Alcoholic Fatty Liver Disease Symptoms

>> good afternoon. we will begin. i think there must be some connection between longevity and the weather. this particular session was moved from the wintertime, it's the only session in about three years, i think, that we've had

to cancel because of a snowstorm, and today it's raining and people are a little slow in coming. but i would point out every week there are between 2- and 400 people at nih wh ar who arewatching this live, then two to three days later, it goes on the video

archive and a youtube, and basically goes out to the world. some of you who were here last week, we talked about planetary robotic exploration and biomedical science. there were almost 500 people watching at nih, and the number outside is about a thousand.

so many people are watching with all different kinds of backgrounds and interests. so this is the 12th year we've been doing this, so we must be doing something right and the feedback we get is encouraging and we welcome all your suggestions and comments, and

criticisms. that's the most valuable part. i would ask if you would be kind enough to sign, you'll see the last page of the book where the pen is as we keep a record more or less to get an idea of the ebb and flow of people in the institute who attend.

those who are taking the course for a certificate, a final exam has been posted electronically on our website, and i encourage you to take it, if you've attended 50% of the sessions and you pass the exam, you'll get a certificate from the nih to that effect.

you can take it as many times as you want, it's a multiple choice exam and i don't think anybody should lose any sleep grinding out studying for it. it's not that kind of an experience. so today we're very fortunate to have two exemplary leaders in

the field of aging, and as a liver tr sor doctor sort of contemplating it and having been around for a few years, i kind of get the feeling that thoughts of aging going back to midevil -- well, way back, much earlier times, we're all linked up to this notion that youth was

something that could be transferred by either the waters in florida or somebody else's snake oil, and to some extent, i think that influenced thinking about the way people thought about aging. then there was a period where it seemed to me that aging was

something that happened, it was inevitable, you could accelerate it, everything ages from molecules to cells, tissues, and people. so maybe it was all part of the same thing. then the tremendously powerful increase in biology as related

to aging, overlapping with the genomic era and other technical types, imaging, so forth, and disease recognition, have created the situation where we are now, that it's an extremely complicated process, but there are some amazing things that have been observed which lead

one to believe not that it is inexorable, but that to some extent, life can be made better, not necessarily inevitably prolonged, and more importantly, that mechanistically, we tbibegin to understand. so today's speakers are going to dwell upon different parameters

of this. so the first speaker is luigi ferrucci, who received his m.d. and ph.d. degree at the university in italy, then took various training in biology, human physiology, statistics. he was the head of the italian national institute of aging,

collaborated with people in the national institute of aging here at nih, and then was back and forth through several years, and in may of 2011, was appointed scientific director. you will hear of luigi's work which is very exciting, provocative and, for some of us

with more than a little gray hair, quite, i don't know, predictive maybe is the proper word. then our second speaker is nir barzilai, who was originally from israel, and he received his m.d. degree in israel at the tecnion and then trained at the

rombon hospital and in various other places in the united states and england, and he joined the faculty of the albert einstein college of medicine in 1993 in the division of endocrinology. he is a bona fide card carrying endocrinologist who has done

very exciting work on regulation of metabolism and so forth. and he now is a professor of genetics and medicine at einstein, and he's the director of the institute for aging research. i came upon nir's work in reading of the extraordinary

studies of centenarians. centenarians, in case you wondered, are people who live to be 100. or older. and some extraordinary things have emerged from this. who are these people? how do they do it?

is it predetermined? is it lifestyle? all of the factors that impact on our current thinking about aging are somehow focused upon this relatively small but increasing population group of people who reach the age of 100 or more and still have

extraordinarily successful and fulfilling lives. is there a fountain of youth in that concept, not to turn the clock back, but to in some way sustain and prevent the degenerative diseases and so forth. so we will begin with

dr. ferrucci. thank you very much for being with us. >> thank you very much for the invitation. it's a pleasure to be here. i hope that the first time that we will be invited, the weather is going to be better.

otherwise i think i should forget speaking here one more time. i wanted to tell you today something about what we can do now to age better. when i go to a party, when i have dinner, i usually have a well, there are a lot of people

that come to me and say, you know, what can i do, what should i do, what should i eat, how much should i exercise, what do i need to do? and i always start to say well, i have to go to the bathroom, i have to make a phone call, my wife is calling from italy.

i really don't work, you know, in this more practical field, and i think you don't want to know about -- and so i try to avoid the direct questions because there's so much uncertainty about what we know and what we don't know, and for this reason tonight, i decided

that i'm not going to do that, i'm not going to say i have to go to the bathroom or i have to escape or my wife is calling me. instead of giving the usual lecture where i only speak about what i do, which is very specific and narrow, i want to give you a glimpse of what can

be done and what is suggested in terms of what can we do now to really foster our ability to enjoy a very long and healthy life. i wish i could do that, but i can't. and so that's really what we are targeting, we are targeting --

some people age so that in old age, they're still able to -- [inaudible] i'm a runner, i'll show you some -- about running, these young teeny tiny women that are just 75 or 80, much faster than me. so that shows you that the potential in the human bo tee

that is not completely exploited, and what you really want to do is to use all the potential that is intrinsic to our genomic material. that's what really it's all about, the study about aging. i wanted to make only one other point which is really important.

we always concentrate on a person and not -- work on aging that has been done on that concept, trying to connect the different parts. you know, we're trying to connect the biology of aging, of the aging individual, the person -- but also understanding

how aging is not an -- occur in a very large environment somewhat influenced by -- vitamins. on top of that, also temporal skill that are important. there are things happening in a fraction of a second, the ability of heart -- so important

for our health, and also when we look at an individual, what's happening in that individual at that time really has -- much, much earlier in life, and we're starting to learn how -- from the time of gestation and many of the things that occur at gestation and later on affect

the trajectory of aging. in fact, some studies show that one of the more powerful predicters is the -- of the matter suggesting that what you do in the first year of life ishas really an important effect on what happens later on. how can we age gracefully?

