Rhonda is a really fascinating person and has made this transition from being a bench scientist, making discoveries to being someone I guess we didn’t even realize we needed, but we do. And that and that’s someone who’s a phenomenal communicator through her podcasts about the field of aging and human health. And she represents not companies, not universities, but she represents ideas and probably knows as much about aging as anyone else on the planet. So delighted to welcome you, Rhonda. 

Rhonda: Thank you, Gordon, for having me. I am a huge fan of the Buck Institute.  

Gordon: You’re very kind, Rhonda. Thank you for that. You know, tell me. I think you grew up  in California, but tell me about how you got into science in the first place. 

Rhonda: Well I grew up in San Diego. And I was about 17 when I — when I started getting into surfing and I was very much a nature girl. I decided that I wanted to spend my life being a marine biologist and studying —

 Gordon:  Me too! 

 Rhonda: — creatures in the s —

 Gordon:  Me too! [laughter]

 Rhonda: Uh, you know, so I spent so much of my time, uh, in the water. And then, when I wasn’t in the water, I was watching David Attenborough on these — nature documentaries. Those were my original aspirations. And it was like, okay, well, I want to be this biologist who goes out to the Galapagos and, you know, surfs out there while I study, you know, all the-the cool animals. And, uh, so I s — I, uh, decided I had to, basically pursue science in order to get that biology degree. Little did I know that I would never leave the lab. [laughter] And I would never go out into the ocean or into Sub-Saharan Africa on a safari, uh, you know. So I think it — you know, I’m probably not alone in that. There are probably a lot of people that start out wanting to be field biologists. So that was the start of my scientific pursuit. And then, I just decided,  “Well, I probably should just do the hardest thing.” And that is, chemistry and biochemistry. And I honestly just kind of got all tangled up in that and then lost track of my-my field biologist dreams and just started to get into, you know, real-real hard science. So — [laughs]

 Gordon:  Actually, that’s an amazing parallel because I was a bird watcher. I wanted to be a field biologist as well. And, uh, I went to my, uh, teachers. Uh, this was in a-a high school in Scotland in-in a steel town, and said, “I want to be a field biologist.” And no-nobody-nobody had ever met a field biologist. And they said, “You should just do microbiology if you’re going to do that.” [laughs] So at-at some point, you find yourself in a lab. Uh, how-how was that experience? Uh, uh, uh, the reason I’m asking you about the lab experience is that you’ve transitioned it into a completely different world, uh, of podcasting and science communication, which we’ll come to. But I want to talk about your lab experience first. So did you enjoy being in a lab?

 Rhonda: I did. So my first lab experience was when I was an intern. And at the time, I was  a junior in college. And I was synthesizing peptides and doing a lot of chemical — chemistry work — organic chemistry. And I did that for two years while I was still in school and decided that I really didn’t enjoy it. [laughs] This —

 Gordon:  Oh, okay![laughs]

 Rhonda: It was just a little — I didn’t feel like I could relate to just the-the-the real chemistry part of it, where —

 Gordon:  Yeah.

Rhonda: You know, it was just too far removed from biology. And that’s when I went to work at the Salk Institute for Biological Sciences. I was doing some of the research that, uh, you do in your lab where I was looking under the microscope at these tiny little nematode worms, C. elegans.

 Gordon:  Yeah.  

 Rhonda: And, uh, this was also an aging lab. And so, uh, I think that sparked my first real excitement for aging and just sort of doing experiments with my own hands and seeing that I can manipulate genes that were homologous in humans, you know.  Seeing that  basically like I can genetically manipulate worms to live 100 percent longer blew my mind.  And so that was kind of… it was a fun experience. But I decided to-to kind of like go more into cell biology and cancer biology. And so I did all my graduate work in cancer biology and cancer metabolism and a lot of animal work: so I went from worm to mouse where I was studying mitochondrial metabolism. And, it was — I spent just like I don’t know how many months of my life under like an electron microscope looking at mitochondria and you know, light mi-microscopy as well I mean just everything, all things mitochondria for years and years. And I was a bit of a mitochondriac. I still am. But n-now, I’ve got a bigger-picture focus  of it rather than looking at the electron level. So, uh, at that — at that same time — and-and, uh, the-the — uh, you know, graduate school was stressful for sure. But, uh, I also learned a lot. And, uh, at the same time, this is when I started to really develop my passion for health and fitness and, uh, applied science —

 Gordon:  Hmm.

 Rhonda: — and-and the science behind the health and fitness because I-I found, for me, that, when I understood mechanisms, I was able to im — you know, basically,  do things in my life that were healthier. And I was –  more motivated because I understood things better. And so I felt like that was really foundational for maybe other people to make these changes in their life is like, uh, understanding why, like the science behind it.  It was something that I just, you know, in my — in my free time, I would do — I would go to coffee shops and started blogging. I started a blog. And I would, you know, just write articles and  you know, try to find science that would back up things like vitamin D or omega-3 and —

 Gordon:  Mm-hmm.

 Rhonda: — what their role is in human health. And, uh — and I would also — I would also try to — tr — I also would try to convince my family and friends, uh, why they should be healthier and, particularly people that were not healthy. And I found that it was very challenging for me to do that because they took it very personal. And so I basically just started putting articles and making videos and sending it to them and noticed that they took it a lot better because it wasn’t like I was directing a lecture at them and —

 Gordon:  Oh, interesting. Yeah.

 Rhonda: — lecturing them about —

 Gordon:  Yeah. Yeah. Yeah.

