 Ladies and gentlemen, it is now my pleasure to introduce to you my colleague from our biology department, Dr. John Lamert, who will introduce our next speaker, Dr. Leonard Hayflick. When I was a kid growing up in Florida, I learned about the search made by Ponce de Leon for a fountain of youth. While governor of Puerto Rico, this former sailor with Columbus heard stories told by indigenous peoples about a wondrous spring. If you drank from it, you would stay young, bathe in it, and your health would be restored. Ponce de Leon set sail for the Bahamas where he heard the magical waters were to be found, but instead his ship took a wrong turn and he ended up being the first European to set foot in Florida instead. Ponce de Leon did not find his fountain of youth. Instead he died from wounds inflicted by a hail storm of arrows released by native Floridians who did not cotton to invaders. The guns were pointing early in life rather than ignoring him late in life. Some people still search for a facsimile of these enchanted waters that will give them good health and a long life, at least postpone death for years. I'm sure that our speaker, Dr. Leonard Hayflick, finds these searches are futile. Dr. Hayflick is best known in the cell biology community for his groundbreaking discovery that normal human cells growing in culture have a finite potential to continue to divide. That is in culture these cells will undergo about 50 population doublings and then stop dividing. What is now known as the Hayflick limit, 50 or so doublings, identifies some sort of built-in molecular calendar that keeps track of cell division. Dr. Hayflick's report of his findings in 1961 in experimental cell research upset the apple cart. The prevalent, prevalent paradigm then stated that normal cells have immortality when they are grown in culture. But as Dr. Hayflick was generous in sharing his cell strains, many other labs confirmed his observations. Life for cells with a normal number of chromosomes is finite. Their lineage will eventually die. A second critical observation was also made by Dr. Hayflick. Normal human cells frozen at very cold temperatures remember how many times they divided before they were frozen. The clock stops at minus 70 degrees Celsius or now in liquid nitrogen at minus 196 degrees Celsius and after the cells are thawed the ticking begins again. The sum of divisions before and after freezing is the Hayflick limit, 50 or so cell doublings. Need me think of Minnesota perhaps for a long life when we go in the deep freeze of winter and then thaw in summer and perhaps that may help us live a little bit longer in Minnesota. Actually, time is not the critical factor, it is the number of times that DNA and chromosomes replicate. In other words, aging of cells is internal programmed in. The Hayflick limit surely must give pause to those dubious entrepreneurs who want to dunk recently deceased baseball players in liquid nitrogen, preserving body parts until the distant future when the mysteries of the fountain youth will be revealed. Dr. Hayflick also developed the experimental strategies used by cell biologists to establish normal human cell strains. One strain, WI-38 also known as Wistar 38, is the most studied of cultured normal human cells. We found that WI-38 cells would support the replication of polio virus. This was important because the monkey cells used for polio vaccine production then carried a cancer causing virus SV-40. Those of us of my generation who had polio vaccines in the 50s and into the early 60s were injected with such alien DNA and unwanted DNA. Today, a very large number of vaccinations, perhaps a billion vaccinations against rubella, measles, mumps, polio, and rabies have been made possible because of WI-38. You should know that Dr. Hayflick has received no royalties for use of WI-38. Scientists in the audience know that this would not be the case today since the ruling by the Supreme Court in 1981 that organisms are patentable. Something you should also know about Dr. Hayflick and his scientific contributions is that of the 40 most cited scientific papers, that is papers that are referred to in other scientific publications and there are several million scientific publications, four of his papers are in the top 100 citations. Dr. Hayflick also discovered the cause of walking pneumonia or primary atypical pneumonia. Other labs interpreted their data to suggest that a virus was the cause but Dr. Hayflick had other thoughts and showed that the cause of devagent is a mycoplasma, a bacterial nudist naked because it lacks a cell wall. The medium he developed to cultivate mycoplasma bears his name. Today, Dr. Hayflick is a member of the faculty at the University of California San Francisco where he is Professor of Anatomy. His human diploid cell work was done during his time at the Wistar Institute in Philadelphia. He has also been on the faculty at the University of Pennsylvania where he did his doctoral studies, Stanford University School of Medicine and the University of Florida in Gainesville. Dr. Hayflick has received more than 25 major awards