The Energetic Cost of Chronic Stress with Dr. Natalia Bobba-Alves

recognized stress experts from UCSF, UCLA and Yale. This is the first of two episodes highlighting the best stress science papers of 2023 the Stress Measurement Network is accepting nominations for the best paper of 2024 now through March 2025 in this episode, I spoke with the lead author of the best basic stress science paper on how chronic stress affects our bodies at the cellular level, and the need for interdisciplinary team science to make these kinds of advances.

I hope you enjoy the episode. Dr. Natalia Bobba-Alves is a post doctoral researcher working in the National Institute on Aging, where she focuses on how stress signaling affects cellular energetics and aging. She received numerous awards that supported both her undergrad and master degrees in Uruguay, and then she was awarded a Fulbright foreign grant, which supported her PhD in nutritional and metabolic biology at Columbia University

in New York. And that was where she started working with Dr. Martin Picard to quantify the energetic cost of stress and the impact on cellular aging. Welcome to the Stress Puzzle. Dr. Bobba-Alves, we're so pleased you could join us, and I wanted to start off by saying congratulations on leading the paper we'll be discussing today, which was named the best stress science paper in the basic science category for the 2023 year by the Stress Measurement Network.

Natalia Bobba-Alves: Thank you very much for the invitation. We are very honored with the recognition of our paper by the Stress Measurement Network. I think our paper is a good example of how valuable interdisciplinary science can be, and I'm more than excited to discuss about it with you today.

Absolutely. I'm really glad you brought up the interdisciplinary nature of it. And you know, It's especially fun for me, because when I was reading this paper, it just reminds me of the Scholastic show the Magic School Bus, which I, you know, loved as a kid, where Miss Frizzle would take her class on a Magic School Bus to learn about science and

sometimes take a deep,deep ride into the human body. And in many ways, this paper truly gave us a Magic School Bus examination of chronic stress and how these effects are really able to be seen at the cellular level. So, before we dive in,I wanted to give listeners a little background on some of the key terms we'll be using in this episode, because there are a lot

of really cool concepts. So first, we can introduce the stress response as an example of allostasis, which is a concept that represents how the organism is able to adapt to cope with environmental and psychosocial challenges, but whosechronic activation imposes an allostatic load that contributes to the cumulative wear and tear of the system and disrupts normal physiological functions and induces negative mental and

physical health outcomes. We'll also talk about chronic glucocorticoid signaling, which is a feature ofchronic stress that in humans results from the chronic release of cortisol, one of the main stress hormones and likely one of the causal pathways through which stress affects health and aging. We'll discuss cellular energyexpenditure, or how much energy the cells consume to be alive and to carry out the processes that are needed to face and overcome any given

stressor. We'll also talk about mitochondria as the main source of energy production in the cell, or, as you likely remember from high school biology, the powerhouse of the cell and how they respond to stress mediators like glucocorticoids. And finally, we'll talk about cellular hallmarks of aging and accelerated aging as a consequence of chronic

glucocorticoid signaling. Returning to the purpose of this paper titled "Cellular llostatic load is linked to increased energy expenditure and accelerated biological aging." This was an enormous contribution in multiple ways, and I'll let you dive into the specifics of these findings and their implications. But, I wanted to start off by asking, sort of, what got you excited about stress research?

Natalia Bobba-Alves: I've been always captivated by the dual nature of the stress response, how it's acute activation serves and as an adaptive response, allowing the valley to face and overcome a stressor, while its chronic activation end up being maladaptive, negatively impacting the organism health.

And there is a vast body of literature highlighting its significant role in causing or exacerbating diseases across virtually every organ system in the valley having a negative effect on both mental and physical health that increase the risk of morbidity and mortality. And yet, we still don't fully understand the underlying basis of this link. So, this knowledge gap that requires further investigation is, in the end, the most exciting part to understand.