 Rhonda: — like what they’re doing wrong. It was —

 Gordon:  Yeah.

 Rhonda: — information. Uh, you should listen to this or –see this.  Uh, so that was the kind of start of my-my-my passion for, uh, science communication. So, uh — so that — so that’s, you know, some — that-that’s kind of — that was kind of the start of it.

 Gordon:  Well, I mean, that was — that’s fascinating because, and I actually want to go back to the worm [laughs] because,  you know,  many people — and-and I — obviously, I have this experience as well where you see a tiny little animal crawling around on an agar plate. And it’s supposed to be dead. And it’s not. And it’s not dead because either there’s a mutation that-that’s extending life span or  you put a chemical compound on these worms that extends lifespan. And it’s shocking to-to see that-that-that the aging is-is not, uh, this-this fixed quantity, that it’s plastic. It’s malleable. We can intervene. And a lot of people just stay there. Right. They just, for their entire careers, pretty much like myself, stay with the worm or with the drosophila or with the yeast. So what was it that took you away from the worm to cancer and did you feel like this was — this was amazing, but you wanted to do something more?

 Rhonda: I think there were circumstantial things that directed me there. But I think also I just kind of realized that, if I had stayed in worms, that I may not learn as much about . . .  It’s kind of a very little — it’s kind of a like  kind of narrow to like the genetics and the similarities between humans —

 Gordon:  Yeah.

 Rhonda: — and worms with genetics. And there’s this whole systems biology. And-and so I kind of just — and I — because you’ll see. I went from worms literally to doing research on mice and cancer biology to-to human trials and clinical trials in nutrition. And so I got this sort of well-rounded sampling of biology, you know, from —

 Gordon:  Yeah.

 Rhonda: — from the real m — from the genetic, you know but there was a big picture still with the genetic research with the worms because, you know, studying the aging process, I mean, it’s very relatable — to like learning all the tools and how to do experiments and metabolism, learning a lot about metabolism —

 Gordon:  Yeah.

 Rhonda: — in-in graduate school and then sort of moving on to humans and-and human metabolism and-and clinical trials and how to correctly do them and how to analyze data from them. And so,  I think there was something just in the back of my mind that I wasn’t quite aware of like-like I am now —

 Gordon:  Mm-hmm.

 Rhonda: — that I was kind of gravitating towards where it’s like I need to kind of broaden — I need to broaden my toolset, uh —

 Gordon:  Yeah.

 Rhonda: — you know, and-and what I’m — and what I’m researching. So, that’s partly it, I think.

 Gordon:  I mean, this decision that you made, between bench science and, you know, running your own lab and, you know, coming to the Buck as a faculty member or something like that, and the route that you’ve taken, which is incredible. I mean, it’s amazing what you’ve achieved. And everyone knows you. And, uh, actually, one of my PhD students in my lab right now, is here because of your podcasts.

 Rhonda: That’s awesome!

 Gordon:  Uh, [laughs] you know, so your influence is huge. But I still want to — I still want to think about, you know, you as a bench scientist. Were you working on vitamin D? Or did I get that wrong?

 Rhonda: I did work in vitamin D. Well, researching. I was looking at DNA double-stranded breaks in peripheral blood, mononuclear cells from participants in clinical trials where we had obese people that, uh, were given a micronutrient-rich bar developed by Bruce and his colleagues —

 Gordon:  Mm-hmm.

 Rhonda: — uh, before I —

 Gordon:  Yeah.

 Rhonda: — came to the lab. And, uh, at the time, it was called the CHORI Bar. CHORI was the Children’s Hospital Oakland Research Institute. And, uh, it was a — it was a micronutrient-dense bar that had a fiber matrix. So it was sort of mimicking what you would find in nature. So, it wasn’t just like a supplement. It was the whole package. And I sort of had a hypothesis that, you know, obesity, causes DNA damage through double-stranded breaks and that potentially, you know, because people that are obese are eating terrible diets, obviously there’s all sorts of refined sugar and terrible things that they’re adding. But they’re also not getting important things like magnesium and —

 Gordon:  Mm-hmm.

 Rhonda: — other micronutrients that are important for the-the health of DNA and repairing DNA damage. And so I was sort of looking at-at double-stranded breaks in their — in their-their peripheral blood cells before and after given these micronutrient bars. And also, we were — we had other clinical trials like blueberry extract we were doing.  And so I had, I was originally doing some of that work.  And then, I got to do other interesting exploratory work. And that had to do with vitamin D. And a lot of this work was me doing my favorite thing which is diving into the literature and finding studies that often end up in a vacuum or in a black hole, you know, where they just don’t get seen by anyone. And, you know, sort of —

 Gordon:  Yeah.

 Rhonda: — putting some dots and connecting them together all with evidence — you know, all evidence based. And so I did some in-silico work as well, looking at vitamin D response elements in, uh, genes that were regulated by vitamin D. Uh, and so, you know, I was looking specifically at the sequence of those elements and how a gene in the brain that converts tryptophan into serotonin — it’s called tryptophan hydroxylase 2 —

 Gordon:  Mm-hmm.

 Rhonda: — is activated by vitamin D according to the vitamin-D response element. And since I published this, uh, early work as a review article, there have now been in-vitro and in-vivo studies that have confirmed that it’s — it is true. They have experimentally shown vitamin D does activate the tryptophan-hydroxylase-2 gene and, uh –that can affect serotonin. And so, uh, I had done some review articles I guess is what you would call published. But they were more integrative, more perspectives —

 Gordon:  Yeah.

