and what kind of opportunities there may be to be effective in changing the course of disease. so just -- this cartoon first to show you the formation of beta amloud as we understand it. there is a normal transmembrane protein, the precursor, app,
this molecule. it is cleaved by a series of enzymes. in particular, the gamma secret tastes, there are two comopponents. ps1 and 2, with cleavage of this into a 4042 amino acid pep side, which itself is a nommer, which
also forms the plaques that are visible. so there are at least 3 jeeps important. one that encodes the app, and the 2 that encode the enzymes that process it. i point that out base importantly, mutations in anyone
of those 3 genes havic shown to produce an early on set, autosomal dominant inheritable form of disease. discovered, beginning in 1990s with families around the world, with mutation in one of those three genes, if you have the mutation with 100% certainty you
develop alzheimer's disease, typically in the 40s, 30s, and if a parent, as kids, 50% chance they'll inherit that generally. if they do, 100% certainty they'll develop dementia. if they don't inherit that, they'll have the same chance as
most of us have later in life having it. i'll just -- an aside, to mention one of the more moving or compelling meetings that i've been at, over the last couple years, meetings on alzheimer's disease have brought together families from around the world,
these early on set families. if you can imagine first, just the impact it makes on these folks with families so effected to know there are people around the world with the same disease and there research happening they can participate in. but picture young adults, your
age or younger, folks in their 30s who have seen their parents die of alzheimer's in their 40s, 50s, who have siblings who may have the disease, who may have young kids and have to figure out if they want to know whether those children have inherited the
allele or not. so i point that out as background to allow us to understand what we can now do to track the disease early before there are symptoms. in these cases we can predict in each family when symptoms will appear.
we can do brain imaging to look at amyloid and tau. we can do that starting in 20s, 30s, and put that together in a composit to track how amyloid accumulates, we can restart this for you -- so we're here starting at minus 25. that's 25 years before on set of
symptoms. and watch the clock tic. 22, 21. 20, seeing some differences already. quite noticeable by 15 years before symptoms appear. ten years before, more dramatic. and by the time 0, which is the
time that the symptoms appear, extensive deposition of amyloid. track the next self years with disease and progression there is some change. but in fact as i'll show you metformin change has occurred -- show you, most of the change has occurred before the appearance
of any symptoms. [inaudible question] >> the question is whether the mutations are gain of function. they're dominant. so in that sense it appears, they lead in general so in the case of the mutations in amyloid, they lead to the -- a
protein itself which is more susceptible to cleavage to give the amyloid the -- the peptide that is deacceptable to aggregation. in the case of the enzymes, in some cases there is quantitative, in other cases qualitative differences in their
substrate. by definition, gain in the sense it appears that there are somal dominance. we should say that in many of these cases, knowing exactly how those mutations, even though they have been well studied, lead to disease is far from
clear. but what you can do is take anyone of those human mutant genes, make it a transgene in a mouse, the mouse will acquire plaques in the brain. the mice do seem to develop more age related decrease in cognition, if you member that in
maze. despite we haven't succeeded in humans, there has been succeed in treating the mice by various strategies to reduce or reverse amyloid accumulation. seems to reduce the amyloid and in some cases improve cognition. mouse models can reproduce some
of this and have some of the desired effects which has led to a lot of attention trying to do this in humans. so far without success. so here we're looking at time versus the biomarker abnormality. first with the clinical
symptoms, this is either high or low risk people, this is developing from normal cognition to mild cognitive impairment on to dementia. if we take -- years before, if we plot accumulation in that graph, it's increasing. if i had the scale here, ten and
20 years before appearance of symptoms, there is accumulation of amyloid. by the time symptoms have appeared amyloid has long been at its maximum. there are other changes which abe including loss of volume of the hippocampus, the part of the
brain important for memory want all of these characters occur well before the on set of what does this mean in terms of what we can do? until now, we've treated symptomatic disease and tried to slow the progression. that's really all we can do.
what this is illustrating, we're treating at that time when many, many changes are far advanced. and now for the first time what we can do and what studies have begun to do is treat prior to the on set of symptoms. so this is an example of one study that is ongoing, this is a
family in the south american country of columbia, the largest cohort of familial autosomal dominant disease. a group of people who are enormously committed and dedicated to research, obviously, with greatnist in making things better for their
families and more globally. so if you look at people who are off spring, who don't carry the gene. this is what they look like in their late 30s and late 20s. about the same. in the late 20s, the people with or without the gene don't
look any different. look what's happened to the gene carriers in their late 30s. these are people who will develop good mentiona on set in their late 40s. treatment has gun with therapies designed to decrease the accumulation in amyloid a decade
or more before onset and hoping intervening early makes a difference. we won't know for some time. if this doesn't have any effect on the intended target, it's going to decrease the optimism for going on. if it does have an effect, if,
for example, it prevent, decreases the accumulation of amyloid that's extremely encouraging to see if it has an effect on the clinical outcome, finally. and this is to show you the history of what's genetics have told us about alzheimer's
diseaseover all. so back in the 1990s, i mentioned these 3 genes, app, ps1 and 2 were discovered. there was relative inactivity between then and when human genome project was successful. we could map genes across the entire genome.
starting in the early 200 oz, until now, here is an acceleration of many genes. every time -- these are not causative. these don't account for disease with 100% certainty. they increase or decrease the risk of developing disease bias.
