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Up One cuts through the noise of health and wellness trends. Hosted by Sawyer Stone and longevity scientist Dr. Bill Andrews, each episode unpacks peer-reviewed research on supplements, therapies, and diagnostics - no fluff, just facts. If you're serious about the science of aging and human performance, it's time to take it Up One.
Sawyer Stone: [00:00:00] Welcome to Up one, the podcast where we take a deep dive into the science behind supplements, therapies, and diagnostics. I'm Sawyer Stone, your Guide through the Maze of Health Claims. Here to ask the big questions.
Dr. Bill Andrews: And I'm Dr. Bill Andrews With decades of experience in medical research, I've dedicated my career to uncovering.
The real science behind disease, aging, and human health. On this podcast, we don't just skim the surface of scientific studies. We conduct a critical meta-analysis separating credible research from misleading conclusions.
Sawyer Stone: There's a lot of noise out there, conflicting studies, bold claims, and endless marketing up.
One is here to cut through it all and bring you science backed insights that you can actually trust.
Dr. Bill Andrews: We're talking prevention, diagnostics, treatments, and the big questions shaping the future of health.
Sawyer Stone: If you're [00:01:00] serious about understanding the science of health and longevity without the fluff, let's take it up one.
All right, Dr. Bell, it's good to chat with you again today we've been talking about menopause or we've been talking about doing an episode on menopause. 'cause menopause kind of comes up a few times throughout our podcast history. And when we brought it up, you immediately thought of Dr. Sandra Kaufman, who is our special guest today, and I'm very, very excited about that.
Dr. Kaufman, thank you so much for coming on up one and hanging out with us. Could you tell us a little bit. Like a little background about yourself, background in your research on menopause or why Dr. Bill maybe thought about you first for menopause.
Dr. Sandra Kaufmann: Um, sure. So, so I set the record straight. I'm not a menopause expert per se.
I'm a longevity physician and I think that it's kind of a canary in the coal mine event in a woman's life. So, um, bill thinks of me 'cause. I love Bill. Uh, we, we have [00:02:00] many interesting, cool, fun scientific, uh, conversations all the time. And so I think it's just fun to chat with him all the time. Yeah. Um, but, but who am I?
So, uh, I was a cell biologist once upon a time. I was a plant physiologist, tropical ecologist. Um, I went to med school. Um, I, I like to think of it as having sort of a liberal arts degree in medicine. I did a year of, uh, neurosurgery. I did a year of general surgery. Ended up as an anesthesiologist. Wow. Did a fellowship.
So I'm a pediatric, uh, anesthesiologist. I was in practice for God a million years. Um, decided to stop aging about a decade ago. Came up with a system, which sort of works. Sort of doesn't work, but it is what it is. Um, and here we are today.
Sawyer Stone: Wow. Fascinating.
Dr. Bill Andrews: And I would like to add, I. Uh, part of my critical meta-analysis is not just learning what's true and what's not true, but it's also identifying the people that really do know this stuff and yes.
Yeah. Sandy, [00:03:00] Dr. Kaufman just mentioned that she's not an expert, but she is, in my opinion, she understands the science and biology of medical things a lot more than most medical people in the field. And that's why I thought she would be the perfect person to be on this podcast.
Sawyer Stone: Great. Thank you. I love that.
I talk about, um, Dr. Kaufman. I, I am 32 just for clarity. So I'm not quite in the menopause area yet, but a lot of my really close circle is, was born in 1979, funnily enough, and so they're all 46. You know, moving forward. So they're all sort of either in the middle of a perimenopause situation, in the middle of maybe an early menopause situation or have been dealing with all of these various symptoms.
And so I hear about it a lot and so this is definitely an important thing for me to be able to discuss. So as we jump in, maybe first things first, what is menopause?
Dr. Sandra Kaufmann: Bill, [00:04:00] you want me to do it? Sure.
Dr. Bill Andrews: We're gonna, trying to figure out who to go. I, I do understand a lot about menopause and stuff like that.
I'm just afraid that if I go first on things, I'll find out that I di di, uh, differ in what I say that Sandy, Dr. Kaufman might say. But I, I can tell you that what menopause is. It is very, very confusing. I don't think really anybody really understands it. And you know, the thing is, is that what makes it really hard to study is that humans are the only land animals that actually have menopause.
Uh, and the only other animals are some whales and things like that. So menopause is very unusual in nature, and it might be totally the reason why humans have menopause is. Simply randomness. Okay. Just by accident. And it, it, we can probably blame one woman for the whole existence of menopause in, in [00:05:00] humans.
And that's Mitochondria Eve. Okay. Probably had a situation that was a different from everybody else. I don't wanna call it abnormal or something like that, but different from everybody else where she had. Uh, lost reproductive abilities before her natural, uh, lifespan was concerned. And that was 150,000 years ago.
And, uh, all, every, everybody's biology can be traced back to Mitochondria Eve, a single woman. And she just probably had this, and therefore, now everybody, all humans have it. There's been no explanation as to why there'd be an evolutionary advantage to humans. To have menopause. It's just completely neutral.
And so there's no and no reason to ever prevent it either. But we do have it and, uh, or at least women have it. And, uh, that's, that's the bottom line. Uh, but it's a, Sandy, do you want to add to that or,
Dr. Sandra Kaufmann: so, so I guess I don't [00:06:00] really, I mean, I should, as an evolutionary biologist, think about why we have it. I think more about what happens to your organs in terms of why we have it.
Sawyer Stone: Hmm.
Dr. Sandra Kaufmann: Um. If you think about, so you, you, you can think about life on many levels, right? There's cells, there's tissues, there's organs, there's systems, right? So depending on where you stepped in and out of med school or whatever, your, your perspective is going to be a little bit different. Um, and I have like a.
An advantage to a certain degree that I started out as a cell biologist. So my focus has always been cells, but as a physician, we were trained in organs, and as an anesthesiologist, we're trained in systems. So I get to sort of think of like, I get to jump through hierarchies rather than being pigeonholed.
So when you think about different organs, for example, your kidneys start failing when you're 18.
Sawyer Stone: Wow. We don't know
Dr. Sandra Kaufmann: why. It just does, right? Your GFR drops when you're 18. Your brain doesn't even finish developing until you're 25, right? So every [00:07:00] organ has some sort of genetic predisposition to peak rise, fail at different times, and we don't really understand why, but it does.