Right. It's so interesting being people that study stress. You go to anyone on the street, everyone believes the underlying concept of stress affects health, but getting to those specific mechanisms is a lot more complicated. So, what is some of the foundational literature that you really drew from to pose your questions and form your hypotheses? Natalia Bobba-Alves: So, I think there's two main bodies of

literature. The first one relates to the conceptualization of the stress response, that is thinking it from an evolutionary perspective. So, what purpose does it serve, and what are its physiological principles, and this is key to understand how an adaptive response can eventually become a maladaptive response. So, when it comes to literature, you could actually go back all the way to the work of Claude Bernard in the 19th century and

the concept of internal environment. He proposed that a critical requirement for any living system to survive is to maintain the stability of the internal environment. And then, you could think of the work of Walter Cannon in the early 20th century, and the concept of homeostasis, proposing that the internal stability is achieved by keeping biological parameters as specific set points within a narrow range and through the

action of compensatory mechanisms. But then you have 50 years later, the work of Sterling and Eyer and the concept of allostasis, as you mentioned it before, proposing that the internal stability is also achieved by allowing certain biological parameters to vary according behavioral and environmental demands and through the action of

anticipatory mechanisms. And then building from these, we have McEwen and Steeler introducing the concept of allostatic load, arguing that repeated activation of these anticipatory mechanisms impose a strain on the system that leads to its progressive volunteer and then furthur extending the model, McEwen proposed that, when sustained over time, allostatic load triggers recalibrations that causeprogressive dysregulation among the organ systems, and an

increased risk for disease, development and mortality, as stated, the term allostatic overload. So, this literature helped us to conceptualize the stressresponse as an example of allostasis, whose chronic activation imposes anallostatic

load that can lead to allostatic overload. So, in other words, it would be the stress response induces recalibrations to maintain overall internal stability, and its chronic activation leads to the wear and tear of the system, which can cause the progressive dysregulation, which in turn can promote the development of disease and increase in the risk of mortality. And then, the second body of literature relates to the energetic recalibrations that comes with

the stress response. So, the stress hormones have direct effect on a myriad of organ systems, including cardiovascular system, increasing heart rate and cardiac output, as well as increasing blood pressure and inducing a blood flow redistribution towards brain cardiac muscle and skeletal muscle, and away from kidneys, digestive system and reproductive system. And then, we have the effects on respiratory system, where it

increases the breathing rate and the bronchial dilation. And we have the liver, which induces glycogenolysis and gluconeogenesis, which both contribute to an increase in the circulating levels of glucose. Effects on the pancreas, where it decreases the releases of insulin, also contributed to an increase in certain in circulating levels of glucose. Effects on adipose tissue, where it induces like policies and then contributes to increase in circulating levels of fatty

acids. So, all these recalibrations basically serve to maintain the effective body blood supply to the organ systems in the body, primarily brain, cardiac muscle and skeletal muscle, maintain a continuous availability of the circulating oxygen and nutrient substrates and also optimize their utilization by vital tissues at the expenses of

others. And these recalibrations are critical, because the mental and behavioral actions required to face and overcome the stressor impose a significant increase in the body energy expenditure, something that we call hyper metabolism. So, the evidence ofstress leading to hyper metabolism dates back to almost a century ago, and it has been shown both in animal models

and in humans, both in acute and in chronic stress. Now another piece of information that is very relevant to this is that hyper metabolism is strongly associated with both negative health outcomes and increased mortality risk and decreased lifespan. So, whether stress induced hyper metabolism arise from specific organs in the valley or from all the cells in

the valley. That's something that is not clear, and whether stress induced hyper metabolism could be behind the negative health outcomes of chronic stress is also not clear, and that's how our question came to us, does stress signaling induce hypermetabolism at the cellular level, and if so, could this be associated to the negative cellular health?

Wow. What a beautiful job bringing those two literatures together and really coming to this foundational question that so many folks have in stress science right, drilling down where is hyper metabolism coming from?Where is this increased energy expenditure coming from? And is it targeted from one spot, or is it, like you said, at the cellular level? Next, I'd love it if you could briefly describe the experimental approach that you took to test this kind of a question.

Natalia Bobba-Alves: Yeah, what we did is we aim to create an in vitro model of chronic stress to evaluate the cellular bioenergetic recalibrations and how they relate to cellular dysfunction, we culture skin fibrillas from three healthy donors andtreat them with dexamethasone, which is a

synthetic compound that mimics the action of cortisol. So, by doing this, we exposed the cells to chronic glucocorticoid signaling, and then we studied the cells throughout the entire lifespan until they stopped dividing, while performing measurements of key hallmarks of cellular function in a repeated, longitudinal manner. So, we evaluated the cellular energetic profile, evaluated mitochondrial calibrations and the associated

changes in gene expression. We also evaluated various markers of cellular function and particularly hallmarks of cellular aging, such as secretion of specific cytokines and cell free DNA, DNA damage, and DNA methylation patterns and other features associated to the cell's ability to divide, such as telomere length and the total numbers of division, then cell can go in their lifespan, as well as cell death.