 Rhonda: — where I-I sort of was putting out a hypothesis and-and giving evidence backed by literature, uh, and hoping that other people . . .Because I’m not — I wasn’t a r — you know, a real researcher. I wasn’t doing vitamin-D work. And in this — in this case, I was talking about the role of vitamin D in neurodevelopmental disorders like autism, uh, schizophrenia — uh, ADHD. And so I was hoping that people in those fields would-would then say, uh, look at — this is interesting. Why don’t we test some of this doing X, Y or Z? So, that was some of the work that I did. But also, like I launched the podcast officially in 2014. I was still a postdoc at the time. And part of my goal for launching the podcast in addition to what I talked about which was really being passionate about everything I was talking about and-and this — the-the science behind why micronutrient insufficiencies can be detrimental to health, and why you may not know that now but you may know that later, and what we can do about it and,you know, other things like running and exercise and sauna and all that stuff. Right?

 Gordon: Yeah.

 Rhonda: Uh, in addition to that, I was also using the podcast as an incubator for ideas — for new ideas. And because we have a large science — you know, scientist following, it’s actually worked out where people have done experiments based off of things they’ve heard on the podcast —

 Gordon:  Yeah. Absolutely. Yes.

 Rhonda: — where you’re getting cross-disciplinary — you’re getting this —

 Gordon:  Yeah.

 Rhonda: — cross-disciplinary effect where, you know, scientists that are doing research on vitamin D receptors are now listening to fasting, you know, researchers on the podcast. And then they start looking at the effect — what happens when you fast on-on vitamin D, you know. So —

 Gordon:  Yeah. Yeah. Yeah. Yeah.

 Rhonda: I think that’s awesome. That’s one of my biggest excitements, honestly. [laughter]

 Gordon:  Just to circle back…micronutrients — can you give us a definition of that?

 Rhonda: Micronutrients are around 40 or so essential vitamins, minerals, fatty acids and amino acids that you have to get from your diet. Your body cannot make them. And so, uh, we need to get-get them from our diet. And the reason they are essential is because they run our metabolism. They run pretty much everything in our body. And about, I think, something like you know, there’s like 22 percent of all the enzymes, which are, you know, proteins that are doing work inside of our cells, require a micronutrient as a cofactor. And —

 Gordon:  Yeah.

 Rhonda: — as you know, you know, people may not know what a cofactor is. But a cofactor essentially just means like it’s needed for the enzyme to function properly. So, micronutrients are important. And there’s huge insufficiencies in-in people. They’re not getting enough — they’re not eating, you know, healthy enough foods to basically, you know, satisfy their sufficiency for magnesium, for example. Obviously —

 Gordon:  Yeah. Yeah.

 Rhonda: — vitamin D is a big one. But that’s something that we u — normally we make from the sun. Uh, and there’s other reasons why we’re not getting that as much. We’re-we’re definitely not outside. And there’s all sorts of problems. But that’s —

 Gordon:  I’m sorry to-to interrupt that. But I mean, vitamin D — I mean, a deficiency is really interesting because it elevates the risk for cancers, uh, for neurological disease, for diabetes. It kind of looks like, uh, uh, an accelerated aging phenotype, deficiency of vitamin D. And we just —

 Rhonda: Have you seen those vitamin-D receptor knockout mice? Are they —

 Gordon:  Yeah.

 Rhonda: — full knockout? Are they — is it embryonic —  

Gordon:  I think they’re full knockout. But —

 Rhonda: Are they?

 Gordon:  Yeah. Yeah. Yeah. I think so. But yeah. I mean,  it looks like accelerated aging. And-and we in worms, we squirted vitamin D on worms. They don’t normally see vitamin D. And  it extended their life span. It stopped protein aggregation. It prevented A-beta toxicity. So it-it seems like deficiency is really, really important. And as you say . . . I mean, many populations are subject to deficiency if they’re not getting it in their diet and they’re not getting . . . so I’m from Scotland where there’s no sun. And [laughs] vitamin-D deficiency is a-a big deal. So it is one of those things you think, wow, that-that’s a — that’s a — almost an easy fix as a public health issue.

 Rhonda: It is! And sev — 70 percent of the United States population doesn’t have sufficient levels which is, uh, defined by the Endocrine Society as 30 nanograms or — 30 nanograms per milliliter or more. And, uh, there’s been all sorts of all-cause-mortality studies looking at  vitamin-D levels in association with all-cause mortality, I mean, over decades and decades of, you know, science that’s been published.  And it’s-it’s pretty clear that levels above 40 or more — you know, between 40 and 60 is a really good sweet spot. Forty and 60 nanograms per mil are associated with the lowest all-cause mortality.

 Gordon:  Yeah.

 Rhonda: And so, you know,   vitamin-D supplements are one of the easiest ways to correct a deficiency. Uh, you know, so [sighs] again, I mean, we could go in — we could talk for hours on-on vitamin D. But, uh —

 Gordon:  I mean, are there dangers to overdoing it? Can you take too much?

 Rhonda: So I mean, I’ve looked really deep into that data. And it’s really — like to get hypercalcemia, which is like high blood calcium which is like the major concern–  

 Gordon:  Yeah.

 Rhonda: — like you literally have to take hundreds of thousands of IU a day for multiple days. It’s really hard. [laughs]

 Gordon:  Hmm.