Is it oxidative stress? Is it glycation? Is it tel your length? We don't really know, right? Sure. Menopause is simply ovarian failure. That's what it is. I'm sorry, boys don't have it. Right. But we do. So it's what it is, right? Yeah. So why do ov, why do ovaries fail at a particular time in a woman's age? Um, and not, you know, it's, it's, there's, there's huge variation, right?
Life is a bell shaped curve. Average age is gonna be like 48 to 50, but some are pre and some are post, right? Um, and I just think that it's just cell failure that occurs based on a very high metabolic and mitochondrial requirements to make eggs. It is extraordinarily, metabolically expensive.
Mitochondria, or we are little organisms. [00:08:00] I love them because they weren't us, right? We, we sort of, we took them in. So if you look at the pieces and parts of mitochondria, they're different from the rest of our, our rest of our cell. Right. And they fail for seven different reasons. And the more you have, the more apparent it is when there's failing.
So I actually like to think of menopause as the canary in the coal mine for women saying, you are aging. This is serious. It's time to like be incredibly proactive so that all of your organs don't take a dive.
Dr. Bill Andrews: Oh wow. Let me add, I mean, we don't know the answers and so we're gonna find out that maybe I'm gonna, I don't know.
I'm calling you Sandy during this conversation.
Dr. Sandra Kaufmann: No, no, absolutely. I call you Bill. I mean like,
Dr. Bill Andrews: alright, so
Dr. Sandra Kaufmann: I call you Dr. Andrews, but that would drive me nuts.
Dr. Bill Andrews: We might have some discussion back and forth on really best guesses and stuff like that, but, but the thing is that. Yeah. Okay. So most biologists, they don't take courses in like, uh, um, statistical theory and, um, [00:09:00] mathematical modeling and things like that.
When I was in college and stuff like that, I complained to my counselors about that and they said, go take classes in. Psychology, experimental psychology. So I, I learned a lot of this stuff in experimental psychology. But one of the things from especially statistical theory in a mathematical model, and then also artificial intelligence, is courses I took back in the seventies, the graph of like when women actually enter menopause.
Doesn't follow the trends of what you would expect if it was due to environmental factors like oxidative stress and uh, things like that. And so it is like there, there's gotta be some kind of timing mechanism, some kind of clock and nobody knows what. Yeah. Try to figure out ways of including teal nerve biology in it, but it makes no sense.
Uh,
Sawyer Stone: yeah.
Dr. Bill Andrews: So it might be just accounting mechanism. Now Sandy mentioned mitochondria. It, it's actually. Mitochondria might be dec mitochondria decline [00:10:00] might be the result of, uh, uh, menopause, not the cause of menopause. It is like, who knows? Uh, but there's, you know, like PGC one Alpha genes and stuff like that, they're controlling.
Totally controlled by the nuclear chromosomes and the telomeres. And they may be playing a role in, uh, causing, uh, well actually that the key thing is that PG one C alpha is controlled by estrogen. I know we're probably getting ahead of things, but it's po that it's possibly that, uh, the mitochondria decline is be, is due to the decline of estrogen causing a decline of PGC one alpha, which are major proteins in mitochondria.
Dr. Sandra Kaufmann: See, well, I would, I would argue, like basically it's not linear at all. It's completely circular, right? It's, it's because you get decreased estrogen, you get the decreased PCG one alpha, so you get decreaser two and three, which means you get decreased energy, which means you get decreased estrogen, so on.
And both, you know, it's, it's the negative spiral. Yes. I think, I don't think it's linear. I think it's a big [00:11:00] cobweb of interconnections. And the question is. Can we, can we intercept some of those interconnections and improve the situation? I mean, that, that's really the question.
Sawyer Stone: So, uh, I have a question. So my basic question is, is menopause associated more with biological age or chronological age?
But then also, does menopause happen at the same sort of rate for your body that you first bled? Like if you first bled early, are you gonna go into menopause early, or are the two things not correlated?
Dr. Sandra Kaufmann: That's a good question and I don't actually know that. Okay,
Dr. Bill Andrews: sure. I've never seen anything discussing the, uh, onset of puberty versus the, uh, uh, age of menopause.
But I do know that there is a range and a lot of the range is caused by. Genetics and, and caused by environmental things too. But it's [00:12:00] like still the, the, it's still a narrow range of age that, that menopause occurs. So it's those, those things can't be the primary factors, but they do have an influence on affecting the timing of menopausal a little bit, but yet timing of it, it just makes no sense.
Dr. Sandra Kaufmann: But what, but what's interesting though, is, so let, let, let's jump to another parallel kind of organ system. Let's, let's think about presbyopia. 'cause this is another one of my favorite things, right? So presbyopia, I don't think I know what that is. You're, that's because you're 32 years old. You are such a child.
So pres, presbyopia, and I don't mean to be insulting, you're just No, it's okay. A child. But when you hit usually somewhere between 50 and 55, most people need reading glasses because the lens becomes glycated, becomes stiff, it can't adjust, so people can't read up close, right. So they either get their lenses replaced or they need bifocals.
Sawyer Stone: Mm-hmm. Right.
Dr. Sandra Kaufmann: So everyone assumes that that is a time-based thing, and it seems to be very specific. Right? Sort of. Sort of like menopause, but it actually turns out that it's completely [00:13:00] changeable. Interesting. So my argument is that. Equally and probably a whiff more complex, well, a lot more complex you menopause is, is manipulatable.
Because presbyopia is manipulatable. Because if you know why cells start declining, you can decelerate those issues. You can also accelerate them, which is why people get, um, cataracts and a whole lot of other early onset presbyopia, presbyopia esque issues. Um, but I think it's changeable, uh, if you intercede early.
Sure,
Dr. Bill Andrews: but only a little bit. I mean, it's like it's still, we still have this. Clock of some kind that actually puts a maximum limit on it and early limit. But, you know, do anything, do you do to reduce oxidative stress and stuff like that? Does not have, or inflammation does not have a really significant, just maybe a, a 10%, 20% change in, in the average age of when menopause comes along.
So it's just, there's some kind of clock that we don't understand. I know [00:14:00] it's not circadian rhythms because. Uh, it's like it doesn't correlate it at all with a moon or anything like that, and it's like still something's missing. There's something that people just don't understand.
Sawyer Stone: Well, you would think that some of it, oh,
Dr. Sandra Kaufmann: sorry.
