Wisconsin Public Television University Place  Living Longer Through Hormone Replacement Therapy  Craig Atwood  12/19/12 UP818  cc >> Welcome, everyone, to Wednesday Nite at the Lab. I'm Tom Zinnen. I work here at the UW-Madison Biotechnology Center. I also work for UW Extension and Cooperative Extension. On behalf of those folks, as well as our other sponsors, Wisconsin Public Television, the Wisconsin Alumni Association, and UW-Madison Science Alliance, thanks for coming to Wednesday Nite at the Lab. We do this every Wednesday Nite, 50 times a year. Tonight is a special time of the year, because we're right up against the winter solstice. It's the shortest day of the year. It's also time to think about looking forward, hopefully, as the days start getting longer. Tonight's talk is on regenerative medicine. 

I think it's really appropriate that, as we bottom out, that we start thinking about better days ahead. Our speaker tonight is Craig Atwood. He is an associate professor in the Division of Geriatrics and Gerontology here at the School of Medicine and Public Health at UW-Madison. He's also Research Director of the Wisconsin Alzheimer's Institute, Research Director at the Wisconsin Comprehensive Memory Program, and a Health Science Specialist with the Geriatric Research Education and Clinical Center at the William S. Middleton Memorial Veterans Administration Hospital, also here in Madison. Dr. Atwood has broad research interests related to the endocrinology of embryo genesis, adulthood and sinesence, as elaborated upon in the publication the Reproductive-Cell Cycle Theory of Aging. Dr. Atwood has published over 200 scientific articles. He's a top-cited author who holds several patents. Dr. Atwood serves as an associate editor, or as an editorial board member for more than 30 scientific journals, including the Journal of Biological Chemistry, as well as on multiple executive and scientific advisory councils. He's a keynote speaker, a chair, a plenary speaker for international and national symposiums, and has been a member on a number of foundations. He has received a number of awards, including the Zenith Fellows Award from the Alzheimer's Association in recognition of his research. 

The other thing that's really interesting to me is that Craig is from Perth, Western Australia. If you've never been to Perth, I think it's the best place on earth. They have splendid people. And if you can take the train from Perth down past Subiaco and Cottesloe, all the way to Fremantle, I don't know what you're doing here. [laughter] So, I think you're in for a really great treat tonight, as Dr. Atwood talks about living longer through replacement hormone therapy. Please join me in welcoming Craig to Wednesday Nite at the Lab. [applause]  >> Well, thanks very much, Tom, for that long introduction, and thank you for the invitation to speak here. Yes, I'm a long way from where I grew up. And to answer your question, I'm hoping the reason that I'm here is to be able to convince you that we can all live a lot longer than what we do currently. So, I'd like to talk about hormone replacement therapy, but I want to put it into the context of why we should even be considering hormone replacement therapy. 

I'd like to sort of look at the aging process, so that we can put into context why we should even consider hormone replacement therapy. So, let's start by looking at a function, as you can see here, function obviously increases in our early years, become stable through the majority of our life, and then starts to decline as we get older. The functions that decline are cognitive, vascular, a whole bunch of different functions in one tissue or another. Wouldn't it be great if we could actually slow this decrease in function so that we could extend our longevity, so that more of us could live into our 90s or 100s? What would be better yet would be if we could actually delay this decrease in function, thereby not only increasing our life span, but also increasing our health span. So let's look at some demographics of aging in the US. This is from the 2010 census. The question that was asked in the census is what is this person's age, and what is this person's date of birth. With this simple question, you can generate a tremendous amount of data. You can see here in the 1900 census that there was about 13 million or so folks who were 65 years of age, or older. One hundred and ten years later, in 2010, you can see that it's more likely to be around 36 million. 

So, we've actually sort of tripled the number of people that are over 65 years of age.  This is sort of also seen in this diagram here, also from the census. You can see there's this burgeoning group of people, the Baby Boomers and Gen X, that are starting to get to an age where they want to start to develop an age-related disease, and obviously, die from one of these age-related diseases. So there's a lot of talk about the fiscal cliff, but really, what we should be talking about is the healthcare cliff, because we have this burgeoning population that are about ready to need therapies for a whole range of age-related diseases. For the most part, they're not there. Another interesting point about this figure is that you can see that women do a whole lot better than men. So this is the number of people, in millions, down here on the X axis, who have reached a certain age. So you can see here where it goes to dark blue, these individuals are 65 years of age or older. You can see that men start to die off much more quickly than women do at this stage.  To the point where if you look at individuals over 65 years of age, for every hundred individuals, and for every hundred females that are 65, there are only 90 males. 

