From Our Neurons to Yours

The secrets of resilient aging | Beth Mormino & Anthony Wagner

• Wu Tsai Neurosciences Institute at Stanford University, Nicholas Weiler, Beth Mormino, Anthony Wagner • Season 7 • Episode 6

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This week on the show, we're have our sights set on healthy aging. What would it mean to be able to live to 80, 90 or 100 with our cognitive abilities intact and able to maintain an independent lifestyle right to the end of our days? 

We're joined by Beth Mormino and Anthony Wagner who lead the Stanford Aging and Memory Study, which recruits cognitively healthy older adults to understand what makes their brains particularly resilient — and how more of us could join them in living the dream of healthy aging.

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Further Reading

References

  • Trelle, A. N., ... & Wagner, A. D. (2020). Hippocampal and cortical mechanisms at retrieval explain variability in episodic remembering in older adults. eLife, 9:e55335. doi: 10.7554/eLife.55335 PDF | PMID:32469308
  • Trelle, A. N., ..., Wagner, A. D., Mormino, E. C., & Wilson, E. N. (2025). Plasma Aβ42/Aβ40 is sensitive to early cerebral amyloid accumulation and predicts risk of cognitive decline across the Alzheimer’s disease spectrum. Alzheimer’s & Dementia, 21:e14442. PDF | PMID:39713875
  • Sheng, J., ..., Mormino, E., & Wagner, A. D. (submitted). Top-down attention and Alzheimer's pathology impact cortical selectivity during learning, influencing episodic memory in older adults.  Preprint

Episode Credits

This episode was produced by Michael Osborne at 14th Street Studios, with sound design by Morgan Honaker. Our logo is by Aimee Garza. The show is hosted by Nicholas Weiler at Stanford's Wu Tsai Neurosciences Institute and supported in part by the Knight Iniative for Brain Resilience.

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Nicholas Weiler:

Welcome back to From Our Neurons to Yours from the Wu Tsai Neurosciences Institute at Stanford University, bringing you as always to the frontiers of neuroscience. Today, we're going to be talking about healthy brain aging. To do that, I want to introduce you to somebody named Harry Tu. Harry was born in Shanghai and spent his career as a coal mining engineer. He's now in his mid-90s, has no medical complaints, doesn't take any medication. He swims laps five times a week, carries his bike upstairs to his apartment after a long bike ride, and he's the one who drives around to visit his family and friends, most of whom can't drive any longer. He flies out to China every year to visit his relatives.

Harry is the picture of healthy aging. He's independent. He's able to live his life and do the things that he enjoys. He's part of a study at Stanford, the Stanford Aging and Memory Study, or SAMS, which is trying to understand what it is that allows some people to live into old age with their mental faculties largely intact, to live a fundamentally independent life. So, the SAMS study has been running for more than 10 years, and it's led by Anthony Wagner in the Department of Psychology and Beth Mormino in the Department of Neurology, and supported by the Knight Initiative for Brain Resilience.

I asked Anthony and Beth on the show to tell us what we're learning about how we can all age more like Harry Tu. I started off by asking Anthony, how did SAMS start and how has it grown since then?

Anthony Wagner:

So SAMS started back in 2014. The initial idea is we were going to enroll a large sample of cognitively healthy, older adults. These are individuals who through extensive series of cognitive testing appear to have entirely normal intact cognition. We've enrolled now well over 200 participants. The idea at that time was to get just this one snapshot of their cognition and to try to understand how variability in that cognition both moment to moment as well as between the different older adults who are enrolled in SAMS, how that variability relates to brain structure, brain function to other biomarkers that are risk factors for Alzheimer's disease, such as amyloid and tau proteins that at the time you could pick up in cerebral spinal fluid.

But as science has evolved over time, you can now pick up with things like blood plasma. Of course, there are also other imaging methods like positron emission tomography, which we've added to SAMS over the years. So, at its outset, SAMS initially was just to have this one time point snapshot of cognitive function with a focus on memory function. We were interested in trying to understand what are some of the factors that are accounting for why somebody is learning or remembering a bit better at one moment versus another moment, as well as then between person variability and memory performance as a function of age, but even controlling for age, what accounts for why one older adult is performing a bit better than another older adult.

Nicholas Weiler:

We know that there's this huge variability between people as we age and so zeroing in on like, okay, let's look at this variability. Let's see, as you said, moment to moment, what are the things that are causing these differences or associated with these differences in performance? What can we learn about what are the factors that are influencing this broader picture of variability? Okay, that makes sense.

