Gordon: I’m very interested in people who have come into the field in the last ten years or so, especially, Academy of Clinical People, but maybe take a step back and, and just tell us, I mean old. Let’s go all the way back. Did you always imagine you would be a physician? 

Andrea: I would say, in the end, yes, but of course, if you would have asked me when I was 16 or 18, I would say no. I grew up in a GP practice. I was always surrounded by patients. Um, I grew up in a very, very rural area in Germany where I was always surrounded by the patients. I really, literally grew up, um  my mother was pregnant, delivered me on a Wednesday because [that], Wednesday afternoons, our clinic was closed 

Gordon: Ah.

Andrea: So that was good, good timing! And the next day, she-she was back, and she handled the patients together with my-my father. So I think being surrounded by people, being surrounded by sick people is quite natural for me. Seeing people who are dying is very natural.

So I was exposed from the early moments of my life to the body, to diseases, to physiology, to pathophysiology, because in rural areas, you also had, at that moment in time, labs, for example. So I still see me as a child in the microscope and looking through it and, to look at some erythrocytes or to yeah, even some cancer cells, so.

Gordon: Oh, wow.

Andrea: There was always the attachment to-to medicine. I wanted to become a sea biologist, and there was also a time when I wanted to become an artist. I love also history of art, but in the end, I have chosen to become a medical doctor. 

Gordon: Were you aware of the patients that your mother and father were following and treating and-and helping,  were you aware of their age-related decline, as it was? Were  you aware at that time of-of the aging process?

Andrea: I would say so, yes, because I saw people dying. I think what I naturally have in my-my genes is that this is a very natural process, of life. Um, and especially if you grew up in-in rural areas, it’s part of your life. And I also saw people deteriorating because of cancer, of-of other, age-related diseases. Absolutely. But I couldn’t really link it that, aging is a disease, as we now know because I just saw and it was it was natural. Now I wouldn’t call aging a natural, physiological, endeavor. But at that moment in time it was-was very clear. Really, the link into geriatrics and into geroscience came when I studied traditional Chinese medicine in China and I was exposed to a tai-chi trainer,  she was 95 and she was so beautifully, young. Uh, and I thought she is really a 60-year-old.

Gordon: Mm-hmm.

Andrea: And that was the first time that I really realized, okay, we have the chronological aging process, and we have something like and the I don’t think at that moment in time biological age was not even coined, but at that moment in time, I realized, “Whoa, this is interesting.”

Gordon: Mm-hmm.

Andrea: And then I had the realization. Okay, I wanted to go into geriatrics. And geriatrics, at that moment in time,  was absolutely not established. I went to medical school in Germany, and I thought, “Okay, where on earth can I do this? Where can I really study the aging process?” Um, and “Where can I treat individuals at older age to-to make them healthier for longer?” And I always was in-involved in research from the early days, when I started medical school, but not in aging. I had, a rough journey, I would say, until I found my path into-into the aging research, but in the end, indeed, I went into the field of cellular senescence and really wanted to translate what we find in-in mice and what we find in in-vitro- can we find a phenotype, a cellular phenotype, in humans? And at that moment in time I took lots of, skin biopsies, muscle biopsies, fat biopsies, to see if we can relate biological mechanisms and especially cellular senescence to a human phenotype.

Gordon: And this was a time where even cellular senescence, like, was getting a little bit more complicated, perhaps, than we at first thought, and this kind of work of-of going back to actual human tissues and many tissues, not just-just skin, and realizing that senescence presented itself in somewhat different ways in-in different tissues. And so you it-it  uh, the  I’m interested in this because I you know, I-I see you at the lab and your microscope and all these things that must have taken you back to-to your-your childhood, but at the same time, there’s this pull away to-to I guess to help people, to actually do something to treat patients. Um, now, I-I  some-some people at this point really become researchers, you know, full-time. They-they sort of don’t do clinical work. Um, they don’t do clinical trials necessarily. They set up a lab and they go off and do that. Did you ever have that tension, or was it always the case that you were going to go back to patients?

Andrea: I never had the tension to leave clinical practice and I never had the pet uh, the tension to, to leave research. So. I think, as a clinical scientist, you love to see patients, not five days a week but at least to get in touch, and to-to be involved in clinical care really helps me to understand what’s necessary to do and also what the value is of the research.

