You Are Getting Older (Part 2)

[00:00:00.11] DEBORAH ROACH: Welcome back, and before we get started, I just want to say, again, please interrupt, discuss because I thought we had a great session last time. And even for those online, please go ahead and submit a question if you have and don't forget to just let me know.

[00:00:26.91] OK, great, so just as a reminder about where we were, basically last time we talked, we were talking about how aging is this due to an imbalance between damage and repair. And this damage and repair eventually gets really off balance because of this increasing accumulation of damage to the body as we get older.

[00:00:52.25] And also one of the positive take-home messages is that about 50% of that variation in the increase in damage is environmental. And so we can do something, and it's environmental. It's behavioral, and so what we're going to do today is I'm going to actually look at a number of different myths that we have, a number of different ideas that are out there about how we can actually modify aging rates.

[00:01:33.09] And what I want to do is I want to link it to those hallmarks of aging that we were talking about before that. Those fundamental processes that are actually causing the aging damage, and then those processes then increase our susceptibility to age-dependent disease. So that's where we're headed today is to look at what sorts of things can be done, and do they or do they not impact these hallmarks of aging, which we want to look at?

[00:02:05.82] Now what I need to do, though, is I need to pick up where we left off, and the last thing we were talking about is this idea-- why isn't my-- let's see if this works. Why are we not able to-- just try the-- there we go. OK, don't know why. OK, thanks, so we were talking about the development of tools to be able to quantify biological aging.

[00:02:45.60] Because remember, any time you look at a group of people that are the same age, you have to recognize that we're all aging at different rates. And so the question is, who is a successful age or who is not? What are the issues going on? And the other very important take home message from last time was that even within our own bodies, different parts of our bodies are aging at different rates.

[00:03:13.65] And that's different within individuals across the spectrum. So we really would like to develop this sort of tool to figure out how we can distinguish individuals of the same age who may be biologically different ages. And the other interest, by the way, in developing this meter of aging is that it will allow us to be able to identify the critical stages that occur in our lifespans that actually may be determining how we are aging and actually then be predictive.

[00:03:54.55] So there would be a lot of very interesting medical uses for this if we can identify that. Now the other thing that I would-- thing that we'll be talking about today is we'd like to use this tool to actually look at these myths of aging, when people talk about different behaviors and so forth that may influence the aging process.

[00:04:22.14] So what evidence can we use to be able to develop this tool and then evaluate these theories and practices. Now I have to tell you that in my lifetime in the field, as a researcher in the field of aging, when I first got started, the biggest thing was grip strength. And someone would come to a meeting with a grip strength meter, and we'd pass it around. And we've come a long way.

[00:05:01.42] But I have to tell you that this is a very active field of research to try to figure out what this meter is going to be, and it ends up to be very complicated because there are so many different physiological traits that need to be put into this to be able to truly understand and to truly validate these methods. But really, what we're trying to do is measure the cell damage and measure the cell damage as it's changing over time.

[00:05:32.99] And remember, and we finished this last time, this idea that this tool will give us a normal change in pattern, if you will, of the relationship between chronological age and some metric that we have of biological age. What are normal individuals doing? What is the average change? And then who are those individuals who are actually aging at a slower rate, and then we can then look at those individuals and understand why they're aging at different rates.

[00:06:13.60] Aging at different rates really means your cell health. Now, the major tool that's being used these days is something that actually quantifies changes, modifications on the DNA that we can look at over time. And I mentioned these because this is actually one of those hallmarks of aging. Remember, over time, the DNA gets certain modifications attached to the surface of the DNA or around the DNA that end up turning the genes off or turning the genes on.

[00:06:55.40] So in fact, these markers on top of the DNA, which are called epigenetic markers, can actually change over time. And here in this figure, you'll see that one thing we know is that these epigenetic markers change ages going down here. And these epigenetic markers increase with age, and a modification is represented here in red as a gene that's been modified.

[00:07:27.27] So we do know that increases with age, but it differs across individuals. And it differs over time, and it also differs with what particular genes you're looking at as well. And so this is a very-- computationally a very difficult thing to put together, and there are lots of different markers using these epigenetic changes that are out there.

[00:07:56.34] And I went out on the web and could easily find several different markers where you can actually order a kit. And some of them are pretty expensive, but don't go out and buy them yet. This is still a work in progress. But on the other hand, there are a number of clocks out there, and people are starting to use these to quantify biological aging. Yes.

[00:08:30.21] AUDIENCE: What would be the point of buying a--

[00:08:31.83] Yeah, exactly.

[00:08:33.12] DEBORAH ROACH: Well, I don't know. I totally agree with you. I mean, what's it going to do if it's going to tell you that-- well, yes, your biological-- yeah, it's fine if it's going to tell you you're younger, but it's not so great if going to tell you you're older than your biological age. So what are we going to do about that? But it's interesting. One of the takeaway messages from the biological aging clocks that we have so far is that-- thanks, thanks.

[00:09:12.71] One is that-- you know what? We were talking about identical twins last week, and identical twins actually converse-- diverge, excuse me, they diverge over time as they get older and older, which is fascinating. Because remember, there were these twins that looked very different ages than each other. And we also know that the rate of acceleration of these marks is actually indicative of different diseases as well.