including the Sandoz Prize from the International Association of Gerontology, the Brookdale Award from the Gerontological Society of America, and the Lifetime Achievement Award of the Society for In vitro biology. He was a founding member and chair of the Executive Committee of the Council of the National Institute on Aging. He was Editor-in-Chief of Experimental Gerontology for 13 years. In 1994, Dr. Hayflick's book High and Why We Age was published and was a book of the month. In fact, as we walked in, a former colleague on the faculty remarked to us that this is a well-read book in his library. It has been translated into nine languages. From those thorough and measured studies of normal cell growth over 40 years ago, Dr. Hayflick has continued with passion to learn more about the biology of aging. We're delighted that you accepted our invitation to participate in this Nobel conference. We look forward to your contributions, Dr. Hayflick. Thank you very much for that very kind invitation. I only regret that my 99-year-old mother wasn't here to listen to it and learn that her naughty son grew up to deserve such a fabulous introduction. Jay Olszanski is a tough act to follow, but I've been invited to do so, and I will. He has covered several areas that I intend to cover, but with a little different slant. But before I do that, I do want to thank very much those who extended this kind invitation for me to be here with you today, and especially for the very generous, magnificent hospitality. During this presentation, I'm going to establish a few goals, and the goals are presented on my next slide that I won't show you until I make a remark that really astounds me in having made this observation. About 40 years ago, when I first entered this field, kicking and screaming, I might have. You couldn't pay six people to come in off the street to listen to Electron Aging. And now we have three orders of magnitude of six, namely 6,000, who will actually pay you to listen to Electron Aging. So this field has clearly come a very long way. There are seven objectives that I'm going to try to complete in a lot of time. The first is my effort to describe the four aspects of the finitude of life. Second, I'll define some key terms, some that Jay has already addressed and a few others. Third, I'll discuss the differences between the three major concepts, and those concepts are the title of this presentation. I also try to explain why aging occurs, why aging is not a disease, and the role of genes in determining longevity, and finally, to discuss what research on aging is and what it is not. The four aspects of the finitude of life, I'm listing here for you to see. The first are the determinants of longevity, and my goal will be to define these hopefully in a way that will be easily understandable. Secondly, aging itself, third, age-associated diseases, and the fourth aspect, of course, is death. I won't discuss the biology of death despite the fact that it's not a simple question to deal with, as you might think, at least in fundamental biological terms. The reason why this is important, I think, needs to be emphasized. The three major aspects that I'll describe now are aging, longevity determination, and age-associated diseases. One of the most difficult problems that we have in this field is defining what we mean by the term aging, and I'll say a few words about that in a minute. But the confusion in failing to understand the distinctions between these three concepts still is resulting in the following, misinterpretation of experimental results, skewed funding decisions, and questionable public policy decisions. Let's talk about the ages of humans, and in particular the definition of aging. This is a very difficult concept to define in biological terms. One can define aging at various levels of complexity, from the molecule all the way up to the whole animal, the whole human, for example, and even demographically as J.L. Shansky has done. So the definition of the word aging is, in its most fundamental form, a definition that must be applied at the molecular level. Having said that, even that kind of definition becomes a serious problem. I live in a state, California, that borders Nevada, where we find what are allegedly the oldest living things, bristle-con pines, which are alleged in some cases to be 4,000 or 5,000 years old. We've all been taught that redwood trees can live to be 2,000 or 3,000 years old. And point of fact, that's not true, and I'm going to challenge one of your basic beliefs. I say that those of us in this audience who are older than 30 or 31 years are older than the oldest bristle-con pine or redwood tree. Now let me try to defend that statement. When you talk about old biological material, and in particular when talking about bristle-con pines or redwood trees, the cells that are several thousand years old are dead. The trees have learned how to hang on to their dead cells for architectural purposes. You and I slough all of our dead cells or most of our dead cells, and so we don't hang on to them for any purpose. So when you call a redwood