Gordon: Mm-hmm.

Andrea: So I always, even when I was a hospital manager in the before I went to Singapore in-in Melbourne, looking after lots of hospital departments, I always wanted to be at the bench, but 

Gordon: Yeah. Yeah.

Andrea: and-and behind the computer to do statistical analysis, but-but I always wanted to see that patient, too. Because getting that feedback of not only participant in a randomized control trial  that’s all  also valuable, but to that end client in [clinical] care  is of absolute importance, and how they react to the stories you tell them.

Gordon: Yeah. Yeah. Were you aware how rare you were as a person? In the sense that, like, Rudi Westendorp, for example. Rudi would turn up to Biology of Aging meetings, and, you know, you would chat away, and you’re thinking, “Why are you here? Why aren’t you at a bedside somewhere?”, you know? That-that  it seemed like there was very few, like, geriatricians that had a deep interest in-in the biology of aging at the same time. Uh, you know, the  at-at one point in-in the U.S., I think, only three individual people held federal grants for aging research who were also geriatricians. Astonishingly low numbers! I’ve seen you describe yourself as a geriatrician, as a cell biologist, and as a  as a geroscientist, all true, as far as I can see, but I-I’m wondering what the-the distinction is for you, perhaps, between a geriatrician and a geroscientist?

Andrea: Um, the geroscientist is really understanding the biology of aging. A geriatrician sees individuals when they have already accumulated lots of age-related diseases. And I moved in the  especially in the past five years, from always saying, “I am an internal medicine specialist specialized in geriatrics”. 

Gordon: Mm-hmm.

Andrea: I moved from saying “I’m a geriatrician,” because my entire research moved from, looking after 80 year olds with either already age-related diseases or just being aged, towards the middle-aged population, because I [see] that’s a huge gap in literature. We are either analyzing 20 year olds or 30 year olds because it’s easy to recruit. These are our students.

Gordon: Yes.

Andrea: Or-or we are looking at 80 year olds, and of course, very importantly, also centenarians and the really distinct individuals, and the-the subpopulation, which is very important. And while having had also a time where I looked at middle-age disease versus-versus healthy, I think now we have to look differently at-at the entire lifespan in populations to understand why we age, how it, phenotypically presents, to us and how we can antagonize it. So I-I think the-the real future lies into not only combining geroscience with geriatrics, but especially combining it with internal medicine, with-with medicine 

Gordon: Mm-hmm. Mm-hmm. Yes.

Andrea: to understand why we age. We understand cardiologists can talk ages about the heart and about every tiny molecule in the heart. We should talk about the aging process, the aging molecules, whatever that is, and 

Gordon: Mm-hmm.

Andrea: in the end  en-entire body. And of course, that gives lots of complexity, but this is what we need. We need a-a fusion of the biology with clinical practice, and I think, for me, it lies in internal medicine. It does not lie in geriatrics,

Gordon: Mm-hmm.

Andrea: because it’s-it’s a different specialty, looking after individuals of 

Gordon: Advanced age and 

Andrea: Absolutely.

Gordon: Yeah. Yeah.

Andrea: And advanced pathology.

Gordon: Yes. Yes.  I mean, this sounds like a revolution, in this whole field of bringing forth trials and interventions and-and thinking about how we apply the biology of aging to human health. Is that how it feels, like a revolution is taking place?

Andrea: Yeah, I think, looking back, I think the conception, sort of, of the of a new specialty was, 5 to 10 years ago, where we really knew, yes, we can interfere with the aging process in animal models and the accumulation of all the knowledge. It’s absolutely, there’s a turning point, I feel, in the last, one to three years, where everything is just exponentially exploding. That’s what-what I feel. It’s being recognized. Yes, we understand how we age. Yes, we can measure it. We are at the edge to bring, really, the interventions which worked in animal models 

Gordon: Yes.

Andrea: into clinical even clinical practice, but first of all, clinical trials.

Gordon: Fantastic! Tell us about some of your own personal passions right now around trials that you’ve done and completed, about trials that you’re really interested in doing.

Andrea: Yeah. So we have two main, very, very good big components in our lab that’s focusing on diagnostics, and the other one’s intervention. It cannot be broader.