 Rhonda: It is really hard. Uh, it is — now, people h — do have certain conditions like k — like kidney disease and stuff. And they might be more prone, uh, to a problem, you know. So —

 Gordon:  Mm-hmm.

 Rhonda: — obviously, that’s something to discuss with a physician. But by and large, the-the-the-the Institute of Medicine, the upper tolerable intake limit was set at 4,000 IUs a day. And  I mean, that is absolutely a reasonable amount —

 Gordon:  Yeah.

 Rhonda: — for-for people to take. It’s-it’s —

 Gordon:  Yeah.

 Rhonda: — that is not, you know, a-a dangerous level of vitamin D.

    MUSIC INTERLUDE

Gordon:   Let’s talk about hormesis. What’s hormesis?

 Rhonda: Well, I like — I like to define it, uh, as Dr. Mark Mattson, uh, has eloquently, uh, put it in so many publications, uh, you know, that basically, not defining hormesis but starting with basically intermittently challenging yourself with stress —

 Gordon:  Yeah.

 Rhonda: — and  why that’s important and I think, and I know probably Mark would agree, necessary, uh, you know, that —

 Gordon:  Mm-hmm.

 Rhonda: — that basically humans have evolved with these intermittent challenges. And-and those challenges are things like physical activity, you know. So before we had Instacart and could order our groceries on our phone and have them delivered to us, we had to go out and hunt our food if we were going to eat meat. We had to go out and like, run, and like we had to be fit to do that.  

 Gordon:  Yeah.

 Rhonda: Uh, you know, so physical activity was a stressor, you know, that is — that is stressful on the body. And also, you know, walking around and getting berries and picking, you know, berries and nuts and whatever, uh, kind of plants and stuff also required movement —

 Gordon:  Yes.

 Rhonda: — uh, as well as, you know, not having food. So if you didn’t catch your prey, or if   if it’s too cold and there wasn’t enough berries or whatever, you know, you were challenged by a food scarcity period. Right. And that is also a type of stressor, not having food.  Nowadays, we have food all the time, so much food. I mean, you never have to not eat. Uh, I mean, we could be eating while we’re talking and doing this podcast. Right. I mean, so, uh, that was another challenge that humans evolved with as well as eating. And this all — this all gets credited to a beautiful paper — review paper that, uh, Dr. Mark Mattson wrote many years ago. Uh, and also, you know, eating these-these compounds from plants   — these are phytochemicals. These are things like, you know, uh, flavonols and polyphenol, things that you hear about. Those things also are a little bit stressful on us and challenge us. So what does that do? Well, that actually activates a variety of stress-response pathways that are — that are built into our genes. They’re meant to be turned on. And when they’re turned on, they are not only good at dealing with that small amount of stress whether it’s the exercise, physical activity or the intermittent fasting or if it’s the plant compounds or, in other cases, stress from heat or cold. Uh, they are active for a longer period of time where they have an antioxidant and anti-inflammatory effect that lasts, far beyond what that little intermittent stress was and helps you deal with the stress of aging, normal metabolism, normal inflammatory pathways being activated. We are aging right now, inflammatory molecules are being released. So if you can have genetic pathways that are basically toning down pro-inflammatory cytokines and bumping up anti-inflammatory pathways and, you know, bumping up antioxidant pathways in our bodies, also helping with stem-cell production and helping with our proteins folding normally so we don’t have aggregates building up, like you can activate those pathways by doing things like exercising and eating some of these flavonols and polyphenols and also by, you know, fasting. So, the idea of hormesis — I sometimes don’t like to start with the blunt definition because it can sound scary. But if you have too much stress, too much of something that is a stress, then it-it —

 Gordon:  Yeah.

 Rhonda: — can be bad. And —

 Gordon:  Yeah.

 Rhonda: — you know, so, uh, I mean, if you drink too much water, uh, that could be really bad. If you do nothing but exercise without a break, I mean you could cause  harm. So, hormesis kind of refers to this-this dose response curve where the amount of stress, uh, when it’s in a — in a small dose, it’s beneficial because it is activating all these stress-response pathways that have a net positive effect on the way — our health and the way we age. But if you go over that like a dose, if you, you know — if you were to drink 300, you know, grams of caffeine, you would die, you know, like . . . 

  Gordon:  Mm-hmm. Yeah.

 Rhonda: So you know? 

 Gordon:  Yeah.

 Rhonda: So basically, uh, it-it’s like — it’s a little bit of stress that’s beneficial. And, uh — and the idea is that we were meant to be stressed. We were meant to be stressed. We were meant to — we have genetic pathways that are —

 Gordon:  [laughs]

 Rhonda: — activated by them. I mean —

 Gordon:  Yeah.

 Rhonda: — you know, to me, it’s like —

 Gordon:  Yeah.

 Rhonda:  it’s so obvious.  

 Gordon: Great. You know, I-I’ve been really interested in this whole thing for a long time. I-I found that, when we, uh, uh, subjected these little tiny worms, C. elegans, to heat shock, uh, they lived longer. And, uh —

 Rhonda: Fifteen percent longer.

 Gordon:  Yeah.

 Rhonda: — I cite your work all the time. Yeah.

Gordon: So, uh, you-you’ve interviewed, uh, Elissa Epel and her amazing work with Elizabeth Blackburn showing that, if you’re exposed to psychosocial stress such as parents with, you know, children who are — have a particular condition like autism or something, that-that there is a telomere attrition that happens  in those parents. And so it seems like chronic stress is really bad. Uh, but the acute stress can be really good. And I guess it’s finding the boundaries? Now, I know you’ve-you’ve written about this in terms of saunas. [laughs] And this actually really is fascinating for me because, as I say, we were — we were heat shocking worms And now, you’re talking about heat shocking humans. So talk about saunas, and talk about doses.