You can see that by the time you get to a 100, for every hundred females that live to 100, there are only about 20 males. Let's look at the oldest-old. That's about 85 years of age. Obviously, you can see that those individuals that live beyond 85 years of age, most fall in the bracket of 85-89 years of age. This proportion decreases dramatically between 90-94, between 95-99, and to the point where you get to 100 years of age, only that one percent of that oldest-old live to 100 years of age. The life span in the US and around the world has increased almost linearly over the last 100-150 years as a result of improved medicine, surgical procedures, sanitation. But in the last couple of years, we've seen a little bit of a plateau, particularly here in the US, where the average has no longer increased. So how do we go about continuing to increase our longevity? One possible route would be to try and understand exactly how and why we age. That might provide us clues as to what strategies we could adopt to increase longevity. Richard Bowen and myself developed a theory of aging about ten years ago, based on work that we're doing in Alzheimer's disease. 

We believe that this theory, which is called the reproductive cell cycle theory of aging, provides a credible reason for why and how aging occurs at the evolutionary physiological and molecular levels. So that's a pretty big statement. I'm going to try to convince you this evening that this theory provides a lot more explanatory power than any other theory on the market.  So the basic premise behind the theory, and I don't have time to go through how we actually developed the theory. You can look at these publications, if you wish to understand how we got to this theory. But the basic premise behind the theory is that the hormones that regulate reproduction in mammals act in an antagonistic pleiotropic manner to control aging via cell cycle signaling. So what does this really mean? This means that the hormones that drive that drive our growth and development early in life in order for us to develop into reproductive adults, become disregulated later in life and drive our sinesence through altered cell cycle signaling. That's what hormones do, they regulate cell division, cell differentiation, and also cell death. So let's look at these main hormonal players in this scenario. To do that, we need to look at the Hypothalamic Pituitary Gonadal Axis, which is the reproductive axis. 

A quick overview of this axis, the axis starts in the periphery, with a group of hormones called the activins. There's many of them, and the biochemistry is very complex. These activins bind to activin receptors on the hypothalamis and illicit the release of gonadatropin releasing hormone. Gonadatropin releasing hormone then binds to the pituitary for release of luteinizing hormone and follicle stimulating hormone in both men and women. These hormones bind to their respective receptors on the gonads for the production of multitude of sex steroids and other steroids, and two of which are shown here, estrogens and testosteronal antigens. These then negatively feed back up on the hypothalamus and pituitary in a negative feedback axis. The gonads not only produce sex steroids, but they also produce inhibens. These inhibens also bind to activins. In essence they act as a second negative feedback loop on the axis. So you have these two negative feedback loops that are regulating the production of these hormones. 

And of course these hormones are the hormones that are responsible for spermatogenesis in men, and for the menstrual cycle in woman. So there's some very important points that we need to remember about these hormones. One is that some of these hormones are very mitogenic. That is, they drive cell proliferation. Another group of these hormones, the sex steroids and activins, are very differentaitive hormones in nature. They're specifying cell fate, specifying function. The other important point to remember about these hormones is that, although they were discovered in reproductive tissues, hence explaining a lot of their names like luteinizing hormone or follicle stimulating hormone, they actually bind to receptors on all tissues of the body, with the exception on the inhibens. Okay? These hormones have receptors in every tissue of the body do any change in the concentrations of these hormones, not only effects reproductive tissues, but every single tissue in the body. Okay, so what happens if the gonads stop producing sex steroids and inhibens? For example, when we reach menopause in women. Here we have a schematic of normal menstrual cycle hormonal changes during female reproductive period. 