[Laughter]

Andrea: But all in humans.

Gordon: Yes.

Andrea: So, first of all, as a clinician, I-I want to measure something. So, if I see a person, I can look at the gait and I can look at the speech, et cetera. That’s great. That’s normal clinical care. I can already utilize all the biomarkers we have not for aging, but for diseases, and that’s-that’s what we do. Now we reutilize these kind of biomarkers, for diseases and reutilize them for the aging research. So we do lots of data analysis, utilizing the UK Biobank, Lifelines, very big, cohorts [to] study 

Gordon: Mm-hmm. Yeah.

Andrea: But we actually see what is their propensity to predict age-related diseases later in life, and can we actually make clocks out of it. So very, very  a sexy term, “aging clocks”. It’s nothing else than, reusing, I would say, the algorithms we already have, because we do nothing else than either predicting chronological age or the incidence of a disease or mortality. And now we are using a different outcome parameter. We use the unit age, and that’s actually the biological age clocks. How different is the biological versus the chronological age? So, statistically, epidemiologically, it’s-it’s a no-brainer to do it, but it really helped the field in bringing it into the public. People understand a biological age and a chronological age.

Gordon: Yeah.

Andrea: So my research group is not only validating, in different cohorts and different disease cohorts at different ages and different ethnicities, these kind of clocks which are already available, but we are now making new clocks and-and making them better. And I think this is the focus of lots of labs, and that is very important, because, in the end, we need accurate parameters to estimate an individual’s age. What we also are very excited about,  it’s a little bit complicated, but we are still excited, is that the pace of aging within an individual, in different organ systems might be very different.

Gordon: Yes.

Andrea: Um, and not only the pace of aging, but also the mechanisms behind it might be very different, which makes it very complicated, because, if you would ask have asked me five years ago, I would say, “Oh, no, the pace of aging is, within an individual, I think, much, much more aligned compared to a group of individuals.”

Gordon: Mm-hmm.

Andrea: And I wouldn’t have expected that the pace of aging might be so different in a heart, in a lung, in my brains, in my kidneys and my skin, within individuals.

Gordon: Yeah.

Andrea: Um 

Gordon: Actually, when you said earlier that we know what causes aging, I kind of sat up a little bit and thought, “Well, yes….” But at the same time, there’s so many mysteries  there, right? And, you know, this is  this is  this is one right now we’re faced with.

Andrea: Absolutely, but I say that as a clinician, because, if I wouldn’t say it, I would never have any entity at any hospital or with other colleagues if I wouldn’t say that we understand it at least partially.

Gordon: Yeah. Yeah.

Andrea: Um 

Gordon: I under yes, I see.

Andrea: It’s the same 50 years ago 

Gordon: I see.

Andrea: for breast cancer. Yes, of course we can diagnose breast cancer. Yes, these are the cells who are replicating all the time and inducing cancer. Did we understand it fully? No, absolutely not. Even not now.

Gordon: Yeah.

Andrea: But we can say now we know what cancer is. And that’s the reason now I can say, quite confident, “yes, I know what aging is”. At least for-for 15, 20, nearly 100 years we are publishing about what aging is, so at a certain time, you just have to be tough, stand there, and say, “I know what I’m talking about.”

Gordon: I think you just put me out of a job.

[Laughter]

So going back to your own research on-on clocks, and you say you’re developing your own clocks, and it does seem like everyone is developing their own clocks,  do you think this is going to distill down to a series of measures that-that everyone is-is confident, or have we entered a world where it’s really the clock applies to the study, the clock applies to the application?

Andrea: I think, in five years’ time, you can order in every hospital these kind of clocks, and there will be a variety of clocks because the pace of aging and the mechanisms of how-how organs age are so different that we need a variety of clocks. Um, as we do now in clinical practice, we are ordering a renal panel, a lipid panel, a whatever panel, and that’s how we are going to apply clocks. And I think that’s also necessary. I don’t think that, in the end, we can say the biological age of that person is X, Y, and that. I think it’s much more important to say tha t organ is at that pace, that’s the problem, and now we are targeting it with a certain intervention.

Gordon: So what interventions are you really interested in?