[00:09:48.71] So we know that there's an increased disease risk, the higher your epigenetic score in terms of cancer, in terms of Parkinson's, in terms of Alzheimer's. These are all markers that are very important. And before I finish, I want to say that the future here in terms of developing these clocks is to not only use these epigenetic markers on the DNA but to also then combine that with things like blood pressure and cholesterol and other blood markers that we have to really get a good comprehensive marker for the future.

[00:10:31.09] AUDIENCE: Do the epigenetic markers eventually get to the same point if we live long enough?

[00:10:38.65] DEBORAH ROACH: No, no, no, just like aging is very different across individuals so people will have different epigenetic markers, even depending on things like early life diseases and early life stresses. And we're going to get to that right now. Yes.

[00:10:57.86] AUDIENCE: The chat says, 2024 AACR meeting offered an abstract reporting that the increase in cancer incidence among young people is a consequence of early aging within the target population drawn from a UK health care database. Conclusions drawn from prevalence of cancer and blood studies showing high inflammatory markers. Any comments?

[00:11:20.72] DEBORAH ROACH: Yes, so high inflammatory markers, in particular, is what I want to pick up on because the inflammation is caused by senescent cells. That was one of our biomarkers-- excuse me-- hallmarks of aging that we talked about. So, yes, I would be curious to know whether or not there were any epigenetic analyses done in that study as well.

[00:11:51.80] AUDIENCE: I might be able to unmute [INAUDIBLE].

[00:11:58.21] DEBORAH ROACH: Shall I go on?

[00:12:00.97] AUDIENCE: I'm here. It was largely a database study. It wasn't clear-- it was an abstract so it wasn't clear to me that epigenetic studies were done. I suspect a full publication will be coming forward.

[00:12:20.35] DEBORAH ROACH: Right, but if I remember correctly, I think that part of this-- the consistency with this study and what we've been talking about here is that it was early life issues that were impacting later life. Is that correct?

[00:12:39.37] AUDIENCE: Yeah.

[00:12:39.97] DEBORAH ROACH: Yeah, and--

[00:12:42.26] AUDIENCE: And I think the frequency of cancer though was in those-- increased frequency was in those under the age of 50. Cancer below the age of 50 and the--

[00:12:58.64] DEBORAH ROACH: Right, huh, well, that sounds that sounds really neat, actually, and I thank you for that. I honestly can't-- does anyone else have any other thoughts on that--

[00:13:19.71] AUDIENCE: Except that it's entirely logical.

[00:13:21.77] DEBORAH ROACH: It makes sense.

[00:13:22.80] AUDIENCE: Almost tautological.

[00:13:24.06] DEBORAH ROACH: Right, right, right, right, right, right, so what I'd like to do is I'd like to, first of all, look at our first hypothesis that's out there that social interactions impact our aging. And of course, I chose this study also because it uses a epigenetic clock to evaluate this. So we often hear that social interactions are good in terms of our biological aging and vice versa.

[00:14:11.20] That in the absence of close relationships, people often experience faster aging. And actually there are studies from other animals, even birds, raised alone versus in groups are aging faster, and you can look at these hallmarks of aging and see that the ones in isolation are declining faster in terms of some of these hallmarks of aging.

[00:14:39.71] And what I want to tell you about is a very recent study actually was published at the end of last year. And this is from the health Retirement Study which is a big group of about 20,000 people, and this is out of the University of Michigan, and all the participants are over the age of 50.

[00:15:02.69] And in this particular part of their study, they surveyed people three times over a span of 10 years. And what they did was at the end of these 10 years, they actually took a blood sample, and they're going to be looking at this epigenetic clock. and I want to tell you a couple of things that are really positive about this study.

[00:15:26.90] First of all, it's a long term study of the same people. It's not just a snapshot. It's a longitudinal study for 10 years. That's great. And also, it's a prospective analysis because they actually measured people's social interactions and so forth at the beginning and then through the study, and then did the blood sampling later.

[00:15:50.58] So the question is, is the level of social interaction, social support, and is that at all reflective of the rate of aging if we can use this epigenetic clock as a measure of the rate of aging?

[00:16:09.20] So they asked these people these survey questions like do you feel like your friends support you and that they understand your feelings? And can you open up if you have a serious problem? The scale goes from no, not at all, to yes a lot. And then how often do you see your friends? And then they also asked this with respect to family and children as well.

[00:16:37.74] So over this time then, so the results were such that individuals who have higher social support and contact frequency with friends had significantly slower epigenetic age than participants who perceived their support to be lower, and they had fewer contacts with friends. And then similarly with family, that the more contact with children and so forth impacted their biological age in the way that we expected. And so they also-- in this study, they also then controlled for demographic traits and took that out and also in terms of health of the individuals.

[00:17:29.71] AUDIENCE: What about sex?

[00:17:30.84] DEBORAH ROACH: And there were no differences between genders.

[00:17:36.36] AUDIENCE: That's interesting.

