Dr. JoAnn Manson 0:00  
There are a lot of genetic factors there are a lot of social determinants of health that can make it more challenging to change our diet to change lifestyle, but there's still a lot within our control, and it can have absolutely enormous impact on improving our health.

Claudia von Boeselager 0:19  
Are you ready to boost your longevity and unlock peak performance and welcome to The Longevity and Lifestyle Podcast. I'm your host Claudia von Boeselager, longevity, and peak performance coach. Each week we'll explore groundbreaking science, unravel longevity secrets share strategies to grow younger, and stay up to date with world-class health and peak performance pioneers. Everything you need to live longer, live better, and reach your fullest potential, ready to defy aging, optimize health, and promote peak performance; visit LLinsider.com for more.

My guest today is Dr. Joanne Manson, world-renowned endocrinologist epidemiologist, and principal investigator for the Women's Health Initiative, the landmark study on HRT or hormone replacement therapy and potential risks to breast cancer which came out over 20 years ago. Joanne is a professor of medicine at Harvard Medical School and the chief of the Division of Preventive Medicine at Brigham and Women's Hospital in Boston, Massachusetts. Dr. Manson has published over 1200 scientific articles and is recognized as one of the most cited researchers in the field of medicine. She's won countless awards and is the editor-in-chief of contemporary clinical trials, to name but a few of her many accomplishments. Welcome to The Longevity and Lifestyle Podcast. Joanne, I am honored and have such a pleasure to welcome you today.

Dr. JoAnn Manson 2:00  
It's great to be here, Claudia. Wonderful to talk with you.

Claudia von Boeselager 2:03  
I'm very excited about our conversation, too, because it's such an important topic for women. And we're going to cover a few different areas. But I'd love to start with women's health and HRT, and for those unfamiliar, HRT is hormone replacement therapy, which is for controversial, and also based on a study that our specialist Joanne here today was involved with. And so we're going to dig into that shortly, but my audience, who have listened to several of different episodes, and some of my previous guests, will be aware of that. There is a spectrum of understanding around the benefits of HRT, particularly anecdotal about how it helps women going through the perimenopausal menopausal, and postmenopausal years insight from biological age testing company glycan age Nicoline allows those who's been a repeat guest the have 20 plus years of research on glycans and biological age testing. And it has been shown that one year when before menopause is declared, so basically the day of your last period, waiting one year a day for menopause to be declared biologically on average, without HRT, women are aging biologically on average by eight years. So that lack of drop of estrogen is really having an impact on them based on the research and clinical trials that they have been doing. So Joanne, before we dig into the landmark study that you were involved with over 20 years ago, how, in your view, is HRT able to reduce chronic diseases such as heart disease, and how has your view changed, perhaps before the study and after the study? Well, the

Dr. JoAnn Manson 3:49  
the pendulum has been swinging a lot on this topic, but the way we look at it with menopausal hormone therapy, timing is everything. In the early days, let's say 3020 30 years ago, it was believed that women could initiate, you know, for the first time start taking hormone therapy at age 6070 Even ad for the purpose of preventing heart disease, and it would be protective to the heart we now know that that isn't the case. However, the earlier in menopause you start, the better the benefit-risk profile. And hormone therapy serves a purpose for women who have moderate to severe menopausal symptoms, hot flashes and night sweats, disrupted sleep, and other symptoms of menopause hormone therapy is very effective, and the benefit-risk ratio is very favourable, especially Usually within 10 years after onset of menopause. So we generally do believe that hormone therapy if there's an indication for treatment, such as moderate to severe or bothersome, hot flashes, other menopausal symptoms that women should be able to have shared decision making with their clinician to decide if hormone therapy is the right choice for them. One big problem is that women often have so much trouble finding a clinician who can have that decision with them. But we really do not recommend hormone therapy for the express purpose of trying to prevent cardiovascular events, such as heart attack, stroke, heart failure, the evidence is really controversial. Still, even in early menopause, is that really a main benefit of hormone therapy? We know oral hormone therapy increases risk of blood clots, probably not the case with the transdermal patch or gel. But we think that the thinking about hormone therapy should be very reasonable clinical role in management of menopausal symptoms, but not use for the express purpose of trying to prevent the heart attacks, strokes, blood clots, and cancer that overall it's really not for the express purpose of prevention of chronic diseases.

Claudia von Boeselager 6:46  
So let's jump in to this study, JoAnn, and you were one of the principal investigators on the Women's Health Initiative study 20-plus years ago, to better understand the effect of HRT when use for chronic diseases prevention. And please correct me on anything that I might have misinterpreted here, can you share more about for people listening, because a lot was based for many years and even to this day, the way thinking is around each show T? Can you share more about the intention of the study, why it was prematurely stopped, and how the misinterpretation of results came about that has caused such a change in perception, if you will, at the time about the use of HRT and the association with a perceived increase in breast cancer.