Go ahead, Dr. Kaufman. No, no, I was just, I was just gonna agree with Bill and say yeah, we don't know. On the other hand, we don't, we can't stop aging either. We can decelerate it. Maybe at some point we will understand. I just think it's a parallel system. I think this is a microcosm of gen general aging.
Sawyer Stone: Yeah. Well, and it's interesting, Dr. Bell, that you brought up the circadian rhythm and being in association with the moon because like. Our functioning from the onset of puberty on is run by the moon in this 28 to 32 day cycle where we bleed and have these hormonal shifts. And so it would be, you would think that maybe that's a clue towards the fact of like menopause is that we are sort of run on this cycle.
Like an X amount of moon cycles from the day we [00:15:00] enter puberty means that like after X amount of moon cycles we are entering into menopause. It just seems like it might would be that cut and dry, but I guess it, isn't it,
Dr. Bill Andrews: it, there's studies now that argue that I, I don't know if they're related to like younger women being up on space shuttles or things like that where you totally get removed from the circadian rhythms and stuff like that.
That's really the data that's saying it. Like,
Sawyer Stone: yeah,
Dr. Bill Andrews: moon is every 29 and a half days, and Meno, uh, menstrual cycles are every 28 days, which are close. So a lot of people thought there was a connection there, but, uh, it's not, the phases of the moon would only be really the light. It's not like it, it's, it, there's,
Sawyer Stone: yeah,
Dr. Bill Andrews: it's trying to make sense out of it has never made sense out of it, so,
Sawyer Stone: yeah.
For sure. Okay. Well, all right, so then let's go back a little bit further or back in time a little bit to basic menopause. What are the symptoms and the effects of menopause, both physical and mental? [00:16:00] And then like, do we know why everybody's different? For example, you know, some people have hot flashes for 12 years straight at the rate of seven to 10.
Hot flashes a day, which would make me miserable. I don't think I'd make it. And then it's so different for other people. Like some people just don't have any hot flashes, but they can't sleep or they get, just end up gaining a bunch of weight, even though nothing's changed about their diet. So yeah, talk to me about that.
Dr. Bill Andrews: Uh, me for a second. I, I, it's like, it's the hypothalamus. I mean, it's like the, uh, the hypothalamus is like the thermostat that's on your wall. You know, you have these. These, uh, set a temperature here, a temperature here. When the temperature goes above or below you, you turn on your regulation, and the, the space in between is called thermo neutral zone, okay.
Where nothing happens, but somehow estrogen has an effect on. So re regulation of those timing things [00:17:00] and therefore people will start, women will start feeling like they are, are too hot. And so they'll start turning on things like start sweating, they'll start vasodilation and things like that just because of the lower estrogen is messing up the um, thermostat.
Um. But, uh, yeah. Sandy, do you wanna have any, add anything to that or
Dr. Sandra Kaufmann: No, you're, you, you're absolutely right. And people have been trying for years to figure out how to make that go away. Mm. Um, and we don't actually know what's going on in the hypothalamus. We know that that's where it comes from, but Exactly.
Is it directly related? Is it some sort of side chain? Is it some sort of, you know, multi-tiered, multifaceted interaction? We don't really know. Um, my, my answer is just don't do menopause, just skip it. That's always my best is just skip it.
Sawyer Stone: Yeah. Well that's interesting to me. And that sort of skips a little bit, but since you brought it up, there are people that skip it.
Like my mom [00:18:00] skipped it, so like I have no idea. What if I chose.
Dr. Sandra Kaufmann: No, she didn't skip it. She had she Well, so the answer is there's symptoms and then there's physiology. I mean, unless she's on hormones today, she didn't skip it. Yeah, she is. She just. Well, good. Okay. Then she did skip it. Yeah, because some people just have no symptoms and then voop you on the other side and then it's dysfunctional.
Like my sister did that. Right. Okay. And you're like, oh, I skipped it. No, you're like, you didn't, 'cause you're still osteo PRI in increased risk of X, Y, Z, blah, blah, blah, blah, blah. But as long as if you, max, I think, and Bill can argue with me on this, if you maximize or optimize your cells, including your mitochondrial function and you are healthy as possible and healthier women.
Do have menopause later, you can stave it off, okay? If you're physically active, if you are optimized, it will happen later and the later it happens, the physiologically more normal. You are the worst side effects you seem to have. And then as your normal endogenous levels start to [00:19:00] dip, if you sort of replete them, you can skim through like, like it never happened.
Dr. Bill Andrews: And, and I agree with Sandy, but there's also another side of this thing that is really interesting and a lot of women that have later menopause have like genetic variations that affect check checkpoint responses. For instance, like we have the ability, if we have DNA damage to our cells. We can shut down down those cells.
Uh, whether it's Artesia or not. I, I, it's, it's irrelevant, but it, it's, it's some women that have delayed menopause actually have, uh, ver gene variations that prevent. Their cells from shutting down when they have DNA damage, and therefore they have later menopause. And that just increases the chances that if they do have a child, the chances that child having, uh, uh, genetic variation that's unlike un unwanted is increases.
So [00:20:00] it's like, again, it's, it is, I think. Menopause isn't one of the most mysterious things on the planet, but it's, it's, but yeah, there's so much we can say about it. It's just so many sides of the coin too.
Sawyer Stone: Yeah. Wow, that's so fascinating.
Dr. Sandra Kaufmann: No, but but what's interesting is, so, so you're so back to the, the genetic damage and it is really, really interesting, right?
Because as an anesthesiologist, especially peds, I get to see all of these children that are genetically challenged, right? Some sort of chromosomal aberration. Um, so it does exist. It's absolutely real. And what's interesting is I think that the energy requirement in a cell to make the divisions right, to make the egg, to, to do all of that properly, to have normal genetics is so energy intensive.
I actually think that that's why you get chromosomal aberrations. Wow. That is my theory. Wow. That is fascinating. Very interesting. I could be interesting, be wrong. And, and maybe it's a combination of many factors. I don't know. Right, right. But, but it's [00:21:00] absolutely true. But then it's asked, but then you're asking two different questions.
Question one is, what happens to a potential child? Question two is, what happens to mom? And I'm old enough that, and I have two normal children, reasonably normal. Um, 'cause we all think our kids are a little bit wackadoodle. Um, like, so I'm past the, are my kids normal bit? Now I'm into, okay. What about me? I want to be as healthy as possible, as long as possible.
Right. And, and I'll tell you that by the time women hit menopause, that's what they care about.