[00:17:36.99] There's two comments. One person suggested that we hold all questions and interruptions until it ends so that you can finish. And then there's a question that says, what is this imply regarding introverts versus extroverts?

[00:17:51.67] DEBORAH ROACH: Thank you for the second as well. I want to address that second question because this is actually-- I don't know how much they took in personality into consideration, and I think that this is really considered the first step, and this is the most up-to-date study that I could find in terms of looking at social relationships, but yes, there are many other layers to be looked at.

[00:18:22.12] And, in fact, one of the other layers that needs to be looked at is they didn't really talk about negative relationships. They kind of offered our lives for family or sometimes even friends. So, in fact, that's missing.

[00:18:36.37] And the other thing that's missing is that this was done in the US and there may be cultural differences elsewhere, and I believe that it was a completely Caucasian population that they used. So again, there may be differences here as well. So there are limits.

[00:18:55.75] I see a shocked look on one of our members here at the table, and I want to explain that this is a problem with any of these long-term studies that-- and I'm very aware of this in aging that asks volunteers to come in and they're often very wealthy, and they're white, and they're-- it is a problem, and they're usually highly educated too.

[00:19:25.07] And so that there's--

[00:19:26.69] AUDIENCE: Like us.

[00:19:27.84] DEBORAH ROACH: Yes, exactly. But there is a bias. There is a bias, and there's a lot of bias. But this is one of the first applications of a biological clock analysis to social relationships. And so I think at this point, things look-- are positive.

[00:19:51.48] Now what I'd like to tell you where this biological clock in this epigenetic marker was really first used because it's kind of an interesting study, and that is-- I need to remind you perhaps of a little bit of history.

[00:20:09.61] I don't know if you recall, but in 1944-45 in Holland, the Nazis were really actually trying to punish the population because they created this-- there was controversy because the Dutch were refusing to transport Nazi troops, and so the Nazis blockaded the food supplies, and so there was a major famine in the Netherlands in 1944 and '45, 20,000 people died. So it had a major impact on the population.

[00:21:02.48] And one of the things that happened, one of the things-- one of the analyzes that was done was that they looked at people who were pregnant during this time, and this is a time when food rations were very low that the graph here is actually looking at the number of kilocalories per day in the population went way down to 500 during this blockade.

[00:21:35.77] And they looked at children born then shortly thereafter, and they looked at their health and basically, they found, number one, that before the age of 63, they had a 12% higher mortality rate than the cohorts that did not suffer this stress. They had increased obesity, diabetes, schizophrenia.

[00:22:04.78] And now we know because of further analysis that there were epigenetic markers on the DNA of these children following because of this famine.

[00:22:20.11] And there's something that's incredibly interesting, is that one of the major epigenetic markers, one of the genes that was turned off was a particular gene that's in high frequency in centenarians. And in other words, people that we know that live to be 100 have a high expression of this gene is called IGF1.

[00:22:44.56] And it influences the anti-aging pathways that are inherent in our bodies and I'll get to that in a minute, but that was turned off in these individuals. And so here we have a scar of a experience from very, very early childhood, which carried over and increased the susceptibility to age-related diseases and also lifespan. Really fascinating.

[00:23:19.03] But it really is something that people are following up with, and it's clear now people are using-- are actually recognizing that, in fact, a lot of these early life experiences do leave these scars on our genome, which then impact our later life. Yes.

[00:23:44.11] AUDIENCE: Someone put in the chat, it actually depended on what trimester.

[00:23:47.98] DEBORAH ROACH: Yes. Absolutely. Yeah, I didn't want to go into too much detail, but that's absolutely right. There was the particular trimester, and I honestly can't remember which one.

[00:24:01.21] And so it's fascinating, and so now actually there are a lot of discussions going on now about how poverty, how refugee status and things like this are impacting people's epigenome, which will then impact their later life and their rates of aging.

[00:24:22.26] Now before I move on, I do want to remind you we had this figure last week and this was basically these hallmarks of aging that I keep referring to, and so what I wanted to mention was that here we've been talking about these social interactions and the early life experiences that are impacted by these epigenetic markers.

[00:24:47.84] And these epigenetic markers are a major component of our aging biology, if you will. And remember the whole point of the reading that we did the other day last week was basically to say we need to understand this basic biology, and we need to understand that and tackle those issues before we can really understand the age related diseases and the susceptibility that we're really fundamentally experiencing and want to follow up on.

[00:25:25.58] So I'm going to leave this epigenetic clock behind at this point, but it'll come up as we're continuing. What I'd like to do-- there are no other questions, right, Kelly?

[00:25:39.47] AUDIENCE: No.

[00:25:41.88] DEBORAH ROACH: I'd like to shift a little bit and talk about some age-related damage that occurs that I haven't told you about yet, and that's oxidative damage, and I need to talk about that before we can evaluate some of the other ways that we can manipulate aging.

[00:26:02.58] So oxidative damage is a major source of damage to the body. So I have-- there's a tomato up at the top there and it's being left out, and it's declining and it's becoming oxidized, if you will. And in the similar sort of way, our cells also become damaged over time, and suffer from oxidative stress.