Dr. JoAnn Manson 7:34  
So the purpose of the Women's Health Initiative, the largest randomized trial of menopausal hormone therapy ever done, was to test the role of hormone therapy in the prevention of chronic diseases, such as heart attacks, strokes, blood clots, cognitive decline, cancer, osteoporotic fracture, and all-cause mortality. That was his purpose. And that's why women were enrolled over a broad age range age 50 to 79. Because, at least in the United States, and I think many other countries, women were being started on hormone therapy, well into menopause, often, women in their 60s and 70s were being started or restarted on hormone therapy feed used to briefly for symptoms, they might be started again at age 65, or 70. So that was the main purpose was stopped early, because, at least for a combination of estrogen plus progestin, it was found that the risks outweigh the benefits. When it came to chronic disease prevention. There was an increased risk of stroke, blood clots in the legs and lungs because it was an oral estrogen, it was the most common formulation of estrogen in combination with progesterone. So it was not showing benefits for prevention of chronic disease overall, but it did have certain specific benefits. It did decrease the risk of osteoporotic fractures by about 1/3 and decreased hip fractures in particular, and would decreased the risk of type two diabetes. And there were some benefits for all cause mortality. It was very neutral, overall, very neutral. But what we noticed as we delve more deeply into the data, was that the women who were closer to the onset of menopause at the time of randomization to hormone therapy did better on hormones and the women who were in older age groups, so in particular, the women who were 70 and older tended to have the greatest excess number of heart attack strokes, blood clots and cases of cancer and all the way down the line. Their risks tended to exceed the benefits, whereas women who were in their 50s tended to have pretty neutral results for estrogen plus progestin. But they still had some risks. I mean, they still had an increased risk of blood clots; again, that may be due to the oral estrogen may not be seen with transdermal, but they did have a signal for an increased risk of breast cancer. Now, the results for estrogen alone in women with hysterectomy were much more neutral and even favourable for the younger women. We found that the women in their 50s did have a significant reduction in heart attack. With estrogen alone, it was just borderline for total coronary heart disease. They did have or at least a signal for some coronary benefit, but they also did have signals for increased risk of blood clots in the legs and stroke. With estrogen alone, there was a decreased risk of breast cancer across all age groups. This may be because the type of estrogen tested, the conjugated estrogen alone without the addition of a progestogen had a what's called a SERM, like effect, almost like a tamoxifen-type effect. And so overall, there was a signal for reduction in breast cancer. This has to be looked at closely with other formulations of estrogen alone, but it suggests that the addition of a progestin or progestogen is the major contributor to the risk of breast cancer seen with hormone therapy. So I think that we can say that overall, the risks of estrogen plus progestin were somewhat greater than the risks of estrogen alone and that in women more distant from onset of menopause, the risks tended to outweigh the benefits were as for women closer to onset of menopause, especially for estrogen alone, it was quite a favourable benefit risk profile.

Claudia von Boeselager 12:29  
So for women listening who are maybe, let's say Peri menopausal. And considering that and I think you touched on an important point also about finding the right clinician, the right physician to actually have this conversation with because unfortunately, this is not widespread knowledge. But assuming they're able to find a hormone specialist who is familiar, and they these women are perhaps anxious about embarking on an HRT therapy, would you say that? What are the type of conversations these women should be having with their hormone specialists in order to best understand if it is beneficial for them in their menopausal years?

Dr. JoAnn Manson 13:12  
So it is really important that women feel comfortable discussing menopause with their clinicians, and they need to be able to find a clinician who's knowledgeable about menopause and open to having a discussion about their symptoms, the chronic disease risks that do tend to increase at time of menopause and the treatments that are available, which include both hormonal and nonhormonal treatments. So if they have trouble finding clish in the United States, there is a website menopause.org where they can actually find a clinician, put in their zip code, and find a clinician who has additional expertise in in menopause. So the North American menopause society, a website may be helpful, at least in the United States,

Claudia von Boeselager 14:03  
but we'll link it in the show notes as well. Thank you for that. Yeah.

Dr. JoAnn Manson 14:07  
So women need to feel comfortable talking about their symptoms. Are they having hot flashes? How often are the hot flashes? How distressing or bothersome are the hot flashes? Are they having night sweats? Are they awakening at night? Is their sleep disrupted? Are they having brain fog, difficulty concentrating, mood swings? These are all symptoms that can be related to menopause and can be related to disrupted sleep. Now, under the circumstances if the symptoms are bothersome, a woman close to the onset of menopause is likely to be a good candidate for hormone therapy unless she has a high risk of cardiovascular disease or estrogen-sensitive cancers. such as breast cancer, endometrial cancer, and luck. But most women, whew are at usual risk of these conditions low or moderate risk and they have bothersome hot flashes, night sweats, other menopausal symptoms will have a favourable benefit risk profile for use of hormone therapy. Now, if they don't, there are other options for them. There are non hormonal treatments such as the SSRI, the selective serotonin reuptake inhibitor antidepressants, the serotonin norepinephrine reuptake inhibitors, the SNRIs. Also the GABA 1010, like medications, and there's a new FDA approved medication that works directly in the brain and thermostat in the brain, which also has been shown to be effective. So there are non hormonal options, which it's important women be aware of because if they're not a good candidate for hormone therapy, let's say the prior history, personal history of breast cancer, or very strong family history of breast cancer, they want to avoid hormones. There are non hormonal treatments for them. Also, if they've already had a heart attack or have multiple risk factors for heart disease, they certainly should not be on oral estrogen in pill form. They may be a candidate for transdermal patch or gel estrogen, but they may want to avoid estrogen under the circumstances if they have a high risk of cardiovascular disease.