we really like this word, gracefully, because it doesn't imply that you need to be strong, it doesn't imply that you need to run faster. it means that you need to enjoy all the part of your life and age gracefully. and i think that there is

evidence for all the different line items that i showed you, because of limit of time, because i don't want t want tosave time for my friend nir, i'm not going to concentrate, i just want to say stop smoking, get but see, have fun, learn something new, see regularly your doctor, and check

your vision and hearing can really improve your quality of aging. thosso i'm not talking aboutthem but they're really important. i'm going to start about something that to me, it's very, very important, and incredible potential, but we still don't

understand at all. i used to have a slide that i searched but i can't find anymore, where i had one little person and then on the slide, the amount of food that this person had been eating for -- i tell you, it's absolutely an enormous amount, and i used to

tell to my students, how come this little person is not affected in health for the enormous amount that they're eating? but in fact, the evidence about changing your eating behavior and improving your chance of healthy trajectory with aging is

very strong -- but in humans, it's -- [inaudible] i'm gonna start with some very -- we know there is increased longevity in dietary restriction in mice, a lot more in -- i'm not going to talk about it today. i want to concentrate on humans, i want to say -- remain the

strongest intervention to prolong longevity in animal models. the human primates -- may actually occur, there's data from the wisconsin -- that show that the age-related mortality was reduced by caloric restriction and more data

showing all-cause mortality may be reduced but -- down in baltimore really is completely -- show really no strong effect. and we can discuss why and the quality of the diet, but that's not what i want to say here. what i want to say is that then

when you translate this paradigm paradigm, powerful in animal, are really, really strong if you have an overweight individual, so if you lose weight, the -- show you can improve health and improve longevity, reduce mortality and reduce the incidence of disease.

you see incredible -- overweight individual much less disease -- [inaudible] then when you translate it to normal individual, when you do -- future, the people that do not need to lose weight because they're normal weight, this becomes even more complicated.

the reason is unclear, but i feel that this -- this article that appeared in the "new york times" very recently was really interesting. one of the few times, i didn't watch the original -- regretted not doing it because when i was reading that article, i didn't

really know what they were talking about. those people lost enormous amounts of weight by doing diet, exercising eight to nine hours a day, and when they did that, they lost incredible amounts of weight. one of them, the biggest loser,

i think lost something like 240 pounds. something short of 240 pounds. so he was the winner. but all of them every day -- in a year or two regained the weight that they lost, and some of them even more -- we have no data on body composition but i

suspect that they lost much more lean body mass and they gained a lot more fat mass. the reason why of this very rapid intervention is that the estimated amount of calories, resting metabolic rate, consumed by this individual, where reducing -- they were becoming

calorically efficient, so they were using that -- such as there is -- that allow -- to slow down, to put the -- on the lower gear, so if we have this mechanism that pitches in when we reduce our calories, it's unlikely that they will see -- calorie restriction in humans,

especially if it's done too quickly. in fact a large study that was done -- the outcome, which was the metabolic rate and reduction in -- but they were able to show some collateral effect that were the data on cholesterol and blood pressure.

but on top of that, not only the study was not as effective we hope for, but the scientists were unable to reduce calorie calories -- required part of following people weekly and having an incredible support and by 24 months, the reduction in calorie -- much lower than

expected. i think i'm going to take questions at the end otherwise i will not have enough time. i'm going to stop this and say the best study probably that show that there is some effect on -- mortality was -- in the new england journal of medicine

somebody follow strong diet. however, when you look at the classification and the way the diet was coded, it's quite difficult to follow the criteria that were reported in that paper paper. i probably use 4-tablespoon of olive oil every day because my

family produce olive oil, but i doubt many of the people in this room are using 4-tablespoons of olive oil. three fresh fruits per day, vegetables two servings a day, fish three servings a week, and legumes three servings a week, sofrito which only the spanish

people know what it is, which is some sort of vegetable that is stued, white meat instead of red meat, red meat will take you immediately out of the -- and seven glasses of wine that could be pleasant in a nice party in the evening but i'm not sure i can drink seven tblases of wine

regularly, you know, every week. probably when i was in italy, i did. i think that i'm being contaminated by being so long in the united states. cardiovascular -- so as far as we know, these remain the best intervention that we know about,

about the possible -- of diet. -- initiative that -- to include five servings of fruits or vegetables every day and supplementation of calcium was completely unable to demonstrate any effect on cardiovascular disease. so there is somewhat of the --

that is just not fruits and vegetables and i ensure this is in the wine but i cannot tell you for sure. i am so happy that nir is here because -- controversial and recently published in the british medical journal. i could make a very long story

because this is just one of those stories where -- and old boxes and i did that -- very passionate about it. but the bottom line is that they took a very old study where there was an intervention, substitution of saturated fat with polyunsaturated fat, the

study was lost and then you reconstructed the -- they found that although the people that had the polyunsaturated fats had seen a very sharp decline in cholesterol, 14% versus 1% in the control, there was no difference in mortality, and in fact, those who experienced the

sharpest decline in cholesterol experienced the highest mortality. we can discuss whatever -- i will leave you with this idea. this is the only piece of evidence i show from my work, a lot of information, i did a study where i -- people with

1,000 calories in the morning, in the fasting phase, i gave them a meal that was not saturated fat and not polyunsaturated fat. we show that the saturated fat -- and when you look at the the -- the y axis is prime and -- the 38 fraction -- you

can see that the ldl, that two hours represent the lipoprotein -- there is a hypothesis now that two hours after a meal -- that you could stop by administering -- that moment when -- we do studies looking at that so it is possible that not what you eat

but when you eat, how -- it could be a lot more complex than just say how many -- how many is it. it's probably -- exercise, somebody needs to tell me when i have to finish. exercise study is so interesting, i took from the

internet, i reconstructed the record for the 5k, and -- by age. you see children, of course, are half but -- is around 18 to 20 and then the pro forma -- tends to go up. this line that you see here, for the 5k, there is -- really well.