[00:26:32.53] And basically this idea that there are all these-- there's a high level of free radicals that are causing this, and I'll tell you about what that is in just a second, but I do want to have you note that there are a lot of diseases and problems here associated with oxidative stress. And so this is a major problem, and this is a major increase-- this is a major issue that we need to address.

[00:27:03.48] Now where's all this oxidative damage coming from? It's coming from free radicals, which are basically molecules that are missing an electron. But no matter what, we end up-- there are lots of different sources of this free radical damage, and so exposure to light, air pollution, and smoking, inflammation that's all causing oxidative damage in our bodies.

[00:27:39.63] And I also want to note right here and we'll get to this in just a second, our basic metabolism actually creates free radicals that cause oxidative damage. The saying is every breath you take hastens your death.

[00:27:57.94] [LAUGHTER]

[00:28:06.40] So some of these things, we can do something about. We can't do a whole lot about. But there are-- we do have defenses against this oxidative damage. Now this is, again, one of these examples of damage increasing with age, but we do have some repair systems.

[00:28:27.92] The central repair system for oxidative damage is antioxidants. So here we have a cell, and these red dots are the free radicals that are damaging the cell caused by radiation, toxins, chemicals, stress. And all those free radicals are bouncing around and causing all sorts of damage in the cell.

[00:28:57.30] Well, we also have antioxidants. They give an electron-- they give up a spare electron and they can stop those chain reactions. They can stop that damage and pull the free radical out of circulation. And basically, they neutralize it.

[00:29:22.38] And so where are these antioxidants coming from? Well, there are two types of antioxidants. We have within our bodies, the primary internal antioxidants that we have. Does anyone know? Has anyone ever-- does anyone want to take a guess at any of this?

[00:29:50.73] I'm going to ask you-- OK, I'll get to the second part in a second. I hope you can. But our internal antioxidants are things like-- you may have heard of sodium superoxide dismutase and catalase, and these are antioxidants in our bodies that actually can attack this oxidation process and stop some of it. We can also we also have secondary dietary antioxidants. Anyone know what those are?

[00:30:33.65] AUDIENCE: Hear about blueberries and dull vision.

[00:30:35.72] DEBORAH ROACH: Yeah, well, they are in blueberries. Yes, there are things like vitamin C and vitamin A. And to get to your point, there are lots of plant phenols and flavonoids and carotenoids.

[00:30:54.65] All of these pigments and so forth that are in plants are antioxidants, and this is for me, when I was teaching aging this was my chance to say, listen to your mother, and these are all antioxidants.

[00:31:13.25] Our foods or our supplementary defenses against oxidative damage, and there's very good evidence that these types of foods and so forth do stop these-- stop this oxidative damage. Now what I want to talk about, though, is to get back to that metabolism a little bit.

[00:31:42.79] So the myth there or fact that I want to address is what about exercise because as I said, metabolism is increasing the free radicals. On the other hand, we went to a function last week at our granddaughters preschool, and on the gym wall, they had this, why should I exercise?

[00:32:13.61] Well, we know that there are some good things about exercising. My stamina is increased, sharpens my thinking, my body gets leaner, helps me relax, relieves stress. So which one's right?

[00:32:27.22] Well, it turns out that we've always thought that exercise was anti-aging, but we haven't really had a lot of good evidence of it except that of course, we do know that there are a lot of positive things that occur.

[00:32:45.02] For example, building muscle and steering away from the decline in muscle gain and that sort of thing. And here, if we just look at the figure for a second, there are lots of other types of positive impacts of aging on the body.

[00:33:08.11] Now what I want to tell you about is a study that was actually published in 2021 where they had 3,500 adults, and they followed them. They were from 18 to 79 years old, and they followed them for 12 years. So again these longitudinal studies to follow what impact does exercise have over time?

[00:33:35.64] And those results are what's pictured here. And so they-- first of all, they compared individuals who were working out about anything greater than 150 hours. In other words, they were-- this is about 30 minutes a day for five days a week in terms of working out, and they compared those to people who did less than two hours a week, so pretty sedentary people.

[00:34:09.48] But these they showed remarkable improvements in all the ways that we might expect them to, and they also had better balance and all that sort of thing. And that's all great, but what about those-- what about aging? And this is really neat because this is the first study that actually ever looked at aging with the markers that we want to use those hallmarks of aging.

[00:34:40.00] And I put a red circle around the hallmarks that were impacted, and you can see absolutely all of the nine hallmarks of aging that we've talked about were improved, and they had markers with from these people over this time to demonstrate that, in fact, yes, exercise does-- it does decrease the number of epigenetic markers.

[00:35:10.15] It does improve protein folding. It impacts every single one of those factors, and so it clearly is a very positive thing. And by the way this happened for individuals at all ages in this study.

[00:35:27.66] But wait a minute-- what about the metabolism? And how do we understand that? And what they found was to go back to our figure here, but now I'm showing the results here. What the exercise did, exercise is a little bit like a stress because it's creating oxidative stress in the body, is creating damage. But it's a levels that these people were exercising in.