tree 3,000 years old, what's old has been dead for 3,000 years? And I think that's an unfair argument. The oldest living cells in a redwood tree are about 30 years old in the needles and the root hairs. So that those of you in this audience who are older than 30 years, when the next time you stand in awe of a redwood tree, you are probably much older than that redwood tree. That's one of the difficulties. Another difficulty is to look at other botanical materials like aspen trees or creosote bushes in particular in Wisconsin. Creosote bushes are alleged to have been in one general area for about, since the last ice age, about 10,000 years ago. And consequently, people argue that they're older than bristlecone pines. And point of fact, the problem with those kinds of botanical specimens is that they send up new shoots from underground roots and give rise to an increasingly wider circle of daughter elements. And making a distinction between the source of those daughter elements and the parent of the daughter elements is a very difficult thing to do in terms of judging age. A final example is cuttings. If you make cuttings from plants, generate a new plant, when is it old and when is it not old? The end of life in a series of plants that develop through cuttings is very difficult to determine. Well, I won't belabor that point anymore, because all of us have an understanding of what we mean by aging, at least in a kind of visual sense. That I've indicated here on the screen. We all know an old person. When we see one, or at least we think we do. But I'm going to emphasize during this talk the aging process at the molecular level. Before I get into that, Jay made a remark that I wanted to cover as well and emphasize, in fact, that is that aging is a peculiar condition of human beings. The only animals that age, at least in the extreme manifestations of the phenomena, are humans and the animals that we choose to protect, like our domestic animals and our zoo animals. By that reasoning, aging is truly an artifact of civilization. We have learned to live longer in a teleological sense than we were intended to live. The proof of that statement is quite clear. For 99.99% of the time that humans have been on this planet, life expectancy at birth has been no more than 20 years. Life expectancy, as Dr. Olszanski defined, is the 50% likelihood of living to a particular age, beginning at a particular age, and usually that's understood to be at birth. Of course, there are people who live longer than 20 or 30 years during the times of ancient Rome, for example. So that life expectancy has increased, but the need for humans or any animal to live beyond the period of reproductive success is not a requirement for species survival. Our species survived for several millions of years, with most of its members dying before the age of 20 or 25. So this provides the proof that living beyond that age is unnecessary, at least for the survival of the species. Of course, we all well recognize the need to live longer than that. Let me now move to a definition of this term in respect to biological aging. Magical aging is the random systemic loss of molecular fidelity that eventually exceeds repair or maintenance capacity. Our bodies, in addition to all the other functions that it has, has an enormous capacity to repair errors in the molecules of which we're composed. And this repair process is at present at birth, continues throughout life, until after roughly the age of reproductive success. The errors exceed repair capacity and essentially lead to the aging process. This occurs in animals that reach a fixed size in adulthood, like humans. There is reason to believe, and I won't be going into this very much detail, we might do it during the discussion, that there are animals like alligators, deep sea cold water fish, several land tortoises that either do not age or age negligibly. They age so slowly that it's almost imperceptible. And as I say, we may return to that during the discussion period. Now having made this definition of biological aging, and the further statement that the progressive loss of molecular fidelity increases vulnerability to age-associated diseases, I have to do something that will require you becoming students. But before I do that, as indicated here, the loss of molecular structure, which is the hallmark of the aging process, increases vulnerability to age-associated diseases. And I'll distinguish these two properties very quickly. But before I do that, I need to make at least two people in this audience familiar with molecular biology. I'm told that there are two people here who know nothing about molecular biology. I have a feeling that they're sitting on the front row, and they might even be colleagues of mine. So the rest of you can read your newspapers or talk to your neighbor while I give you a three-minute course in molecular biology. The university assures me you're going to get no academic credit. Our bodies are composed of trillions of cells, and molecules, of course, are what our cells are composed of. There are many, many classes of