okay. so the effect of physical activity on health was established many, many years ago. there are papers as long as 1963, but -- in cambridge, and so demonstrating that those that were sedentary had a much higher

rate of heart attack. however, in 2015, there was a paper that was published showing that even doing moderate physical activity was good for you, but doing intense physical activity was associated with very large mortality. this was a very well done study

at least on paper. i can tell you that when this paper was published, my email was filled in a day. i got so many email of my friends that are runners, they were worried that they were really shortening their lives, and i had the conversation with

my boss, dr. hodes, about this on the next day, and we start to say, well, it's really physical activity, not -- forptlfortunately nci decided to publish a very nice study that included more than 600,000 people, i think with more than 100,000 deaths, showing that exercise is very

good for you. even when you exercise, that last point was very small and clear -- the numbers more -- recommended which is 15 minutes of intense physical activity five times a week -- per day five days a week. i don't think anybody is doing

that, it takes somebody very, very competitive to do that. also one of the effects of exercise that should really be relevant today is that exercise exercise -- life expectancy. not only you have the increased survival but the percentage of life which aren't there in those

columns where you have improved and increased length is the percentage of lives that is characterized by the absence of disease and disability wise, you know, the part of life that is characterized -- so you are really delaying the initiation of disease and less -- part of

what about attitude about aging? one of the things that's really weird and i don't understand. 40 years ago, somebody much, much smarter than me decided to study people in their 30s and 40s, what they thought about somebody thought that aging was great because you were retiring,

you can do whatever you want, you no longer have to be -- to your job, but somebody else thought that aging really sucks because you've got disease, all your friends die, you know, you're shrinking, you're losing your air, and they have all those effects of the aging -- so

they were pretty healthy at that time, then we followed them up. well, those who are the positive stereotype experienced half of the incidence rate of -- those that reported -- 30 years of time much less cortisol produced. cortisol is the hormone that

express the response to stress. -- that went to autopsy. we were able to see that the -- the plaque and the deposition of -- were much reduced with a positive stereotype, and those experience much less decline in the -- volume in our study on imaging.

you know that there is something really weird about alzheimer's where there are people despite -- you find incredibly severe pathology for alzheimer's, you find that when they die, they're perfectly -- those people had characteristics with lower neuroticism and

higher conscientiousness, protected them -- [inaudible] so i will finish with two things one is sleep. and sleeping is really, really important. to make a very long story short, our neuroimaging study demonstrates that those that

sleep seven hours have much less -- in the brain than those that sleep more than seven hours. seven hours appeared to be prely magic. and i'm going to skip everything else so i'll have time to show you this.

this is a very -- group of people, and many, many years ago, i think this is 1948, and the tbie that yo guy that yousee on the left -- study of aging and that also really was the person who was the first nia director. i want to tell you what he was writing in the newspaper in

1950. so far they can give you only very few points about aging. a few of the don'ts, dr. shock said, are these: don't overexert. exercise after the age of 40 won't keep you young and may, if overdone, hasten old age.

if you're already middle aged, don't play or work to the point of being short of breath. don't indulge in diet fadz in the hope of staying young. if you want to give up eating eggs or drinking milk, it's probably all right, provided that you substitute other items

which are equally nutritious. there's no indication that alcoholic beveridge has any effect on longevity, and i think we can do much better than that nowadays. thank you for your attention. [applause] [inaudible]

>> no, no, they were asked what do you think about aging? they asked about the number of -- well, this was a question that was called -- that was created by number of questions about what you think about and this is work by -- i forgot to -- at university.

>> [inaudible] -- weight reduction following diet restriction. i would actually argue that the merck nism for helpinmechanismfor losing aging, bayically you're not losing weight because your metabolism slowing down which is causing less ros and whatever side

effects of metabolism are happening, so that you're maintaining yourself equally at a lower functioning speed. >> well, the body composition will remain the same, you will be right. but the body composition, the percentage of body fat and the

low percentage of lean body mass is one of the strongest -- of mortality that we know. so other ways -- up to 27 or 30, there's really no difference with a bmi below 25. i think 25 should be used, the aim of sefnlt when you go over a bmi of 30, you're right, i think

that there is a declining -- in metabolic rate that's physiological with aging -- the peoplpeople use that energy todefend themselves. they are under attack, and [inaudible]. >> hi. i've been reading and listening

to a number of talks regarding exercise and longevity, and you touched on it and a question that i need clarification for is with regard to intensity versus so for example, am i better off exercising at the very top of my target heart rate or above that, assuming i can tolerate it, or

am i better off exercising much longer at the lower end of my target heart rate if my bowl is a healthy heart and for longevity. and part 2 on the exercise is, a lot of lecturers, when they talk about exercise, they're referring to cardioexercise, and

you hardly hear them talk about other exercise, strength training, strengthen deurns, flexibility and so forth, and if you have any comment about that, i would appreciate it. >> i would say that your -- i would tell you that we don't know.

>> i didn't want to hear that. >> when the people make comparison between aerobic exercise and resist stance exercise, the effects on health and parameter of health have been very, very comparable. so i have a rule of thumb that i use for myself.

i think -- because it's important for -- you need to maintain -- and you need to do something that includes your core. so these are the -- that age more than any other due to the aging process. >> are there other questions?

the lady behind you. >> i apologize, i came in late, maybe you covered it. you mentioned cortisol levels, this attitude about aging and that's going to be fun, but that study, it seems, started how many years ago? and our economy is very

different. and aging looks different to a lot of us now because, one, our diets changed, when we started 40 years ago, people have died in that period, and also our concerns about having enough money to live long enough. so is there another study that's

going to go on? worry about paying for retirement -- >> longitudinal study now and even longitudinal study in chirp. the problem is that when my success in 50 years we'll be talking to this audience,

somebody will tell them, yes, but in 2016, the -- condition was different. so we are dealing with issues all the time. we start being to see -- for example -- papers showing that -- mortality. the optimal bmi for mortality

has shifted over the -- era, so that it's much higher now, 27, 28, than it was 50 years ago that was 24 to 25. the reason why it's shifting is really unclear. certainly you're right, trend that we can't really capture in long teudal study because of the

the -- >> i saw you flip through a slide about interleukin, and i'd seen some studies about how that was beneficial to your health. walking in nature, having awe experiences and things like that that. >> my work is on inflammation

and that's why i did not touch on inflammation at all, but i think it's medically -- exercise of reducing body fat at the level of the girth -- and -- multiple -- strongest predicter on developing morbidity -- >> we'll save questions until the end.