[00:36:00.76] What happened was these primary internal antioxidants were up-regulated, and they were actually working harder. And this is actually very-- it's very promising because it's like it's saying basically a good behavior going to-- working out and going to the gym and so forth actually makes your body respond and fight this process of aging. And it's really neat because it says that, in fact, we do have inherent processes that aren't maximized.

[00:36:40.27] Now I need to mention that-- I think you can go back to this slide and you can see-- see the but here? Longevity effects on aging, but the last-- if, in fact, you're exercising an extreme amount, so that extreme amount is about five hours a day for seven days a week. now that's a lot.

[00:37:08.65] But there's very clear evidence from a number of different studies that this actually causes more damage and the repair processes can't keep up. And in fact, there is no upregulation of these internal processes because they're just totally overwhelmed and it's too stressful. There's excessive weight loss, there's chronic injury, and decrease in the immune system and all sorts of things.

[00:37:38.32] So there is a limit, but it's very nice that a mild stress does actually up-regulate the anti-aging pathways that are inherent to our bodies, which is really kind of cool. Now so let me now-- so yes, in fact, exercise does improve your agent in multiple ways.

[00:38:07.45] So what I'd like to do now is to look at caloric restriction because you-- my gosh, this gets so much publicity about people doing fasting, people doing all sorts of reduced diets and so forth to improve their aging.

[00:38:35.08] And a lot of the interest in this has come from studies that were first started with rodents and also with some non-human primates, and I'll show you two-- these are two rhesus monkeys who were put under caloric restriction.

[00:38:59.98] So we have canto here and Owen over here, and they're both the same age. It's kind of like looking at those twins the other day. Now this says-- in the fine print here, it says although a senior citizen is-- average lifespan and capacity is 27 years, and he's aging fairly well. Actually, I'm not sure he looks so happy, but that's how I look. And his skin is smooth and his blood work shows he's as healthy as he looks.

[00:39:32.60] Well, he was getting what? He had about 50% less-- fewer calories than Owen who gets more food. His posture has been affected by arthritis, his skin is wrinkled, his hair is falling out, and he's frail, and his blood work shows unhealthy glucose levels. So clearly, there's evidence from animals.

[00:39:58.88] Some of the other-- in some of the rhesus monkeys studies, there were differences in lifespan, and that's been shown in rodents as well. Lower core body temperature is another common feature, lower blood pressure, delayed reproduction is also a common response to this treatment.

[00:40:27.13] But again, we haven't had many studies done with humans, although many people want to just believe this and just go for it. Now there is a long term study that's been going on. It's actually started in 2007, and this is-- it's called the calorie study, meaning the comprehensive assessment of long-term effects of reducing intake of energy. That's where calorie comes from.

[00:41:01.18] This study was started in 2007, and it has about 220 individuals in it. My first exposure to people who were part of this study was at a meeting in the middle of the summer in a big auditorium, and it was-- I remember giving a talk and asking someone later, who are those people in the back row with their ski jackets on? And they said, those are the calorie people. They come to all these meetings. And their core body temperature was clearly being impacted by their treatments.

[00:41:42.27] Another common response to this is extreme fascination with food and psychological issues and depression and so forth associated with having to live under these-- to do this type of cutting back now because most of these in the calorie study, the goal is generally to have a target reduction of about 25% of normal calorie intake.

[00:42:20.54] And what I want to tell you about, though, is a study that was just published in 2003, and this was, again, one of the very first studies to be able to look-- that actually looked at these hallmarks of aging, and asked the question, does this work in humans?

[00:42:45.20] And the target now was that they were going to go-- they were aiming for 25% reduction in caloric intake. It actually ended up to be about 12%, and they can measure this by doubly-labeled water and so forth. And there was also lots of behavioral support for people to stay on the diets, and to keep the participants from dropping out of the study and so forth.

[00:43:16.89] So the results were-- the graphic shows that basically the muscle health was something that was well preserved in this study because that was quite surprising because, in fact, on average, individuals lost about 20 pounds in the first 12 months, but then after that, they didn't lose weight.

[00:43:46.86] But their muscle mass was conserved, and their muscle function was preserved. The only other treatments that have ever been shown to actually do that are exercise to preserve this.

[00:44:02.78] The other thing that's very interesting is that now this study went on, they followed these individuals for only two years, OK, and so this is just a two-year study. So we don't know how it impacted their mortality rates and that sort of thing. And the study was actually relatively small because in the end, the they had only 220 individuals monitored, and the numbers were too small to be able to do a lot of analysis, but they did do some good blood work.

[00:44:38.12] And looking at these hallmarks of aging, in fact, they did find that things like protein folding, things like cellular senescence, and epigenetic markers were all improved. Everything that has a red line around it suggests that, in fact, that this did work and that this short-term study does suggest that there are some positive things about caloric restriction.

[00:45:12.57] Now as I said, it's a very difficult thing to think about doing, and it's very hard to do, and in fact, many people are trying to look at the pathways and say, OK, so what's going on when we're doing caloric restriction? And can we impact it in ways other than reducing calories? And it turns out that just like exercise, this is a mild stress.

[00:45:40.32] Caloric restriction is a stress and in response to that stress, the antioxidants and other pathways are actually up-regulated, and there's very nice evidence that there are these-- the anti-aging pathways that are being affected here are again inherent to our organisms-- to our bodies, excuse me.