molecules, but I'm only going to focus on one class in order to streamline this presentation and focus almost entirely on proteins as an example of the complexity of molecules. And that's the take-home message, and if I can put it in one word, it would be complexity. Now the complexity results, of course, in molecules that have very strict functional duties, but they also can be repaired. And that concept I will also illustrate in addition to which they can be replaced very much like the things you do with inanimate objects. You either replace them or repair them if they fail. Well, how are protein molecules made? Let's have a shot at looking at this. Here we find the cell, and in the center of the cell, the nucleus. In the nucleus are chromosomes illustrated here. Chromosomes, as most of you well know, consist of a web of nucleotides that compose a molecule that we call DNA, and here it is illustrated here. The DNA codes, it has a code as you see these letters indicating here, the DNA codes for the structure of proteins that you see illustrated at the very bottom here. And this, what looks like a structural mess, is illustrative of the kind of complexity that I'm talking about. Let's look next at this complexity. This is called a ribbon representation of a protein molecule. I won't go into the details. My only purpose here is to convince you that it's complicated. And here is greater complication, unless if you're not completely convinced. Let me go one step further and give you what I think is a good analogy to the complexity that I'm talking about. The proteins are made up of roughly 20 amino acids, that is separate little units of chemicals. And they're then strung out on what looks like a bead arrangement, and then coiled. So each of you in this audience was given a box of beads with 20 colors, and in the box were a few thousand of these units. And I gave you a piece of thread that was at least a city block long. You would then string your beads, and you would now, I think, recognize that each person in the audience would have a string of beads that would be completely different in the pattern of colors that would be strong. Furthermore, suppose each of you then took your string of beads and dropped it on the floor. It would then form some odd pattern of coils and turns and twists, and I would suggest that virtually every one of those would be different from person to person, because it would be a random process. That gives you some idea, I think, of the complexity of protein molecules, and that even the loss of one turn, or the failure of a part of the molecule to bend properly, will destroy or at least change its functional capacity. That's how subtle these changes are. The whole pattern is held together, of course, by minute electrical charges. This is what it would look like. Not only string of beads, but a plate of spaghetti would give you a pretty good idea of what a protein molecule looks like in respect to complexity and what appears to be disorder. Actually, every twist and turn in that ball of spaghetti is important to maintain the structural integrity of the molecule, and hence its function. This is just another example of a misfolded protein. Again, I'm not going into detail. This is the protein here, there's some changes in the folding structure here, and I think I won't belabor this point any further. Now, is the misfolding of proteins, as I indicated earlier, that makes changes in those entities and gives rise to age changes. Now that's the end of your three-minute course in molecular biology. You can consider yourself now professional molecular biologists. This is the kind of changes, these are the kinds of changes that misfolded proteins can produce. Some of them are subtle or annoying, like gray hair or age spots or nearsightedness or wrinkles. You usually don't rush to the emergency room when you see that happening. Then there's a category I've indicated that are not life-threatening, but more annoying than perhaps the top most group, cataracts, hearing loss, etc., increased reaction time. And finally, of course, some life-threatening problems like insoluble amyloid fibroles that are the underlying cause in the minds of many people about Alzheimer's disease and Parkinson's disease, and we'll hear from subsequent presenters in detail about this situation. Immune system losses, of course, when damage and mischief occurs in those proteins, we can also incur serious problems. So the subtle changes in protein configuration, or what we call loss and fidelity in the protein, can cause a wide range of age changes from subtle to serious. Okay, so why does aging occur? Through natural selection, all complex biological molecules have evolved energy states, the energy state, meaning the electrical properties that keep this complex entity together properly, sufficient to maintain the fidelity of that molecule until most of the animals that they constitute reach reproductive success. That has to happen, or else the species would disappear. If our molecules went to pieces before reproductive maturation was reached, then clearly the species wouldn't