every time we find the gene of this sort, it provides a new clue for how we might design interventions targeted at those genes or pathways. and the genes are colored, because also telling is the fact they tend to fall into pathways. so the ones that are in a color
code here, the darker blue, happen to all fall in the inflammatory response system. there are a number of these. that's encouraged a good bit of interest in seeing whether interfering specifically with components of the pathway might be airstream for intervening.
might be another strategy. so another fun fact, relationship between sleep and amyloids. so you can decide which group you're in. 7 hours or more a night, 6 to 7, less than 6. and again, by statistical
analysis there is more amyloid accumulation age adjusted more amyloid in those that get less than 6 hours of sleep. now, cause or effect. maybe you sleep less well because you have something going on. or maybe something about
sleeping is protective. i can tell you very, very interesting recent laboratory experiments have shown in animals and some human studies that during sleep, a limp faultic so called lymphatic system in the brain, until recentl was not appreciated to
exist, is more effective in clearing, including the climb peptides during sleep than when you're awake. so there is actually a biological credibility as well for sleep and among the many things, we all try to imagine what is it about sleep, we say
it's restorative. this may be one of those issues. a good bit of research is going on, using animal models as well as human studies. so let me turn in the last minute to talk about this relationship between biology disease and biology of aging.
and a field that's been called gero science. gherao science is basically the hypothesis that basic aspects of age related changes, illustrated here, depending upon whether you read this cell paper or this journal paper, there may be 7, 9, it's arbitrary.
with a lot of overlap there are common things. damage accumulation, response to a number of stresses, epigenetic changes, stem cell, metabolism, protease, inflammation, mitochondria function. the notion is that if we understand these changes, and
can do something to address any adverse effects they may have, this may have consequences on multiple diseases to which they relate. so i'll just end with a few examples of the kind of research that has been quite intriguing, suggesting that we have ways in
which we can understand at a molecular level just what these changes are that happen with aging. this is one approach to ask whether you compare a young and old, in this case, mouse, we can identify factors in the junk or old mouse which are responsible
for aspects of its biology and the technique that's illustrated here is parabiosis. i don't know that many are familiar with it, but it's what the cartoon shows. take two mice in a rather limited surgical procedure, you fix them together at the level
of skin and underlying tissue. they go on to develop a common so circulating factors, and cells, are in common now between the two partners. and what's been called heterochronic parabiosis, just means different aim, young and old, put them together and see
what happens to the young or to the old mouse in these combinations. there have been some rather dramatic findings that -- one of thiest findings had to do with muscle. and repair of muscle from experimental injury.
when you connected and old mouse which had slower muscle recovery from damage than the young mouse, and connected the two, now the old mouse repaired muscle injury nor like the young mouse. something in circulation do the heart is shown here because
again, in certain mouse models of aging, there is a hyper trophy of the heart that is associated with poorer cardiac the picture is meant to indicate that once again, if you connect an older to a younger mouse, the older mouse with the enlarged heart actually reverts to a
heart more typical of younger aim. and shown around the center here are the fact, this effect, a number of cell types. gdf11 is one of the growth factors that's been identified as playing a role here. so i mentioned this technique
tells you something is in common in circulating. could be cellular, so people have done proteomic analysis and others comparing young and old serum. found candidates. one is gdf11. part controversy, part not.
you can see the pathway we're converging toward, identifying molecules which may play a role in the function of multiple organs and tissues, and may be relevant, therefore, to dysfunction or disease in multiple tissues. epigenetic changes.
we're used to thinking we're born with the genome for life, largely true. but epigenetic changes ra common with age and respond to environmental influences, and what a couple of groups have done is to plot, in this case, dna methylation and other
aspects of change as a function of age. found that there is a very strong correlation of genome wide methylation increased with two groups. this first slide is just to illustrate that two laboratories who did the same experiment
found very concordant results. interestingly, because at each age there is a variation, not every one of a given age has the same methylation. if you ask the relationship of methylation to aging in a relevant way, this is the lower and higher kwan tile of
methylation. the group with less methylation here and low here, less methylation survive more with subject stably. so survival is better in the group with less methylation. if you take that as translation of genome-wide, perhaps organism
wide parameter of aging, gives a clue as to the mechanisms which aging may have an effect and one can effect methylation. it's not clear that's the right thing to do but points out the very salient and central parameters of aging that do have relevance, not just because
instead of looking at the calendar or watch you can tell time, but as a function of time whether someone is more or less likely to live a longer period of time. based on these differences. sin necessariant cells. so senescence means a lot of
things, but it comes to characterize cellular sen necessariance, a state of which cells lost the ability to proliferate. essentially in response to any stimulus, the usual definition, erreversably. and it's more apparent that
those cells are not simply passive but also required some active properties, so they're secretary phenotype has changed, too. so we have with increased age, increased number of sin necessariant cells. how can you tell?
