Basics of MCCs and Aging: Epidemiology, Biology, and Knowledge Gaps

Join Jay Magaziner, PhD, University of Maryland School of Medicine; and Stephanie Studenski, MD, University of Pittsburgh School of Medicine & National Institute on Aging; Luigi Ferrucci, MD, PhD, National Institute on Aging and Rafael Samper-Ternent, MD, PhD, UT Health Houston as they discuss important epidemiological and biological aspects of MCCs and aging, as well as, some knowledge gaps, where more work is needed.

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Transcript

Jay Magaziner, PhD: Well, greetings everyone. Welcome to the AGS/ AGING LEARNING Initiative collaborative webcast. The goal of the LEARNING collaborative, for those who are not familiar with it, is to provide learning opportunities in the science of multiple comorbid diseases or multiple chronic conditions for those interested in pursuing research in this understudied area.

Today, we're going to focus on some of the important aspects of epidemiology, biological aspects of multiple chronic conditions, and some of the gaps and knowledge where more work is needed. We hope this will provide some background for those that are interested in this area, and some thoughts on where more work is needed for those new to this area, as well as others who are launching new areas of investigation. 

We're very fortunate to have three experts who [01:00] have given considerable thought to this issue. And are going to talk to us in turn about epidemiology, biology and unaddressed areas for those who are interested in delving into this area more, more deeply.

Let's start by asking Dr. Stephanie Studenski, what is meant when we talk about multiple chronic conditions? And what, what do you view as some of the most important things those new to the study of MCCs. Should know about? 

Stephanie Studenski, MD: Well, Jay, as you said, the definition is two, or more coexisting chronic conditions and that can be measured as a disease count, it could be weighed by severity, and it could include indicators of functional status.

Some of the basic things everyone needs to know is, how common this problem is. Overall, among U. S. adults, about a [02:00] quarter have multiple chronic conditions, but age is a powerful influence on this, so that only about 10 percent of young adults have MCC, whereas two-thirds of adults over age 65 are likely to have multiple chronic conditions.

If you're interested in international issues related to MCC, what we know so far is about a third have, MCC. But that it's very difficult to measure because a disease detection varies greatly between countries. Also the age distribution of the population varies between countries. What we do know is that MCCs are increasing in prevalence over time, in part due to the overall population aging. Some of the things we know about what affects prevalence is sex overall. It's about the same for men and women, but in older age, more women than a man. [03:00] We know that lower socioeconomic status affects the prevalence of MCCs. And we know that mental health issues are associated with a higher prevalence of MCC.

Jay Magaziner, PhD: Well, that's all very helpful and I think it really sheds a lot of light on how epidemiology can provide some of the insights and information as background to the study of MCCs. 

Why do you think MCCs are so important for population health, health care and policy makers. Why is it important for them all to consider?

Stephanie Studenski, MD: Because we know that having multiple chronic conditions, increases the risk of death, of functional disability, of the need for a caregiver, reduced physical and cognitive function, depression, and reduced quality of life. In addition, MCCs increase health care use and cost. And have [04:00] major implications for how we organize health care for older people.

Jay Magaziner, PhD: Well, let's turn next to Dr. Ferrucci. Luigi, in some of your work, the whole area of geroscience comes up. For a group of people who may not really appreciate what is encompassed by geroscience, can you talk some about what geroscience is and what it represents? 

Luigi Ferrucci, MD, PhD: In general, we have been accustomed to study each disease as if they had a very unique pathophysiology that lead to them. And so they need specific treatment. More recently, people have been starting to believe that the biological mechanism of aging are the root cause of multiple chronic diseases. So, so, for example, when you try to dissect, in longitudinal studies, you know, [05:00] those who have a disease and those that do not have a disease, then you look at the aging process and the disease, you know, kind of, evolve into each other without a clear dissection and cleavage between them.

This has important implications because if the biology of aging is at, at, at the cause of major chronic disease, then, then, intervening on the biology of aging, will be extremely powerful to not only reduce morbidity, but also expand the health expectancy, the period of life that is characterized by health, where individual can really enjoy everything that life has to offer.

And one of the proof I think that this hypothesis is probably correct is that with age you have an increased global susceptibility to disease and disease tend to [06:00] accumulate and aggregate even though they may not be pathophysiologically correlated. And these, increase in susceptibility to the disease is what is causing multimorbidity.

There's evidence, for example, that some of the characteristic, of biological aging, a risk factor for not anti multimorbidity, but also the rate of the increase in multimorbidity, individual, the most typical is inflammation. So those who have chronic inflammation, such as a high level of IL-6 or C-reactive protein, tend to accumulate disease earlier in life and more rapidly than others that do not have inflammation.