[00:46:06.63] And so , again, the sample sizes are small. It's very, very difficult, and there are a number of pharmacological mimics that people are trying to develop that would actually try to touch these same pathways and get these same results. So we'll see.

[00:46:29.76] This is something that I'm sure there'll be more written about in the future, but yes, it's very interesting and, in fact, caloric restriction does seem to be working-- does seem to work.

[00:46:45.00] So how about-- thinking back to Madame Calmette from last week, what about that red wine? Remember I said--

[00:46:53.35] [LAUGHTER]

[00:46:54.71] That sparked a little conversation last week. So does red wine decrease your rate of biological aging? And this came out of what was called the French paradox. This idea that how is it that the French can have this high-fat diet, so much cheese, and actually still have a relatively long lifespan within the population?

[00:47:27.07] And so one suggestion was that it was the wine. And, in fact, there's something particular in the wine. It's this substance called resveratrol. And resveratrol is on the market, and you can buy it online, and it's supposed to help fight dangerous free radicals, help slow the aging process and all that sort of thing.

[00:47:57.66] AUDIENCE: Oh, come on.

[00:47:59.19] DEBORAH ROACH: Yeah.

[00:47:59.34] [LAUGHTER]

[00:48:00.72] OK, well, wait a second. This is still out there as a suggestion for aging, but I have to tell you about another study that was done with mice. Now these mice, there were three groups of mice.

[00:48:25.29] In group 1, they had a high fat diet, 60% of their calories from fat. Really high-fat diet. Group 2 had the high-fat diet plus resveratrol. And group 3, which is our control group, is a normal diet.

[00:48:43.74] Well, the mice in group 1 gained a lot of weight, and they started dying early and they had issues with a lot of blood markers associated with diabetes and that sort of thing. They were having a hard time. They had a relatively short life span.

[00:49:07.51] The individuals in group 2, they still had a weight gain, but they did not have those markers associated with diabetes. And, in fact, they had an extended life span that was the same as those mice in group 3. So the resveratrol had some impact, and that's why this got so much excitement and so much publicity. I think a cartoon in The Washington Post really summarizes the issues.

[00:49:46.38] So honey, you'd be better-- you'd be healthier if you lost some weight. Listen, there's good news. Scientists gave obese mice a compound found in red wine, and the mice stayed healthy. The study said that to get the same dose as they gave the mice, a person would have to drink between 750 and 1,500 bottles of red wine.

[00:50:14.51] [LAUGHTER]

[00:50:17.47] And see? It's getting better and better. OK?

[00:50:23.37] [LAUGHTER]

[00:50:26.22] It doesn't work. It doesn't work. But there are-- right now there are studies that are being done by the same group that in fact, tried to push resveratrol as an anti-aging cure.

[00:50:50.11] They're now working on trying to figure out what this pathway is, and can we find some other pharmacological solution to do this? Right now they don't have anything. There's nothing out there, and the resveratrol itself doesn't work. So what I'd like to do--

[00:51:14.26] AUDIENCE: Yeah, but we still want to drink our wine.

[00:51:16.15] DEBORAH ROACH: Yeah, you can have your wine, yes, but at least you don't have to poison yourself with alcohol--

[00:51:20.71] AUDIENCE: --1,500 bottles.

[00:51:23.59] DEBORAH ROACH: That's right. That's right. Now there's something else. I've presented this last thing as a myth or a fact but, in fact, it's really something that I-- the only reason I want to present this in this way is that it's something we all need to be looking for and at. And what I'd like to talk about is some future work that's being done. It's actually going to target some of the damage and removing some of that damage.

[00:52:03.81] And so because-- the whole idea here is that if we could remove damage from the cells, then maybe, in fact, we will then reduce our susceptibility to age-related diseases, and maybe we'll be able to maintain our health span if we can remove damaged cells.

[00:52:22.32] And I want to tell you the basic problem here is that-- so here we have a young individual, and we have healthy cells, all these white cells, and then we have a few senescent cells. And senescent cells are really defined as cells that have stopped dividing, but they're still alive, but they're non-functioning.

[00:52:51.20] And what happens is that these cells that are still there but they're not dividing anymore, actually excrete these red substances which are called senescence activating substances. And so they're causing-- they're starting to cause a little bit of inflammation.

[00:53:11.75] And as we get older, we have even more of these senescent cells, and the excretion of these senescent activating substances is actually decreasing the function of healthy cells and making healthy cells decline in their function as well. And so we have lots of-- this is actually the major source of information.

[00:53:42.14] So the idea is, what if we could remove some of these senescent cells? And the reason that this is so important for us to want to talk about removing senescent cells is that, first of all, we have this increasing number of senescent cells as we get older, and that just exposes us to more and more of these age-related diseases.

[00:54:10.80] And as you can see, we get all the way out to the end there. And we've got frailty sarcopenia, which is muscle declines and decreased healthspan. And all of that can be traced back to this accumulation of aging cells.