Sawyer Stone: Right, right. Okay. Very interesting. Well, that's a very interesting anecdote. You're, again,
Dr. Sandra Kaufmann: you're still young. You will understand this in about 20 years.
Sawyer Stone: Yeah. Thank you. Yeah. Okay. So we've talked about this a little bit where you were saying that even these people that skip, not hormonally skip, but like genetically normally skip menopause.
They still have these symptoms on the other side. That are clear that they did go through it. And so one of them is the osteoporosis. And so what, why does the risk of osteoporosis increase during menopause and what [00:22:00] combination of nutrients? Like we all know, calcium helps your bones, but also vitamin D and vitamin K two is needed to restart that building process to build those bones back up.
Dr. Sandra Kaufmann: Do, bill, you look like you wanna say something. So you'll start and then I'll add to it. I,
Dr. Bill Andrews: I'm one of the inventors of osteoinductive factors, so I do know a lot about osteoporosis and stuff like that, but you know, bone bones are constantly being remade and re and broken down by. Cells called osteoclasts and osteoblast.
Osteoclasts are like pacmen that chew up bone osteoblasts come along and make new bone, but their functions are completely controlled by estrogen. Uh, and so the osteo, you know, so estrogen actually inhibits to some extent osteoclast. It can't inhibit completely. It has, there has to be some bone remodeling, but o estrogen will inhibit osteo class.
Enhance osteoblast so you have stronger bones, but when the [00:23:00] estrogen declines, and we haven't really talked about why estrogen declines yet, but, but as the estrogen declines during menopause, the osteoblasts become more active and the osteoblasts become less active, and therefore you start breaking down bone.
And that's, that's, uh, one of the main causes of osteoporosis and
Dr. Sandra Kaufmann: things. So, so I, so I would just, I would just add that, yeah. So. Estrogen does that in addition, as you are also perimenopausal, you're aging, right? Right. And you are inflamed as you age. There's inflammaging, right in inflammatory cytokinins come from a variety of sources as you age and inflammatory cytokinin, um, cause osteoclasts to be more active.
So the more inflamed you more, the more you are breaking down your bone and the same factors turn off osteoblasts and to make life easier, I just think B for build. So osteoblast build bone 'cause Sure. I would, 'cause I just make things incredibly stupidly. Simple. Yeah. [00:24:00] Well I think that's great and, and, and just to.
Sort of just not be annoying, but to say something that's moderately annoying. Um, everyone says calcium's the way to go and calcium is not the way to go.
Sawyer Stone: Okay,
Dr. Sandra Kaufmann: so let's make that very, very close. Calcium is rarely unless you've got a parathyroid thyroid disability. Calcium is not the rate limiting aspect for calcium.
That was a great ad by the milk people. Yeah. But
Sawyer Stone: the
Dr. Sandra Kaufmann: fact, what happens is if you have too much calcium, it gets deposited in your blood vessels and it bumps your calcium score. 'cause it sticks to tissue. Yeah. So you don't necessarily wanna be calcium deficient, but more calcium is not going to make your bones better.
Okay. Um, they are brittle as you get older because of ags, because of collagen deficiency 'cause a variety of things. Blood vessels to your bones fail. Um, all sorts of things fail. Um, so osteoporosis in general is a multifactorial problem [00:25:00] made significantly worse than women by lack of estrogen, which you can semi boost by phytoestrogens.
It works a little bit, but true estrogen is sort of like the gold standard and. My last little snippet here 'cause I get go on little tirades. Oh good. If you don't replace estrogen within five to six years of being deficient, you downregulate the receptors on your cell. So therefore, if you end up taking estrogen years later, the effects are gonna be very minimal because your cell doesn't recognize it.
Because it doesn't have receptors for it. Fascinating. Wow. So I tell people you gotta take it within five to seven years or it's pointless. Sure.
Dr. Bill Andrews: I wanna add something. And that's that runners, you know, one of my favorite things to talk about, runners actually have lower rates of, uh, osteoporosis than non-runners.
And it's thought to be due to the pounding of your feet on the ground induces better bone remodeling throughout your body, not just your feet in [00:26:00] lakes. And now I'm gonna put a, make a plug here because I really believe in something and that's, there's a company called Osteostrong. I think Sandy knows a lot about that, has actually done a lot of science.
The founder of it, uh, Kyle Gorsky or something like that, he's, he's done a lot of scientific research on this and he is found that there's actually more pressure on the bottom of your feet actually induces. Repair or prevention of osteoporosis even more. And so he now has companies where people can actually go to, the companies are called Osteostrong.
You can go to these companies and you can sit in these machines that put pressure on the bottom of your feet and other things to actually decrease the rate of osteoporosis. And, and I'm, I've been amazed at the science behind that. So it's a good thing to do. And, and if women are trying to decrease osteoporosis, that's what to do.
Dr. Sandra Kaufmann: Yeah, that's fascinating. The, the other thing you can do is if you're not near one of those places, and, uh, and if they're a little bit pricey, if, if any woman is at the [00:27:00] gym and they have the vibrating plates
Sawyer Stone: mm-hmm.
Dr. Sandra Kaufmann: That vibrating motion, probably not as good, but better than nothing increase or triggers osteoblastic activity.
Um, okay. And, and, and as the other thing I like to do is just tell women to jump rope. Oh, sure. Yeah, because it's, it's, it's the same sort of mimicking. It's, it's the compressive factor on the bone that triggers osteogenesis.
Sawyer Stone: What if, um, like I know a lot of women that are about this age that are playing like an active sport, like a, like a very recreational kickball or very recreational soccer.
Is that like the same sort of, not like long running, but like same sort of, sort of compounding against the ground.
Dr. Bill Andrews: Maybe not. Just the pounding, the more pounding, the better. Um,
Sawyer Stone: more pounding, the better. Okay.
Dr. Bill Andrews: Of course, a lot of those sports require running, so, uh, there's gonna be some of that, but probably not as good as running a hundred miles.
Sawyer Stone: Oh, well, okay. Just not pickleball. Just not pickleball. You don't like [00:28:00] pickleball, Dr. Kasman?
Dr. Sandra Kaufmann: No, no. It's really funny. So I, I can't stand pickleball. It looks like adult humor. Fong. Um, it looks ridiculous. I agree. That being said, all of my friends that are orthopedic surgeons love it. 'cause you get these old fogies out there trying to do it, and they all end up with knee injuries.