they have changes in the expression of a number of molecules. one has to be p16, which many may be aware of, as relevant to cycle regulation involved in tumor genesis, well. p16 accumulates with age. so what the investigators did
was create a mouse first in which p16 drives a reporter. life gfp. so as mice age, you can look at various tissues. the proportion of cells expressing high levels of p16 goes up. only a small percentage of
minority of cells. the question is whether those cells were physiologically important or not. if they were just passive, losing a couple% of cells when the rest were normal might not make a big difference. if they're doing something
active to interfere with cells around them that's more they designed a way to eliminate this sinecessariant cells, so basically, p16 driving a genetic cascade, a transgene cascade such that if you give drug, you will now suicide all the cells that are expressed at high level
to p16, you can tell that works because you can look at the mouse and see if those gfp positive cells are phone. you can ask what difference that makes to how the mouse works and this is -- i put arrows here. looking at a couple muscles. abdominal, after deleting
sinecessariant cells, fiber diameter is increased with so you are maintaining mump. if you look -- muffle. muscle. if you look at the ability to work on treadmill, the time they walk, the distance they cover, they are capable of doing more
work as a result of having reduced population of senistant cells. so this is a little hard to envision directly translating to human. but it's lead to a series of screens for so-called listing people screening small molecules
and others and have reported some results in which this will do the same thing as with genetic manipulations, selectively removing these cells, and they have gun to show, some just coming into press, the same kind of positive effects on health pie removing
those cells with drug. what you can imagine the interest there that arises in translating that into humans, how that will happen, whether this is a good or bad thing overall, hard to say. but pointing out how complicated things can be in real life.
senescent cells appear to have some beneficial effects. for healing, normally, there is an increase in necessariant cells during wound healing. it may be where they have to senecessary, maybe produce wound healing. you can eliminate those cellis
by this genetic trick and down here what happens, it turns out that the wound size heals best in groups [technical difficulties] it's going to comp pli at, as always, the translation of this to real genetics. there are endless studies.
i'm not going to show you any of them, which in yeast, worms, flies, have shown that single gene mutations can double, triple, in combination up to 6 fold increase. that's led to a lot of speculation we ought to be able to do the same in humans.
you may have read some of those articles. again, the translation is not so simple. it's one of the few cases in humans what's known about genetic polymorphisms that are associated with age and how long one lives.
this is fox 03, for example, which does make a difference. what fox 03 does, how it does it, that information is doing something good for people. live long and healthy, we don't know. so the summary of these few dimensions i, the world is
growing older. life expectancy is decreasing for some groups. not everyone is having the advantage of biomedical and public health changes. we have to do something about that. age is a risk factor.
we learned about some of them. made very important differences. and now gero science is a new perspective, asking whether as we learn about basic under lying processes of aging that contribute to many disorders of aging, decreases, functional decreases thaty company aging,
we can use that information to make a difference not just for single disease at that time. perhaps a global and positive impact. so i thank you for the time and patience and leave you there. >> thank you very much. that was spectacular.
so we have time for some questions. could you elaborate between tangles and deposits, a paper in science, the specific correlation of tau of position 38 reduced tangles and reduced deposits, although i think it was in a mouse.
>> so plaques and tangles and i showed you from 1906 have been the sentinel changes. in recent research history, there has been a great deal of discussion that and controversy about the relative importance of the two. so beta amyloid plaque has been
the favorite of so-called baptist and tau, for tauists, have character iced the groups that somehow by belief favor the freedomance. if you track what happens with progression in humans, now that we can do that, it's interesting to see what occurs.
amyloid occurs first. and you accumulate amyloid. appears when amyloid load researches a certain point, then tangles which initially appear in just an isolated area of the brain, begin to spread. and the spread itself is interesting.
it appears to be a transcellular spread of tao abnormalities that is moving from cell to cell. so the -- in the end, i think, people would generally say that cognitive change now correlates better with tau than amyloid. but whether the t.u changes are triggered by amyloid and both
are important for the ultimate pathology, remains a subject of very important conversation, if that's clear. >> anchor: so [indiscernible] contribute anything to our knowledge of aging? >> so pro jeria as a general term really referred to
premature aging. and perhaps the condition that has been associated with it is mutation in the lamen, leading to abnormal splicing. among the people who have studied this is francis collins, and it pro does abnormalities in nuclear membrane.
some of these changes also happen in aging cells. the kids that have this have a lot of characteristics of premature aging, hence, the connection. and so as we're learning or trying to learn the way in which we can treat the kids with the
genetic disease, the question in parallel arrives whether the same treatments or interventions will also effect the changes, similar changes that occur with normal aging. >> if i understand it correctly, in one of your graphs, looked like the fcd pet with increasing
after the beta amyloid increases? does that mean dikohl'sis was increasing, why would diocoelsis increase there? >> feg pet is general hey regarded as a reflection of metabolism and maybe related to synaptic activity in the brain.
so as a surrogate, indirect one for the number of brain cells, number of synapses and the metabolic activity of the cells. that fact it's occurring rater means that it's down where down stream, for example, of the accumulation of amyloid before you start to see neuronal cell
deaths and synaptic dysfunction all reflected in decreased metabolism. >> yes, i'm sorry. what was -- way -- yeah. if the slide was misleading, it was showing the increase in in some of those cases. i have a better one to show some
up and down. guideline the changes occur early. so hippocampal volume had been posted there the same way, it looks like it's going down. so it's percent abnormality, whether that be up or down. sorry for that confusion.