[00:54:28.74] And so the hope here is that maybe-- what happens if we could remove some of these cells. And so normally, our immune cells will help to remove some senescent cells, but our immune system declines with age and that process becomes more and more-- becomes less efficient.

[00:54:55.97] And so there are these drugs that have been developed, these senolytics that basically-- the idea is that they will then repair-- they will then eliminate these senescent cells from our bodies and repair and help us maintain function.

[00:55:17.08] And the neat thing is that there's good evidence in mice that this is going to work because-- so what they've done is first of all, they took old cells and they put them into a young mouse, and the young mouse got older really very quickly. And then they actually gave these senolytic drugs to old mice, and actually they maintained their health for longer, and they actually lived longer.

[00:55:52.70] And they even did it the other experiment where they put these senescent cells in the young mouse, and that they also gave them these senolytic drugs and they live longer, and it lived they lived-- there wasn't the same declines that they had found without the drugs.

[00:56:11.04] And so in many ways, this drug is a fountain of youth, and people are really actually very excited about it because it can be used to target cells. For example, it can be used to target cells that are causing neurodegeneration, cells that are causing osteoarthritis, and arterial arteriosclerosis, and there are-- so there's a lot of interest in using these target drugs to look at different systems.

[00:56:46.86] And so I looked up this morning to see what human trials are going on, and they are starting to recruit. We don't have any data on this yet, but they are starting to recruit people to actually use these senolytic drugs, and they have been approved to do so in some situations.

[00:57:08.12] And interesting thing is that you might want to ask what is this senolytic drug? What is it? What's it all about? It turns out it's a combination of a leukemia drug and also the plant compounds that are found in fruits and vegetables, and it's this cocktail that is somehow, at least in mice looks very promising. So I can't tell you whether or not this is fact or fiction yet, but it's something to look forward to.

[00:57:43.88] I'm running short on time, so let me just-- I'm going to skip forward and say that, yes, you can modify your rate of aging, and remember when we started out, we talked about-- the goal of research in aging is to try to minimize this period of time here, this age related-- when we were suffering from age-related diseases and to expand our health span as much as we can.

[00:58:17.55] Factors that are slowing aging that we have talked about are having a robust social support, healthy nutrition rich in antioxidants, low calorie intake, no smoking, moderate exercise and appropriate responses to stress. And factors that are accelerating aging are just the opposite of those.

[00:58:39.18] And in fact, there is increasing evidence these days, and in fact, we can modify our rate of aging, and then also improve our health span, which is actually pretty exciting. So I'll leave it at that, and I know I've just come to the end, but if there are any questions, I'm happy to answer them.

[00:59:08.05] AUDIENCE: Now the red wine comes out, right?

[00:59:09.76] [LAUGHTER]

[00:59:11.59] DEBORAH ROACH: That's right. That's right. So are we all set on line 2? Good.

[00:59:17.92] AUDIENCE: We're going to talk again about the lobster because it sounded like that's what we want to do with this. We want to--

[00:59:24.61] DEBORAH ROACH: Throw away our bodies now. We can't do that. That's right. That's right. That's right. That's right. Yeah, we can't really do that.

[00:59:33.04] AUDIENCE: Where were the studies that you saw.

[00:59:35.41] DEBORAH ROACH: Pardon me?

[00:59:35.89] AUDIENCE: Where were the studies that you saw?

[00:59:38.43] DEBORAH ROACH: All over the place. And this is something that-- this is one of the reasons I really enjoyed teaching the biology of aging was that every time I looked and including for these talks, things are updated, and it is a fast-moving field, and that's we-- it's nice. And there was more and more coming for sure.

[01:00:04.99] AUDIENCE: I want to ask if your slides would be available.

[01:00:07.91] DEBORAH ROACH: Sure. Yeah. Yeah.

[01:00:11.26] AUDIENCE: Can you talk a little bit about appropriate stress response versus a poor stress response?

[01:00:16.81] DEBORAH ROACH: Yes, well, we could go back to the exercise and see that extreme exercise, of course, was bad for the body, but appropriate exercise actually regulated natural anti-aging pathways.

[01:00:33.61] And in a similar sort of way, when we think about psychological stress or any other types of stress where we up-regulate our corticosteroid levels, and if we stay-- if we have a high level of sustained stress for a long period of time, that actually costs the body.

[01:00:57.49] And it will cost the body in terms of epigenetic markers that we've been talking about and it'll also stress the body in other ways, whereas if appropriate response would be somehow to modulate that and address stress issues in a managed way that keeps those stress hormones at a low level. Yes.

[01:01:25.16] AUDIENCE: I'm so stressed right now, and have been for months that I cannot find a good stress response. Sorry. I've seen shrinks, I don't know, It's hypothetical, of course. So what it's suggesting there is really not that--

[01:01:50.84] DEBORAH ROACH: No, well, I think what I'm suggesting is recognizing that and trying to figure out what is an appropriate response and try to figure out things like-- well, what other things could you do that are good for you? Make sure you diet. Make sure you're exercising. Make sure you're getting out in nature. Those types of things.

[01:02:16.85] AUDIENCE: Do something about the politics of the society that I'm in.