 Rhonda: First of all, I became interested in saunas just from using them when I was in graduate school. Uh, I lived across the street from a YMCA. And I used to go into the sauna every day before I would go into the lab. Literally, I was doing it seven days — I was doing like seven days a week sauna.

 Gordon:  [laughs]

 Rhonda: And this was back in like 2009. And of course, I had also, through my early work in Andy Dillin’s lab, been exposed to heat shocking worms and heat — and expressing lots of heat-shock proteins, which is part of that stress response pathway I was talking about. When you’re — when you are exposed to heat, one of the — you know, many different pathways that are activated is a — is the heat shock proteins. And they are involved in helping proteins keep their three-dimensional s-structure inside of your cells to prevent them from, uh, you know, aggregating and forming plaques. And among other things, they also have antioxidant activity as well. But anyway, so I, you know, was kind of aware of that while I was doing the sauna. But the sauna really just started having really profound effects on my anxiety and-and my ability to handle stress. Uh, again, which was — and-and this was like mental stress. Like I was able to handle a failed experiment that was a six-month setback —

 Gordon:  Mm-hmm.

 Rhonda: — that would have been, uh, uh — you know, those things are hard to deal with.

 Gordon:  Yeah.

 Rhonda: So, the sauna was really helping me. And that’s kind of where I got interested in it and the effects on the brain. But a lot of the-the sauna — the research that has been done on saunas and human health have come out of Dr. Jari Laukkanen’s lab at the University of Eastern Finland. And, uh, he’s — he has shown — he’s d — he does beautiful epidemiology types of analyses and, uh, observational studies. But he’s looked at sauna bathing in men and women and risk of, you know, cardiovascular disease and death from a variety of different cardiovascular diseases and death from all causes and dementia and Alzheimer’s. And what he’s found is that there’s a dose dependent manner, you know, that basically is protective. So people that use saunas four to seven times a week versus two to three times a week have the most robust protective effect on all these mortalities. So for example, cardiovascular related mortality is 50 percent lower in men that use the sauna four to seven times a week versus one time a week.

 Gordon:  Incredible. Amazing. Yeah.

 Rhonda: It’s only 27 percent lower in men that use it two to three times a week versus one. So there’s a dose dependent effect for frequency. But also, there is a temperature and duration effect meaning most of the temperatures of these saunas were about 174 degrees Fahrenheit. And if you look at the data in some of their — in some of their tables, you’ll see that men that spent only 11 minutes in the sauna, even if it was four to seven times a week — they only had like an 8 percent reduction in cardiovascular related mortality compared to like a 50 percent reduction.

 Gordon:  Yeah.

 Rhonda: The 50 percent reduction came to men that stayed in the sauna for 20 minutes. And this was like true for other cardiovascular related mortalities.There was like, uh, coronary heart disease mortality was 68 percent lower in men that did the sauna four to seven times a week versus one time a week. And all-cause mortality was 40 percent lower compared to men that only did it, you know, one time a week.

 Gordon:  Yeah.

 Rhonda: So, uh, with the observational data, uh, there’s always the, okay, well, that’s not establishing causation. However, the dose-dependent nature of it, the frequency as well as the duration in the sauna to me is very — is very much, uh, reassuring that there is, uh, more of a causality that can be established, you know, because it’s just — you-you just wouldn’t see that if it was like some other effect, right, like a — it’s like a — you know, having the-the healthy user bias kind of effect, not to mention they corrected for all kinds of problems, you know, high lipids, exercise, socioeconomic status, like anything, you name it.

 Gordon:  Yeah. Yeah. Yeah. Yeah.  So — uh, uh, w — so, uh, many people leave the sauna and jump into a very cold bath or have a cold shower. So what’s the cold exposure story to this?

 Rhonda: Yeah. That’s definitely common in-in-in, uh, countries that culturally use the sauna like Finland. And also in Russia, they do  he Russian banyas. And they also do some cold. Uh, interestingly, there’s a lot of overlap between these intermittent stressors, you know. Uh, so-so you’ll find that cold exposure also activates heat-shock proteins. You’ll find that, uh, eating some c — plant compounds like a sulforaphane found in the Brassica family activates heat-shock proteins.

 Gordon:  Yes.

 Rhonda: Heat does it the best. But the-the idea here is that, back to that concept of, you know, intermittently challenging yourself and-and the genetic, you know — it’s-it’s hard-wired in our genes that these genes get activated by stress, by like a low-level type of, uh, good stress. Well, there — you know, there’s definitely a lot of overlap. And so, uh, cold-cold — it’s kind of nice to know that, you know, cold does a lot of things that-that-that heat also does and vice versa. So like there was a recent publication showing that heat local heat application can-can brown fat —

 Gordon:  Hmm. Yes.

 Rhonda: — uh, which is something that cold is known to do. So cold exposure —

 Gordon:  Mm-hmm.