What a comprehensive approach. I mean, for folks out there at home, what they're really doing here is looking at cell specific changes that occur related to how we think of chronic stress exposure in the form of a stress hormone, right? And so by linking this longitudinally in these cells and really being able to track cell aging and all of these important parameters around function and aging of these cells, what were you able to find from the study?

Natalia Bobba-Alves: Well, the first thing we found was that chronic glucocorticoid signaling increased the total cellular energy expenditure by about 60% so in other words, when the cells were continuously exposed to this cortisol like molecule, they consume approximately 60% more energy to live and divide throughout their lifespan.

Wow. Natalia Bobba-Alves: And this increase can be interpreted as the energetic cost of chronic activation of the stress response in the cell, essentially the energetic cost of chronic cellular allostasis. That is the energetic cost of cellular allostatic load. Now, another important finding was relative to the pathway to produce the energy molecules, the ATP. So, the cells have two main pathways to produce ATP, cytosolic glycolysis and mitochondrial oxidative

phosphorylation, or OXPHOS. And of those, mitochondrial OXPHOS is the most efficient and effective pathway, because it produces about 18 times more ATP than glycolysis from a molecule of glucose, and because it can also produce ATP from fatty

acids and from amino acids. So, in our experiments, the cells chronically exposed to glucocorticoid signaling produce most of their ATP by mitochondrial force and had an increased mitochondrial force capacity to generate ATP and all of these were supported by changes at the gene expression level, specifically, genes involved in mitochondrial biogenesis, mitochondrial maintenance and mitochondrial ATP production were all upregulated, so the cells under

chronic glucocorticoid signaling were using more ATP and presented long term mitochondrial recalibrations that enabled them to cope with increased energetic demand. But, then there's the other side of the story, which is related to a cellular function and cellular aging. And what we found was that these biogenic recalibrations occur alongside phenomena typically associated with an accelerated cellular aging. So, specifically, there were changes in the secretion of

age related cytokines. There was an increase in the release of cell free DNA, an increase in DNA damage. Changes in DNA methylation that indicated an accelerated biological aging. And consistently with this, we also serve an increase in telomere shortening rate, a decrease in the total number of cell divisions that the cells could go in their lifespan, and an increase in cell death. So, all of these are typical

hormones of accelerated cellular aging. And finally, we found a robust association between hypermetabolism and cell death, aligning with this observation in human studies and suggesting that hypermetabolism could indeed be underlined the negative effects of chronic stress.

It's really remarkable when you think about how many of these points we've seen on that sort of whole body level, or maybe, you know, drilling into immune cell subtypes and things like that, but really being able to bring it to the individual, single cell level that we're seeing these connections again, just a monumental step forward in our understanding of that association between stress and accelerated aging and how that is actually potentially

happening in our bodies. What is, for you, the main takeaway from this study? Natalia Bobba-Alves: I think that the main takeaway is that chronic stress affects our bodies all the way down to a cellular level. Imposing an energetic cost that is accompanied by an acceleration in the cellular biological aging, and this could represent the underlying basis of the negative effects of chronic stress.

Absolutely. And I mean, I think just from our conversation today, I think it's pretty clear how these findings can be pushing the field forward. But, what is your perspective on on how these findings push the field forward? Natalia Bobba-Alves: I believe that our findings push the field forward primarily due to our simple yet effective

experimental design. So, if you consider this, we work with a monolier of cells that do not play a central role in the stress response and were not exposed to any direct stressors. Rather, these are just cells that were chronically exposed to a stress mediator. And despite this simplicity, we observed features mirroring those seen during chronic stress at the organism level, so an increased energy expenditure, metabolic recalibrations aim to cope with it and negative outcomes that

increase the ris of mortality and compromised lifespan. What are the implications for this? Well, first, it confirms that allostatic load extends beyond the organism level and can be traced all the way down to a cellular level. And this supports the notion that allostasis and allostatic load are not unique to complex organisms, but are likely evolutionary conserved phenomena that might have originated in

unicellular organisms. Then, it validates the use of culture cells exposed to a stress mediator as an in vitro model of chronic stress, and this is crucial for determining the mechanisms underlying the stress disease connection, and which is the kind of science that we need to do to facilitate the development of interventions that enhance resilience and

promote health. Then, it demonstrates that virtually all cell types in the body, regardless ofhow central the role is in the stress response, are affected by chronic stress, and this aligns with the evidence that chronic stress plays a significant role in causing and exacerbating diseases across virtually everyorgan system. Negatively affecting both mental and physical health and increasing

the risk of morbidity and mortality. Then, it also suggests that the presence of stress mediators can initiate hyper metabolism in virtually every cell of the body, which then would contribute to the overall stress induced hyper metabolism. So, we propose that hypermetabolism reflectsthe magnitude of allostatic load at any level of biological complexity, essentially how much energy the cells, tissues, organs, systems, and the organism are expanding to maintain their internal stability.