Claudia von Boeselager 16:39  
No, that's helpful. JoAnn, what's your view on the bioidentical versus synthetic formulations of HRT,

Dr. JoAnn Manson 16:48  
it's really important for women to understand that there are the FDA or government approved formulations of bio identical hormone therapy and also listen to that. Hormone therapy does not bio identical, as well as what's called the custom compounded bio identical hormone therapy. And women should tend to choose government-approved or FDA-approved formulations of bio-identical or other hormone therapy because those are the types of hormone therapy that have been well-tested for both efficacy and safety. And if they use the compounded form that is not FDA approved, there is less regulatory oversight in terms of whether it is truly effective. Are they getting the content that they think they're getting, you know, in terms of the amount of estrogen or progesterone and is, and is it free of contaminants and impurities, they don't have a guarantee of that, as they do with a government regulated government approved formulation. But bio-identical, approved forms regulated forms of estrogen estradiol and progesterone micronized progesterone are very good options and even have advantages over the let's say the oral formulations that may be like the conjugated the oral conjugated estrogens, or the synthetic progestins. First, these, the transdermal estradiol is safer in terms of not going directly to the liver and not increasing clotting factors. It has, in observational studies, been linked to a more neutral effect on blood clots, you know, not seeing the increased risks that have been seen with the pill form that goes through the liver and can increase clotting factors. So I think that there are a lot of advantages also micronized progesterone in observational studies has not been linked to as much of an increase in breast cancer as the midroc see progesterone acetate MPA tested in the Women's Health Initiative. So I certainly wouldn't discourage the use of bio identical estradiol. micronized progesterone, if it's FDA approved, I think it's a very good formulation. These are good formulations to use. And also, I would tend to encourage women to choose transdermal patch, gel spray, you know, types of FDA-approved products, rather than the oral estrogen switch have been linked to increased risk of blood clots, but some women prefer oral. And if a woman is in early menopause and generally in good health, and she really has a preference for the pill form of estrogen, she should still have a good benefit risk profile with that

Claudia von Boeselager 20:18  
excellent. Also, I know your audience who are around the world. And so, in different countries, they call it bioidentical, and in others, it's called body identical, but it's when the formulations are regulated or approved, versus when they are made up in the pharmacy, if you will. So just to make sure if anyone's listening and looking into it, to make sure that they are from one of the approved compounds, be it from the FDA or elsewhere around the world,

Dr. JoAnn Manson 20:44  
who don't just provide a clarification on that. When they say bio identical, they're referring to the extra dye or progesterone is very similar, if not identical to what the woman naturally produces. But it may not be an approved form, she does still have to check that it's FDA or government regulated. And then there are all of these hormones basically simply testosterone

Claudia von Boeselager 21:15  
as well, right? I mean, those

Dr. JoAnn Manson 21:19  
are all basically synthesised in a laboratory of some sort. But the, for example, the conjugated estrogens are different from what a woman would get no naturally makes, they're in fact, the conjugated estrogens is more similar to what a female horse you know, the pregnant mare says. So that doesn't mean it's not a good formulation because it has been extensively tested. And in younger women, you know, that formulation of conjugated estrogen, especially when used alone without a synthetic synthetic progestin actually a good benefit risk profile for the younger women, not not for women, you know, who were decades past onset of menopause.

Claudia von Boeselager 22:13  
Thank you for clarifying you. And I have a question for you also around timing. I know that based on the study, you were looking at women sort of early 50s up to I think you said late 70s. And is there a too early timeframe to start HRT, I know that for different women, menopause can come a bit earlier, I think they'd say the average age is around 51 years old, but people's experiencing Peri menopausal symptoms change in sort of cognition, more brain fog, maybe even hot flashes already. Is that a time to already look at HRT as a support for helping with these symptoms?

Dr. JoAnn Manson 22:52  
That's a great question, Claudia. Most of the randomized trials of hormone therapy, menopausal hormone therapy have been done among women in menopause, who are at least one year past their last menstrual period, their final menstrual period. So there's actually very little known about the benefit risk profile of starting hormone therapy earlier in the perimenopause or during the menopause transition, but certainly a woman who is very symptomatic, and if she already has evidence from some laboratory tests, like the estradiol level and the follicle stimulating hormone level, are consistent with go and beginning to go through menopause or early menopause. Many clinicians will start to treat at that point. Another distinction I want to mention is women who go through menopause at an early age. If for example, they have what's called premature menopause or onset of menopause, before age 40, or even early menopause, which is between 40 and 45. That those women may particularly benefit from the use of hormone therapy, menopausal hormone therapy, because the early loss of estrogen and the decline in the ovarian hormones at an early age has been particularly linked to an increased risk of heart disease, other cardiovascular outcomes, cognitive decline, osteoporosis, and some other adverse health outcomes. So I think clinicians may want to treat women who have early or premature menopause and don't have contraindications. You know, they don't have prior history of cancer estrogen-sensitive cancer, that type of contraindication They may want to particularly consider the use of hormone therapy in that clinical scenario. But it's important that they understand the randomized trials have not been testing that specific scenario of early premature menopause starting the hormones and women in their 30s or early 40s. It's almost entirely after a more typical age of menopause, women who are age 5048 50 or older than that, that's usually what's been seen in the trial.