So then they, then they all like, need their ACLS redone and then they all sit around with like, you know, partial surgery and then they get fat and blah, blah. It's just this whole like delinquent behavior. So. No pickleball.
Sawyer Stone: Oh, that is so funny. Okay, well, we did touch on the fact that we haven't talked about why we dip an estrogen.
Do we wanna talk about that really quick before we go to our next question?
Dr. Bill Andrews: I mean, again, it's the timing. It's not really understood, but the estrogen's actually produced by the, uh, follicle cells. Okay. The, the pro uh, granulosis cells. Actually encapsulate the, uh, uh, the egg or the, um, cyte, uh, and the, there's a layer of cells on the outside of these, [00:29:00] uh, follicles called, um, theca cells, and they actually produce the androgens that, that then get converted into estrogen by the follicle cells.
And then the follicles release the estrogen, but. For some reason, our women's follicle cells start decreasing. Okay. And it's, it's a process called at Atresia. I don't know if I pronounce it correctly or not, but it's, and, and there, there's all kinds of explanations for it, but none of 'em, to me make any sense because, again, it doesn't apply to statistical theory or mathematical model.
And to explain the, the range, the, the, the consistency that we see from. In, in women all, all over the world. So it's, so I don't really understand it, but it is, the decline is the, the, the decline in the number of follicle cells that actually reduces the nu amount of estrogen that's produced in the body.
And so hormone uh, replacement [00:30:00] therapy is something that's, is something that's really common to do, is to replace that estrogen that's not produced.
Dr. Sandra Kaufmann: So, so I would, I would make one more statement. 'cause I have to, 'cause that's what I do. Um, if you think, I always like back to, back to cells, right? And not a specific cell, but a generic cell.
Every generic cell has a capacity to make 10,000 different proteins. Um, all of them, right? A kidney, cell, liver, cell, they can all make the same, the same number, the same amount. And of course, epigenetic makes you make certain ones over other ones, right? But. If you were to record or measure most of these proteins, they all fail over time, right?
Sawyer Stone: Hmm.
Dr. Sandra Kaufmann: They do. And in men testosterone fails. Women estrogen fail. Why? 'cause we're, we're very much aware of it, but other things fail as well. All contributing to the aging process. Estrogen and progesterone are a little bit different. Yeah. Because they're in the ovary and they have these specialized cells and so it, it's obviously more sophisticated system, but it's not unusual for all things made by the cell [00:31:00] to fail.
With the exception of things we don't want. Bizarrely enough, those always go up over time. Um, so failure production is not an unusual consequence with time.
Dr. Bill Andrews: I'm glad progesterone, because I've been thinking we're only saying estrogen, but progesterone and estrogen are both involved in all, in a lot of these processes.
Um, the, the, the thing about. I mean, the estrogen receptor is actually a, a, a receptor inside the cell that binds to estrogen and then regulates genes as a transcription factor. And the, uh, the, the frequency of a estrogen binding site in a DNA is like, there's like 10,000, if not a hundred thousand different sites in the human genome, but only something like.
Five to 500 to a thousand of 'em work. And, and, and it's, or they bind my work, I mean, binds to the estrogen receptor to regulate genes. And it's like, it's still a big, I, it is just the mystery just keeps getting on and on. I'm just mentioning [00:32:00] that because that's one of the things that I'm always stumbling about is like, how is estrogen playing such a role in things?
Uh, yeah. I, I don't have answers, just questions. Yeah.
Sawyer Stone: Well, I have a question, and this is sort of on topic and sort of like pre menopause topic. So I recently, within the last year, got diagnosed with PMDD, which is premenstrual dysphoric disorder, which is like CR qualifies as a chronic illness and, and, and is in layman's terms, the most aggressive form of PMS.
And the way that everybody describes it is that like my hormones for. My luteal phase, which is the last 14 days of my cycle, just like bottom out. So much so that it sends me into this like depressive state where I don't have any serotonin because the serotonin just like dips out with those hormone changes, which is so interesting.
And so I'm wondering like. If someone has like severe PMS or PMDD or something like that, where like their [00:33:00] estrogen, progesterone are like not even working at the regular rate that is normal during their cycle, are they gonna go into menopause early? Are they gonna have a completely different type of menopause?
Is maybe there's no research done on subjects like that. Just curious.
Dr. Bill Andrews: I have to defer completely to Sandy on this one.
Dr. Sandra Kaufmann: I, I don't know. We, we don't know. Okay. I'm pretty sure we don't know. I mean, we can extrapolate, we can make some really good educated guesses, but in terms of retrospective or prospective studies, I don't think we have any that I'm aware of.
Dr. Bill Andrews: Okay. Okay. So this part of this podcast series is critical meta-analysis of peer reviewed studies and stuff like that. And so a lot of times, like I don't really look into something until actually somebody questions it. But now that you just brought this up. I would like to look into that and provide you with an answer.
Now I've, in a lot of my podcasts, I've been actually providing my email address and I've been finding that I actually enjoy answering these emails and answering questions during breaks. So I'd like to [00:34:00] provide my email address right now to the audience, and if anybody has any questions like what you just ask, I can look into it.
I can dig into it and give you an answer. And my email address is B as in boy, Andrews. At Sierra Si. That's S-I-E-R-R-A-S-C i.com. And I welcome the questions, but I, I would like to look into that and give you an answer.
Sawyer Stone: Thank you. And we'll also include Dr. Bill's email in the podcast description as well, just for folks that are driving and don't have a pen.
Um, but thank you, bill. I appreciate that.
Dr. Sandra Kaufmann: So, so. I would like to have a theoretical conversation about this bill. Yeah, so 'cause 'cause my brain is going, okay, there are two, two potential answers, right? If your body is used to slightly lower levels. Mm-hmm. Right. And therefore your, if your, if your, if your normal homeostatic level is lower than than normal, but you've become accustomed to it, when it drops [00:35:00] off, the drop is less precipitous.
So I would argue that your peral per menstrual area, not menstrual per menopausal time would be less traumatic for you.
Sawyer Stone: Okay, well, I am supplementing my hormones with, uh, I was trying a birth control pill, and that did not work. It made me bottom out worse. Um, and so she has recently put me on a patch that has both progesterone and estrogen in the patch.