>> no. i used to, but -- >> thank you, win, thank you, luigi, thank you, all the other people that i know here. i was told that the audience is mainly postdocs, and my observation is those at the nih are quite old.

i'm assuming it's you guys there, but whoever you are, it's nice to be here. i also enjoyed to have this title of demystifying aging. i think i could have -- if somebody was giving you a lecture of -- in concert you would have learned a lot but it

wouldn't have changed much for you if you were in the niddk, nia maybe, but demystifying aging is something that i claim that by the end of this talk, you might actually think wherever you are, if you're doing any research to do with aging, that you can see that

what we're doing is very much related to you. we're in couraging you to taking into account the biology of aging, because a lot of those diseases that you are looking at are in aging and a lot of the mechanisms of aging are important for a disease to

appear. at the nih, demystifying aging is called something else, it's called geoscience. the director of the division of aging biology, and i hope the true -- us being his disciple understanding better and better. so demystifying, i'll start with

the biology of aging by making just a few statements based on data that is not mine. the first thing is to see this relationship that was there when i came to the field and many of my colleagues, it's the relationship between age-related disease and aging.

please note that the y axis is a long scale, so take each up with oeach one ofthose diseases, andtake heart disease or cancer or diabetes or alzheimer's and you see the risk of death depose fro goes from 1to 1,000 when you go from young age to old age. you kind of get the inflation --

therefore it might have the common mechanism. for us, when we looked at this, we said that's kind of terrible because let's say we make amy juror advancmake amajor advancein one disease -- it's only if we target aging that we can move it on. think about it.

if you go to the emergency room with chest pain, now i'm glad there are people with some white hair. you go with chest pain and you get the scan, it's fine, but you know what happens to the people -- within two years, they get cancer or alzheimer's or

they have another heart attack because we never did the aging part, we only did the technical heart part. so this is the one thing to remember in a defensive mode, i always say, of course, what you get first, okay, depends on your interaction with the genetic --

i'm not saying that the nih needs to stop being siloed and be only aging. but of course there's a lot of things here. what is the evidence that we succeeded in delaying aging so yet we are -- by the way, luigi, a lot of what you said is really

good for me to repeat in other words because i think we're making statements here. yeah, can you look at cellular aging and you can look at the metabolic age, and we've done something really clever in the field, we started looking at animals that live longer.

and through that, we learn a lot about aging but more important, we got clues of how to actually target aging. i will make those two statements statements. healthy lifespan. not only lifespan. having extended -- it has been

extended to mice, to rats, to primates, by interventions such as genetic interventions, by environment, by caloric restriction, or by drugs. okay? we've done all those studies. and second, in some of those drugs are actually in human use,

not anything that has to do with aging, but in human use, i would say the following. if those pre-clinical studies that we have done can be translated to humans, we're talking about you spending 18 years in the -- starting with the next decade, 80 years to

become biologically 60. that is the extent of what we have done in variety of animals, and we are a little frustrated that this is not moving on, and i'll tell you in humans how we deal with this frustration. i think -- do humans age at different rates, here should be

your slide with all the people who are either in the hospital or jogging the marathon, right? everybody knows intuitively we age at different rates, yet we haven't been really good at understanding why some people are aging fast and some people are aging slow, and that was

behind my thoughts almost a couple decades ago that we should start looking at 100-year-olds that are so rare, only 1 out of 10,000, by the way, now it's like 1 of 5,000 but they're more bionic, but 1 of 10,000 when i started were 100 years old, and i have two

studies i'm not going to describe because it's not so important, but we have over 600 families of centenarians and we have about 1200 of their offspring and i'll tell you how we use those populations. when you do genetic study, it's always important -- the best

population are the icelandic, children of five vikings and four irish women, okay? brothers cousins. so some of them get diabetes, you can find genes for diabetes much nicer. and this is kind of behind why we're speaking to the population

of -- jews. and as we and others started looking at centenarians, again with the idea that their aging has been slow,, we discovered there's a strong family history within 100 years -- so having a rare occurrence and with the combination of being in the

family was very encouraging for us and so started making two hypothesis, all this other garbage that we hear about, you know, mutations for cardiovascular disease for alzheimer's, for other things. or another hypothesis is maybe they have mutations or --

something that makes them -- makes their aging slow. of course what's important to convince you, 100 years old, it's not that they got sick when everybody got sick, then they lived sick for the last 40 years of their life. what this graph shows you is not

the mortality of those people, but it's when they became sick. the blue and red, one is my study, one is new england centenarian study, and the green and the red on the left are the control group. basically what you see here, the lifespan, health span, okay, the

time that their disease was extended by 20, 30 years, okay? so it's not only they live longer, they lived healthier. but there's something even much more exciting, and that is they were sick much less at the end there was a compression of their morbidity.

the compression of morbidity was depicted by the cdc looking at medical cost in the last years of life, and you see here that in the last two years of life, medical costs for somebody who died at 100, a third of them, somebody who dies at the age of 70.

it's not the whole story because those hundred years old, when they were 60, they even didn't go to the doctor. so you can actually find what we call a longevity dividend. if we can have people live healthy, and die in a shorter period of time, this is

$7 trillion likely to the year 2050. so win asked me to introduce one of our patients, i'm going to do it right now, it's a 3-minute clip, and the reason i'd like you to see this clip is it's a guy that's almost 105 years old, he died when he was 108, but the

point here is to see that you were healthy, at 105 years old, life is good, okay? that's what i'd like to you take from it. so let's watch it for a few minutes. >> 104-year-old investment advisor irving kahn is working

hard as he has when his career began in 1928. he shares his secret to a long and healthy life. >> to wake up in the morning and have something to look forward to. >> irving's curiosity and keen business sense has led him to

become a widely respected value investor, a member of the new york stock exchange, and chairman of kahn brothers, the company founded more than 30 years ago with two of his son, including thomas, who is the president. irving works five days a week

with his 67-year-old son and 29-year-old grandson, andrew. >> and how are you going to link the underwriting project? >> playing an integral part in managing over $700 million in assets. >> irving says not working is unthinkable.