I'm just pausing to take in the magnitude of how this does push us forward. And you know, I want to come back to something you were saying really at the very beginning there, which was around the importance of these simple but really drilling down into the mechanisms, kinds of

experiments. And, you know, I think it points to sort of a goal through this podcast that we have, which is really emphasizing, again, the interdisciplinary team science, nature of stress science, and the many different approaches that we have to have to actually be able to move the needle on translating any of the science to people's lives, right? And I think about this sort of in the context of thinking about social

status, right? We've, we've talked with Professor Sir Michael Marmot about his really foundational work, looking in human populations, at how social status and differences in social status are tied to health, again, really focusing in humans

on these larger epidemiological samples. And then, we've talked with Dr. Jenny Tung, who's studying similar questions in populations of baboons and then doing experimental methods in populations of macaques in her lab, and what y'all are really contributing here is, again, that really fine grain,

mechanistic work at the single cell level. So, it's really by bringing together all of this kind of research that is the larger, longitudinal, epidemiological types of studies of humans, animal model work that is observational and experimental, right experimental work in humans, and then similarly, at the single cell level, being able to tie all of this together, to me, is really how we move forward as a field, and that means that our trainees, and anyone who's

interested in this, you really benefit from learning how to read each of these different literatures. And so, you know, I just wanted to come back to that, because I think what you're pointing to is how foundational this paper is for so many different areas of science, and stress science specifically. And I just wanted to come back to the variety of methods that are really needed to push our field forward at

this moment, right? It's, it's not the 1800s anymore. When we are we are really approaching this as a with a team science perspective, as as is clear from the team behind your paper. Would you like to speak to the sort of interdisciplinary nature of that team before we move on? Natalia Bobba-Alves: Yes, I think that it's, it's crucial for the kind of answers that we're trying to get. As you mentioned, we are now, you know, in a moment of science in which

we have the opportunity to work together as a team. You know, technology has enabled us not only to move forward when it comes to thethings that we can measure, but also when it comes to the science thatwe can share and the knowledge that we can share. So, now we can have a team with experts of every single part of cell biology, and then every single part of organism physiology to all the way up to epidemiologic studies,

and we can all work together. So, this is an example of how we can move forward in our science, and I think it's fascinating. It's a great time to do science, and I think we have to take advantage of that. So, this paper, which is mainly cellular paper, cell biology paper, it's still within the cellular biology field. It's a very interdisciplinary because it really touches upon a lot of different aspects of cell

biology. And in order to not only measure all those things, but also integrate all that information, we had tosit down and work together and and hear the, you know, the interpretation of all of these experts to put together a story

and understand, okay, what's actually going on here. So, it was a great experience and full of amazing insights from all these people and yes, and still, cellular biology paper that now we're trying to extrapolate to whole body science and whole body stress related science. Yeah, and you've also been examining how stress affects whole body energy expenditure with your paper that came out in 2022 and I wonder if you could briefly discuss those ideas as well?

Natalia Bobba-Alves: Yes. So, what we did was we proposed what we call the energetic model of allostatic load, which relates to general constraints on total energy flux that can lead to intracellular trade offs between competing energy consuming

processes. So, the model begins with the understanding that the total energy expenditure of an organism is distributed among various processes, including vital functions, awake functions, growth, maintenance, repair and also allostasis, with a reserve capacity that completes the total energy

budget of the organism. And we propose that under chronic stress, the energy allocated to Allostatic processes increasesconsuming the organisms reserve capacity, but eventually, whether because the reserve capacity is completely depleted or partially used up, the allostatic processes began to draw on energy resources that would normally be devoted to other processes, specifically expendable processes like

growth, maintenance and repair. So, these processes might not be crucial for immediate survival, but are vital for long term health. So, over time, this leads to accumulated damage that manifests as accelerated aging and promotes development on exacerbation of diseases. Now, more studies will be necessary to fully test and refine this model, but if validated,it could impact design of resilient building interventions. So, under this model, we can think of these interventions as