 Rhonda: — one of the main things it does is, uh, it changes the metabolism inside your adipose tissue and also can-can do it in your muscle tissue. And that is by, uh, a couple of mechanisms. One is by making your body — both of them help your body generate heat, which is what you’re trying to do. Your body is trying to survive. So the stress response pathway in this case is, uh, norepinephrine is elevated. Norepinephrine is a neuroendocrine hormone that’s generated in the adrenal glands. It’s in the plasma circulating. But it’s also a neurotransmitter in the brain. So it’s robustly increased when you — when you get into the cold. And that activates a pathway inside of your fat cells called UCP1, which essentially freaks your mitochondria out, as you know Gordon, and your mitochondria are essentially trying to — they’re kind of — you can think of them as a battery. And they’re kind of trying to maintain a, uh, electrochemical gradient, a negative charge on the inside and a positive charge on the, uh, outside so to speak.

 Gordon:  Hmm.

 Rhonda: And what ends up happening is the UCP1 totally takes that away. All these protons start leaking out. And your mitochondria freak out. And so they start making energy. Uh, they’re not actually making ATP. They’re making energy in the form of heat. But they’re burning substrates to do it.

 Gordon:  Yeah.

 Rhonda: And so — and so you end up having, uh — you know, you end up actually burning more glucose or more fatty acids, which is kind of a good thing, uh, even if it’s not necessarily making ATP, which is the real energetic currency of the cells. This is what runs everything in our — in our body. But,  so that’s one adaptation. And the other one is actually your body goes, wait a minute. What if I’m going to be exposed to cold again? Like how am I going to make sure I don’t die? Like how am I going to make sure I can keep myself up? And, uh, as you know, Gordon, the way it does that is by making more mitochondria in adipose tissue.

 Gordon: Mm-hmm. Mm-hmm.

 Rhonda: And that is also regulated by norepinephrine. It increases a protein called PGC-1alpha, which is involved in the growth of new mitochondria. It’s called mitochondrial biogenesis. And essentially, your body has figured out a way, uh, to make more of these mitochondria. That way, when it’s exposed to heat — I mean, sorry — when it’s exposed to cold, it can make more heat.

 Gordon:  Yeah.

 Rhonda: So —

 Gordon:  Yeah. Yeah.

 Rhonda: So that’s-that’s kind of the-the — those adaptations that occur. And, uh, of course, there’s all sorts of science going on, thousands of labs trying to understand brown fat. And the reason this is called brown fat actually I should say is because, when you have more mitochondria in an adipocyte cell and you look at it under a microscope, it looks dark.

 Gordon:  Yes.

 Rhonda: So it looks darker. And so it’s called the browning of fat because, uh, it looks — it looks brown under a microscope rather than white with all the lipid droplets.  

 Gordon:  So I’m just thinking about a-a classic paper from Nikki Holbrook many, many years ago now. And it-it made the connection between, the molecular processes of stress response like the, uh, induction of heat-shock proteins which are molecular chaperones which, as you said, you know, are involved in protein folding, protein shape, something that’s, uh, really, really important in aging and also really important in neurological disease, Alzheimer’s, Parkinson’s and so on. And her experiments were to-to subject, uh, rats to a-a-a mild psychosocial stress just basically restraining their movements and showing that actually that was enough to turn on the expression of molecular chaperones. So there’s this connection between this molecular process that we knew was really important — well, we now know it’s really important in aging and age-related disease — to psychosocial stress. And I know you’ve thought about this as well.

  You-you-you-you’ve talked about mindfulness and, uh, cognitive behavioral therapy. And so-so we’re-we’re going from hormesis here to these-these-these areas of, uh, uh, psychology. Can you talk about that a little bit?

 Rhonda: Well, psychosocial stress — and I know l — as you mentioned, a lot of work has been done by Dr. Elissa Epel from UCSF —

 Gordon:  Yes.

 Rhonda: — uh, who was on the podcast years ago. And, uh, you know — and-and many others have done a lot of work on this just looking at the effects of psychosoc-soc-social stress, whether it’s, uh, taking care of s — a-a sick family member or-or f-financial stress or, uh, relationship stress. Like these things — and there’s been some-some research by, uh, various different groups showing that actually these types of stress, the psychosocial stress actually affects the release of endotoxin from our gut. And endotoxin is, for people that don’t know, it’s also referred to as lipopolysaccharide. But it’s essentially the outer membrane of a bacterial cell. And, uh, when the bacteria are killed, uh, in this case in our gut by our immune cells, uh, they release endotoxin into our bloodstream. And this activates inflammatory pathways. And so you end up getting this causal between, this causation between stress, inflammation and then depression. And so like there’s been some-some studies done showing that you can actually even just inject lipopolysaccharide into healthy people and activate their inflammatory response and cause them to have depressive symptoms. And this is compared to people given a saline injection. Uh, but you can also then give those same people omega-3 — in this case, it was EPA — and basically blunt the inflammatory response from the lipopolysaccharide and actually prevent the depressive symptoms. And so the connection between health, you know, the stress, health, the way we feel, the way we think, uh, but also the way — the way we’re aging — so this inflammatory process is not only affecting the way we feel and our mood, but it’s affecting the way we age. And so there’s been —

 Gordon:  Hmm.

 Rhonda: — so much research looking at the effect of inflammation and chronic inflammation on aging whether we’re talking about some of the-the data l — clinical data looking at, you know, semi- centenarians and supercentenarians and centenarians and all the panels of biomarkers and how, you know, basically, inflammation was shown — the reduction of inflammation or suppression of it was shown to be the only thing that was a determinant of going to the next stage so becoming an actual supercentenarian and also maintaining good cognitive health. So nothing else really mattered as much as inflammation. And then, there’s been a whole —

 Gordon:  Yeah.