Claudia von Boeselager 25:40  
So yeah, I think it's a conversation for someone to have right in that circumstance with their clinician. And I guess just keep an eye on biomarkers and see how the impact is and the benefits and keep an eye on any potential risks as they go along. Is there a time to stop? Would you say is there been research around women taking HRT for menopause? And then after 10 years, 15 years, like, is there an ideal time when women should be stopping with HRT

Dr. JoAnn Manson 26:12  
there are a lot of controversies and debate about how long is best to be on hormone therapy. We've generally said that the risk of breast cancer with estrogen plus progestin begins to increase around four to five years of views. Generally, there's an encouragement for clinicians to try to reduce the hormone therapy or stop the hormone therapy in that period of time if a woman is no longer symptomatic and she's very receptive to stopping hormone therapy, but there is no magic age, or duration of hormone therapy where a woman has to stop at that particular age or time period. It is a very individualised decision. It depends on first, how well is she doing on the hormone therapy? Is she feeling you know, much better than she was without the hormone therapy? Does she have a very good sense of well being? Is she free of adverse effects of the hormone therapy? And if she starts to reduce the amount does she, you know, restart the symptoms, the symptoms restart, does she become you know, really symptomatic and unhappy? That might be a woman where you continue much longer. Also, it's important to take into account the underlying health status of the woman, she's very healthy, she may be able to stay on longer than a woman who's developing several chronic health conditions like diabetes, heart disease, other forms of cancer, you know, you may want to try to avoid hormone therapy under under those or continuing hormone therapy longer under those circumstances. So it's a highly personalised individualised decision that is made with a woman herself and the clinician, you know, shared decision making. And it will depend on how significant the symptoms were whether they're reappearing after trying to stop, and just her general health. Also, there's the question of osteoporosis. If a woman, for example, has an increased risk of askew product fracture, and she's doing very well, on hormone therapy, she's at very low risk of breast cancer and heart disease, and some of these other health conditions that you worry about with increasing or continuing long term hormone therapy she made that type of patient may be a good candidate for long term treatment,

Claudia von Boeselager 29:06  
when I have a question for you a little bit on the personal for me to better understand as well. So before we started our conversation, we were talking offline, and as I mentioned to you, I'm taking part in some clinical research. I'm 41. I had my hormones tested using the, and my estrogen levels were low. My testosterone was also non existent. So I started on Easter dial and a body identical or bioidentical testosterone as well. Very small doses, transdermal, notice definitely a benefit in it. My glycan age test result, which is the biological age testing reduced by three years so I've gotten down to biological age of 26 years old now I'm trying to get it down to 20. The estrogen is helping right so obviously, biohacking and science

Dr. JoAnn Manson 29:56  
to be a teenager again.

Claudia von Boeselager 29:57  
Well, that's okay. I'm okay with that. Right, And but it's I definitely noticed personally, anecdotally, anecdotally, I'm obviously doing other things and cold therapy and all these other wonderful things, etc. But, so it's always hard to just pinpoint one thing, but I do definitely notice a difference in that particularly with the testosterone because it was pretty much non existent, but obviously, the estrogen is beneficial as well. And through my tracking of sleep, right, I wear an aura ring, which obviously isn't always perfect, but it shows that my REM sleep is so low. And so what's thought to support REM sleep is progesterone and progesterone hormone replacement therapy as well. Would you say that the benefits of obviously, and I know this is maybe an area I don't know how familiar you are with the sleep dynamic of things, but I know your brain brain health specialists as well, but of taking progesterone as well as the estrogen. The benefits are larger in order to repair that that REM sleep, which, for me is pretty much always at a one to 2% of my sleep at night. Or are the risks because of the combination of estrogen and progesterone to hide that it's better to avoid the progesterone.

Dr. JoAnn Manson 31:05  
So we recommend that any woman who has an intact uterus take a cut if she's going to be on hormone therapy, she should take a combination of estrogen and progestogen in order to protect the uterus from endometrial cancer endometrial hyperplasia, and a woman who's had hysterectomy. She can be on estrogen alone, does the addition of a progestogen help with sleep? Yes, there is quite a bit of evidence for that. Would I recommend that a woman who's had a hysterectomy and would not otherwise need to add a progestogen that she add that for the purpose of assistance with sleep? I would probably say no, it may not be worth the trade off because of some of the concerns health concerns about the added progestogen. However, I think, again, that is an individual decision. And that if it's micronized progesterone, the evidence from observational studies and randomized trials have not been done of the other formulations of progesterone progestogens. But the observational studies suggest less of an increase in breast cancer with micronized progesterone than then with Provera or MPa. So she might make that decision based on her own personal circumstances, together with the doctor, you know, discussing all the benefits and risks and her individual, you know, circumstances. But generally, I would not recommend a woman who could take estrogen alone because of hysterectomy is probably advisable to just stay with the estrogen without the addition of a project.

Claudia von Boeselager 32:57  
So I will get on to it, to make sure I'm the producer on that as well. And what areas would you say are really still missing? Where are the biggest gaps in research around HRT and women's health in general? Where do you see the biggest need at the moment?