>> he believes mental challenge is key. >> the important thing is to keep that flame going, you see. >> to stay sharp, irving reads materials online. two financial newspapers daily, and a wide range of non-fiction. >> i read a lot of science.

i read no fiction, no mystery stories, and no -- that leaves a lot of time. science. >> it was irving's interest in science that led him to participate in a longevity genes project at albert einstein college of medicine, led by

researcher nir barzilai. nir and his team have recruited more than 500 el thee elderly, ages 95 to 112, and their children. irving and thomas are part of this study, as is irving's big sister. 108-year-old helen rykert, a

former television host and fashion historian. so far, nir and his team have found several team variants that are more common in this group and protect against cardiovascular disease. type 2 diabetes. and alzheimer's.

>> -- has the genotype that seems to be protective against several age-related diseases, including cognitive decline. >> nir's team has also -- >> i think you got the gist. so yes, you see here in the picture, the four siblings that were born to parents between

1910 and 1920, and all of them achieved the age of 102. they were absolutely shocked when the little sister died at 102. helen got to be 110, 106 and 108. so it just demonstrates the special population giving you

this clue of exceptional genetics here. so as luigi said, you know, maybe what happens, those guys did what the doctors tell us to do now, you know? maybe that's their secret. maybe it's all about environment.

so let me show you that. overweight and obesity almost 50% of the people. smoking 60% of the men and 30% of the women. helen, which you saw the sister, she celebrated 95 years of cigarette smoking. [laughter]

so if you smoke for 95 years, you are going to live a long life, but i think it's really -- really tells you about the protection that those guys have. alcohol daily, as luigi said, not enough, physical activity less than 50% of the people, we're talking about moderating

in our paper, we had all kinds of -- i know there's a vegan here in the crowd. we don't have any vegans, and the number of vegetarians is really very low in this population. so i think it's not the environment, the paper was

compared to enhance which is their cohort pretty much, and they're either the same or worse than their cohort. but as a group, it's not that they were interacting with the now let's go to the demystifying from the genetic point of view, and i will tell you that until

we came with these centenarians, a lot of what we tried to learn is rapid aging, people aging very rapidly, having severe disease, lots of aging phenotype and trying to understand them, and see if we can learn from aging from them, which we learned to great extent.

when we went to exceptional longevity, this was the state of genetics, thank god the human genome was cloned and people started creating these diseases with gwas or -- mixed around the genome, to have a great handle of diseases. it really didn't happen the best

way. there's lots of common variants and common phenotypes, 90% of the variants are in -- regions so we don't know exactly what to do with them. all the knowledge we have from gwas comes from maybe 4% from the phenotype of any disease.

we did gwas and we got nowhere with the gwas all over the world, and it's really in parallel, we chain chainged and we said we should go to candidates and find re-mutation. the mutations are not going to be in everyone, but if we find a cluster of mutation, this will

be really good. first of all, we're going to look only or mainly at the -- verity yants with strong effect and we have really several people with those mutations, we can start more of -- okay. so this is kind of the introduction to genetics, and

the firgs thing i want to show you is what happened to our theory, our first hypothesis that maybe these guys have the perfect genome? nothing special, just nothing killed them. so in our first 44 centenarians that underwent a whole genome

sequencing, huge project, the first thing that we went is went to this website called clinvar, they had 50,00 15,000 mutationsthat are most probably going to cause a disease, okay? so the idea was centenarians should have one of those, right? because one mutation with 100

years of life, they should be sick. you have no idea what you're going to see here. in 44 centenarian, we have more than 230 mutations that should have made them sick. if you're asking what are they, yes, two parkinson's mutations,

alzheimer's mutation, degenerative disease, neoplastic disease, cardiac, other dominants. it's immense. by the way, there are some snps less present in centenarians. you understand first of all -- you wonder if the clinvar had

really the right -- people who had the mesoand nobody know what it is, they find some mutation and say okay, that's the disease, and it's probably not the disease. but it does -- because some of those mutations are very well characterized and they -- and

not get sick in 100 years of so the other thing is to find variant or mutations and basically the idea is to show something that is rare when they are young, and that they overrepresented when they are old. i'm going to show you a picture

and i'm not going to go into any one of those, just make general comment because i want to show you a pathway that i think is really very important to humans. but what you see here is those mutations, they're all functional that between eight and 12% basically when you're --

represented when you're old. two of them, the lower two, the blue and the red, are those -- one is -- really has to do with agl cholesterol -- it's interesting that the pharmaceuticals looked at our data and they developed two drugs not for aging but for

cardiovascular disease, because they fail -- centenarians carry those mutations, it means that the safety of this drug should be great, because you have a naturally occurring people like so merck in phase 3 trial of the -- inhibitor and the unfortunate pharmaceutical by

the name of isis is developing an -- but it's also to show you the genetics can be immediately translated to drugs, right? people are saying o you're doing genetic studies, do we have to have gene transplants? no. but i think the most i'm excited

with is the growth among igf pathway, and i think it's also important clinically because there are lots of anti-aging people out there that are administering growth hormones to elderly. there's a billion dollar industry in administering growth

hoe moan to thgrowthhormone tothe aging. so now in nature, ilts it's areally different story -- when you --aling pathway many animal, they live longer -- are living longer than -- growth hormone, et cetera, et cetera. i have to tell you, i was very skeptical about the role of this

pathway in aging because being in endocrinology, i looked at the data and said yes, when you have high igs, then you have increased risk for many of the cancer, okay? but when you have high igs, you also have decrease in several other -- osteoporosis, diabetes,

cognitive function. so i thought, you know, it's just going to balance itself out. until we found the great human geneticist basically sequenced the whole igf1 receptor, growth hormone, liver, here's the liver, igf1, so growth hor mon

has its own actions -- but a lot of the growth are through igf1, so we were looking at the igf receptor because mutations of the igf receptor is associated with longevity. -- found two new mutations in our centenarians, so it's a cluster.