Upon hitting menopause you get this complete endocrine dyscrasia. Instead of seeing this nice balance of hormones, all of a sudden the body is seeing this disaster here on the right. Decreases in sex steroids and inhibens, elevations in activins, LH, GNRH, FSH, cortisol. There are dramatic changes that occur around this menopausal window. Remembering again, that these hormones regulate key cellular functions in the body. Men don't get off lightly either. In fact, we perhaps have it worse, because starting at about 30 years of age we lose about one to two percent of our testosterone and inhiben levels every year. We also see this endocrine dyscrasia, but it's more gradual. You can sort of see, you know, that men sort of fade away much more early. Men are under the influence of this diotic signaling, as we call it, under the influence of this altered HPG axis hormonal milieu for a good 20 years earlier than woman are. 

And we believe that this is why men develop age-related diseases earlier, and why we also die earlier.  This schematic is supposed to summarize a vast body of work as to the mechanism behind how these hormones might regulate cell cycle signaling and lead to one age-related disease or another. In essence, we have mitogenic signals, LH, FSH, GNRH, hCG, and we have differentiated signals. If these signals are in balance then obviously we have cellular homeostasis, and also growth and differentiation during that period of our life. But if we lose the sex steroids come menopause and andropause in men, which again, starting around 30 years of age. Then we get this endocrine dyscrasia and we get this aberrant cell cycle signaling. Basically, there's this overwhelming drive for cells to re-enter the cell cycle. Okay? So what happens when cells aberrantly try to re-enter the cell cycle? Well, in the brain in neurons, there's a lot of evidence suggesting that neurons that have been connected up for 40, 50, 60 years, acting to transmit signals throughout the brain, are all of a sudden being asked to divide. There's a tremendous amount of biochemical and pathological evidence showing that these neurons are trying to replicate their chromosomes, they're undergoing mitochondrial biogenesis, growth hormone signaling pathways are obviously regulated, -- is become phosphorated, a cardinal feature of Alzheimer's disease. That only ever happens when a neuron needs to disassemble it's microtubules to divide. 

You get amyloid disposition, which also has functions in cell division and differentiation. What we believe is happening is that neurons in the brain are receiving this signal to divide, they re-enter the cell cycle, but they can't undergo sitokinesis to form two daughter cells. They become disregulated and eventually they die, and/or they lose synapses. When a neuron divides it retracts its synapses and -- processes. So what's happening in the heart? Although the hormonal component hasn't been linked in the heart, certainly in cardio miocites in the heart there's also evidence that these cells are attempting to re-enter the cell cycle. Both of these are very differentiated cell types, but there's evidence that they're starting to re-enter the cell cycle. This is only speculation, but it could be that these cells are pulling in lipids into the cell in order to form the membranes for the daughter cells. But the signal to complete the cell cycle is not there. They get stuck in the G2/M phase of the cell cycle and so they continue to pull in lipids and you end up firm cells and then arteriosclerosis. What about tissues that contain totipotent stem cells like the lung, liver, colon, reproductive tissues? Well, a disease that we often develop in these tissues is cancer. 

Obviously, the more times a cell divides, statistically there's more chance that there'll be a chromosomal abnormality or a mutation that might lead to neoplasia. On top of that, these hormones are also down-regulate the immune system. So immune surveillance is decreased. Obviously, we're all producing a lot of cancer cells in our bodies every day and our immune system eliminates those cells. As we get older that immune surveillance is lost. And obviously, cancer rates, you know, start to dramatically increase when we get into our 60s, 70s and 80s. We have published evidence that even the vasculature in the brain alters upon diotic signaling, upon the initiation on diotic signaling. When we ovariectomize an animal, the blood/brain barrier starts to break down. This could be a precursor, of course, to stroke or the other cerebrovascular changes that are seen with aging. There are significant cerebrovascular changes with aging. 

Bone, okay, so there's a lot of evidence coming through now that it's not necessarily the decline in estradiol, but the elevation in many of these other hormones, like FSH, that are actually driving osteoporosis, driving calcium and phosphate out of bones. The way that it's doing this is that FSH is driving osteoclast production verses osteoblast, and when you change that ratio of osteoclast to osteoblast you have net calcium and phosphate movement out of cells. Then metabolism. There is also evidence of course that hormones regulate metabolism. Obviously the do during pregnancy, and one of the reasons we developed centralized adiposity as we get older, is because of these hormonal changes. This HPG axis disregulation has multiple impacts on the body as we age. It determines, you know, the rate at which degeneration, these degenerative changes, occur, is dependant on how disregulated that axis becomes. The theory doesn't explain who is going to develop what disease and when, but if none of us went through this change in life we'd probably all live a lot, lot longer. What determines what diseases we develop is really up to our own specific genetic and environmental influences. Of course, we all do eventually die, even Jeanne Calment, who is the longest lived individual ever reported, at 122 years of age. 