And so is that, am I negatively impacting myself for future soil? Well, so that's another
Dr. Sandra Kaufmann: question, right? If you are, so, if you're artificially raising levels and now you're resetting your homeostasis. Right, because receptors response to natural levels. Yeah. Well, not flat, natural, but like whatever the levels are.
Sawyer Stone: Yeah. Right.
Dr. Sandra Kaufmann: If then you immediately start dropping. I I would, I would. This will be interesting to watch. So in 20 years what I want you to do is chart this so we can figure it out. But anyway, but my, my, my, [00:36:00] my, my go-to answer is going to be the greater the change, the more dramatic the symptoms. And Okay. I have, and the reason I sort of say this is because if you look at obese women, their.
Their, uh, issues are significantly greater. Uh, okay. They bleed more and they tend to have terrible, uh, perimenopausal symptoms. And I think the estrogen that they have is so great because of their obesity that when they drop. It's significant,
Sawyer Stone: fascinating,
Dr. Sandra Kaufmann: especially in women that are fat and then lose weight because they're super high.
'cause estrogen comes from, a lot of it gets stored and produced in fat, right? So it comes down and then they go, mm-hmm. I think it's the delta. Okay. And I could be wrong. I am completely, this is me. This is guessing, but Phil, help me out.
Dr. Bill Andrews: Well, I'm, I'm actually quite intrigued by your, your, uh, guest there. Um, but I'm, I'm thinking that, you [00:37:00] know, most hormone, uh, birth control, uh, situations are involving adding.
Way in excess, more estrogen and progesterone, at least mimetics of estrogen and progesterone than normal. And so your delta would be increasing a lot there and if,
Dr. Sandra Kaufmann: right. But see, but people only take birth control until they're done having kids. Right. So they, they stop at what, the 40 and then they do nothing for a while.
And then they hit menopause. So there's a period where your, your receptors are then gonna normalize before you go down. Very few people continue to take birth control until they hit menopause. Right. Unless they have a, unless they have an issue. Unless they have a, yeah, have a right. And, and anyway, so it's, it's just a thought, but something is triggering it and I think it's a precipitant.
Drop. Now some ex is gonna call and say she is full of shit. And that may be absolutely true, but this is called medical hypothesizing. [00:38:00] Yeah, no, I appreciate it.
Dr. Bill Andrews: Well, hormonal replacement therapy, that's, that uses a lot less estrogen and progesterone mimetics than birth control does. Um, and think, I'm trying to think about that delta type of thing.
And so. It menopause you, you, you go on HRT, which is very different from birth control in terms of just in the terms mm-hmm. Quantities of estrogen and progesterone. Or progesterone. Um, but, uh,
Dr. Sandra Kaufmann: I, I don't know.
Dr. Bill Andrews: It's, I'm just thinking out loud and trying to
Dr. Sandra Kaufmann: No, it's, so, it's, what's interesting is, so when I started, my levels started to dip a few years ago.
I just went on birth control. Mm. Totally worked. Okay. Like what the hell? What's the difference?
Sawyer Stone: Yeah. I mean, yeah, I have, I mean, I, I am, I'm in a lot of queer communities and so I know a lot of people that are not using birth control for its birth control usage and they're using it for the way I'm using it or they're using it for the way you're using it.
And one of my close people in my life [00:39:00] has like started back on birth control for that purpose of like trying to maybe skip the menopausal symptoms. That's very fascinating. Interesting. Hmm. Can you tell me a little bit, 'cause we've talked about, we've, we said this word a little bit in our conversations just now, but I'm not quite sure our audience is gonna understand what it means.
Can you tell me what you guys mean when you say Deltas?
Dr. Bill Andrews: Oh,
Dr. Sandra Kaufmann: go ahead. You're, you're, you're, you're the, you're the science, you're the PhD. The range.
Dr. Bill Andrews: The range. The range. I'm trying to think of an analogy, but maybe Sandy's better at coming up with analogies, but, but, um, one dose versus another dose. The difference between 'em is called the delta.
Sawyer Stone: Yeah. Okay. Thank you. Alright, well, so then let's talk about another symptom of menopause. Many women complain about crushing fatigue. Is this a side effect of poor sleep? Because of menopause. Are there specific molecular changes in the brain or in energy producing cells, the mitochondria [00:40:00] that caused this drop in mental and physical energy?
Is it like a side effect of the thing itself, or is it an actual effect of going through menopause?
Dr. Bill Andrews: Again, it's decreased estrogen, and estrogen plays so many roles in so many different things. And I had already mentioned the PGC one alpha on mitochondria, and that's probably a major cause, but, uh, that's, I'm probably gonna overlap in other subjects, but, but, uh, brain fog and things like that are also, uh, you know, they're, they're affected by neurotransmitters.
Air estrogen plays a big role in. The, um, communication between neurons and things like that. Um. Uh, again, you know, seizures is something I think we were gonna be talking about. I'm jumping the gun here. It's, it's, 'cause it's all correlated to that too. The, um, uh, seizures are, are not as common as brain fog, but they're, they're very related to the same thing.
And they just increase when [00:41:00] menopause starts. But post-menopausal, they completely disappear again, uh, because everything returns to normal. So,
Dr. Sandra Kaufmann: so, so I would argue so wait, wait, wait, wait, wait. So let, let's go back a little bit. Like estrogen is not the answer to absolutely everything. It's a lot, but it's not everything because you have to remember that your body is aging at the same time, right?
So sleep. Is, is is not all estrogen driven. Sleep is a very simple biomechanical or not biomechanical, biological driven system. There are two proteins that put you to sleep. There are two proteins that wake you up and there are two proteins that change the vacillation of the curve, right? That is all controlled by sirtuins one and six, which is all controlled by NAD.
Yes, estrogen plays a role, right? But as someone's going through perimenopause, they're also aging and their circadian cycles are going fluey because by the time you hit 40, 45, your C two and one is dropped. C two and six is dropping your NAD level's dropping. So I would say [00:42:00] you've got multiple layers of problems.
So you put menopause over here. Men are going through the same thing. Men aren't sleeping either because of sirtuin deficiency and NAD deficiency, but you can fix that and you layer that onto mitochondrial deficiency that's also going on. So you've got a multi-tiered problem. So the answer is not always just estrogen, it's.
You have to solve the aging part at the same time.
Sawyer Stone: Can you tell me what you mean by the tuin deficiency and the other things that you said and Dr. Bell, you said something that was like maybe a couple letters and a couple numbers. Can we just say that for the listeners that may not understand what y'all mean when you say that?