we had nine centenarians with those mutations, it was functional mutations, i'm not going to show you the data, there's the reference there, the women who had these mutations were shorter and had higher igf1 level, in other words, the cluster of women that this

system must have protected them against something. now, this wasn't the only thing. we're working on this paper for three years and the reason we had to validate it, but we found that our centenarians -- you see the line here goes from 4% to 12%, they have deletion of x on

3 in growth hormone. we found three other populations, the amish, the french caucasian and the white from the chs study, all of them exhibiting increase of this mutation with the exception of aging, suggesting that it really plays a role.

so this is going to be submitted soon but that's not the only thing. the way i'm starting to be convinced is, okay, the igf receptor is 2%, we can still say, okay, 2 perg 2% mutationbut that doesn't mean -- centenarians have growth hormone deficiency.

but now we have 12% with deletion of growth hormone factor, and then we found -- found micro rna, clusters of micro rna that counts for more than 30% of our centenarians that are actually inhibiting the igf receptor. so 2 and 12 and 30 all of a

sudden we're talking about we find something i inhibitingtheir growth hormone igf. so we have the centenarians that got to us kind of healthy, and we asked, what is the phenotype that's going to predict best their mortality? their mortality is almost 30% a

year. the answer in female was those with the lowest in igf-1 levels live basically twice as long as those with a higher. again suggesting this is powerful even in those very old, and as it is in nature, it's gender-specific.

the growth hormone igf is very actually the i tb. f i igf isreally more female and the growth hormone receptor is more male. so this was just an example or several examples to show you that this population is very unique, it's extreme population, it's very unique, and there's a

lot of findings, those are not the only ones, but clusters of findings or mutations that seems to be associated with delaying their aging. and the question now is, what do we do inside the environment, and let me again emphasize what i showed in centenarians is not

what we recommend, that you smoke and not exercise, right? luigi said it right. so are we ready to do something in order to show the public and convince everyone that ainltingaging can be targeted. what happened -- we got the grant to get the buy oj of aging

that have find all those great things and the geriatrician or the intervention geriatrician getting them together and trying to educate each other, but the way, biologists always think take eight people, trick them and see if it works, and the geriatrician looking at the

biology of aging and saying they're crazy for other reasons. so this communication was really important, and one of the things that came up was this idea of using metformin to target aging. and i have to say that we're using metformin as a tool and i'll explain later, but why

metformin? first of all, in the biology of aging, in a lot of animals between nematodes and mice, metformin extends lifespan but even more important, it expands one thing. so this is the buy oj o biologyof aging. second, if you take non-diabetic

and in the same -- dpp, disease prevention trials, half of them metformin, it prevents diabetes by about 31%. if you have diabetes, in a controlled -- you have 30% less cardiovascular effect. throughout the years, it became apparent that with diabetes who

are treated with metformin have much less cancer, also around 30-something%, almost all cancer except prostate. also there's a study from this month on non-diabetic people with nci that metformin delays cognitive decline as well.

but i really want to show you this study, this study is a phase 4 study, not very popular in the united states, but nobody -- metformin is generic and cheap, nobody studies, but you go in to the u.k., into the pharmacy, and you identify people, in this kai 78,000

people, that's the green line, 78,000 people that were put on metformin, and you just look at mortality, you match them with the black group that are 78,000 people who visit the same doctor but do not have diabetes and, therefore, they're not on metformin.

you take 12,000 people not treated with met for bin minnesota but another drug for diabetes, you match them with 12,000 people in the red that are non-diabetic, not on sulphonylurea. you see that is associated with more mortality, but really the

interesting thing is that people on metformin, the green line, that are obese, diabetic, begin the metformin when they had more disease control, actually have less mortality than non-diabetic people, so it shows you that metformin has a strong effect on the biology of aging, it has a

strong effect on mortality. and all those data together convinced us that we can use metformin as a tool. and why am i saying as a tool? because i'm personally not so interested to row pete studies that were done for each disease before.

bull we want to show that in the elderly, we can delay multiple co-morbid it by using this drug for the main reason for the fda, we want to get from the fda an indication that it will be equivalent for aging. we have talked with fda and clearly the fda is instructing

us and we're working together to get to it. we are talking with the fda, the fda understands the interest and we have a way to target aging without needing to call it aging but the working morbidities associated with aging. this is our main goal.

you have to understand, if the fda does not approve drugs that target aging, the pharmaceuticals -- we have some and they get better all the pharmaceuticals are not going to develop a drug that the healthcare system is not going to pay.

so we think the break through in our effort to delay aging will come when we break through with the tame, bunch of findings coming to the fda without any pharmaceutical backing us saying we want to do this. at the fda they never mentioned met for pain minnesota because

everything you want to know -- what we are doing also, we are doing a template so the pharmaceuticals that want to develop a drug know what kind stuff di to do. it's much less than it takes to develop a drug for diabetes or -- much fewer people.

also we want to be able to tell those antiaging charlotte tans, if you really think that you have something against aging, this is the study that you have to do in order to comply with in short, what we're doing is we are taking basically everyone over the age of 65, we're taking

3,000 people, and we are doing a double blind placebo controlled study in about 14 centers. the primary outcome here is the time until any of those clinical outcomes that are card low vascular, dementia or death. so there is no statistically significant -- let's say you

have cancer, we want to see that we prevent cardiovascular if you had cancer, we want to see that we prevent dementia or the time. so there's no one disease that we're interested. we're interested time to any of those disease.

we have the development of this thought and what it means from statistical perspective, but obviously the more outcomes you have, the less people you meet. and when you take people between 65 and 79, in a five-year study, six-year study, you have lots of outcomes.

so the secondary outcomes are basically those that are related to phenotype of aging. again the reason we have -- the more phenotype we throw in, the more -- the less people we meet pretty much. so that's how it goes. and in a way, what we're trying

to do is the following. i showed you the -- scale in the beginning. after the age of 60, that's where -- people who have more than three conditions, it just skyrockets here, okay? it's equal to mep and women and equal among races.