And that is one of the proofs, or at least element that people make people think that the general science hypothesis, it's really a window of opportunity for a new [07:00] medicine. 

Jay Magaziner, PhD: So I think you said inflammation might be one of the key factors that people are paying a lot of attention to now. What are some of the factors that might produce increased levels or decreased levels of inflammation and how that then might affect many organ systems. 

Luigi Ferrucci, MD, PhD: I think that that's a great question. You know, certainly we know that smoking is associated with higher inflammation. We know that obesity is associated with high inflammation. We know that certain diets are pro inflammatory while other diets seem to be anti inflammatory, such as the Mediterranean diet.

We know that acute exercise associated with high level a pro inflammatory marker. But over time, those who exercise tend to have a decline of inflammation. So there are elements [08:00] in your behavior and in your environmental factor that can increase or reduce inflammation. And those are as valuable as you can think of.

For example, it's been demonstrated that people who have doing some meditation work, people that try to reduce stress by this method tend to have experienced a decline of inflammation, while people that are subject to a stressful environment, to a stressful work, tend to have a higher inflammation. So I think there are, we need to understand that. What are the recommendations that we can give to people? You know, one of the things, for example, that very few people know is that good sleep is fundamental. You know, sleeping less or more than seven hours is associated with high inflammation. To accelerate the aging and recently has also been associated with a higher risk of developing, you know, [09:00] MCC.

And so I think that we're not bored with multimorbidity, but to some extent, you know, we can do something to reduce the burden. 

Jay Magaziner, PhD: If someone experiences this inflammation and there it's occurring, isn't part of the geroscience principle or how does that play into understanding what could actually interrupt that or, or prevent the further progression of disease what you've talked about is how the inflammation might be prevented or modified. I mean, there's a lot of seeking sort of what's the magic bullet here? Or is there a magic bullet? 

Luigi Ferrucci, MD, PhD: Everybody is looking for the magic pill, which, as you well know, does not exist. But I think that, you know, we started with the wide range of theory of the why of inflammation. And I think that we're converging with on two main phenomena.

One is, [10:00] you know, the dysfunctional mitochondria, you know, the mitochondria are those powerhouse that are in cell and when they become dysfunctional, they produce a substance that are strongly pro inflammatory and that's why probably exercise is anti inflammatory because make your mitochondria healthier.

But the second, even more interesting, is that we know now that with aging, you have the accumulation of cells that are stressed. We call them senescent cells, and one of the things that characterizes them is that they arrest replication. They can no longer replicate, and they produce, what we call the senescence associated secretory phenotype. It is a number of molecules. Many of these molecules have a very, very strong pro inflammatory state. And for example, in humans, those cells accumulate mostly in pre adipocyte, [11:00] and that's probably why obesity has been associated with inflammation, especially central obesity. 

So those are the two main theories. There are many, many other Some of them, for example, associated with the change in the microbiome that occurred with aging, but this will be a long list. 

Jay Magaziner, PhD: Yep, well, thank you. 

Now, now let me circle back to Stephanie. And Stephanie thinking about those that are new to this area of MCCs and thinking of your both your clinical background and your work in epidemiology for many years, what do you think are some of the areas that someone new to this field, who's inclined toward population health and epidemiology, and with that kind of background would want to focus on to get more substantive understanding of MCCs in a way that could really [12:00] inform this, this problem that we're, that we're going to continue to see more of.

Stephanie Studenski, MD: Well, thanks for asking Jay. I think there are several things the new young investigators should be thinking about. The first is, if you're not a clinician and you're pursuing research related to population health, I think you should ask to go see real old people. You know, whether you accompany patients in the clinic or perhaps interview patients in epidemiologic studies, get out there on the front line. I think there's tremendous opportunities to come up with creative ideas by really experiencing the life and situations of people with multiple chronic conditions. 

Another is of course to read the literature. I think that epidemiology is most effective when it is working within a conceptual framework [13:00] to identify what is already known, where are the gaps in knowledge. And so, for example, there's a paper by Dr. Salive of the NIA and others in medical care in 2021 that sets up a framework that relates multimorbidity to causative factors and outcomes. I think more could be done, frankly, to expand this so that it is more translational. So again, the idea is to look at what is known and identify gaps in knowledge, either purely, at the, population level in terms of evidence for causative factors that might be intervened on, to, look at where we're at in beginning to actually do population intervention studies, to look at, interactions among specific conditions.

But I also think there's tremendous opportunities [14:00] for translational research and I, I think that includes reverse translation. So if you're a population scientist, make friends with some biology of aging people and think about things that you observe in populations that might be evaluated in animal models or what's coming up in animal models that you might be able to evaluate in human studies. I think there are more and more low invasive, low burden assessments that can be done in humans. Those would be some of my thoughts, Jake. 