Dr. Bill Andrews: Well, well what letters and numbers that I said,
Sawyer Stone: I can't remember what you said. Did you say PCG one Alpha? Is that what you said? That's it.
Dr. Bill Andrews: PG pgc one Alpha, tho those are, there's two different proteins that make up a. Major part of the um, uh, mitochondria electron transport chain and crib. It was more so electron transport chain of where we get our energy from and it produces NAD and [00:43:00] a TP and things like that.
Uh, but most people don't realize is that 90. 90% or more of the proteins encoded that are make up am mitochondria are actually encoded by the nuclear chromosomes. And, uh, but so if I've addressed that answer, lemme just go back to a little bit about what. Sandy just said, because I look at the decline in serin one and Serin six and Nads as a result of aging, not a cause of aging.
And the question is, what causes serin one and serin six and NAD levels to decline? Um, and those are things that I, I keep coming back to this whole business of telomeres. Okay.
Sawyer Stone: Yeah.
Dr. Bill Andrews: And, but the reason why I keep emphasizing the estrogen is because. I believe in the case of menopause, telomeres have nothing to do with menopause.
Okay. And it's, it just, there's no correlation. And so I just resort to this. [00:44:00] Estrogen level decline, and I don't understand why it occurs, but I believe that a lot of the other things like serin one and Serin six decline and entities are very much controlled by telomere lengths. It's just why there's a connection between the two might be just coincidence or correlation, but I'm, I'm just not in all my studies.
I just have not been able to make sense about the connection between. Menopause and aging, and I know Sandy and I have talked about this before, but I believe menopause is not. Something to do with aging. I believe it's, it's mostly just a counting mechanism of getting rid of the, uh, egg cells. And, you know, there's a certain number of egg cells that can actually, uh, be used, but most of the other ones are just used for nourishment of the, uh, like 400 or 5,500 different egg cells that can eventually become, uh, uh, part of the reproductive process.
I I, [00:45:00] it is just the count, the, I think the counting mechanism of just losing egg cells is pretty much all that, the explanation of menopause that there is, and ome biology and other functions of aging might play very little role in menopause. Again.
Sawyer Stone: Yeah,
Dr. Bill Andrews: it's all curiouser and curiouser. Um,
Sawyer Stone: fascinating.
Well, okay, so you guys talked about seizures for a second, and I wanna understand a little bit more what you're saying. Are you saying to me that females that are in the middle of menopause. Or maybe from when they start bleeding or at a higher risk of having a seizure. I, I'm not sure I understood what you're saying.
Dr. Bill Andrews: The initiation of perimenopause menopause. So as soon as, as soon as estrogen levels start and progesterone levels start to decline enough to start giving the early symptoms of menopause, that's when you have increased chances of seizures, because estrogen and progesterone do play roles in the [00:46:00] neuron communications.
Dr. Sandra Kaufmann: Fascinating. So, so let's just make sure that people don't think that they're gonna start seizing. Like if people have, so normal people that don't have epilepsy or predilection to seizures are not all of a sudden gonna start having seizures. Right? Okay. But if you do, then you are more likely to, at that time.
Okay, great. Okay, so somebody is probably because you've never had a seizure in your life and you have one and you happen to be perimenopausal, you can't blame menopause because you probably have a brain tumor. Um, oh. So I'm just saying I don't want people to go, ah, and blow it off or whatever because like, it's, it's, it's, it's atypical.
It's certainly can happen because your threshold changes based on changing of brain chemistries. Yeah. But it would not be, check it out. Like, just don't blame menopause. Like get a scan.
Sawyer Stone: Okay. Um, so you brought up, um, that, that brain fog was a symptom of menopause, and the other time that I hear a [00:47:00] whole lot about brain fog is when someone is just becoming a mother.
And so I'm curious that, do you think that, is brain fog just a lady thing? Do we think that men have brain fog or is it like our internal hormone changes throughout? You know, maybe when you're young and you're in puberty to like when you have a child to like, menopausal is like, are those hormone changes?
What sort of causing our brain fog? Uh,
Dr. Sandra Kaufmann: clearly you've never had children.
Dr. Bill Andrews: I have not,
Sawyer Stone: no.
Dr. Bill Andrews: Men definitely have brain fog. Uh, it's like,
Sawyer Stone: okay.
Dr. Bill Andrews: But it's just really it. Menopause is just one of the things that can cause it just by affecting neurotransmitters and brain neurons and things like that from firing normal and stuff.
So,
Dr. Sandra Kaufmann: okay, so, so having gotten through two children, I can tell you that as soon as a baby pops out of you, you are under unbelievable physical, emotional, and sleepless stress.
Sawyer Stone: Yeah,
Dr. Sandra Kaufmann: [00:48:00] your body is completely wackadoodle. You're, you're. Every cell in your body is doing things. It's never really done before.
Right? Your hormones are going up and down. Your boobs are getting bigger, you are not sleeping. Your diet has changed. Your life is upside down. So there is no doubt that once again, like these things are, it's not a single problem. It is a multifactorial brain fog. Sure. Okay. And your brain. Your organs like homeostasis.
It is one of my favorite words. Homeostasis. Meaning like, yeah, I
Sawyer Stone: like to be,
Dr. Sandra Kaufmann: it is just like, right. You wanna be as normal and calm as possible, and as soon as that gets shaken up, all of your organs are very unhappy. And the one that we see in terms of our thought processes is our brain. Right? We don't see kidney, you know, we, we don't know our kidney or our liver's upset necessarily.
Yeah. We know our brain.
Sawyer Stone: Yeah. Okay. Well there's so many other side effects that come with menopause, and some of them I feel [00:49:00] like are sort of widely experienced, like. Uh, no sleeping or the brain fog or the hot flashes. Um, but then there's some of these other ones, like a random onset of tinnitus. Um, some people have like frozen shoulder, frozen joints or their LDL skyrockets or suddenly they gain a bunch of weight, but like nothing changed in their diet or exercise.
Is there anything, like, are these all just genetic factors that are unique to each person experiencing menopause?
Dr. Bill Andrews: I can address each of those first, but first of all, nobody knows what causes tinnitus. Okay. Like, it's like so many different, there's people can go online and buy all kinds of thousands of different products that deal with tinnitus, but it's, uh, and it's pronounced.