survive very long. So that's an absolute necessity. And I've indicated that here by saying that the species would vanish. All molecules include those that compose repair, turnover, and maintenance processes. You have to remember now that these repair and replacement processes are themselves made of molecules that also undergo the same deteriorative processes over time as do the substrates on which they work, on which other proteins work. So it's very much like the analogy that Dr. Olszanski used and that I will also use further in this presentation. I think it's a good one, and that is the analogy with the automobile. Not only does your automobile age, but also the shop that repairs it ages as do the repairmen themselves. So it's a never-ending cycle of age changes. One of the things that people sometimes ask is, well, why don't things end quickly? Why don't we all die at the age of 30 or 35? Or at the stroke of midnight on that particular birthday? Well, the answer is that it's too costly an energy to do that. You can imagine, for example, that you and I go into business to sell a cheap pocket watch that will only run for one year and sell it for $5. We develop such a watch and it has to work for one year or else we go out of business very rapidly. What we find, of course, is that many of the watches continue to operate for 13 months or 14 months or even two years. If we decide that we want to have all of our watches stop working on the 366 day, we would have to put into the clock a complex mechanism to make that happen. And that, of course, would destroy our capacity to sell the watch for $5. So this is the reason why there is a randomness in the pattern of the aging process, not only in living things, but in inanimate objects as well. Engineers call this the mean time to failure. When you drive your Mercedes Benz off the showroom floor, you have an expectation of its mean time to failure, which is probably about eight or nine years. When I drive my Hugo off of the showroom floor, I have a completely different expectation. And that's what I mean by mean time to failure. The mean time to failure of human beings today is about 78 years to use the engineering term. Let's continue this question of why does aging occur. The loss of molecular fidelity that characterizes the aging process results from decrements or losses in the energetics of molecules that are vital for maintaining their structural and functional integrity. I think I've already covered this, and so I won't restate that. Now let's look at the molecular properties that are thermodynamically unstable that cause these changes, these so-called spontaneous changes in molecules after the passage of time. I'm going to give you a few examples of this. Those of you who are trained in physics will understand this in the simple term increasing entropy, but I won't say any further about that because the physicists will understand what's meant by that. Most of the changes actually that occur in molecules are due to the action of oxygen, to oxidation. The older you get, the rustier you get, that's not far from the truth because there are processes known as reactions with free radicals, that is, oxygen entities that act vigorously with proteins and other molecules and damage them. These reactive oxygen species are well known to produce a lot of molecular mischief. So when you say that the older you get, the rustier you get is not too far from the truth. Okay, let's look at a few examples of molecular instability. These are just a few of hundreds of examples and they're only presented to give you some overview. Hydrogen bonding, covalent bonds, van der Waal forces, these are all the technical names for the kinds of fancy chemical bonds that hold this mess together. Here's one illustration of the kinds of electrical forces that are necessary to keep a molecule intact. There's a twisting motion that occurs between the elements in a particular molecule that must be kept from twisting too much. I'm doing this to give you some idea of the subtle, very subtle changes that can occur and cause mischief. Secondly, we have angle bending, the angle between this element and this element. If that changes at one or two degrees, the molecule is incapable of functioning. And then we have the third one, bond lengthening. And here you see this illustrated at this point. Let's look at a few of the forces that act now on molecules that are called van der Waal's forces. These are subtle forces that occur between two molecules. And again, I'm not going to go into that detail. I just want to try to impress you with a subtlety of some of the changes that damage proteins. Now let's look at a list, and this again is a very short list, of the kinds of damage that these subtle changes at the molecular level can cause. And I'm not going to explain these very much further than to list them. Those in the audience who have some biological training will appreciate these. Confirmational alterations, which means simply that the tangles of spaghetti were rearranged in such a way that they were different from the arrangement that