Here she is at 20 in 1895. The closest individuals to 122 at the moment are sitting at about 115 years. We've got a few more years to see if this limit is going to be pushed back a little bit. But I'd like to try and convince you that we can adopt strategies to significantly increase our longevity. In doing so, offset the diseases. Halt the progression, or halt this aging process, which obviously leads to us developing one disease or another. 26% of us will die from a disease of the heart. 23% will die from a cancer, 5.7% from cerebrovascular disease such as stroke, 5% from lung diseases, diabetes mellitus, Alzheimer's at 3% each. Even the influenza and pneumonia that elder men are particularly susceptible to could be a result of the altered hormone milieu that is in their systems. The theory explains why we develop the majority of our aging related diseases. 

And again, if you want to read more about the theory behind this, you can look up the first paper that was published in 2004 which explains, sort of, the logic and conceptualization and some of our experimental data that led to us formulating this theory. There is a more recent update that was published a couple of years ago, which is really a summery of the experimental data that developed over the last seven or eight years. I've put up here this, sort of, overarching theory of aging, but what's the evidence supporting this theory. I'd like to go through and talk about the epidemiological, clinical and experimental evidence. Maybe we can gain clues from this data as to how we might increase our longevity. Let's look at epidemiological evidence. Women that have a later menopause, i.e. their axis is in balance longer, have a decreased risk of cardiovascular disease, dementia, cognitive decline, osteoporosis, colorectal and breast cancer, although they have an increase in uterine and ovarian cancer. There are ten studies indicating these results. So the longer you have your HGP axis in balance, the less likely you are to develop an age-related disease. Let's do the reverse. 

What happens if we look at those individuals that go through menopause early, or have a hysterectomy? Those individuals have an increase in cardiovascular disease, stroke, dementia, cognitive decline, Parkinsonism, increased osteoporosis and bone fractures increase, late-onset diabetes, increased lung cancer, increase depression and anxiety, but decreased breast and ovarian cancer. So endocrine dyscrasia earlier is associated with earlier onset of these age related diseases. There's 16 studies, many being reported every year at this point. Let's look at some experimental evidence. Let's look at hormone levels as they change. There's a positive relationship between age-related diseases and decreased circulating sex steroids and increase gonadotropins in both men and women. The lower your sex steroids but the higher your gonadotropins, the more likely you are to develop one of these age-related diseases. And of course, men don't get off, low T and elevated LH is associated with frailty, increased prostate cancer, decreased sexual desire, low sperm count, height loss, hot flushes, and many other symptoms.  It's important to remember that these hormones are responsible for our growth and development early on, but they're also responsible, when they're in this balanced milieu, to maintain our tissues, to allow for normal cellular turnover in these tissues. Just as a couple of quick examples, hCG which is the hormone that you measure in urine to determine if you're pregnant of not, human chronic gonadotropin, is the fetal equivalent of luteinizing hormone, which become elevated later in life. 

We've shown that hCG is really essential for driving human embryonic stem cell proliferation. It could be the key hormone given that it comes up very, very quickly upon fertilization. Progesterone, which is produced from the actions of hCG and LH, we show is essential for driving a pluripotent stem cell into a neuronal phenotype. During adult tissue maintenance, LH, estradiol and progesterone have been evoked not only in the brain but in many other tissues as being essential for normal cellular turnover. So important are these hormones that in the brain there's even a feedback axis. If you look here at number two, this was the HPG axis that I described earlier, and what you can see is that we have identified in the brain a number of hormones and hormone receptors and steroids that are identical to other tissues, the the reproductive tissues. The brain can produce its own steroids, known as neurosteroids, and so it appears that there are feedback axes in the brain to be able to control the production of these hormones. That suggests to me that these hormones are crucial for normal brain function. And you might be interested to learn that estradiol levels, E2, in the hippocampus is an high as about eight nanomolar in the male and .5 to 2 nanomolar in the female, which is actually higher than circulating concentrations. So the brain is producing a lot of these neurosteroids and other hormones for its normal function. 