 Rhonda: — you know, animals studies, all kinds of just, it’s pretty well known. Inflammation does play a causal role in accelerating the aging process. It’s not the only thing, you know. So I think that anything that we can do prec-preconditioning ourselves — so if we can get in the sauna or go for a run or get on the Peloton or do some yoga or something that’s going to activate these genes that are anti-inflammatory and activate them so that, when we are exposed to rush hour in traffic or whatever is that we can’t predict that’s going to stress us out, that we’re able to handle that stress better. And I think that’s the bottom line is that, you know, you can’t predict —

 Gordon:  Mm-hmm.

 Rhonda: — when a family member is going to die or get sick. You can’t predict when you’re going to lose your job or when a relationship goes bad. Like things happen in our life that are devastating. And we have to be able to cope with them. And we have to be able to deal with them and our bodies — you know, our bodies and our brains. And obviously, there’s a whole aspect to meditation that’s aside from activating stress response pathways and stuff. Right. There’s just being able to, uh, handle stress and, you know — uh, through mindfulness and stuff. But, uh, I think the stress response pathway activation does help. It helps blunt the inflammatory response. And there’s been a lot of elegant studies done in pre-clinical models like mice where you give them, you know, sulforaphane. Or you give them curcumin. Or you make them run. Or you expose them to heat. And then, you give them a stressor. Like you cause them to have an ischemic stroke or something. And they actually do better —

 Gordon:  Yeah.

 Rhonda: — if they have that preconditioning.

 Gordon:  Yes.

 Rhonda: And to me, I always look back at those studies. And I think, well, I want to be that mouse. Like I want to be the one that has the good plant compounds, that’s getting the exercise, that’s doing the sauna, that’s getting all the beneficial stress, that’s doing some beneficial fasting that way, when something challenges me in a way that’s not good, that I can deal with it better.

MUSIC INTERLUDE 

I’d like to talk about science communication. You-you are an-an amazing science communicator and, uh, have a great influence in your-your website, FoundMyFitness.com. Uh, you-you’ve talked a little bit about how-how you got into this. But  could you just tell us about what you think are the major challenges? So we’re living in an era where s-science is accepted by some people but also, uh, ignored by many others. And people like yourselves who were real bonafide scientists doing experiments, making discoveries have moved into this area of science communication. How do you see the challenge right now for  in general, not just in aging communication but in general?

 Rhonda: Well, first of all, thank you for that very nice compliment, Gordon I appreciate it.  I think that there — science communication, you know, oftentimes, you’ll find — and there’s a lot of good science journalists. You know, I don’t want to like naysay everything. But you’ll find that there’s a lot of sensationalism and sometimes, there’s perverse incentives that motivate people.And so you can get a sensationalistic story that makes headlines, and just everyone becomes aware of it. And it might not really be true. Or it could be a terrible study th — where you look at — you look at the statistical analysis. And you’re like, wait a minute. Like this isn’t really significant. Or you know — or you look at the data. And you go, wait a minute. They didn’t measure anything biochemically. They’re looking at a clinical endpoint. How do you even know, you know, that something worked without measuring it? Right. And so I — for me,   it’s an important role to fulfill, I think, is to help actually accurately analyze the data using  my ability to analyze science, uh, and-and look at the quality of the data and not only the study in isolation but the big picture, like knowing, okay, well, this is a clinical study. What do we know mechanistically about this? What’s the big picture here? Because that all matters. Like you could have one — there are so many conflicting data out there. And a lot of the conflicting data has to do with methodology. Uh, you know, it has to do with the way experiments were done, the way studies were conducted. And if people don’t know that, they hear a headline. And they get confused. So to me, I think it’s important for more scientists  to help communicate accurately, you know, to the public like the science of what’s actually being published and what that even means. So, uh — so that’s kind of what-what I do. I have a small team that helps with that as well.  

 Gordon:  Hmm. Hmm.

 Rhonda: But it’s a bigger problem than-than I can even handle. You know, it goes back to just even scientists not communicating with each other. You know, like —

 Gordon:  Yeah.

 Rhonda: — you know, someone just having the tunnel vision where it’s like, okay. You know, maybe — I know you’re a clinical person that always just looks at heart attacks as a-an endpoint. But like —

 Gordon:  Hmm.

 Rhonda: — if you’re going to give someone a vitamin-D supplement, measure their vitamin-D level. I mean —

 Gordon:  [laughs]

 Rhonda: — see if it even went up. Like — and that’s getting better. But, you know —

 Gordon:  Yeah.

 Rhonda:  I started out coming out in the public — this was like 2014. There were a lot of studies coming out. And-and it was, you know, vitamin D does nothing. And-and the studies — literally, they didn’t even measure vitamin D. They just gave people a-a-a 400-IU supplement and-and then looked at a clinical endpoint. And so, uh, you know, even data like that where, yeah, it was a randomized controlled trial with gold standard. But was it a well-conducted one? Like you know —

 Gordon:  Yeah.

 Rhonda: —  because, let me tell you, 400 IUs of vitamin D ain’t much. And it takes about 1,000 IUs to raise bl — your blood levels by five nanograms per mil. And that’s in people that don’t have [snit] that regulate [them — the h –] vitamin-D metabolism.

 Gordon:  Mm-hmm. Mm-hmm.