Jay Magaziner, PhD: That's great. Those are really some creativity and some thinking beyond what the traditional epidemiology may have taught you and moving, moving beyond that, if you haven't already.

Stephanie Studenski, MD: I think we already, have some examples of creative thinking, Luigi could probably clarify if I'm correct, [15:00] but I believe that dentists have suggested that, gingival disease, periodontal disease is a major source of inflammation. It's very interesting to think about going beyond just what doctors see, and looking more broadly at sources of, some of these biological drivers of inflammation or, changes in energy metabolism.

Jay Magaziner, PhD: Well, Luigi, coming at this now from the biological perspective, where would you either connect to the epidemiology or to the population level in a translational manner, or how would you advise the biologists, someone who's really grown up in a microbiology lab or a in a lab and immunology or or a physiology lab.

Where should they focus their attention [16:00] to understand more about MCCs. 

Luigi Ferrucci, MD, PhD: Well, thank you, Jay. And Stephanie, you're absolutely right. I think that, you know, we know that the gingival tissue is the strongest productor of interleukin 6, which is a major inflammatory mark in our body. So it's very clear epidemiologically, but not so also clinically that, maintaining oral health is really tantamount for the entire health, not only for the mouth, for the heart, for the lungs, for everything.

And this is an important basic principle because all the tissues are connected. We started, when I was studying medicine, you know, everything was in chapter. We studied the lung, we studied the mouth, we studied, and now we're thinking aging is pervasive across the entire body and the different tissues are [17:00] communicating each other.

So the dysfunction of one tissue really percolates in another tissue, you know, almost always. And so that, that's a, it's a different way of approaching patients. But, but for the specific of your question, first of all, I, I, I have experienced that, you know, I started as a clinician, a geriatrician. And then I became an epidemiologist, and some of my friends will tell you that I went to the dark side, and I started to be interested in mechanisms, but I think those, I think, are very much connected.

So, my experience is that, the people that are in the lab and do the molecular biology, I'm really curious to know whether what they're doing is, it's true. It is relevant. It's important as implication for health or not. At the same time, you know, the clinician have a lot of questions that they not addressed by only looking at [18:00] patient, but they would like to go back.

You know, I think that my frustration as a geriatrician was that I couldn't do enough for my patient. And many can see research as a possibility to expand our possibility to improve the health and quality of life of our, especially those that are affected by multimorbidity and disability. 

Now, if you have multimorbidity, what you want is an intervention to work across disease. Because otherwise, you end up having 20 different drugs to cure the 10 diseases that are affecting people. Why, ideally, you want to have one, two interventions that work across multiple diseases. So, I think that the tension for this connection is there. Structurally, We don't facilitate that. You know, the most of the time the building where the molecular biology [19:00] where the labs are in the building where the geriatric program is developing are separated.

So the important opportunity of meeting it is related to the few formal meeting your creator, all that informal possibility of communicating to your colleague is not there. So I think that we need structurally to put this together. A little bit has been done with the Pepper Center, but it's really single, you know, experiences.

I think that generating a movement that connects, you know, the geroscience expert and the clinician, maybe by having the geroscience expert to spend some time with the clinician and see what are the problems that they are confronting and, and asking to the geriatrician, what is that you really need from us?

You know, what are the issues that we would like us to address? And I think that, that [20:00] will make us make a lot of progress and also make the life of the clinician and of the biology more satisfactory. They will enjoy it a lot more. 

Jay Magaziner, PhD: Stephanie, did you want to say something else? 

Stephanie Studenski, MD: I just wanted to say that I think there are opportunities for some cross training and cross exposure. I think if you're in epidemiology, you ought to go to the labs. I, I think you can also see not just how things are done, but just like in your own field, you know, where the weaknesses and the bugs and the methodologic challenges are. I think it's important for scientists to understand the challenges that scientists and other fields play.

The other thing I wanted to add is that I think the Baltimore Longitudinal Study of Aging, which Dr. Ferrucci leads, is an exemplar of trying to look at issues like MCC and the relationship between [21:00] human and preclinical and bench based studies, both directions and finding more ways to apply what we learn in the lab to humans.

So, I don't know if you've written about that lately, Dr. Ferrucci, but I think it's an example of how to do that integration. 

Jay Magaziner, PhD: Okay, hold on, Luigi, we're going to leave that as a challenge for you if you haven't written about it, because I think we'd all be waiting for that next chapter. 

But I think what we're hearing for the new investigator is that new work is needed at the interfaces of the biology, the clinical, the population that we need to be looking at the space between.

And if we're thinking of new areas for the future, and the growing older population, those may be some of the most fruitful and to your advantage, so many things are untapped. You [22:00] really just need to master what's there and look at how to really start bringing them together. 