What sort of strategies could we adopt? I'm giving you this story of this foundation that may be keeping this HPG axis in balance might allow us to live longer. So what strategies could we adopt to keep this axis in balance longer and live longer? One would be to go through menopause later. If anybody works out how to do that let me know. [laughter] Later puberty, the later you go through puberty, the more likely you are to live longer. It's highly correlated both within species and between species. Pregnancy and lactational amenorrhea, under those circumstances we're not utilizing follicles, for example, in the female. So the axis is going to remain in balance for longer and interestingly, stresses such as caloric restriction and cold. These strategies, or at least the stress, it keeps the axis in balance, but it suppresses all hormones to lower levels. All the hormone ratios are still in balance, but it suppresses reproduction. Why does it do that? Well, obviously, when an animal is under stress you don't want to reproduce. 

Evolutionarily, this is a way of coupling the environment to our reproduction. Under stressful conditions, no food, predators, cold, we suppress our HPG axis and essentially what we're doing is maintaining our ovarian and testicular reserves, keeping them in place, until a later time, when hopefully the environment will be better and we can then switch on reproduction again and hopefully reproduce successfully.  So two, pharmacological solutions. This brings us to hormone replacement therapies. Obviously, we could attempt to give back the hormones that we're loosing from the testies. The easiest way at the moment to do that is to give back sex steroids. We can give back estradiol, we can give back progesterone. We can give back testosterone, and probably a sloe of other steroids. But we can't replace all the hormones in the axis. It's only a partial replacement. 

We not doing anything to solve the inhibin/activin issue. Hormone suppression therapies, again, a little bit like caloric restriction. You suppress all the hormones to very low levels. This has been shown to be beneficial in Alzheimer's disease, but it's also been shown to have some negative influences with osteoporosis and heart disease. With these strategies maybe we could get another five to twenty years, like in the first scenario. These are the best strategies we can adopt at the moment. I'm going to spend a fair amount of the rest of the talk talking about this. We want to really be driving that axis to the left here. We don't want to be down the right hand of this scale. We want our hormones to be back in balance. 

There's a lot of evidence coming out of hormone replacement therapy studies indicating that in fact this is a strategy that does delay the onset of diseases and increase longevity, so obviously, people are supplementing with sex steroids. Women are supplementing with estrogens and progestogens. Men are supplementing with testosterone. The sources vary however. And this is an incredibly important point that I want to spend some time talking about. What happens of course, is when we give back the sex steroids, LH, FSH, GNRH levels come down. Our sex steroids are normal. The inhibins come up a little bit, but our inhibins and activins really aren't being completely rebalanced. So let's look at some data from Alzheimer's disease trials for the use of physiologically relevant sex steroids. That is, 17 beta-estradiol in women and testosterone in men. 

There are three controlled studies and one uncontrolled study that shows that 17 beta-estradiol actually improves cognitive performance. There are two studies in men that shows that testosterone improves cognitive performance. If we look at prospective cohort studies, 17 beta-estradiol has been shown to reduce the incidence and delay the onset on AD in five studies in older woman. If we simply look at studies where 17 beta-estradiol has been given to older females, typically in their 70s who don't have Alzheimer's and aren't cognitively impaired, 12 of these 15 studies demonstrate that there is actually an improvement in cognitive performance. There's a lot of data out there showing that these hormone, these physiologically relevant hormones are actually very important for cognitive health. Let's look at one of these studies. In this estradiol study elderly women were followed over five years. They either took estradiol or control. Those that took estradiol, 1.7% developed Alzheimer's disease. Those who took the placebo, 16% developed Alzheimer's disease. 