Anthony Wagner:

Absolutely. So, that was the initial idea and we've done a tremendous amount of work there, but the exciting thing about and the privilege of being at a place like Stanford is you're surrounded by amazing colleagues. So, I'm a basic systems neuroscientist, cognitive neuroscientist, focused on memory. What are the mechanisms of mind and brain that build memories that allow us to retrieve or reactivate those memories? What's giving rise to this moment to moment fluctuation, in between person fluctuation? As SAMS began to take off and we're doing this deep dive with our collaborative team, other science advances and there are other tools that one could bring online and add to the SAMS study.

SAMS as a project and I as an individual scientist have been incredibly fortunate that Beth joined our faculty and immediately reached out when she landed on campus. SAMS was a natural intersection for our two research interests, Beth's tremendous expertise in the pathology and the imaging of the pathology related to Alzheimer's disease along with other areas of expertise. So, over the years from beginning in 2014, SAMS has expanded. We've added additional imaging methods, which I'm sure Beth can comment on, adding positron emission tomography with new tracers that can allow us to measure the burden of tau in individual brains and where that burden is in particular locations in individual brains and trying to understand how variability of memory relates to that.

At the end of the first wave, we thought SAMS would be a one-time point, but we've now added a longitudinal arm where we're bringing individuals back seven to eight years after their first enrollment. This is actually allowing us now to answer or explore the very questions that you've surfaced with the start of this question, which is can we try to understand which of these various factors might be drivers or predictors of change, maybe leading to cognitive decline over time, as well as trying to understand mechanisms of resilience, what factors enable somebody to both maintain intact neurocognitive health, maybe perhaps in the face of some of the risk factors, some of the early pathology associated with Alzheimer's disease or other conditions.

So, we're excited about where SAMS is ultimately going to go in terms of being able to address these questions of resilience.

Nicholas Weiler:

Yeah, that's so interesting. So, again, now that you've got this seven or so year time point, you can say not only what are some of the things that are associated with variability in people's cognitive performance as they age, but also what are the things that are associated with big change if potentially you see some people go from being 80 to 87 and you see a big decline. Some people are still on a baseline and you can start to piece apart what are the things that might account for that? In my mind, the goal, it seems like, how can we replicate the Harry Tu story? How can we all live to a ripe old age and still be able to do the things we love?

So Beth, Anthony brought up the technological developments, things like PET imaging of biomarkers of Alzheimer's disease like amyloid and tau in the brain, large scale proteomics where we can get samples and really see what are the differences in proteins or in gene activity and so on. I'd love to hear more examples of how some of these developments in your SAMS study and maybe elsewhere in the field are changing our understanding of the biology of how our brains age and what resilience looks like.

Beth Mormino:

Yeah, absolutely. I mean, so we as a field have seen an explosion of tools that we can readily apply to humans in a non-invasive way. Before this explosion, really the only way to know pathologically what was going on in an individual's brains was at death.

Nicholas Weiler:

You'd get an autopsy and have a look at the brain, and after the fact, you could see if they had amyloid in there.

Beth Mormino:

This would be done in the context of an individual living with dementia. So, it would really just be to confirm that the dementia was due to Alzheimer's disease, so it was very limited. Now for about 20 years, so we have been able to reliably measure the amyloid protein, which we think is quite central for Alzheimer's disease. For about the last 10 years, we've been able to measure the tau protein, which is the other hallmark pathological feature of Alzheimer's disease. But maybe most excitingly, just really in the last few years, there's been very reliable, robust plasma markers of these AD proteins of amyloid and tau.

So, we really can get a readout of these core pathologies in a quite straightforward, easy to collect way. We also can sample the plasma more frequently than we would do with a PET scan.

Nicholas Weiler:

So that's just a blood draw and then you extract the plasma. You can see signatures of whether there's amyloid or tau in the brain.

Beth Mormino:

So that's where we are as a field. I mean there is some devil in the detail. So, for instance, spatial information of these proteins is probably important.

Nicholas Weiler:

Where is it in the brain? Yeah, you're not going to get that from the plasma.

Beth Mormino:

We don't get that. There's known comorbidities that might influence these plasma measures. So, for instance, kidney function may push around these measurements and be less reliable. So, still there's some details to sort out, but in terms of a research tool, this is really an incredible opportunity to understand the consequences of these pathologies associated with Alzheimer's disease. So, circling back to the normal aging question, another layer of this is that these pathologies do not appear when somebody actually has dementia. We know that they are present in some individuals decades before the onset of actual dementia. So, dementia itself is defined by pretty much the opposite of Harry, it's lack of functional independence.