>> you mentioned chromosomes and senescent. also what about telomeric activity? in senescent cells? like lobsters don't have where they can live forever. so how do they do? tela meres.
just to catch every one up, the structures at the end of chromosomes. they are in mammalian cells. they're multiple repeats. because of the requirement for [indiscernible] in rna replication during myosis, mytosis, there is imperfect
elongation of the telomeres at the end. you don't reproduce the portion where the template so in theory, you lose nucleotides. maybe 1500 with every cell division. tela meres get shorter and shorter.
if they get too short, they actually loose their t loop configuration. they no longer are protected. they look like dna breaks. this is a response, as if they damage and cells are dysfunctional. having said all that, you can
show very well in, frequent, a mouse mod, my own lab and others have made mice -- telocal race is an enzyme, added repeat. so it compensates for the fact that you're losing telomeres with cell division. telocal race extends them again. knock them out, it doesn't
repair. in every generation of mouse telomeres get shorter, to the point that aging happens, amongst, they become sterile, infer until, they can't reproduce. you can repair that by putting telomerase back in.
in humans if you plot with aiming, telomere length verses age, telomeres decrease with angela. there are specific diseases of telomere race dysfunction in humans which cause disease because of short telomeres. there is what's called
anticipation, meaning successive generations of this inherited disease, the condition gets worse because in the germ line, telomeres are getting shorter. each generation has less tolerance. so this is long about to get to your -- answer your question.
there are diseases in humans as well as animal systems where shortening leads to serious consequences, even death. if you ask the question, though, in normal humans, absence of a specific genetic syndrome, what is the evidence that telomere shortening plays a role in
senescent cells or health or longevity, it's far less clear. there are many reported correlations between telomere length and even life expectancy. which is cause and which is effect, not yet clear. and there are people that are talking about intervention to
elongat telomere, stimulate to treat and provide health. so cases where that can be applied right away, if you think this is an age we're all very interested in immune therapy, for example, for cancer. take cells from an individual, activate them in a way that
they're anti-tumor cells, put them back in. if those cells typically t cells, have short telomeres they won't live long. in the person you put them back into. they'll disappear. if you ling the them, they may
work more. so that's more immediate cell transfer regenive medicine kind of approach. whether in the whole human aging can be impacted by affecting telomere shortening, not clear yet. that was marvelous.
[applause] there will be time for questions afterwards. it's a pleasure following richard. it's good to know, i was impressed that you got less than 6 hours at sleep you're at risk for dimensiona. when i'm talking, i see people
nodding off and dozing. i interpreted that as being boring. now i know they're protecting themselves from dementia. so go to sleep. ask questions, do whatever you wish. i'm going to talk about aging
and why i think it's so interesting biologically. so i think all of us can recognize what aging looks like. it doesn't take an einstein to figure out what old and young look like. but as richard mentioned, the underlying mechanisms of aging
have been really relatively elusive. i think for me, at least, aging represents probably the most important but least understood biological process out there. i think one of the interesting things and why i like talking to audiences like this is to get
people more interested and excited about it. i think it's so fundamental and so fundamentally poorly understood that we need more people interested in the -- i think very important question. so why is it important? to understand the basis of aging
so i was trapped as a cardiologist. -- trained. cardiovascular disease is the most number one killer of people in the u.s., hard disease kills more people than any other condition. but if i were to say the national heart lung and blood
institute, which i'm a member of, research finally paid off. we were able to cure all cardiovascular disease. so that someone like myself was now immune from getting a heart attack or a stroke, or heart failure. or any other cardiovascular
conditions. there for we have eliminated the number one cause of death in the u.s. how much longer do you think -- this is not a quiz here. how much longer do you think i would live because of that great research break through?
anybody want to give an idea infive? any other ideas inten? right here. i feel like an auction another. the answer is about 3. 3 and a half years which is not bad. but not that much if you think
about it. if we took all the money from the heart, lung and blood institute which i'm not recommending and gave it to the nci, the second leader cause of death and eliminated all solid tumors, we'd gain another maybe 3 and a half years.
so getting rid of all cancer, all heart disease, would only extend the life spokesperson of someone like me about 7 or 8 again, not terrible, but not as much as you would think. why is that? as alluded to before, when we get older a lot of bad things
happen, unfortunately. when i got interested in aging, as you get further to the right they become more and more personal. i can assure you. so here is the incident for alzheimer's disease and cardiovascular disease and
cancer in the u.s. population. they all look the same. and other diseases. very rare, young, and they rise at as we get older. and so one of the tenants of aging and one of the promises is that most of the nih is devoted to thinking about curing these
diseases by focusing specifically on the y axis, that is, coming up with drugs or treatment strategies that will effect cardiovascular disease specifically. or alzheimer's disease the -- what i'd like you to think about today is not the y
axis. but think about the x axis. and that is the promise i think of aging research, is that we don't worry about the specific causes, per se, but try to move things along the x axis. try to extend life span, push all these curves to the right by
slowing down the fundamental process of aging itself. howcan we push these curves tothe right, how long can we live? the answer is probably shown me. this is the woman's 121 is it birthday. exclude moses, the oldest recorded life span in history.
and this is her, as i said, 121 is it birthday. she lived almost 123. she had a very nice life. she lived in southern france all her life. it's spark tacular. her uncle owned -- she lived during the entire period of the
french impressionist movement. her city was the center of much of that. her uncle owned an art supply company. a lot of the french impressionist painters would buy supplies. she had very nice things to say
and she said van government was very -- van go was very disagreeable, as you might expect. my favorite story about her is that -- this custom doesn't exist in the u.s. if france, if you have a nice apartment apartment, people can
pay you a monthly retainer with the idea when you pass away, they will get to -- get to basically have your apartment. when she was in her late 80s, a nice gentlemen down the block in his 40s began paying her this monthly supplement with the idea he would inherit her
apartment. as you can imagine, 30 years later when he was in his 70s, she passed away and she remained in that apartment. no one else took her up on the challenge, so she actually lived there until about 118. there is another story why she
had to move but i won't go into did she do something that was extraordinary that explained her life span? the answer is no. she smoked. this is her smoking. she smoked to 119. she drank every day.