permitted functionality. Aggregation, precipitation, and denaturation. You know denaturation best when you fry an egg. The protein, or the white part of the egg, becomes denatured and becomes white and edible. Ameloid formation, I mentioned that as a contributing factor to Alzheimer's disease. And finally, rate changes in degradation synthesis and repair of DNA and lots of other things. And finally, one illustration of the repair process, because it's important to know that repair does happen. This is an illustration of repair DNA, the vital message containing, or information containing molecule that's found in virtually all cells. I'm not going to go into this in any great detail, but I simply want to emphasize that these processes are well known. There's a huge scientific literature on DNA repair. In fact, there are thousands of repairs taking place at this very moment in the DNA of virtually every cell in your body. So repair is a very common phenomenon. Now, having given you some idea, at least at the molecular level, of how I think of the aging process, let's talk about the differences between aging and the determinants of longevity. There are three premises involving making this distinction. The first is that for any species to survive, natural selection demands that the energy that's necessary to maintain molecular fidelity, that includes repair and maintenance, must be retained from the moment of conception to reproductive success and if necessary to raise progeny to independence. And I think I made this statement earlier, but I emphasize it here because this is one of the keys to understanding the difference. It doesn't mean that the loss of molecular fidelity does not occur before reproductive maturation. It does occur, but repair processes are capable of making those repairs and the error rate is so low that the repair processes can easily cope with the errors that do occur. A second premise, the best strategy to guarantee survival to reproductive success is to select for redundant physiological capacity and vital organs and better survival skills. Well, this is a principle also known, well known to engineers. When we design a Mars flyby whose purpose is to take pictures and send them back to Earth, if we're smart, we double or in some cases triple the key components of that Mars vehicle in order to ensure that if one of them fails, the second can move over and take its place and that's the insurance of redundancy. And the same thing happens in our biology. We have a pair of kidneys where you can get along with one. We have excess lung capacity. You can, in fact, live with part or all of one lung removed. You can live reasonably well with part of your liver damaged so that redundant physiological capacity is one of the keys to longevity determination. The more redundancy, the greater the longevity. But of course, there's a limit. You can't overload the Mars vehicle with 25 computers because it'll never take off. It'll be too heavy. So there is a trade-off. But this concept of redundancy is key to understanding the difference between aging and longevity determination. The final premise is that this excess physiological capacity gained after reaching the age of reproductive success is what indirectly determines your longevity. In other words, longevity determination is a building process, a process of creating molecules to better guarantee your survival to reproductive maturation. The aging process, on the other hand, is a deteriorative process. Aging doesn't occur in a vacuum. It has to act on something. And the somethings are molecules. And this, then, I suggest is the key distinction between aging and longevity determination. There is a third. There is some conclusions, of course, that follow from these premises. First conclusion is that redundant physiological capacity at the time of sexual maturation governs potential additional survival time. The genome, and by the genome, we mean the genetic apparatus in yourselves, all those things that contribute to your heredity, directly determines events from conception to sexual maturation. Post-reproductive longevity is determined indirectly. Nature didn't devise the redundant philosophy in order to have aging occur. Nature devised the redundant capacity of animals to better ensure their survival to reproductive success. And then what happens after that nature really doesn't care. But the level of redundancy is a good determinator of potential longevity so that this is essentially an indirect determination. The direct determination of your genes is to have you reach reproductive success. The indirect outcome of that is the determination of your potential longevity. Potential longevity is determined by how long the fidelity of molecules can be maintained and how efficient repair and turnover capacity is from the time of reproductive maturity. I've already mentioned that. Fourth, the molecules present from the time of reproductive maturity and those subsequently repaced or repaired form the substrate that ages. Fifth, molecules must first exist free of age changes. Otherwise, babies would be born