But what we're understanding now about these diseases is that just like most health conditions, that the processes start well before symptoms. So, in the case of dementia, the symptoms are overt cognitive issues and eventually loss of independence. So, now what we're able to do is measure these processes in a time in which there are no symptoms and there's many implications for this. So, one interpretation is that this will give us a window into risk if you have these profiles early on, and this is what we're seeing. You're more at risk for eventual decline.

Nicholas Weiler:

So someone who doesn't have any obvious clinical presentation, if you start seeing these signatures of amyloid and tau in the brain, that gives you a sense of maybe they're at risk of developing more clinical presentation later.

Beth Mormino:

Yeah, at the group level. So, on average, this is associated with a higher risk of progression later on. However, we're also seeing that there's individuals that have these signatures that do not progress. So, it's another form of this variability and another potential window into mechanisms of resilience. So, why do some individuals harbor this pathology that we know it likely isn't good, that it increases your risk? However, it's also possible to have this signature and remain healthy. So, it provides these specific mechanistic opportunities to tease apart resilience.

Nicholas Weiler:

I found this so interesting. I mean, talking with folks in the Alzheimer's field for a number of years now, this comes up again and again that so often you see someone who passes away from natural causes in their 80s or 90s and they seem perfectly cognitively healthy and then you look at their brain and it's full of amyloid plaques. If someone had just looked at the brain, they might think, "Oh, this person probably had Alzheimer's disease," but in fact they didn't. I don't know if you happen to have these numbers offhand. Do you have any statistics to give us a sense of how common that is? Is that unusual to see someone who's cognitively healthy but has lots of amyloid plaques in their brain?

Beth Mormino:

So actually this is very well studied. So, amongst 70-year-olds that have no symptoms whatsoever, this includes even mild cognitive impairment, so even excluding folks that would fall into that bucket, it's about 25 to 30% of 70-year-olds would have an amyloid signature that is consistent with Alzheimer's disease but do not have symptoms. The patterns with tau are a little more complicated. So, what we believe is happening as it begins in these brainstem areas and then it's in the medial temporal lobe focally and then eventually spreads throughout the brain. So, having this focal presentation of tau is quite common in normal older individuals. Having a very widespread tau is extremely uncommon.

So, that marker is more better aligned to the actual clinical presentation and that I think also gives us a hint of these mechanisms. So, a potential resilience mechanism might be that there's some folks that are experiencing this amyloid pathology, but whatever these protective mechanisms might be in that brain, the tau is not spreading from the medial temporal lobe to cortex.

Nicholas Weiler:

These biomarker studies that we now have, whether through imaging or through plasma, are these helping to explain differences in cognitive performance as well? I think you were saying that the tau does a bit more than the amyloid. In your research, I know you've been looking at amyloid PET and risk for developing Alzheimer's disease, but does it also show differences in where people are within those classifications like if someone has some more memory problems or is starting to slow down?

Beth Mormino:

So the way that we design our studies is what Anthony was mentioning in the beginning of the study, it was a cross-sectional look at the data, and now we're starting to look over time. So, yeah, so I think what you're asking is within this healthy range, there is variability even though everybody's clinically normal. Do these markers explain that variability? Interestingly, we have measured AD probably five different ways now because we have PET scans. We also do cerebral spinal fluid. We have these now these emerging plasma measures. So, we have many measures of this one pathway, and we do see associations. If you have more of these proteins, you tend to be on the lower side within that normal range.

But the total variability explained by these pathways, even though we have these very good measures, is minimal. That will probably change when we look at the data over time. So, when we look at change over time, we are seeing larger effects of these proteins. But again, the percent of variability explained by these protein signatures of Alzheimer's disease, it's at most about 10% longitudinally. So, I think it's telling us two things. One, it's telling us, yeah, it's important to measure these biological pathways associated with Alzheimer's disease, but it's also reminding us that we're missing a lot of the explainable variability that we actually aren't really doing our jobs and unpacking what's really driving this tremendous variability within our aging cohort.

Anthony Wagner:

If I could maybe build on that, Nick?

Nicholas Weiler:

Yeah, please go ahead.

Anthony Wagner:

So that was really great and complementing what Beth just noted, the exciting thing and the powerful thing about studies like SAMS where you are following people now over significant periods of time and with many behavioral, imaging, and other biological measures from each individual is you can start to weigh in and ask some of these questions and maybe perhaps reveal new predictors of perhaps resilience or decline. Beth already alluded to this. We're seeing when we're looking at the SAMS participants who've already come back after their seven to eight-year period is some of them, their cognition, their memory isn't changing at all over that seven to eight-year period. They're remaining as best as we can tell, cognitively healthy, neurobiologically healthy.