Andrea: So we are working on lifestyle interventions being very, very dedicated to individuals’ needs. Um, I will come back to that in a second.  We do lots of randomized control trials, using supplements, nutraceuticals, for example. And we’re also repurposing drugs in our clinical trials, and we are now, really at the edge of embarking also on clinical trials where we are testing new compounds in-in humans, which is very exciting. So, again, here I think I’m more the octopus in the field.

[Laughter]

I love to do lots of different things. Um, we are  uh, we are focusing at the moment on supplements, but also integrating lifestyle interventions, but also integrating repurposed drugs. And I think, in the end, that’s  our aim in the next coming one to two years, that we are testing combination of these kind of-of interventions, because in the end, I would say, because of the complexity of the very, very nice biology of-of our human body and the beauty, we have to have a cocktail of interventions to target, the biology most accurately within individuals.

Gordon: Here’s-here’s something I’m-I’m curious about, and I could be completely misleading myself here. Um, I feel like every second paper is about metformin, 

Andrea: Mm-hmm.

Gordon: and the other ones are about rapamycin.

Andrea: Sure.

Gordon: And you can go to about 10 interventions that come up a lot in publications, and then it really drops off quite precipitously, and it’s not that there aren’t any really interesting things amongst the top 10, top 20 list. Okay, so here’s where I-I could be so wrong… I feel like we don’t have enough interventions and we’re not providing clinicians with high-quality, you know, interventions with a cloud of information around them, saying, “This really affects aging. This really targets aging. This is a geroscience intervention, if you like.” Um, how do you feel about that? Or do you just feel that there are so many things to test, you’re not worried about that right now?

Andrea: I’m-I’m worried about the number of trials and the variation we are doing uh, not only looking at in whom we are testing it, but also what we are testing. You are absolutely right. If you are. Googling, if that’s a word, if you are.  

 [Laughter]

Gordon: Used to be!  

Andrea: Has to be cut!  Googling! 

Gordon: Used to be.  

[Laughter]

Andrea: If-if you are looking at PubMed, most often it is indeed metformin, and it’s rapamycin or it’s rapalogs. However, we just did a systematic review how many trials we actually have testing rapamycin and rapalogs and what the outcomes were, and the number is so low, and the knowledge, even about rapamycin and rapalog, how that is influencing the aging process, is really, really so, so, so, so minimal.

Gordon: Yeah.

Andrea: That’s the reason why we also do a rapalog, study, the longer study testing rapamycin in 40 to 60 year olds who are healthy and then really looking at all the organ systems. What our field did not learn, I would say, in the past two decades is tackling the clinical phenotype of aging. We always neglect women’s health, oral health. We very often even not do not look at cognitive, function of-of individuals who are being exposed to gerotherapeutic interventions. So what our group really is doing is not only looking at biomarkers of aging, which are predictive, but also how can we measure the phenotype of aging individuals, and especially at middle age. Of course, we have lots of markers in children. We have lots of markers in geriatrics. But nobody really had an idea, and now there are lots of working groups in establishing that- how to measure muscle health, how to measure brain health in middle-aged individuals, because that’s a gap in the literature.

Gordon: Yes. Yes.

Andrea: It’s very often that we are borrowing geriatric markers but there are so many ceiling effects, and they are just not applicable, these kind of-of diagnostics, to a 50 year old or a 40 year old. So there, there is a huge amount of research we have to invest in to measure it correctly, and then implementing it into our cohort studies, but also especially in the randomized control trials that we [are] actually measuring something which is sensitive to change. 

Gordon: Mm-hmm.

Andrea: That we know if a certain organ system is reacting to a rapalog or metformin or to an AC inhibitor or whatever you would like to-to study.

Gordon: Is-is-is, is the number of people in your studies a major challenge right now? Is that simply a resource issue? I’m thinking about that middle-age group where the variability starts to expand, probably, and, and the older groups where the variability is probably quite high, the numbers of patients enrolled in your studies must be really important or? 