It's quite a marked difference in the number of individuals developing the disease. So the question becomes, why are we not all taking hormone replacement therapy as we get older? Not only estradiol and progesterone in the case of women, but testosterone in the case of men, to prevent not only these cognitive issues, but also these other disease-related issues. The reason, of course, is Women's Health Initiative studies that came out about 10 years ago. In this study they compared Premerin and Prempro to controls. Premerin and Prempro are non-human sex steroids, for the most part. They were developed by Wyeth because it's difficult to patent estradiol and progesterone, the physiological forms. They thought, well, let's just change up the structure a little bit, and we'll patent these hormones and make billions of dollars, which is what they did. They were used initially for menopausal symptoms and they proved to be very effective in decreasing menopausal symptoms. Then of course, women continued to take these forms of hormones, and later on it was found that taking these hormones led to some health risks, including increased risk of cancer, stroke, heart disease and cognitive decline. Let's have a look a little more deeply at the biochemistry of these hormones. 

Premerin is composed of conjugated equine estrogens. These estrogens that are extracted from mare urine. Mares are made pregnant, they collect urine, they extract from the urine 15, 20, 25 different estrogens. It's a mixture. Prempro is conjugated equine estrogens together with a compound called medoxyprogesterone acetate, which is an analog of progesterone, but it's not found physiologically. So let's compare the estradiol and conjugated equine estrogens. I have two steroid structures up here. Would anybody like to guess what they are?  Nobody? They're very similar. This is the only difference between these two steroids. One is progesterone and the other is testosterone. 

And they, obviously, have very different physiological functions. Okay? Small charges in chemical structure can lead to very, very different signaling and functional physiological changes. Let's look at progesterone and medroxyprogesterone acetate. Here we have just a couple of small changes, but biologically we might expect that these hormones have very different functions. And in fact they do. I've just completed a review of the literature for just about every study that's ever compared medroxyprogesterone acetate with progesterone, and in every tissue that we've looked at there are major changes in function. In fact, giving medroxyprogesterone acetate is worse than giving progesterone in many cases, because it's actually blocking any androgens progesterone that might be present from actually having a good function. But unlike progesterone, in these examples in the brain or in neuroscience, you can see that medroxyprogesterone acetate does not protect against glutamate-induced neurotoxicity. It does not protect against neurodegeneration induced by traumatic brain injury. So progesterone is incredibly protective for TBI. 

But it does prevent neurogenesis. One of progesterone's major functions is actually neurogenesis. Let's look at 17 beta-estradiol. Here you can see that it's almost the same as testosterone. It's only two enzymatic steps to estradiol from testosterone. A little bit more conjugation here, and a hydroxyl group. Here is Estrone sulfate which is also found in the human body, but the other 15 or 20 estrogens that are found in Premerin may or may not be. If you just simply look at Estrone sulfate which is often considered to be an excretory product, again you see that there are major biological differences in the signaling of estradiol and Estrone sulfate. Estradiol binds much more avidly to the receptor compared with Estrone sulfate. So when you're giving Estrone sulfate, again, you could be blocking any physiological action that might have resulted from the indigenous estradiol that still remaining in the system. 

Let's just do a quick summery here. 17 beta-estradiol, 100% of studies show impairment in cognition in AD subjects. 80% of studies show improvement in cognitive performance in healthy older women. Those are the studies that I showed you earlier. If you look at the conjugated equine estrogens in the brain however, only 50% of studies show a delay in the onset or halting of the progression. So not an improvement, but you know-- some show a delay in the onset and halting. Others show no change. 50% of studies show an improvement in cognitive performance in healthy older women. And then there are, of course, the one study, the Women's Health Initiative memory study, which showed that women taking conjugated equine estrogens, or CEEs and medroxyprogesterone, were more likely to show cognitive decline. So different forms of estrogen vary in their effects. 

Obviously, the bottom line here is we need to be supplementing our bodies with hormones that are physiologically relevant. In fact, this is predominantly a US problem. In Europe and in other parts of the world, most people do take estradiol and progesterone as their main forms of hormone replacement therapy in the case of woman. Small changes can lead to big differences. This guy has obviously found the magic anabolic steroid. Although it looks like he might be a little Photoshopped as well. [laughter] Okay. Of course, cancer risk. Everyone is worried about cancer risk. This is obviously gained a lot of media attention and is a subject that is constantly thrown up in the air whenever anybody talks about hormone replacement therapy. 