she did all the things that we're not supposed to do. so as mentioned before, it's a little hard to gain that much inference from people like this. let me ask you another set of as i said, how many people here believe that genetics is the most important determinant of
their life span. that genes they inherited is what determines their life span. how many people think it's the environment? obviously it's both. but most important. yes, so -- what? true, if you live --
[inaudible]. so it's probably not a simple answer. and there are -- especially for people that live very long lives. but for most of us, the answer is that genetics account for about 25% of our life span.
most of it is environmental. so her children tied in their 40s. one from a car accident, one got pneumonia in the days before antibiotics. what are the judgmental influences that are -- environmental influences that
are important. one of the things very interesting for people like me to analyze is this idea of caloric restriction, the amount of calories as a determinant of our life span. it's been observed, known for about 100 years if you take
laboratory animals and feed them less, they tend to live longer. and that's a very robust phenomenon. robust in the sense that the effects are quite large. in animals such as mice and rats. and robust in the sense it's
pretty well evolution. you can see similar effects in yeast. if you -- under certain experimental paradigms. that response can serve all the way up to mammals, at least row dents. the data in higher mammals like
primates are a little more controversial. but people have been very interested in trying to understand what about -- what is it about eating less makes you live longer? i won't go through all the details.
to say that there is two -- my lab has been interested, mediates at least partially these effects. one of them, families of enzymes that i won't talk about, the family, nid dependent asset laces. the other is a protein, mtor,
which i will talk about, a mice model. again, not because it's incredibly interesting but this gives you a sense of what can be done and understood about aging in experimental paradigms. so what is mtor? many know it's a large protein,
kinase that acts inside the cell as sort of an energy sensor. so it senses the availability of growth factor simulation or nutrients. when those factors are present and abundant, mtor is activated and acts to allow the cell to grow, expand and get
bigger by regulating a variety of processes, including protein synthesis and metabolism, as well as inhibiting a process, which is autophagy. in tron trast, when nutrients are low, emptor is inhibited. and the reciproll k happens in these processes down stream.
so in lower organize ins, it's been shown that reducing mtor activity gently produces increase in life span. the national institutes of aiming has interventional testing program. they test different molecules every year, usually about five
molecules a year. to see whether or not they can prolong the life span of mice. and several years back, they got a very nice hit, as they would say, by giving mice this drug rapamycin, an mtor inhibitor. they had a little trouble, even though the molecule was accepted
into the program, had trouble formulatings the rap amycin for the mice. they fed it to them at about middle age. even giving them from middle age on produced about a 10% increase in life span for the animals. again, here is this idea that
maybe we -- that aging, which we've accepted as being a risk factor to disease, but we've always thought of as being unmodifiable. now begins to feel that you can begin to say well, maybe aging is not unmodifiable, and you can manipulate it by small molecules
such as rapa mycin. and sort of extend life span. therefore, can you begin to think you'd have effects on so we're interested in this phenomenon that inhibiting mtor might increase life span. so we wanted to provide a genetic example of this.
and that's a little difficult with mtor. as i mentioned, mtor is a very important protein. and it appears from both the rapa mycin studies in mice and studies in lower organisms, if you reduce mtor activity, that animals live longer.
so the prediction would be that if you got rid of mtor you would live forever but that's not the case. if you get rid of mtor, they die in embryos. so the secret in all of this is you can't get completely rid of it.
but somehow reducing its activity is beneficial. so i won't go through the mtor comes in two protein complexes distinguishable by the differences in associated protein. but basically, if you delete mtor or these associated
proteins, all of them are embryonically lethal. fortunately, beverly, a colleague at nci, for reasons i won't go into, generated a mouse in which there was a [indiscernible] inserted in the locust. this was inserted in the intron
of the jeep. it doesn't effect the coding sequence. but it did effect the transcription and translation of this mtor allele. so we called this the delta allele. the expression of this delta
allele was much -- was the normal impor tore, expressed at much lower amounts. if this is an example of a western plot of mtor expression in wildtype mice. these are cells from wildtype mice or cells derived from what we call the delta delta or hyper
morphic mtor mice. this is from cells. we did it from tissues too. and found this mtor was the normal emptor, expressed at about 25% of the normal level. so this work was done by [indiscernible], a post cobbing cobbing -- post-doc in my lab.
what is the effect of reaccusing mtor expression by about 75%? we're not getting rid of the genome. this is one of 30 or so thousand genes in the mice. just changing the expression of this one gene by about -- and
reducing it, this expression, by about 25%. so these ra the mice. they're born, a little smaller than the wildtype mice. i should say this paper came out, the wall street journal did a story on it. they wanted a picture of the
mice. they normally draw things by hand. it's very hard to get mice to pose. i don't know if you've had this problem. they were a little nervous. this mice pee, he was nervous,
what can i say? these mice were smaller but otherwise healthy. this is the life span. so after 3 years, julie found these mtor hyper morphic mice, the males or females or whole group, lived longer. we're changing one jeep,
reducing one gene out of 30,000. by extension, life span for reducing mtor was quite significant. it was -- they lived about 20% longer. so that's the equivalent for us, if you make the equivalent, of going from a mean life span of
about 75 years to a life span of 90 years, just by altering a single gene in the genome. not even getting rid of it, just redecemberducing the level and which is remarkable. so we're supposed to end at 5:30. i'll speed up.