Dr. JoAnn Manson 33:15  
So I started out by saying when it comes to menopausal hormone therapy, timing is everything. I think we need more research on the cognitive effects of estrogen and hormone therapy women who are in early menopause, and particularly women who are symptomatic with hot flashes, night sweats, disrupted sleep, are there in fact, some cognitive benefits of that taking a hormone therapy, or is it just neutral? We are seeing in most of the randomized trials that in terms of cognition, if a woman is in early menopause, or below the age of 60, the effects of hormone therapy on cognition and memory tend to be neutral. There's not appear to be an increased risk of cognitive decline in the randomized trials, looking at cognition in fairly great detail, according to the age of the woman at time of randomization, however, in women who were 65 and older, in the whi memory study, there was an increased risk of dementia and cognitive decline. Among, you know, the women who are randomized to hormone therapy compared to placebo, especially for combination estrogen plus progestin. So, with cognition, it does appear that timing is relevant. You know that age is a factor just as it seems to be for heart disease. Um, but we don't have a lot of data on how this affects the benefit risk profile of hormone therapies affected by whether the woman has hot flashes, night sweats, disrupted sleep, because it may be that women who are symptomatic, especially with disrupted sleep, may be most susceptible to some cognitive adverse cognitive effects from the symptoms gets their sleep is disrupted, and they may benefit the most from taking hormone therapy. And right now, there isn't a clear message such as, oh, if you're having those symptoms, you really should seriously consider hormone therapy because it may be protective of cognition. We don't yet have enough data to be able to say that but I think there's a gap in knowledge women would really benefit from having more research on that particular subject. I think we also need more research on the effects of different formulations of hormone therapy. Even in terms of breast cancer, you know, there are some surrogate markers such as mammographic breast density that may be could be used to see if there are differences between Ester dye all and conjugated estrogen and different progestogens micronized, progesterone versus medroxyprogesterone acetate and other types of progestogens. I think we need more research on the effects of different formulations of hormone therapy, on mammographic breast density and, ultimately, the risk of breast cancer is the, you know, an endpoint of great importance, but it takes very, very large trials, randomized trials to look at, you know that that endpoint that's why the Women's Health Initiative was 17,000 women, you randomized to either estrogen plus progestin or placebo and nearly 11,000 additional women randomized to estrogen alone or placebo. Overall, this more than 27,000 women in the whi hormone therapy trial. And these are obviously very, very large endeavours. It's not going to be possible to do a trial of that magnitude for every formulation of estrogen and combined with every formulation of a progestogen. But we can look at intermediate markers. We can look at surrogate markers, imaging studies, we can do more with cognitive testing, you know, trials that are testing memory change and cognition change. So I think more can be done even with smaller randomized trials. But the trials, the randomized clinical trials are so important for getting really clear answers rigorous answers for women

Claudia von Boeselager 38:11  
to understand. Thank you for sharing that. And just on the cognitive aspect as well. It was interesting. I've had Dr. Dale Bredesen, who I'm sure you're familiar with his work he's at of the Buck Institute. He's a neuroscientist. His very popular book The End of Alzheimer's programme, which really helps people to understand, and in his view that he has uncovered 38 different drivers of neurodegenerative diseases, one of which is low estrogen levels, particularly for women. And so my mother who suffers from dementia, as my audience knows I talk about this regularly. And through the analysis that we did, based on Deborah Edison's protocols, discovered that the lack of hormone replacement therapy and essentially her low estrogen levels, as well as several head trauma events, were the main drivers of her dementia cause so when I would did my DNA testing, I have a single copy of the APO e4 gene. But it turns out, my mother doesn't have a single copy. Yet she's the one with dementia. My father who has also a single copy, he's fine at 84. So this is also something through Deborah Edison's work that has become very obvious in terms of understanding estrogen and its impact on cognitive health in later years as well. So just to highlight that point, some other guests I've had on as well, Joanne are experts in ADHD. And they see a lot of women coming to them sort of late 30s 40s saying that they went to the doctor, they're experiencing difficulties focusing concentration, so they're not particularly menopausal yet. But because of fluctuations in hormones through perimenopause, they're going to their doctor saying I don't know what's going on, and they're saying, Well, typically, they're offered an antidepressant. And instead of actually having their hormones addressed as well, so are you familiar with research around the incident of increased ADHD and ADD symptoms? So for those who may be unfamiliar and attention deficit hyperactivity disorder, if I say correctly, the correlation between that and hormone levels.

Dr. JoAnn Manson 40:20  
So I certainly familiar with ADHD and ADHD and that women generally have been perceived as being at lower risk. And we're not often as often diagnosed with this condition earlier in life. But now there's an improved understanding that women are also very vulnerable to this condition. And the prevalence is quite high in women as well as men. So I think that's progress, that this is being detected and diagnosed more commonly in women than it was in the past. The association with hormone levels, I haven't yet seen that research. I'm very interested in that possibility that it could be linked. But I do think this is another area where randomized trials can be so helpful in women, especially as they're beginning the menopause transition, getting into the perimenopause, if they have these issues with attention deficit, hyperactivity, or just attention deficit disorder, that they could be tested, compared to placebo, is there a benefit? You know, of hormone therapy for the symptoms, I think that that would be very, very important to do.

Claudia von Boeselager 41:39  
So I'd like to shift gears and talk about a further research field. I know you're doing many but one that you cover around dietary supplements and separating facts from fiction. Can you share more about a recent study that was a randomized trial, I believe as well on multivitamins and their impact on memory and slowing cognitive aging in older adults?