From my analysis of the literature, there's certainly an indisputable increase in the risk of a reproductive cancer, whether it be breast or ovarian or uterine, if you take as estrogen unopposed, meaning, by itself. This is about a one to two women per 100 risk. That's quite a lot. I mean, that's not a percentage that many people can really live with. But we have to ask the question- We know that estradiol replacement therapy decreases the risk of a whole sloe of diseases. I put all the data up just earlier. Does the risk of cancer or other diseases from hormone replacement therapy outweigh the risk of developing other diseases of aging? The answer is no. Okay? There are around 20 studies now that show that even if you take the conjugated equine estrogens, which the majority of these studies are, you actually live longer. About 20% to 50% decrease in mortality. There are no studies that have looked at estradiol. 

One might anticipate, that given that's the major estrogen in females bodies, that for women that do take estradiol, they might be expected to live even longer. Here we have nine studies demonstrating that, again, if you keep this HPG axis in balance, not only do you offset age-related diseases, but you also see an increase in longevity. Women that have later menopause have an advantage. The data that's out there, in terms of the physiologically relevant hormones, indicate that you have a lower risk of Alzheimer's disease, stroke, coronary heart disease, osteoporosis, obesity, metabolic syndrome, late-onset diabetes, depression, anxiety, menopausal symptoms. But maintaining sex steroid levels increases the risk of cancer. It increases the risk of quality of life. And it increases your risk of living longer. You've got to remember, this is only partial hormone replacement. What could we do if we could actually get the whole axis back in balance? I think that the Women's Health Initiative studies have been an unmitigated public healthcare disaster over the last ten years. We should not have been taking these hormones in the first place. 

It's taking a lot of work by basic scientists and others to try and educate the public that in fact those studies, while so important, and we certainly don't want to be taking those hormones, are really not the appropriate hormones that we should be taking in the first place. The good is the physiological hormone replacement. The bad are these analogs that have been developed by pharmaceutical companies to make profits. And the ugly could be considered the negligence of US researchers, healthcare systems, and the FDA, that have suggested that hormone replacement therapy is inappropriate. What should you be taking? That's a large question, and I'm going to very briefly cover that now. What we should be taking are compounds that would get our axis back to where we were at 25 years of age. Who knows what their 25-year HPG axis hormone profile looks like? Anyone? Well, go out tomorrow and get some blood drawn so that you can understand where your hormones might be. Obviously, for women, 17 beta-estradiol and progesterone, preferably transdermal administration, although Prometrium seems to work fine for progesterone also. Opposed, 17 beta-estradiol should always be given with progesterone. Given together you have a decreased risk of cancer. 

The timing and duration, well, as you're coming into menopause it's very important to start on hormone replacement therapy. It's been shown that in the first two to three years leading up to menopause that you can loose up to 15% of your bone mineral density. The window-- They're finding that the first five to eight years is the most crucial. It's the critical window. If you take hormones at this point, you appear to get protection for many years after that. In essence, what we think is happening is that we're blunting this large increase in the gonadotropins, LH and FSH and GNRH. Continuous progesterone might be useful to avoid breakthrough bleeding, although there are advantages to taking these hormones cyclically in order to allow receptor levels in tissues to calibrate. In men, testosterone and perhaps progesterone. Again, we need to know what our levels are. It's easier for men because our hormonal levels tend to be more stable. 

Although there are circadian rhythms in our hormones, we can maybe get a better gage as to what of 25-year levels might be. Excuse me. It's very important that we know this level, because at the moment, physicians are prescribing these hormones but they don't know what your 25-year old level, your optimal level, is. They could be over-shooting it, under-shooting it. Again, route, transdermal. There's lots of AndroGels out there. Progesterone, it's incredibly important for the brain and many other tissues. Do we need to be giving progesterone? I think that's still a question at this point. When do we start giving back these hormones? At 30? Well, maybe that's a little bit young, but I can tell you that getting close to 50, I can feel the change in time. For those that are interested in actually following through, Vicky -- in Waukesha understands these hormonal changes and has been performing hormone replacement therapy for both men and women for about 12 years now, or longer. 