all or partly old. It's the energetics or the electrical properties of molecules prior to undergoing age changes that determines potential longevity. Now, let me continue and hopefully make another critical distinction. The distinction between aging and disease. And this is an area where many people fail to grasp what I consider to be a key element in this field. There are six reasons. Unlike any disease, age changes occur in every animal that reaches a thick size in adulthood. Unlike any disease, age changes cross virtually every species barrier. Unlike any disease, age changes occur only after the age of reproductive success. Unlike any disease, age changes occur in feral or wild animals protected by humans. Even after that species may not have experienced aging for thousands or even millions of years. We can find rare or unknown species in the wild, put them in a zoo and find out that they go through an aging process which they probably never experienced in the wild. Feral or wild animals are usually die either by predation or disease or accident after reaching reproductive maturation so that they rarely, if ever, reach the extreme manifestations of the aging process, except under circumstances where humans have tampered with their ecological niche. Fifth age change, unlike any disease, age changes increase the vulnerability to death in all animals in which it occurs, 100%. Finally, age changes at the molecular level occur similarly in both animate and inanimate objects. As I described earlier, the loss of molecular fidelity is a universal property of matter. Now let's ask a question that I try to answer a question that's commonly asked. What if all of these age-associated diseases were to be resolved? After all, that's the goal of every medical center, every physician, the National Institutes of Health, every hospital. What would happen if we put all these folks out of business? After all, that is our goal, isn't it? OK, let's tackle that question. Our success in resolving childhood diseases like polio, iron deficiency, anemia, or Wilms tumors did not increase our understanding of childhood development. Similarly, the resolution of age-associated cardiovascular disease stroke and cancer will provide no new insights into the biology of aging. And that's, I think, an important point. Now let's address this question of resolving causes of death. What would happen if all causes of death were resolved? In developed countries like this country, there could only be an increase in life expectancy of about 15 years, period. That's it. If all of the causes of death currently written on death certificates were resolved, a real miracle, this would be the outcome. This is illustrated, I think, in somewhat more detail on a subsequent slide. But life expectancy at birth in the United States today is about 77 years. So 92 years would be the maximum. Absent the ability to perturb the aging and longevity determination processes. So you must keep this clear. If we resolve all disease causes of death, we're still left with the aging process. And to the extent it's mitigated by longevity-determining processes. So the aging process will continue. What we'll have to do in that case is invent a whole new language to put on death certificates because people will not become immortal. They will continue to die either from accidents, of course, or through the loss of physiological capacity in some vital organ, where the loss of molecular integrity will result in the inability of our kidneys, or heart, or lung, or some vital organ to function, and we will then die. Let's look at some of the data on this point. I'm going to list the causes of death in order of their occurrence. Cardiovascular disease and stroke, if that were eliminated tomorrow morning as a cause of death, people born tomorrow would have an additional 6.7 years of life expectancy. People age 65, about 6.25 years of life expectancy. So you see that the numbers between these two extreme ages don't vary a great deal in respect to what would be gained if this miracle occurred. If cancer were cured tomorrow morning, 3.4 years of additional life expectancy would occur in newborns tomorrow, 2.19 of additional years of life expectancy for those age 65. I would suggest that this number is probably much smaller than most of you would have guessed. Then we come to accidents. I won't review these numbers. And then all other causes are lumped in a single category. And this information was derived from this particular source. Of course, we can't resolve causes of death attributable to accidents or homicide, suicide, violence, wars, et cetera. Jay mentioned then what would cause death. Well, before I mention a similar area that Jay discovered, the aspects of the aging process would be the cause of death. And I mentioned what some of those aspects were. The aging process, which usually begins well before most diseases appear, would continue. There's no reason that resolving cardiovascular disease, stroke, and cancer, would interfere with the aging process. It simply would continue. A new vocabulary would be required. And