 Rhonda: So I guess what I’m getting at here is that, uh, the problem — there’s many-fold problems.  I think one is that we, as scientists, we need to sort of all get together and establish more protocols and, uh — for doing clinical research, make sure we’re measuring things. Like that’s key, measuring things. Like you can’t — like publishing a randomized controlled trial — I think it all comes back to like drugs and, you know, randomized controlled trials are the gold standard for a new drug. And — but you know, drugs — you never have a drug in your body before you take the experimental drug. You know, when you’re doing nutrition studies, we all have different levels of vitamin D. We have genes that regulate how we metabolize it.

 Gordon:  Yeah.

 Rhonda: We have different levels of magnesium. And if you don’t measure those . . . You know, I get with a drug it’s like, well, yeah, obviously they’re going to have, you know, zero and then they’re going to have something. And it’s going to do something. So — but with-with nutrients and-and nutrition, it’s different. And I think there’s a different standard that needs to be there for all clinical research and nutrition.  And then, there’s the problem of sensationalism and —

 Gordon:  Yeah.

 Rhonda: — click bait and, you know, journalists wanting to make a story. And it’s like, well-well, is the story real science, or is it click bait, you know?  So there’s just — there’s multiple layers of-of problems. And so what-what-what I really try to do with my team is to be cross-disciplinary, is to look at multiple, types of data from-from worm data, to mice, to molecular, to human and-and to, uh, look at the methods and methodology and find, well, maybe possible explanations for contradicting, you know, data and explain them to people. So –

Gordon:  And your podcasts are very data driven. In fact, I love the-the way that you display scientific papers, uh, at the same time as you’re interviewing your guests. So you bring up the evidence-based, uh, data at the same time as you’re-you’re talking about things.  I think that’s fantastic. I think a large number of people are in absolute awe of what you do. Uh, you’re-you’re serving the science community, especially the aging community in amazing ways. And, I thank you for that. And I just wanted — obviously, as a — as a deep thinker about this, uh, you might have some predictions. I know we all hate these predictions questions. But where do you think — where do you think the aging field is going to be in 10 years?

 Rhonda:  I’m certainly not sure, for certain. But I do — I am very excited about a lot of the interrupted cellular reprogramming work being done by —

 Gordon:  Yes.

 Rhonda: — people, by, uh, Dr. Juan Carlos Belmonte and, uh, collaborators. And, uh, I-I do — you know, I — it — I’m not sure — uh, there hasn’t been enough research done yet. And I know there’s going to be a lot more coming. But I do — uh, this idea, you know — I’d always thought about it, you know, totally independently that, you know, when-when Shinya Yamanaka, uh, discovered these y — four transcription factors that could essentially take an old adult cell and revert it to an embryonic-like state, uh, it was like, wow. That’s like the ultimate reverse of aging, uh, in a way. And so, uh, I think what, you know, Juan Carlos Belmonte and others have done was so brilliant in figuring out a way to kind of just, you know, pulse this — these-these factors on and, uh, essentially wipe clear the-the program — uh, the epigenetic program of the — of the adult old cell and make it, you know, not-not a stem cell. It keeps its identity. But it-it wipes away, you know, the whole program. And somehow, all the gunk and protein aggregates and DNA pieces and everything goes away with it. It’s amazing. So, I’m really interested in that process. But I’m also really interested in a lot of the work done by the Convoys at U.C. Berkeley and —

 Gordon:  Yes.

 Rhonda: — and, you know, essentially diluting out what other — what-whatever pro-aging factors in our plasma are accelerating the aging process.  Uh, I think they’ve-they’ve nicely done that through a variety of experiments where they’ve, uh — this therapeutic plasma exchange.  I mean obviously they started out with the parabiosis studies where they were hooking organisms up together in — uh, young and old and exchanging their-their-their blood and plasma. But we’ve-we’ve-we’ve developed, uh, since then. And-and things have-have gotten a lot more interesting. So, uh, that work is also really interesting to me. But I’m the most excited about-about the interrupted cellular reprogramming work. And I think that  there is a potential there for potentially really  possibly reversing some aging.  I don’t know how it’s going to be implemented. I mean, you know, it’s going to probably have to be something that you have to continually do. Uh, you know, it’s not like a lasting effect because you’re going to — continually having cells age and stuff. But,  you know . . . And so finding-finding all the hurdles and stuff that you’re going to have to overcome to make it actually clinically relevant will definitely be quite a few years, but I am excited about that.

 Gordon:  Fantastic. Uh, Rhonda, thanks so much for your time. Uh, your insights  are  — fascinating. And, uh, it’s been great to talk to you so, thank you again. And keep doing what you’re doing. It’s-it’s really, really valuable to the field and to-to human health.

 Rhonda: My pleasure, Gordon. It’s really, uh — I appreciate all those kind words. And, uh, anytime you want to talk, let’s do it again. And thanks to the Buck Institute —

 Gordon:   Excellent.

 Rhonda: — as well for all the-the research on aging and advancing our knowledge.

 Gordon:  Thank you, Rhonda.

SHOW OUTRO

Thank you so much for listening. If you’ve enjoyed this podcast, please subscribe, share and give us a five star review on Apple, Spotify or wherever you get your podcasts. 

  “We’re not getting any younger, yet!” is made possible by a generous grant from the Navigage Foundation. The Navigage Foundation is enhancing the lives of older people through the support of housing, health, education and human services. Our podcast is produced by Vital Mind Media: Wellington Bowler is here with me using sign language to keep me on course and recording the podcast. Stella, who I love spending time with talking about science, as you know, is our editor with the Creative Direction of Sharif Ezzat and the Buck Institute’s very own Robin Snyder as the executive producer.

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