Dr. JoAnn Manson 42:04  
Yes. So in our large randomized trial that we've done the Koko supplement and multivitamin outcome study also known as Cosmos, this is overall a trial of 21,000 participants. We have looked at cognition, the effects of these interventions on cognition in two separate ancillary studies, one involves a very detailed telephone administered cognitive assessment, and another a web based cognitive assessment. And in both of these studies, we saw a clear signal that the participants randomized to multivitamins as opposed to placebo did better on memory and cognitive testing than the participants. They did better than those randomized to placebo, which is, actually when you think about cognitive tests like this, there's a lot of noise, you know, the, the noise to signal ratio can be quite high. And despite that noise, the signal did emerge. That multivitamins were associated with greater improvement in memory and cognition than the placebo and generally better results than the placebo group on these memory tests and cognitive tasks. We have one other ancillary study, that we're analysing the data. This involves a very gold-standard in-person assessment of cognition. And so we'll be publishing that relatively soon and moving forward with that relatively soon. But it's, it's somewhat remarkable that in these two separate randomized trials, there would be this signal for a benefit of the multivitamins also we saw in the in those who started out with low flavonol levels, you know, from the diet, you know, foods such as fruits, berries, apples, you know, pears, the different fruits that are higher in flavonols. And then there's tea and other sources, cocoa products. Those who started out low benefited from the cocoa flavanols in terms of cognition, but the you know, we are seeing this repeated signals for the multivitamins, and we want to pursue this further with additional studies because there's the multivitamins as you know, they contain just the usual intakes, you know, the daily intake levels These are not mega doses. These are not doses that have been associated with risks or toxicity. They're They're very, like the recommended dietary allowances or the daily intake levels. And it may be that people who are deficient in one or more of these micronutrients will benefit from taking a multivitamin. We know there are multiple nutrients that are important for brain health. Some of the top candidates have been B, 12, vitamin, other B vitamins, vitamin D, lutein, magnesium, zinc, there are many, many micronutrients in multivitamins, and correcting deficiencies in any one or more of these micronutrients may be beneficial for brain health. And I think that this is really promising research and needs to be pursued further because multivitamins, they will never be a substitute for a healthy diet or healthy lifestyle. We're not talking about, oh, just throw a multivitamin at a really unhealthy, fast food diet with lots of processed foods. No, we're talking about still striving for healthy balanced diet and healthy lifestyle, physical activity, not smoking, all the things we talked about frequently and are so critically important. But many people may have a low level or even a deficiency of just selected micronutrients and may benefit as a complementary strategy by taking a multivitamin, especially at older ages. And we think that these are very interesting findings. This was age 60 and older. So these are not really you know, older adults. This is more like midlife and older adults. And there was this clear signal emerging. So we thought this was quite interesting. This does not mean that taking mega doses of individual nutrients, micro micronutrients, such as taking really high doses of beta carotene, vitamin E, vitamin C, would be a benefit for brain health or would have a favourable benefit risk ratio, because in fact, some of these isolated micronutrients have been tested in randomized trials, and have not shown benefits for cardiovascular disease cancer or cognitive function. We're thinking that this may be something that is more specific to a multivitamin multi mineral supplement that contains the daily intake levels of 2030 or more, you know micronutrients conferring this benefit

Claudia von Boeselager 48:11  
to ended this study, look at any deficiencies that the participants might have had. Previous to partaking in the trial and taking the multivitamins

Dr. JoAnn Manson 48:22  
we have measured the micronutrient levels on only a small subset, and we haven't measured everything we are seeing, first that the micronutrient levels such as of vitamin D, A, folate, B 12, they do increase as we'd be expected with the amount of the micronutrient in the multivitamin, and that suggests that absorption and bioavailability of the micronutrients tend to be good. We are planning in the future. Of course, all of this takes, you know, funding and money. Hope to look at a much larger number of nutrient levels at baseline and follow-up. And they'll also look at things like epi genetics, DNA methylation changes, and whether aging is affected in terms of that marker of biological aging as well as telomere length and many other biomarkers for aging.

Claudia von Boeselager 49:31  
Beautiful, JoAnn; what are some of the most harmful myths in your view about dietary supplements? I know a lot of people hear like Oh, supplements, you know, there's Is there any nutrients in them at all, etc. So, what are some things you would warn people about in terms of just in general dietary supplements?