so these mice lived longer. one of the things we wanted to ask -- we can go to 6:00? we're all aging together, them. these mice lived longer. ask is does intervention that makes you live longer slow the aging in your tissues? and if so, is that sing uniform
or -- slowing uniform? that is, what is the relationship between our life span and the aging in our tissues? we said let's phenotype these mice and look for the age dependent decline in organ function, and control mice or
mice that we know will live longer? so we did this. we did a lot of tests. so i don't want to go through all of them. here is an example of -- this a test of memory and learning in and again, this is an example
where you take the mice and you put them on a raised platform and in one of the -- there is a a bunch of holes. and one of the holes is an escape for the mice. the mice don't like to be up high. it's very bright.
they don't like to be bright. they're very motivated to find a way out of this situation. as i say, they don't know this has been approved pie the nhlbi. that nothing bad could ever happen to them. they're very motivated. they haven't read the protocol.
in one place there is an escape. you train them. they're just frantically looking for it in the beginning but then realize there is an escape. and after a few days they guess less nervous and they basically beat a line to where they should go to escape.
so you can do a number of tests to show that they're actually focused and directed and you can time how long it takes them after 3 or 4 days of training to find the right place to go. so again, in the beginning when they're young, they're very good at this task.
and there is no difference between the wildtype and these long lived hyper morphic mice. the ice get older, they don't remember as well and learn as quickly. like i don't remember where i parked my car today. i'm a little nervous i won't
find my way home. the mice are the same way. takes much longer, not as good in memory and learning. you can appreciate, that is control mice at sort of an old and these are the hyper more if i can mice. they're not like young mice but
they're better than the control and we could do tests to show the capacity to learn new things was much more youthful. so that would suggest, their age dependent did he decline and learning was also better. here are some other tests we did.
here is a test of their ability to stay on a rotor rod. which is a complex thing, sort of muscle function and neurological function. you can appreciate as the mice get older they're less good at this task. but again, these hyper morphic
mice are between the young and old mice. their function is preserved. here is another example. this is measuring stride with variation in gate, a very good predictor in elderly people, elderly humans of who will and will not fall.
mice never fall, but again, their ability to main tape normal -- maintain normal stride, variation, is impaired as they get old much. the hyper morphic mice are actor more useful. we did a bunch of these tests. in the vast majority of them the
mice that lived longer by manipulating mtor looked like they had improved their function, organ function. but there were exceptions. so here is an example of bone density. and again, as the mice got older, bone incidencety declined
in the -- here is an example of superficial infections that the mice get as a function of age. these are the control mice. and these are the hyper morphic mice that live longer but generated, got more of these infectious problems than the control mice.
so what's the -- what is the conclusion from all this? i don't know. but the -- i think the -- two things we took away. first, again, and this is i think again the power of genetics and the power of, i think of aging biology.
that on the one hand you can make single genetic changes that have profound effects on life span. this is one example but there is many other examples in both mice and other organisms. the second thing is when you do indepth phenotyping, what i
can't do, you can't ask flies to do much. even mice it's difficult to figure out what is going on. but when you start phenotyping mice in depth and looking at the aging of organs as opposed to the organisms, that you find that manipulation that extend
life span do not effect each organ similarly. and it suggests that aging, which is complex already, is probably not the same thing in that each organ may age at different rates or under different mechanisms. and i think that's something
that clinically, people are well aware of. you have people who get older who have terrible blood invests, but very good bones, vice versa. there is something -- aging is not uniform and probably thising is it's not mechanistically uniform as well.
so i'm going to -- how long -- should i keep on going? the short or long version? >> [inaudible] >> i got nothing to do. all right. so how does mtor work? we don't know. as i said before there is a
bunch of things that it controls and it's very difficult to sort out at this point why reducing mtor makes you live longer. what ra the downstream effects that are the most important for driving the phenotype? but i can say what we're the most interested in.
we're interested in the process called auto fagy. i wanted to spend time on how trying to look at autophagia, and genetic motels that we created to understand the relationship between aging and auto finally, swell other model this is the process described in
yeast but very well conserved, by which damage proteins and damage organelles are incorporated or encapsulated in a double membrane structure that is formed in the cells, that engulf these damaged cargo in what's known as the auto sagosome, which fusses to the
lysosome and delivered the damaged cargo for degradation. so there is a variety of evidence that suggests that auto fagic flux declines as we get older. and i think you can appreciate what the -- how that might provide a lot of problems for
us. so if autophagy declines and it's a way you get rid of damaged proteins and damaged organelles. you're going to start to accumulate garagage. if the montgomery county didn't take your recakeling, the trash
builds up. in your cell, if you think of autophagias a recycling system, then you can imagine that as you age, if this process slows down for whatever reason, that is the trash will build up. it's damaged protein and damaged organelles that would have been
removed normally. and we're particularly interest in this accumulation of damaged mitochondria. we showed previously and we've always been interest in the oxidative stress. and certainly in the absence of autophagy there is a build of up
mitochondrias normally removed that we contribute to this high rate of x dative stress in elderly tissue. one way we approach this is to try to say does a defect in autophagy recapiulate aging? the models that we looked at was the blood vessel.