what we're trying to do with the tame is flatten this curve. this will be the first two we think we can make it, there are other challenges, because we don't have a pharmaceutical behind us, so there's other challenges, but we think we can make it and we think that it's

going to be a cheap study compared to how we are going to intervene with aging and delayed disease as it comes on. so i'm going to finish now, i want to emphasize, what did i try to demystify and why? so i kind of said the way for us to look at the aging is to

connect it to age-related after all, that's kind of what fda will approve for us, right? the important point, and i'll say it, the important point for those of who you are at the niddk, at the nhlb, the nci, is that there is a biology of aging, and a lot of your studies

are done on two month old mice. i think it's out of the context of disease where the major res being for this disease is aging, cardiovascular disease isn't cholesterol, age something a thousand fold -- so i think this geroscience initiative applies immediately for some of you of

how would you like to do the study, and i will tell you that the nih negotiating of how they can allow you to get mob ee to usmoney touse -- also, we wantto make everybody understand that in the silos that we have, aging needs to come across. the nia with 3% of the budget

cannot take care of all this intervention that has benefits to so many institutes. so there is a biology of aging. i wrote that the target is well-defined, but we still have a lot to learn about aging. we're not done. as i said, i think tame is a

tool, but i think there will be more mechanism and better drugs and that can happen rapidly. i showed you the intervention that delays aging in many species, and also that i told you about this targeting in humans. if you can see, if you're

interested in ron howard, the director did a great -- about aging, it's called the age of aging, this is a great film that takes you through some of the -- it will be nice to see. so thank you very much. this is the consortium that is doing the tame, there are lots

of other people involved in the other study. thank you for listening. >> [inaudible] >> you know, i meant to come back to it. it's not going to be a long answer. it's going to be published, cell

metabolism coming up with a metformin action soon, but basically what i put the slides is to show you that there's some things in ainging tha aging thatwe kind of agree on, okay? you see mtor and amp kinase and inflinflammation and and this is kind of what we know about

it happens that metformin, as you see there in orange sh affects a lot of those pathways. the question for me is, does metformin have one action that is maybe upstream to everything and then aging and other things -- or is it a super drug? i'm kind of debating, maybe it's

a little piece of both. maybe there is a major mechanism of action but other things help, but we know a lot of what metformin is doing in this biology. >> the fact that it's a base eck compound. yeah, it's more than that.

it's more than that, because there are other basic compounds that do nothing for longevity. >> no, they drink -- our centenarians drink one cup of wine a week in 24% of the men and 12% of the women. much less. >> yes, i wish you heard this

question because this is what i want to propose in our phone call. mechanism of action of metformin, i think what i believe personally is that it inhibits complex 1 and then it change -- ratio, activate amc kinase and -- and that means

that we have not really looked terrell vant biology of aging mechanism of metformin, and i think it shul be should be astudy because we have enough knowledge to know that it's important. i'm not sure that the glucose lowering effect of metformin are actually the major mechanism.

maybe there are side effects but not the major mechanism, because we can lower glucose in other ways and not get the longevity. >> you want to say something about that. well, it wasn't more effective in the elderly. but the -- in metformin

intervention and lifestyle intervention where they did exercise three times a week with those people is just as -- actually is more effective in metformin generally, but in the elderly, it was just as effective as metformin. >> so we have actually -- you

should -- win, you should visit us. we have a nathan shock center, they're coming from the division of aging biology, and in our nathan shock center, we have a core that does a parabiosis, so in our case, cro -- we connectthem like twins -- so they share

similar blood circulation. so we're doing young and young and old and old, but also young and old. and what we are finding, we were not the first, i think the first is tom ran tall tha randall thatshowed that when you do that, you can improve muscle regeneration

after injury. by stimulating stem cells. but what we show is basically that the old are getting younger and sometimes the young are getting older. by sharing their blood circulation, and if you think of an experiment like that, we can

provide this for thousand dollars, you can get a trio, young-young, young-old, and if you do it three times, you really can find -- you can start finding things that are important to the blood. your question is -- you're asking me as a doctor, and my

price for private consultation is $3,500. the metformin is around 1500. you can give metformin up to 2550 and probably 3000 is not toxic either. >> well, i showed -- i don't know what i said but what i showed is that there are a

cluster of functional mutations in the igf-1 receptors. in nieb - 2% of centenarians, so they're a little bit shorter, and they go to 100 and we don't find it in control. that's what -- >> i said one of the problems is people are using growth hormone,

which -- to prevent aging. the reason it works, growth hormone is like -- their face becomes more tight so they feel that that's an anti-aging effect, but in effect, the growth hormone can promote cancers and do other things and the safety of that is really

terrible. >> so there's a study -- growth hormone receptor, columbia? ecuador, and actually those people, they never develop diabetes or cancer. in all the people. they have history for -- we have long history and there's never

been one case of cancer. so the role of low growth hormone seems to be -- not just in cly gans. > -->> those are the people, bythe way, that's one of the -- and they have low iff, i took it out of the lecture, and here is the relatives without the mutation

and here the one with the mutation, and you see that they had the diabetes, 5% diabetes, those that don't have diabetes, and those guys have a cancer, those guys don't have cancer. so beside our centenarians, those guys and some of the discoveries suggest in human,

it's a very relevant study. >> are you taking the metformin yourself? >> i'm sorry? >> well, unfortunately i do but let me explain to you, i have -- i had a diabetic mother and i was prediabetes, and when i was prediabetes, which was three

years ago, before we conceived the tame trial, my physician put me on metformin. i don't mind it, but i wish i could say -- i wish i didn't take it and i wish i could say that until the study is done, i'm not recommending it to each one.

sorry? >> well, it will be five, six years when it starts being funded. but why are you of all people are you asking? are you older than you look? >> so if i remember, there was a famous swedish endocrinologist,

jan gustavsson who studied growth hormone in relationship to the hypothalamus, and how in turn, that regulates a lot of the distal functions of growth hormone that were quite ipped pept of the hormone itself. and i'm sort of curious whether the mutations that you're

talking about could be affecting the central nervous system responses and signaling rather than directly the hormone with the peripheral receptor. >> so i think it's reasonable to think that we're intervening with a major endocrine function, there's going to be the bad

effect and the good effect. and i agree that we don't know enough about them, but let me tell you what we're trying to do. so we look at the women in our study, the centenarians, right, the lower igf versus the high igf, and the first thing that

we're worried about is the brain, owe kea th okay, thecognitive function. women with the lowest level of igf is an amazingly better so they're not paying by the brain. in other words, the effect of low i tb. f ogf on ainging ismuch more

important than what it could to in other ways. then we looked at muscle function, and they're similar. in other words, it's not better but they didn't pay for the fact that igf1 level was lower in those people. so we have to really understand

better what's low i tb. f-1 -- and i think it's probably the worst than anything else, and what low igf-12 is good for in preventing major diseases. >> what is the major limiting problems sent newerrians have? what is it that they find the hardest in life?