Next we have, Dr. Raphael Samper-Ternant from University of Texas in Houston. 

Rafael Samper-Ternent, MD, PhD: Thank you. So it's good to be here. I'm an associate professor in the School of Publich Health at UT Health Houston, and I'm also part of the Division of Geriatrics and Palliative Medicine at McGovern Medical School. And I lead the research and clinical innovation core for the Institute on Aging at UT Health Houston.

Jay Magaziner, PhD: Okay, Dr. Samper-Ternent, having had this discussion about some important issues in the epidemiology and biology of aging, what do you view as some of the most important knowledge gaps in the study of multiple chronic conditions? 

Rafael Samper-Ternent, MD, PhD: So I would say that there are three big ones that I can think of right now.

So one [23:00] is, I think we need to do a better job describing trends in, multimorbidity and also disparities. So it's clear that certain groups of populations, I work a lot with older Hispanics, have disadvantages that really impact how they experience multimorbidity, but I still think that we need to better understand the pathways that lead to those disparities.

The second place where I think we need to fill in gaps is when we think about multimorbidity, it's not just the number of clinical conditions, right? It's not the same thing to have dementia, hypertension and diabetes, than to have congestive heart failure and chronic kidney disease and diabetes, right? They, they have different implications in terms of screening in terms of management in terms of medication regimes in terms of outcomes. So, I think we need to do a better job [24:00] understanding and studying the clusters of conditions in adults with multiple chronic conditions.

And that leads to the 3rd gap where there's a lot of opportunity for research. And it's to describe those clusters and identify how they impact disease burden. And we can define disease burden in in many ways, but I think what are the implications of those clusters of conditions in outcomes that are important and significant for diverse older adults? 

Jay Magaziner, PhD: Thank you. I want to track back to a couple of these.

You mentioned more description of of the disparities and diversity of the population in terms of trends or, or, occurrence of comorbid conditions. You talked about pathways. What did you have in mind when you talked about pathways? 

Rafael Samper-Ternent, MD, PhD: So when we talk about disparities in certain [25:00] groups of populations, being Hispanic or being Black, it's not the cause of the difference in outcomes, right?

So how things like stress get under your skin, how differences in how guidelines are used or not used, how access to health care and different types of preventive or specialized care lead to different results. I think we don't have a good grasp and understanding of the mechanisms that lead to those disparities.

And I think this is a prime time to look at large data sets, longitudinal data sets that include both longitudinal data and biomarkers to actually get into those biological pathways that actually lead to those disparities. 

Jay Magaziner, PhD: So, when you think of the many things that are yet to be investigated in this field, which is really just getting its sea [26:00] legs and taking off as an area of interest and investigation, what do you see as the areas that are sort of where a new person to the field might want to focus some attention.

Rafael Samper-Ternent, MD, PhD: This is prime time for a lot of research going into multimorbidity. So I think anyone that wants to go into multimorbidity is, is coming into it in a great moment in time, because we have lots of data sets. We have lots of clinical data, lots of buy in from systems that want to understand multimorbidity.

But I think from the clinical standpoint, and it's closely related to some of my work, I think we also need to shift the paradigm of how we manage older adults with multiple chronic conditions. So the guideline-based approach where we take hypertension and diabetes and congestive heart failure and try to treat each of [27:00] the 3 conditions separately, that's gotten us into a lot of trouble and very poor outcomes for older adults in general. 

So I, I think we need to take advantage of the more holistic approach that we're now taking to actually do patient-centered care and focus on the values that patients have their health care goals and then focus a lot of the work into what patients actually want.

But from the basic science perspective, I think there is a universe of opportunities to go into a link data sets that have, as I mentioned before, biomarkers and clinical data and try to look at the more basic biological pathways that lead to differences in- so we know that a kidney of a person with hypertension and diabetes is not the same as the kidney of a person without those conditions, right? 

So what does that biological variability mean in terms [28:00] of functionality, morbidity, burden of disease, hospital admissions, functional status? So you can go on and on and on and looking into. So I think there are opportunities for both the basic sciences, the clinical sciences and obviously the translational science is trying to feed the basic science into clinical interventions and back and forth.

So I think there's a universe of opportunities. 

Jay Magaziner, PhD: So, what I'm hearing you say, and I agree with you, is that with so little known already, someone new to this field, the only thing really holding them back is knowledge of the little that has been done and their imagination and observation of the many factors that might come into play in their own special areas of expertise or interests. So I think that there's really, really a tremendous opportunity. 

I [29:00] want to thank you all for joining us today, and I want to let everyone know that each of them have prepared a slide set, which should be readily available to you at the AGS / AGING LEARNING Collaborative website. So, I hope this has been informative, and we thank you all for listening.