Tinnitus, not tinnitus. Tinnitus, sorry. Oh, did you? I thought you said tinnitus. Okay, so, so, no, I, yeah, I just, but, uh, so, so what's going on there? I don't think anybody's really [00:50:00] gonna understand until somebody really solves the whole business of tinnitus in terms of, um, what else did you say? LDL. Okay. Mm-hmm.
So, LDL goes up, but that's because estrogen plays a, a big role in LDL receptors on cell services that get rid of LDL and. Also, um, estrogen inhibits PCSK nine, which is a major thing that reduces, um, uh, LDL receptors or at least the function of LDL receptors on the surface. So. When you lose estrogen, PCSK nine goes up and therefore inhibits the ability of LDL receptors to get rid of LDL, and it also decreases the number of LDL receptors.
So, so your LDL goes up because of that and, and the solution is just all the different things you can do already to anybody can do to reduce their LDLs.
Sawyer Stone: Okay. Dr. Kaufman, earlier in the call you, or in the pond I should say, you mentioned that estrogen is [00:51:00] stored in fat cells or something maybe to that effect.
Can you tell me, some women find that they suddenly gain weight or become sensitive to sugar during menopause, and so can you tell me how the loss of estrogen and maybe where it's stored changes how our bodies and fat cells respond to insulin and glucose?
Dr. Sandra Kaufmann: Yeah, so excellent question. It's just estrogen.
I. Let me think about this. I haven't thought about this in a while. Uh, so there are enzymes in your fat that create estrogen. Okay? It's not necessarily like you created, so people that are fat or tend to release more estrogen, okay? Which is what? Right. And, and Bill's gonna have a conniption fit 'cause I'm gonna go back to Sirtuins here.
Um, as you get older, wait, can we
Sawyer Stone: do, can we say what a sirtuin is? I think we have not done that yet.
Dr. Sandra Kaufmann: Okay, sure. Because I love sirtuins. Uh, cer two ends are, I consider them in a very simplistic fashion on off switches. That controls cellular homeostasis. Back [00:52:00] to my favorite word. All right. There are seven Alion, sirtuins, and they live in your cell.
One, six, and seven Live in the nucleus. Two FLS around the cell. Three, four, and five run your mitochondria. Of which three is the most important. They are technically are histone deacetylase, but they also deacetylate a variety of different, uh, proteins. So they basically take acetyl groups on and off.
Right. Turning different proteins on and off. Right. Okay. Some of these changes are super fast, some of them are generational, but this is what they do. Right. So they control, one of the things, sir, two and one controls is where you store and how you store your fat.
Sawyer Stone: Hmm.
Dr. Sandra Kaufmann: So as you get older, either a cause or, or.
However, bill wants to say it, right, either because of your aging or causing aging. So two in one declines as well as NAD, you change the way you store fat and you tend to get what I call the abdominal tire syndrome. And abdominal fat tends to then [00:53:00] create more estrogen stores. Mm-hmm. So sometimes people will say that as you get older, having a little extra fat isn't so bad because then you don't.
Theoretically, perimenopause won't be as bad 'cause you have a whiff more fat. On the other hand, you don't wanna be obese necessarily. Alright, so then the question is, is why do women as they get older, they're blaming fat accumulation on menopause. And the answer is, it's, it's, it's bimodal. It's one because you're sirtuin deficient.
Two, because you're also estrogen deficient, which is causing your cells not to work very well. Therefore, your sirtuins are failing, therefore you're storing your, it's just this circular problem. I always like to say that it's an interconnected net of pathways, so it's not one thing, it's just this massive net, and it's all sort of failing in conjunction.
Sawyer Stone: Okay. Does that make
Dr. Sandra Kaufmann: sense? Yeah, it does. I'm sure if that was a good answer or not, say it better. No, it makes sense.
Dr. Bill Andrews: That was a really good description of the whole process.
Sawyer Stone: Yeah, I appreciate that. Okay, so as we wrap up [00:54:00] here, you know, this, this conversation has, um, has not been quite as uplifting as some of our other conversations have been.
Just 'cause the sort of, it's kind of like a tough subject to like endure if you go through it. And so can we offer any sort of like supplements. Or any sort of, do you guys have any advice for folks that are going through menopause that they may not know about? Or maybe the obvious ones too, just in case someone's new.
Dr. Sandra Kaufmann: Well, Bill's the king of making these supplements. He's really good at this. He's, because
Dr. Bill Andrews: menopause in my wheelhouse. Uh,
Dr. Sandra Kaufmann: well, what I, I usually, I mean, I, I do this. Frequently, and what I usually tell women and, and most people, but especially women, is that I think, and I could be wrong, but a lot of of problems is, is just generally related to mitochondrial failure.
So knowing that menopause is coming, knowing it's gonna be there somewhere between 45 and 53, by the time you hit [00:55:00] 40 and your cells are starting to become dysfunctional, there is no downside to optimizing your mitochondria. And there are. A plethora of options that you can do. I mean, I like to think that mitochondrial fail in seven different categories.
So I think that if you fix things in seven different categories, or at least get the easy low hanging ones, uh, you'll have more energy, you'll be more optimized. Theoretically, you can sort of delay or if not minimize some of the effects of, of, of menopause. And then at the end, my. I think you just have to turn to hormone replacements.
Granted, there are pros and cons. Talk to your physician. Obviously there are times when, you know, risk benefit ratio suggests that it's not a great idea, but for most women with normal physiology, it is the way to go to reduce risk of disease going forward Thereafter.
Sawyer Stone: Well, Dr. Kaufman, thank you so much for joining us on Up One Today.
Can you tell our listeners and video watchers where they might find [00:56:00] you? Do you have some social media you'd like to share or a website?
Dr. Sandra Kaufmann: Absolutely. So my website is kaufman protocol.com and my Instagram is Kaufman Longevity.
Sawyer Stone: That's great. And Doctor, and we'll put Dr. Bell's email in the podcast description as well as Dr.
Kaufman's, um, places where she can be found. And thank you both for joining me today. It was a great episode of UP One.
Dr. Sandra Kaufmann: Thank you, Sawyer. It's my pleasure.
Sawyer Stone: Thanks for joining us on UP one. If you found today's conversation valuable, be sure to subscribe and share this episode with someone who's curious about the real science behind help.
Dr. Bill Andrews: Have a topic you want us to break down. Send us your questions. We're here to help you separate fact from fiction.
Sawyer Stone: Until next time, stay curious, stay informed, and let's keep taking it up [00:57:00] one.