She follows individuals very closely. A recent Danish study has shown that the combined use of estradiol and progesterone delivered in a cyclic fashion doesn't increase the risk of cancer. Approximately a thousand healthy woman, ages 45 to 58 recently post-menopausal, half received hormone replacement therapy. One group had an intact uterus, the other group had had hysterectomy. They stopped the study after 11 years, this was started in 1993, because of the Women's Health Initiative findings, which is crazy in retrospect. They did continue to follow these patients through for about 16 years. The studies were published in the last couple of months. You can see that there was a significant reduced risk of the combined endpoint of mortality myocardial infarctional or heart failure. So there was a 43% reduction in mortality, a 50% reduction in cardiovascular events, a 42% reduction in breast cancer. There was no overall increase in cancer, stroke, or venous thrumboembolism which can be a problem with some sex steroids. 

There's no perfect solution. This is not a miracle treatment, but certainly the evidence is there to suggest that hormone replacement therapy can slow the aging process. Here again we have, from this study, you can see, this is the mortality curve of the hormone replacement group verses the control group. All right, so let's look to the future. Hormone replacement therapy is only partial at best. What can we possibly do to get the HPG axis completely in balance? One way, obviously, is to replenish our gonads, or prevent our gonads from loosing their ability to produce these sex steroids. For this we're looking at ovarian and testicular implants, or hormone replacement-- Oh, sorry, I mean human embryonic stem cell technologies, to actually correct this issue. Obviously, this is currently not possible for humans, but if we could do that, I predict that we could live many decades longer than what we're actually living now. Just one quick experiment here. It's sort of proof-of-concept. 

About the time we published the theory, this paper was published by Dr.Carey out of UPITT, and what he showed was that if you take young ovaries, three month-old ovaries, from a mouse and transplant them into a middle-aged mouse, of 11 months of age, not only do these mice start cycling again, the estrous cycle starts up, but they actually live longer, as you can see from this curve. There was no increase in maximum life-span, but there was certainly a 40% increase in life expectancy. Of course, the new ovaries would have run out after a few months because a mouse is only futile for many three to five or six months. It would be interesting to know if at around this point another ovary had been transplanted in, would we have seen an increase in longevity? But what we do know, and this is information from a Wisconsin longitudinal study, that those women that go through menopause later certainly live longer than those women that go through menopause earlier. Again, keeping this axis in balance is incredibly important for extending longevity. There are many advantages to developing therapies based around manipulating the HPG axis. Not only do we off-set age-related diseases, we can actually off-set all of our age-related diseases. In fact, we're slowing down the aging process. This is not a strategy that is being adopted by most academic or industry folks. They're completely focused on one disease and trying to find a drug or chemical that will solve that problem. 

Obviously, there are other strategies to holding aging. Exercise in my mind is the most important. Certain other compounds have beneficial activity at least in animals models, are shown here. And staying socially and intellectually engaged is obviously a very important component to living longer. Life and death is about balance. It's about hormonal balance. This gentleman obviously has too much testosterone. [laughter] [inaudible] Yeah. I'd like to thank the Live Longer Foundation that has been set up and is supporting research into hormonal-based therapies to extend our longevity. The foundation, basically, supports biomedical research to regulate aging. 

It also promotes educational and informational activities on healthy aging within the community. The mission is to increase our healthy life span through the support of biomedical research through an endowment fund that they've set up. -- interest of which would goes to support these activities. We really are on the brink of being able to extend our longevity. We should be able to extend it many decades. Many people see this as being very skeptical, but the science fiction of today is the reality of tomorrow. Most people didn't think a man would be on the moon back in 1960s. We have the technologies and we the know-how. We understand what's causing aging, and we also have the technology and the resources there, particularly the stem cell technologies. We can couple these now and make huge strides. 

We need to do it now if we want to avert this healthcare cliff. I think we really can push life span out many, many years. The life span was only 50 about 150 year ago. It's now up to 80. It's going to continue to increase, but if we want to make a major leap forward, then we need to adopt these strategies. I'd like to thank members of my lab. Over the last ten years I've been at a number of different institutions following this research path. In particular I'd like to thank Richard Bowen who has been very much instrumental in development of this theory over the years. Also, Siven -- a senior scientist in my lab who has been pushing this research forward also. I will leave it there, and I will take any questions. 

Thank you. [applause]