the question is there are a in you of changes that occur in the blood invests as we age that contribute to vascular disease. and to what degree can we mimmick orphineo copy these by distributing autophagy? and we're just beginning but we have some preliminary results i
want to show. here is one example. where we have knocked out ought family in the endothelium of a and fed those mouse high fet, and asked what happens to agent they arero sclerosis. here is the control artery, and here is an example in which
we've disrupted autophagy only in the endothelium. you can sigh that there is significantly more atherosclerosis that formed in these verses the control administrations. another example that we're working on, and this we've
disrupted autophagy in the smooth muscle layer. this is an example. this is work from another lab, from francis collins' lab in a paper published in 6:00 in which they have a mouth mod -- 2006, they have a mouse model [indiscernible].
and those mice and those people suffer from cardiovascular -- the major cause of death is if you look in the blood vessels, in the mouse model and humans, there is a lot of smooth muscle cells that occurs over time. a change in what's called the
lamina as opposed to the control mice, these are all nice and wavy. there is straightening, and breakage of the internal lamina with loss of smooth mump cells. what was found in our mice, where we have disrupted autophagy in the smooth muscle
cell layer is a similar phenotype. a defect in autophagy in the smooth muscle cell is fino copying this accelerated aging again, this link we think between perhaps decline in autophagy and the phenotype of that's something we're obviously
verinisted in pursuing. okay, so let me end by talking about ways that we can begin to measure these processes in vivo. we're very interest in mitochondrial turn over, this process of my dodge family, how mitochondria -- how damaged mitochondria get removed.
and so what we have done is develop an inviewpointo assay to measure this. this is work done by [indiscernible] in the lab. and it's really based upon this assay, this group in japan first described by this protein, which is a coral protein.
it has 2 nice properties that make it useful for this. when we direct pita coma, the keima important here is that it's excitation, it's -- ph dependent. so it can be -- when it's in the mitochondria, the mitochondria are actually the most aclon
organelle in the cell. they have a ph have about 8. keima will be excited in the green under those conditions. when it's delivered to the limosome, very acidic environment. most avidic. and keima can be excite in the
red wave lengths. that's one property that's very important, it's ph dependent. the other property is that although it's a protein, it's very resistant to lymosomal degradation. it's delivered but it stays in the lysosome.
one can imagine with a green excitation and red, and generate an image like this from a cell, and get a sense of keima in mitochondria or that's been delivered to the lysosome. this green to red fluorescence is a measure of mitoughgy. i family after movie to show, so
this is cells that express keima. they also express a protein, richard, you described the role of parkin in this process. so in this top row, these are ke mitch a cells and parkin cells where we damaged the mitochondria with these farm
collagical inhibiters. in the bottom row we're managing the cells without mitochondria damage. and what you'll see is that these cells that get damaged will recruit parkin to the mitochondria so this parkin, which is sort of homogenous in
the cell, will rapidly go to the that will start the process which changes the green floristance to red floristance. that's a lot to say. let me start it. i'll stop there. now you can see that parkin is now recruited to these structures,
mitochondria, and you're beginning to see these red dots appear which represent mitochondria and have been delivered to the lysosome, and this ke mitch a protein is now able to be detected in the red wave lengths. if we let this go over 18 hours
in the control cells, relatively low rate, in contrast, in the cells which we've damaged the mitochondria, all the parkin basically is gone. it's been delivered to the lysosome. it's degraded there. the keima has also been
delivered but it's relatively stable. you see the persistent red floristance. all the mitochondria have been turned over in this very harsh damaging condition. so this in vitro. so [indiscernible] created a
mouse that expressed this in all the tissues. that we thought would give us a way to look at this in negativo for the first time. we did a number of things to show -- i won't go through it, but we saw very large differences in mitofagic flux in
different tissues. there is incredible differences within tissues. here is an example in the brain. interesting, this is the hippocampus. this is another region in the brain where there is high levels of stem cells.
in those regions, high levels of mitoughgy compared to other reasons where that doesn't exist. this is why we performed the experiment. this is looking in the area of the hippocampus. either young mice or old mice
expressing this keima report you are. in the young mice, the area of the hippocampus, there is very -- red, orange color represents high rates of mitochondria turn over. same region of mice that are old now, the mitochondria are still
there but there is relatively little turn over. as evidenced by the absence of the orange and red color. so this is -- this provides an example of -- where there is clear evidence that rates of autophagy or mitophagy decline as animals age.
remember i told you about this memory and learning test. this ability to remember and learn is all encoded in this region of the hippocampus. and so as we get older and mice get older, as i mentioned, your ability to remember and learn goes down.
and at the same time, what we're showing here is that this rate of mitophagy goes down as well. we're very interested does the decline contribute to this problem of remembering and learning. and one way to go about that is to develop drugs that simulate
this process. and so [indiscernible] have used this same keima based assay. so we're just starting this process but we screened 3,000 small molecules that will simulate this keima based assay in cells. we got about 20 or so of these
compounds that looked like promising compounds. just as a read-out, and again this is very preliminary. we took some of these compounds and gave them to flies that had a model of parkinson diseased. at least in the first go around, it appears that some of these
compound may be efficacious in treating that condition. suggesting that if you can increase mitochondrial turn over, you may have beneficial effects in parkinson disease. we would argue a variety of other conditions in which mitophagy may contribute to the
the pathology. let me end by saying that i think this is a phenomenal time to be interest in aging. i hope some of you are swayed by our talks to throw away what you're doing now and get on the aging bandwagon. and the hope is that as i said,
if we can move the x axis, if we can treat the underlying fundamental mechanisms by which we age, that we might be able to develop a way to treat a variety of diseases and i would argue, you know, since we're talking about x and y, this is truly ornothingenal.