i'm not talking so much about physical illness, but -- >> you know, luigi talked about personality and -- i don't know to answer what you're saying, if we looked at their personality and we publish $3 papers showing that they have great personality, they're extrovert,

positive, optimistic, they don't say anything wrong about their daughter-in-law and things like that, and of course the question is, is it association or is it causation? so let me tell you just this little story of a 104-year-old guy that i went to see, and i

sat with him and he was the nicest guy i've ever met. he was so good and so consider at and everybody was important and he tells me about his life, he was just a complete person. now, i go out of the room and i bumped into his son, who's 82 years old, right?

and i said -- i tell him, you know, your father was amazing. and he looks me in my eyes and said, you should have seen the son of a when h bithc when hewas my he was terrible! then you realize a personality toant change maybe until 87, but i'm telling you, when you live

long enough, personality changes. in fact, in university of pancreatiuniversityofpennsylvania, they took young and old people and showed them good slides, like islands in hawaii, and bad slides like pizza with -- they showed many slides and the people have to

recall. and the young people recalled both the bad and the good. the old people recalled ohm the good. by the way, i'm looking forward to this trait. but i think there is a physiology and the physiology

tends for people when they live long enough to be more adaptable and reasonable and optimistic maybe because they've lived so many years. >> you actually opened up the door to a second question. my first question is you showed four groups, the icelandic

people and the -- and so forth. i assume you were just intimating that these were groups that were easy to study because of common amount of genetics as opposed to groups that have a higher probability of living longer? q.no, actually the amish is

true, but the -- is people with diversity genetics, italian, jewish. >> okay. and the second point which you opened up the door to, and this goes to both speakers today, is the whole emotional/psychological ritual

impact on longevity and intuitively, i feel that that might be a factor because we talk often about the mind-body interface, how the mind controls our physiology, and you refer to the older people have the more upbeat personality or more extroverted or came to the

realization that there's no use to being bitter or to be a crotchety old guy, once you get to 82, you'll be nice and live longer. >> luigi? >> i will tell you that -- have done a number of studies on personality, and using -- that

was partially created for the -- there's a number of effects that positive trait of personality have the intervention of depression -- with lower risk of cardiovascular disease, lower metabolic effect, seems to be less associated for example with a metabolic syndrome, so i think

that the brain-bo tee associatio-body associationisreally, really strong. now, i think that nir is right in saying that when you reach extreme longevity, probably the maybe changes in personality. and i had guys -- talk to many, many centenarians, when i was at the beginning of my career in

interviewer -- i can tell you that lots of those were not sick but incredible and extraordinary but after old age, personality really does not change. i think that's a trait that develop in old age. >> both of you showed like -- in population [inaudible] so the

implication is that the people over the age of 100 are just the lower part of a statistically dawesian curve. is that correct, or are they really an entity unto themselves? >> [inaudible] the -- curve that they increase -- genetic

according to age has been showed to be violated in very, very old -- because there is a selection of individuals so the increase is not as proportional when you go beyond the age of 95. so i don't think that is just -- the distribution, i think there is a survival effect that it's

due to something where we don't know, maybe igf-1 or maybe some other combination of genome, gene environment interaction, i don't know what you think. >> i totally support that. i think -- the demographer and -- agree on many things, for example, the demographer says

longevity will continue greatstraight through. we know that the oldest -- was122, so how do we get -- is what's important for us rather than for now trying to find out if we can break the limits later on in some generation or something like that.

but i'm saying this dawesian for me doesn't mean that those guys, the people are not special, right? it doesn't contradict. >> i'm from the general public, i'm not a gentleman net cyst, i don't belong to the nih, nothing.

i'm on the board of something called village of tacoma, and there are a lot of village of georgetown, village of du pont and it's neighbors helping neighbors. people helping other people to get to the doctor, getting to church, get to choir practice,

whatever. >> people who are older, living alone, can't get out or what i saw in one of the slides -- the video that you had of the gentleman, what i saw in his office was that part of his environment was a huge bulletin board filled with photographs of

family members, friends, everything, and all along, his -- photos of friends all over the place, and he's working with his son, his grandson, and i'm kind of wondering if socialability is really one of the things that lead to longevity and maybe even as

organizations like ours develop more and neighbors are helping neighbor, that people will be whriffinliving longer becausewe're helping them psychologically. >> i would say just one thing. you can be extremely social in that age of 60. i mean, what we're showing here

is people with extreme -- in extreme age, and they are what they have, they have -- you know, a lot of the -- have lost -- so i'm talking about the very unique situation so i don't want you to read too much into i agree the social thing is very important maybe luigi you want

to put but things that i showed you -- to say that this guy and his family live to be 110 because of social interaction. >> one of the things i have said many time is that centenarian has the awareness of being special, the awareness of being survivors, the awareness -- that

nobody else has, and that involved the family so in general, i will say that the -- is a study that is strong social context. i'm not really sure that whether this is -- probably more -- that doesn't mean that being social maintaining strong social ties

and interaction is not fundamental for equality of life -- aging and has incredibly extraordinary effect on your health. it's absolutely important. we have shown many times that other people with the strong -- do not develop -- they do but

even if they do, the consequence of depression in them when there is a social network around is they're able to overcome the trauma in life such as disease or disease or the death of somebody that is close to them. so absolutely, i think that i said that at the beginning of my

slides, this will require an entire different story. i think that creating the ties allow you to be well in old age, it's something that you should start preparing when you're 30. well, i want to thank both of you very much. >> thank you very much.

it was great. >> thank you all for being here.