Andrea: It is important, and I would say nobody knows what  and of course, we cannot do power calculations, because nobody really knows where-where  how to power. But what we do is risk segmentation of the population. And we are doing now is a study with AKG, alpha-ketoglutarate, and we are highly selecting the individuals who are coming into our randomized control trials. So we are selecting only 40 to 60 year olds who are healthy and do not have any age-related disease, but within that group of individuals, we are only selecting the ones who are biologically older compared to their chronological age, and we are measuring it with epigenetic clocks, and we’re using four clocks and taking the median. And only the ones who have a higher biological age based on methylation clocks, four is the median, will be included in the trial. So why do we do that? We know that alpha-ketoglutarate is interfering with methylation of our DNA, and we also has already been shown in mice, but also in an observational study in humans, that the epigenetic age is lower if people, mice, take AKG. So we really want to optimize the health of healthy individuals. We are health-oriented. We are not disease oriented in my group. But to make it more likely that we find a positive outcome parameter and help the ones who really need it, we are choosing only the individuals with no diseases, very healthy, but having already a higher biological age, using just one of the mechanisms of aging, and that’s the epigenetics. And that’s what we do, in all other randomized most of the randomized control trials. We know how we intervene. We are looking for conventionally healthy individuals following the conventional medicine, and then choosing the ones where the pathways we would like to interfere with are being not well maintained. I wouldn’t say that they are abnormal, but they need something, and that’s the reason why we do that intervention.

Gordon: This is a profoundly ignorant question, but is this unique to longevity studies, where we’re thinking about treating people who are completely healthy? Um, obviously, those are control groups in other types of clinical trials, but we do have this question of going back in time towards thinking about interventions early, and do you think about, or do your colleagues worry about the idea of intervening in a healthy 20 or 30 year old to try and prevent a disease that may not show up for another 50 years?

Andrea: I think these are a couple of questions in one.

[Laughter]

So, first of all, there are not many, many trials including just-just healthy individuals.

Gordon: Uh-huh. Yeah, I see.

Andrea: And we are the only ones who [are] now risk-segment that healthy population to really target the ones at the higher needs  for that intervention. And that makes, for me, absolutely sense. So if I do a trial in individuals with hypertension, I first want to know that they have a little bit of hypertension or are at the risk of-of being hypertensive to give a drug. And it’s the same what we are applying now in geroscience trials, to just risk-segment, the-the individuals. The second question was what do my colleagues think about the trials we are designing, and we can then also talk about what we already implement in clinical practice. Um, they are watching.

Gordon: Mm-hmm. Mm-hmm.

Andrea: Um, I think now they understand, yes, if you look in your own mirror when you are brushing your teeth in the morning, you see that your face is different compared to 20 years ago. So nobody neglects, I think, anymore that there is an aging process. And the scars we have in our face are the scars also inside of our body. And even colleagues 

Gordon: Apart from you and I, of course. We look fantastic when we’re brushing our teeth.

Andrea: [Laughs] Even my colleagues in internal medicine, of other colleagues, even surgeons now get it. And they understand it. So how beautiful could it be that we are interfering much, much earlier. But we need to do much, much more education from, I think, already on high school or even in-in primary school,  that aging is something- 

Gordon: Mm-hmm. Mm-hmm.

Andrea: – we-we experience,  but we might also treat at a certain time. Um, so I-I, I would say that there is growing understanding in the medical field. 

Gordon: Yeah. I guess that most of us in the aging field are asked quite frequently what we do for ourselves, and, maybe a more nuanced question is what do you see in your own lab and-and your own trials that influences what-what you do yourself in your life?

Andrea: Uh, most important is that people get to know themselves, before doing any interventions. Very often we are going to a shop or Amazon, even online, and buy something because it looks nice and the label is looking nice and there is a nice claim. Um, I don’t think that this is the way to optimize your own health. Very important is: measure yourself first. Know what your endurance capacity is, for example your VO2 max. Know what your microbiome looks like. If you want to go even further, know what your genome looks like. So know yourself first. And even if you don’t want to really embark on looking at the biology of aging, look at the clinical phenotype. Look at your pictures of yourselves. Look how your skin looks like. Look at how strong you are. Um, if you, the listeners, if somebody can stand up out of a chair five times in a certain amount of seconds, that’s a very, very important indicator already for health, or if you flip it, for mortality. So knowing is the first step before doing something, and of course, everybody should have a very good lifestyle and-and think about their sleep. But analyzing, for example, with digital phenotypic measurements, for example, watch- a Garmin watch, an Apple Watch,  there are so many devices out there. Track yourself and then act on it, and that’s so powerful.