efficiency induced or capacity induced. So, in the efficiency induced interventions, the energetic resources devote to every process are reduced, and then the available reserve capacity is increased. An example of this could be meditation practices that are known to reduce the overall stress reactivity and overallenergy consumption. And then, we have the capacity induced interventions in which

the reserve capacity is itself increase. And an example of these would be exercise which is known to increase mitochondrial content and mitochondrial force capacity. So, bothtypes of interventions aim to expand the energetic reserve capacity of the organisms, which then protects it from energetic trade offs under stress, and therefore enhances its resilience and its ability to maintain and healthy life.

As we're thinking about stress and the variety of types of stressors that we might experience, I'm curious how you think about the continuum between social stress and molecular stress? Natalia Bobba-Alves: If you think about it, so social stressors are either real, imagined, anticipated, or recalled environmental events that the individual interprets as a threat to its own integrity, and the interpretation is carried out by the mind. And the mind, it's an

immersion property of the brain, and the brain is an organ. It's a very complex and intricate organ, but it's still an organ which is, in the end, a conglomerate of cells, which are a conglomerate of macro molecules, which are a conglomerate of molecules, which ultimately follo physical

chemical principles. So, the continuum between social stress and molecular stress is a result of the continuum between social events and molecular events from the mind all the way down to the molecules, and from the molecules all the way up to the mind, and the brain is connected and sends information to every single organ in the valley in the same way that every organ in the valley is connected and sends information to the brain. So, anything that happens at the mind will affect the body, and

anything that happens at the body will affect the mind. So, your mental state will affect your physical state, and your physical state will affect your mental state, psychological health and physiological health. In the end, is just health. Beautifully said. I mean, especially that last point on the sometimes needless separation, I think that that

that's something I really relate to in describing. You know, a lot of the kinds of research interests, you always have to say mental and physical health, but what you really want to say is just health, which includes these overlapping experiences that affect one another, and exactly what you're saying. So, what questions remain for you, and where do you think we should go from here as a field to continue answering questions like this and and really moving forward?

Natalia Bobba-Alves: Well, I think that when it comes from, you know, follow up questions from our paper, in particular, future studies should aim for maybe more physiological conditions, so including using cortisol concentrations of serve under chronic stress, and ideally with its natural circadian variations,incorporating catecholamines like norepinephrine and epinephrine, including changes in other hormones, such as tired hormones, growth hormones, insulin, and also changes in

metabolic parameters like glucose and fatty acid levels, all of those who are a crucial part of the stress response. Then, we should also evaluate these in other cell types, both from organs with a central role in the stress response, like the brain, the muscle, the liver, as well as organs whose activity decreases during the stress response, such as the kidneys

and digestive system and reproductive system. Then, there's more to do to actually establish the causality between hyper metabolism and cellular aging and cellular dysfunction, even though the stress induced hyper metabolism is well established and human studies and animal studies and our in vitro work show a strong association between hyper metabolism and poor health. Further in vitro studies are

required to establish the actual causal directionality. Lastly, Further work is needed to determine the mechanisms by which hyper metabolism causes damage. So, there are authors proposing that it could be through increased demands on mitochondrial activity leading to oxidative distress. We propose that it could be due to energetic constraints, causing energetic trade offs, and it could actually be both, and both these hypothesis need testing to confirm their physiological

relevance and their interplay. So, yeah, a lot of work to be done, all the way from the cells to the mind, hopefully with the work and collaboration of experts in every field, and hopefully to get more answers and try to understand this connection between stress, disease and aging. What a comprehensive agenda. And you have such a

wonderful career ahead of you. I know you're going to be the one answering many of these questions, and again, really pulling the teams together to be able to do that kind of science. So, Dr. Bobba-Alves, I just wanted to say thank you again for joining us. Congratulations on what a heavy lift of this paper, the persistence that it takes to get this kind of work that is so interdisciplinary, so team science, so comprehensive

and, so impactful for the field, it takes a lot. And, so thank you for doing that work, and thank you for joining us today for the Stress Puzzle. Natalia Bobba-Alves: Well, thank you very much for the invitation. Thank you very much for honoring our paper. And yeah, I'm excited to listen to the rest of the podcast episodes. Thanks for tuning in to this episode of the Stress Puzzle. We'd love to hear your thoughts and feedback on any

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