Dr. JoAnn Manson 49:51  
First, I want to emphasise again, even though I already said it, that dietary supplements will never be a substitute for a healthy diet. It shouldn't. They should not be perceived that way, but rather as a complimentary strategy. Secondly, more is not necessarily better. In fact, it can be worse, and mega-dosing on a single isolated micronutrient could interfere with the absorption and the bioavailability. of other micronutrients, particularly related micronutrients. For example, if you take beta carotene in very high doses in randomized trials, which was linked to an increased risk of lung cancer in smokers, and the US Preventive Services Task Force has clear guidelines now not to take supplements, you know to really avoid taking high dose supplements of beta carotene or vitamin E, vitamin E, also was found to increase risk of hemorrhagic stroke. And in high doses, we're talking mega doses, not the amount that is recommended because these are really essential for good health, but only a small amount is needed more isn't necessarily better, and avoid mega dosing. Those are other really important points. Also, I think the need for the supplements is individual, you know really needs to be individualised assessments. It can depend on life stage, we know that it's really important for women during pregnancy to take prenatal vitamins. It's so important for a healthy pregnancy and to avoid the neural tube defects, but also prior to conception. You really don't want to delay taking these vitamins until you're into a second trimester in a pregnancy. So if a woman is in, for example, if she is a reproductive age, and is not taking, you know, contraception, usually contraception, really avoiding pregnancy, it's not a bad idea to be taking a multivitamin just to be sure it's on board at the time of conception. The American Academy of Paediatrics has certain guidelines for some vitamins, vitamin D, iron, you know, breastfeeding infants up until a certain age. I'm not a paediatrician, I'm an endocrinologist, adult medicine endocrinologist, so I won't talk further about paediatric guidelines. But I think we already know certain life stages are prior to conception during pregnancy lactation. at older ages were calcium, vitamin D can be achieved through especially calcium we're recommending more just trying to get it through the diet. But some people do need supplements of vitamin D calcium, magnesium; certainly if their underlying health condition B 12 deficiency that can happen with pernicious anaemia with different medications that can interfere with the absorption like anticonvulsant medications tuberculosis treatments can interfere with absorption and metabolism of some of these micronutrients and people who have ulcerative colitis, Crohn's disease, celiac disease, gastric bypass surgery, they may have some malabsorption, fat malabsorption and need to take higher amounts of these micronutrients and not only a multivitamin, but even additional supplementation of some of these micronutrients. Macular degeneration is another example. There's some evidence that in randomized trials adding certain types of vitamins and minerals can be helpful to slow the progression of macular degeneration they errand to trial for example, there are supplements on the market for macular degeneration. So the decision needs to be individualised. It can relate to for multivitamins, it may be more broad, especially in older age groups, but for some of the other micronutrients that may relate to life stage, certain age age groups, and they may particularly benefit and also underlying health status people who have certain health conditions or taking certain medications may particularly benefit from taking the supplements.

Claudia von Boeselager 54:41  
Would you say there's certain supplementation for helping to optimize female hormones and female hormone health

Dr. JoAnn Manson 54:49  
so the interaction between micronutrients and hormones has not been extensively studied. We even in terms of healthy diet, you know, general composition of the diet in relation to hormonal status and menopausal symptoms very, very limited research on this question, but I actually do agree that more research is needed certain types of dietary factors have been studied for reducing hot flashes, night sweats, you know, soy products are effective in some individuals but not in others. You know, it does depend on how you metabolise soy products, so there are genetic factors that can influence that. But but overall diet has been minimally studied in terms of menopausal symptoms and interrelationship with estrogen levels of the declining estrogen levels during the menopause transition, and menopause and more research would be very valuable on that subject.

Claudia von Boeselager 56:04  
She won a question I asked all my guests of late is that if you could live to 150 years old, with excellent health, how would you spend your time?

Dr. JoAnn Manson 56:15  
Oh, that's it? That's a great question. I will, right now, maybe for the next 510 years, you know, I'm really enjoying kind of the balance of working and spending time with my family and trying to make time for a lot of different things, you know, being with friends, family, as well as work, I think I could live to 150, I probably were a little longer, but not much longer. I have; I think keeping your mind active is always tremendously important. And learning new things, I would just really enjoy having more time to delve more deeply into some topics that I haven't had a chance to, including, you know, more in both the science and nonscience fields, at tremendously interested in history, I would be really interested in learning more and having opportunities to do more recreational leisure time reading, I would say most importantly, I'd want to spend time with my children, and eventually grandchildren as much as they're willing to spend with me. Of course, they're gonna have their own priorities. But I would say if I could live that long, I would really want to be spending most of the time with family and friends and personal interactions. But also just, you know, trying to keep my mind active learning new things, exciting, exciting new things, and even kind of keeping a hand in medicine. You know, in terms of the science and the scientific research, I probably wouldn't be as actively involved in, you know, the actual randomized trials and the day-to-day activities of the research, but I would want to really keep up on it

Claudia von Boeselager 58:28  
uniform Here on what excites you most about the future of health and well-being and longevity over the coming years and beyond? As you

Dr. JoAnn Manson 58:37  
probably have guessed, I'm a very strong proponent of testing the effectiveness, you know, of different interventions in randomized trials. So that's what really gets me excited about science. Actually, if something looks promising, I think all these forms of research are so critically important. You need bench research, basic science research to suggest biological mechanisms, and observational research to generate hypotheses that many can have that can be tested in randomized clinical trials. Now, not everything can be tested in a randomized clinical trial. And very often, observational research is just so overwhelming. And so compelling, you know, examples would be cigarette smoke gain. We don't need randomized trials to tell us that that's very bad for health and people should stop or never start smoking. But, you know, for many dietary factors for many other potential medications interventions, i.e., the randomized trials have been very helpful in understanding what really works and what doesn't and when. And even the randomized trial ELLs prove something doesn't work. This often gets very little attention, you know the importance of randomized clinical trials that have disproven that some intervention is effective. But think about it. If it's proved by a trial that an intervention is not effective, then it can spare people the risks of the intervention, the expense and costs of the intervention, and it redirects the energy and the scientific investment in other topics, other areas, so they're no longer wasted pursuing something that doesn't work. So I think if there's any scientific question that's worth answering, then the answer is important to whether it's positive, negative, or not. And that does not receive as much attention as it deserves.