Gordon: Fantastic. Thank you. Great advice.

MUSIC BREAK 

Gordon: There’s a certain image of, not just aging medicine, but-but-but medicine in general, of the sort of high-end clinics for the-the uber wealthy, if you like. And I know that-that you’re very concerned about, the egalitarian approach to all of this. 

Andrea: Because we have at the moment, lots of private clinics, which are not well regulated, by the way. Um, I think there is a huge risk within our field that something is being implemented which might even be harmful, because it’s not science-backed, so very important, independent of whatever bias, who’s coming to whatever clinic, it has to be evidence-based, and this is what I stand for. Um, I’m not sure if I have many friends, but because I’m very, very vocal that we only should do evidence-based interventions and diagnostics in clinical care. At the moment, the longevity field, or the healthy longevity field, has a problem, that healthy longevity medicine is not being recognized yet, therewith, also, there are no standards. If you are looking at oncology, endocrinology, all the fabulous innovations in medicine, they are fabulous because they are following guidelines. And the cur uh, the term  evidence-based medicine is actually coming out of the conventional field, and I would love to integrate that into our health longevity medicine field.

Gordon: Yeah.

Andrea: Because otherwise we will not be around the table with the FDA, with the EMA, with the WHO, the  United Nations. In their [ways], it’s very unlikely that ever it will be democratized, and that’s what we want, because everybody is aging. Everybody. I would say it’s a human right to keep your health up-to-date, to make it as-as best as possible, to optimize it as much as we can, with the knowledge we have. That’s the reason why we have to bring evidence, based medicine into the field. That’s the reason why, as a clinician, I do the randomized control trials. I validate all these biomarkers. I try as much as possible, build consortia, build societies, to build the ecosystem as a  to build the bricks, to build this very, very nice castle we could build together, and which-which should be very stable, because otherwise it’s there’s the likelihood that our beautiful field will implode because of interventions which might be more harmful. And what I really would like to prevent is that we are doing harm. Of course we can take risk, and every risk there is a propensity of harm, but it’s likely that-that we can avoid whatever we can avoid in terms of side-effects, and also that our field is not only a money-generating activity, because people want something and they love to get injections and IV drips and whatever, which, most of them have no evidence behind them. And I would really love to see that-that-that business-oriented longevity field really now turning into an evidence-based generating field, and that’s what we do. 

Gordon: Wonderful. Wonderful. That was a great response to that-that question. Thank you. Um, final question. What does success look like for this field?

Andrea: In three years’ time, the medical societies in at least five countries have acknowledged that healthy longevity medicine is part of internal medicine.

Gordon: Mm-hmm. Well, there we go. There’s a goal.

Andrea: Absolutely. So we need guidelines therewith. We need the recognition. Therewith we need to be recognized as a specialist. We need training, and-and we [integrate] it into the mother of medicine, I would say, and that’s internal medicine, before we are giving it to the family medicine and to the general practitioners, et cetera because, in the end, if 100 percent is exposed to aging, then it has to be delivered also in the public health sector and by general physicians.

Gordon: Andrea, I could talk to you all day, but this-this has been an eye-opener. It’s wonderful to talk to you. Um, thank you for your research. Thank you for being the point of the spear in the clinical trials and interventions in aging. And thank you for your advocacy, which is obviously a big  a big thing of-of what you do, and you’re-you’re driving the entire field forward by doing that, so. Andrea Maier, thank you very much for this time you’ve taken today.

Andrea: Thank you.

SHOW OUTRO

Thank you so much for listening. 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 produced by Vital Mind Media: the Buck Institute’s very own Robin Snyder as the executive producer, Wellington Bowler is right next to me here directing the recordings, Stella B is behind the scenes ready to debrief when we wrap, and the esteemed Sharif Ezzat weaves the show together for you. If you’re listening to this podcast, you know that there’s never been a more exciting time in the research on aging. Discoveries from our labs or moving into the clinic to help us all live better, longer. The Buck Institute depends on the support of people like you to carry on our breakthrough research. Please visit us at Buck Institute dot org to learn more and to donate.