[01:02:21.62] DEBORAH ROACH: Stop watching the news. There you go. Yes.

[01:02:27.14] AUDIENCE: Perhaps consistent mild exercises you're taking seems to reduce stress. I mean, if you're under-- if you have a stress that you can't change the stress but you may be able to change your response to it.

[01:02:45.88] DEBORAH ROACH: Right. Yeah, I think that's right.

[01:02:49.51] AUDIENCE: James said, I'm 83. When do you think the senolytics will be available?

[01:02:53.92] [LAUGHTER]

[01:02:56.62] DEBORAH ROACH: I wish. Yes, there are a number of things that are being developed these days. That was just the one that I chose to talk about, but yeah, there's a lot of stuff that's out there.

[01:03:09.05] And there are also a lot of these pharmacological solutions that are targeted at the dietary restriction, and there's one that's called rapamycin, which actually was discovered in the soil on Easter Island, and it was first discovered because it's an anti-inflammatory agent and people were interested in that with respect to the immune system of people who are on Easter Island.

[01:03:44.03] AUDIENCE: Are there studies of taking through fields as it were the reserve patrol, so you don't-- I mean, a few glasses of red wine is fine, but 1,500 day is a bit much. But can you take enough resveratrol not to have side effects? Perhaps you wouldn't get the pleasure--

[01:04:08.04] DEBORAH ROACH: This is one of the-- these side effects are a major issue on all of these types of pharmacological interventions. And with respect to the resveratrol, it turns out that, in fact, it has a very short shelf life. And so by the time you get the little bottle of pills, a lot of them may have lost the-- be out of date. And so that's another issue with respect to that particular drug.

[01:04:35.33] And as I was saying with this substance that they are now working on with respect to dietary restriction and this idea that maybe there will be things out there that we can up-regulate these pathways, but then still have a regular diet, and not have to take reduced calories and that kind of stuff.

[01:04:58.24] AUDIENCE: Is there a theory to why women live longer?

[01:05:01.50] DEBORAH ROACH: Well, I'd love to TALK-- So the question is-- the question is, why do women live longer than men? And does anyone have any thoughts before I--

[01:05:14.98] AUDIENCE: We do a lot of those things that you talked about.

[01:05:20.05] DEBORAH ROACH: You're saying better-- you're saying we're better behaved.

[01:05:21.99] [LAUGHTER]

[01:05:25.30] I'm not going to go there.

[01:05:30.40] AUDIENCE: Female babies do better than boy babies in the nursery. So some of it is probably genetic.

[01:05:37.81] DEBORAH ROACH: They do. And, in fact, this difference between males and females starts really early stages in life.

[01:05:49.47] AUDIENCE: Yeah, you talk to a pediatrician.

[01:05:50.57] DEBORAH ROACH: That's right. And I have to tell you, though, that it actually-- there's no evidence right now that in humans, that females have a slower rate of aging than male in terms of the biological. If we could measure biological age at this point in time, there's no evidence.

[01:06:11.61] And so a lot of it has to do with the fact that we have two X chromosomes and then males have XY chromosomes, and any genetic diseases that may be carried on an X chromosome that may on one of our X chromosomes-- would be expressing it from the chromosome that actually does not have that defect.

[01:06:42.33] Whereas a male they have an X chromosome disease. They have to express it because they don't have that duplication of genes. And in fact, there was also a really neat study in today about two weeks ago, about the disappearing Y.

[01:07:01.65] Someone at UVA was doing-- is doing a study about the Y chromosome and diseases on the Y chromosome. And in fact, so that-- in fact, the Y chromosome itself may carry some genes that impact lifespan in males. And then there's also questions of hormones. Estrogen is generally positive impact and testosterone is it can be associated with some behaviors that are not positive. Yes.

[01:07:38.41] AUDIENCE: I don't know whether it was a UBI study or not, but I read recently there's been a number of new genes discovered on the Y chromosome. So yes, and I don't know whether they're good ones or bad ones.

[01:07:49.69] DEBORAH ROACH: Yes, right. No, but that's right, but the trouble is that there's no duplication, and so you're stuck with what have. Yes and so, yes-- that's another reason that females live longer than males.

[01:08:06.70] In some situations and there's also a lot of discussion about whether or not there may have been some selection for females to live longer than males. In other species because of their maternal care.

[01:08:21.01] And so if there's any selection for longevity because it increases it's survival of the offspring, may be the case. And there's a bit of a controversy about that with respect to human populations, and there's evidence on both sides.

[01:08:38.32] But it's absolutely true with whales. And pilot whale females live to be 90 years old. They stop reproducing when they're 40, but they live to be 90. And but if the female dies then her offspring have a higher chance of dying as well. And if she's not around because she is beneficial-- primarily because she's a wealth of knowledge about when best to find the salmon and food sources.

[01:09:08.45] And so it's neat and similar sorts of patterns are found in elephants as well, the elderly matriarch is quite critical to the survival of her offspring, and if she dies, then it's a problem. I could keep going.

[01:09:26.68] [LAUGHTER]

[01:09:30.95] But thank you very much, all of you.

[01:09:32.58] AUDIENCE: Thank you.