I just mentioned what that vocabulary would entail. This is Jean Calmont again, the famous lady who lived to be 122 years plus. And I mentioned this because I was going to make a distinction between lifespan and life expectancy. But Dr. Olszanski has relieved me of that responsibility. So I'll simply show you her picture again. And what she said later in life to a reporter, for those of you who can't read it, Jean Calmont said, she survived her only child and grandchild. Recalling Vincent van Gogh, she described him as dirty, badly dressed, and disagreeable. He lived in the same town of Orles in France where she grew up. The next point that I would like to cover is why is aging not determined by genes? You have all read, I'm sure, that aging is determined by genes. I and several other of my colleagues do not believe that this is true. And let me explain why. And again, Jay Olszanski touched upon this earlier. Age changes occur spontaneously. And the molecules are both animate and inanimate objects as molecules lose structural integrity and functional capacity over time. Genes are unnecessary to drive a spontaneous process. And finally, the last time I looked at the blueprints for my automobile, I couldn't find anywhere in the blueprints a design feature that caused my car to age. Didn't come as a very great surprise, but the automobile seems to do it all by itself, and nobody has to tell it how to do it. I don't understand why that concept is so difficult to grasp when it comes to biological material. Blueprints contain no information on how a car is to age, so your genome or your genes don't have to contain that information. And nature is very parsimonious. She's not going to introduce unnecessary processes. Conclusions, aging is not a disease, but the process increases vulnerability to disease. The genome indirectly determines longevity by governing the energetics of molecules at sexual maturity, and their subsequent maintenance, repair, and turnover. Now, before I go into that, well, let's do this final conclusion. Genes don't govern the aging process because age changes occur without requiring instructions. I think I mentioned that already. What is research on aging? And I'm going to end on this note. That is some of my own views of research in this field. The rubric, or term, aging research embraces all aspects of the finitude of life, and I've discussed three of them extensively and didn't discuss death at all. Bio-gerontologists do research on the fundamental biology of aging, which is only one small part of what has come to be called aging research. The resources committed to bio-gerontology are small, compared to what is available for other aspects of aging research. Relatively little work is done on the fundamental biology of human aging. Contrary to popular belief, no large research effort is directed toward understanding the fundamental biology of human aging. Example, in recent years, less than 8% of the National Institute on Aging Budget was spent on research on the fundamental biology of aging. You might add that's a liberal calculation. Half the budget was spent on Alzheimer's disease research, the resolution of which will add 19 days onto life expectancy. Now don't get me wrong, I'm not arguing that we should stop research on Alzheimer's disease, not at all. What I'm arguing is that depending on what your goals are, if it is to understand the aging process, understanding Alzheimer's or cardiovascular disease or stroke or cancer is not gonna help. The reason for this and many other funding and priority distortions is a failure to understand the distinction that must be made between the three aspects of the finitude of biological life that I discussed, longevity determination, aging, and age-associated diseases, where most quote research on aging and quote is done. Now, let me be very presumptuous and assert that every morning when a physician wakes up and begins to think of the job they have to perform that day, they utter the following mantra. The greatest risk factor for the leading causes of death, and I've listed them again, is the aging process. So I'm a very simple-minded guy. I'm asking this question, so why is the funding for research on the fundamental biology of aging infinitesimal when compared to funding for research on the leading causes of death? Simple statement, I think. The most important question in research on the biology of aging, in my view, is this. Why are old cells more vulnerable to pathology than our young cells? And unfortunately, I don't know of anybody who's attempting to answer this question. This ends my formal presentation, but before leaving, I'm going to end as Jay did with a couple of cartoons just to try to put a positive note on what is generally a negative subject. Here we find two trees talking to each other, and one says to the other, it's not how many rings you have, it's how many rings you think you have. And finally, we find an old guy on his deathbed surrounded by his family, and for those of you in the last row who can't read this, he's saying, the hell with yogurt. Thank you very much.