Claudia von Boeselager 1:01:04  
If people want to find out more about the results of randomized clinical trials, where would you point them to where's a good resource to find out more,

Dr. JoAnn Manson 1:01:12  
I think if there's a specific intervention that they're really interested in, such as hormone therapy, and the trials of hormone therapy, I think women in the general public can get a lot from the menopause.org, North American Menopause Society website because it provides a lot of information about the trials and about the research. And it provides, you know, short write-ups to help women understand the changes that they experienced during menopause, and the treatments that are available, and all of that. So I think that's a very good website. I think that clinical trials.gov is a good website for information about the clinical trials that are out there that are being done; some of them are being been undergoing recruitment, still, others have ended recruitment, and the results may be posted. But there's a lot that can be learned from clinical trials.gov. And generally, if there is a specific intervention that you're interested in, you can go to government websites tend to have very reliable information, or even search on some of the commercial websites that are known to be reliable; you do have to look into, you know, it can be a little complicated figuring out whether the information is reliable or not. But you know, there are websites such as WebMD, you know, that do provide reliable information on a lot of topics; I think we could PDR is not bad for looking. I mean, you obviously have to be a little skeptical. But I think there are a lot of processes in place for double-checking on that information. But generally, I would recommend, if possible, reading the actual article, you know, you can search on PubMed and find the articles go to the original sources and medical societies, the American Heart Association and the European Society of Cardiology, you know, there, there are many other I'm probably mentioning too many US American, I don't want to be US-centric here. There are many, many other websites that can be very helpful for this purpose and that are throughout the world. International websites.

Claudia von Boeselager 1:04:05  
Yeah. And I think one thing a researcher told me when I was following the money, look who funded the study if you want to know how biased or unbiased a study might be. So just a word of caution when doing research on studies as well.

Dr. JoAnn Manson 1:04:20  
To some extent, and, you know, most of my research is government funded, you know, through the National Institutes of Health. But I do want to put in just some defense of industry-sponsored research because I think we need to have that collaboration between industry and academia. And very often, the government will not fund certain types of trials where they feel that there could be a company commercial benefit to a company, and it is so important that the, you know, pharmaceutical companies and industry be willing to test these products very rigorously. But what's really important is that there be a firewall between the company and the academic researcher and that the results of the research need to be published no matter what, whether they're favorable, unfavorable, or neutral, there can't be an arrangement where the results will be suppressed, if they're not favorable for the company. So I think if that kind of contract can be worked out, and a firewall, you know, erected between academia, and industry, that research can be very credible and very important in building the scientific database.

Claudia von Boeselager 1:05:57  
Here's to more of that, for sure. So that a lot of research will get funded. Jennifer Garrison, Professor Jennifer Garrison of the Buck Institute, you know, is looking for ways to optimize funding for women's health research that through what she's doing as well as the struggle. I mean, she was on the podcast recently, you know, saying that, at the moment, she spent so much time managing grants and, like, this one's ending in six months, this one's in 12 months, and, you know, trying to juggle, you know, where do I get the grants and the funding for that as well. So, finding that beautiful model where research can be funded over seven, even 10 periods of time, something that she was mentioning, is where you get to that Nobel Prize breakthrough-worthy research, that hopefully we will be able to shift more towards she wanted was such a pleasure speaking today, where can people learn more about what you're up to? Online? Or websites? And I'll link everything in the show notes.

Dr. JoAnn Manson 1:06:56  
So I am on Wikipedia. Yeah, people can just search for my name. And I do have a website through Brigham and Women's Hospital, you know, if they, they search on my name, I think that they will Dr. Joanne Manson, they will get to one of my websites, which would be either at Brigham and Women's Hospital, or the Harvard Chan School of Public Health. And they can read more about me there. And also, there's information on the websites about the research, and if they really want to contact me, I don't want to get I already get 550 600 emails in one day.

Claudia von Boeselager 1:07:44  
Yeah, exactly. To allow my blood for research purposes. If they're looking for some articles, then on your website, you have resources there too.

Dr. JoAnn Manson 1:07:52  
And people find my email address, so I'll be able to find it if they really do want to reach me.

Claudia von Boeselager 1:08:00  
Yeah. JoAnn, do you have a final ask recommendation or any parting thoughts or message for my audience today?

Dr. JoAnn Manson 1:08:07  
Well, I want people to feel empowered, to really improve their health, to be able to ask the questions that they have, for example, their clinician; they need to be able to find a clinician who listens to them and can help them with problem-solving. I mostly just think it's so important. And I mean, I've decades also of clinical practice experience. And I think it's so important for women in particular because so often they feel that they can't find a clinician to help them with the issues related to menopause and midlife health; they do feel that there are clinicians out there; there are strategies for finding a clinician, even if you're just calling a lot of medical centers and asking for women's health specialists and for menopause clinics, many hospitals and medical centers have established those. And then women need to feel free to talk openly and request shared decision-making with their clinician, and also to understand that there is really strong evidence that we can take charge of our own health. You know, there are a lot of genetic factors. There are a lot of social determinants of health that can make it more challenging to change our diet to change lifestyle, but there's still a lot within our control, and it can have absolutely enormous impact on improving our health.

Claudia von Boeselager 1:09:54  
Here's to that as well. Yes, lifestyle interventions are living our best lives, thriving with what's of energy for longer. So thank you so much, JoAnn, for coming on today. It was such an absolute pleasure.

Dr. JoAnn Manson 1:10:05  
Wonderful talking with you, Claudia.