the way we treat diseases now. that's the hope and promise and excitement of i can't studying aging is so fundamentally let me thank a few people that did the work. julie now works at the patent office here in town. [list of names] thank you and
i'd be happy to answer any >> you can just shout. >> [inaudible question] why are the -- are they particularly more defective than other intracellular organelles? why don't they repair their little bits that go wrong and keep on going?
so there is some evidence that -- and i don't know if it's published yet. there is some evidence that mitofhagy does not have to involve the entire organizational, that you can bud off the damage and leave the remaining part of the
mitochondria. there i think the better answer is that mitochondria don't have the sort of dna repair machinery that the nuclear have. they're also the site of metabolism, which is an oxygen dependent ros generating phenomena.
so they are the -- by estimates, produced about 90% of the reactive species within the cell and their dna doesn't have the intrinsic dew point repair mechanisms that nuclear systems have. they're is he sight of basically the epicenter, the ground 0 for
ros production without the repair mechanism that the nucleus has. there has to be a way to sort of-- people think of regenerating them. >> i wonder if the drugs that you use for reconstituted [indiscernible] -- do they have any feedback effect on mtor?
>> we don't know yet. we're just playing around with them now. and so we don't know. but that is certainly a potential. >> so i know that rapo my asoon has unfortunate side effects. but are there any studies
looking at lowe does of rapamycin in aging and humans? >> so some of the side effects are atrophy. you worry about half the population signing up for rapamycin therapy. so i think the good news about rapamycin is, as i mentioned,
the first study, they gave the mice, basically -- there have been now in mice studies of using lower doses and intermittent rapamycin. they can get many of the same effect by using those types of strategies. and so the data on rapamycin and
[indiscernible] has not been done. one small study has used rapamycin aplog in people. in one of the rapamycin inhibitors. mtor inhibitors. rapamycin was developed as a immune suppressant.
as many of you know, as we age, our ability to generate immune response goes down. so they took people over 65 and gave them this mtor inhibiter, this analog, and asked whether or not it actually improved their immunological phenotype. and when they -- the
intervention was a flu vaccine. many elderly people cannot respond well to flu vaccinated. in the small study, it was shown that people who got the rapamycin inhibiter actually did mount a better immune response than the controls, which is counter intuitive, if you -- so
i mean it's small, it's one study, it's one aging phenotype but it is at least suggestive that maybe things along this will work. >> i was just wondering if you looked at metabolism between your old and young mice and whether there was actually any
significant differences in [indiscernible] or anything like >> so in the mtor mice. so right, so we had made some connections. farce we could tell in these mice, the mice are smaller. at least in total body oxygen consumption, when you normalize
for body weight and people differ on how they do that. but when you -- the way we did it, we could see no difference in metabolism between the wildtype and the hyper more. so we don't think that there is a clear metabolic basis in life >> do you think there is a
connection between the studies and the parabiotic mice? >> and -- >> what was the name of the -- >> gdf11? that's supposed to work in the tdf beta molecular. i don't know what connection that has, if any, to mtor
or to mitofaghy. we didn't see any effects. so -- >> i'm sure they have. i mean i don't know if -- what the equivalent chloraplasty -- i don't know. >> yeah, absolutely. i don't know to what degree it's
been studied. >> do you want to say a comment about mitochondria dynamics in tissue culture cells compared to an an organ? >> i think fission -- so fission infusion are related to might toughgy. a lot of people you need fission
to occur. the rates in vitro are much higher than they are in certain tissues like the heart. you basically don't see fusion. you don't see fusion and fission with any sort of, you know, regularity. so i think there is -- in cancer
cells and culture you see a lot more of these phenomenon than you do in vivo. >> do you think the aging phenomenon, different tissues, is related to the morphology, different movology of mitochondria in different tissues.
>> i don't know to what degree -- in that case we're making a genetic mutation in mtor. i think the simple explanation, the role of mtor varies between different tissues in terms of role of aging. >> could you pull out the slide
with mtor? >> the cartoon of what mtor does? so mitofhagy goes down, and this is -- when all the factors and nutrients are abundant? and metabolism goes up. >> well -- >> so the equation comes -- like
in young growing organisms, the protein synthesis goes up, [indiscernible] goes a little bit down? so why -- there is decreased so when mtor goes down, protein synthesis goes down, so people think that it's not that you have not enough protein
synthesis, but that the people that believe in the protein synthesis being important, think that slower rate of protein synthesis produces less -- protein aggregates. that could be protective and make you live longer. people that believe in
metabolism have another reason why, and people that believe in autophagy think that mtor going down produces an increase and you have more recycling and you live longer. you can make arguments for any of this, reducing mtor makes you listen long.
what's needed are mutants of mtor which has different inability to effect one pathway or another. >> all right. i want to thank you lila, very much, and richard, and toren for a most informative afternoon.