Others are showing some decline. So, we now have this opportunity to try to understand what are some of these predictors. As you just discussed with Beth and Beth emphasized, these amyloid and tau protein measures are predictive of some of the change over time. There's a new paper out just this week from our collaborators, Hamilton Oh, Tony Wyss-Coray, and others, where they're looking at the CSF data from our SAMS participants as well as from participants in other large aging samples.

Nicholas Weiler:

So that's like cerebral spinal fluid from a spinal tap or something?

Anthony Wagner:

Exactly, exactly right. They're also looking at the blood plasma, and what they reveal is that while there's some change in cognitive function that's explained by the presence of amyloid and tau, some portion of that change over seven to 10-year period depending upon which sample the data are coming from. A significant portion of additional independent change is coming from other proteins related to synaptic functional integrity.

Nicholas Weiler:

Interesting.

Anthony Wagner:

A synaptic function that are explaining independent change or resilience over that seven to 10, 12-year period, as well as if you use imaging methods to look at brain aging, change in terms of brain aging scores and things along those lines. So, it's studies like that are harnessing these different measures we have from individuals that allows us to both test leading hypotheses like what is happening with respect to amyloid and tau, but what are some of the other unknown biological variables that might be riding together, maybe conferring some resilience we don't know yet, but some resilience to the emergence of amyloid and tau because of these other pathways, these other mechanisms?

Of course, as Beth noted, there's a modest percentage of that change that's explained by amyloid or tau. We're very much interested in identifying what are some of the other factors as well in terms of other systems, structural change within the brain, functional change within core systems of memory that may be occurring independent of and it's sometimes undoubtedly interacting with these AD pathways. So, it is an exciting time because there's more and more of these samples. There's not a lot of them, but samples like the SAMS project where we have so much data from individuals.

Our SAMS participants are so generous in how much time they're dedicating to participate in the study, spending four days with us during the initial visit, coming back, spending four more days with us, allowing us to collect a tremendous amount of different kinds of measures from them. It's these kinds of projects that are actually enabling this testing of existing hypotheses but also doing discovery science.

Nicholas Weiler:

I mean it's just such a remarkable finding. You can tell me if there were hints of this earlier, but there's been such a focus on particularly amyloid and tau as well. I mean the biology there seems fairly clear that those are involved. There are other things like inflammation and microglia and vasculature and all these other contributors to the disease. But if you go in and look at the amyloid and tau and say, "Well, yeah, that affects how people's cognitive function develops as they age," but less than 10% of the difference in someone's cognitive function is determined by the level of amyloid and tau in their brains.

As you've been saying, this leaves open the question of, well, what's the other 90% of contributing factors to whether someone stays cognitively healthy or goes into this decline that I'm sure many of our listeners have seen in their loved ones as they get older? Anthony, I'd love to stick with this for a minute. What are we starting to learn about some of the variable biology of aging and resilience? I mean, what are some of the things that affect some of these other cognitive functions that allow us to maintain our independence into old age?

Anthony Wagner:

That's a great question, Nick. Let me maybe highlight first a few points or principles that we've discovered in recent years or past few decades. One, if I look at the field of cognitive aging and age-related change in memory, I would say that our sense of how much change was occurring, independent of now disease processes, how much change that was occurring, we probably overestimated it. A few decades ago, we realized time of day, when we're assessing somebody's memory, behavior really matters. Our memory function isn't static.

I alluded to these moment-to-moment fluctuations and we're studying how small fluctuations in our attentional state and arousal over the course of even just seconds to tens of seconds to more sustained periods of time over the course of a day impact how well we're learning or how well we're remembering it that particular moment. But we also know that there are these larger time of day effects.

We discovered this a couple of decades ago that for quite a period of time we would often bring in our participants and assess their cognition. At times, that worked particularly well for the research team who are younger adults and later afternoon and evening often would be particularly good times. It turns out those are peak times of day for performance for younger adults on average.

Nicholas Weiler:

Interesting.

Anthony Wagner:

Older adults, their peak cognition, it's earlier in the day, early mid-morning. If you actually measure cognition in older adults and in younger adults, aligning those measurements to the peak time of day for the two groups, a significant percentage of what we thought was age-related decline in true cognitive ability actually goes away.

Nicholas Weiler:

Oh, interesting. This made me think it's so important when we read headlines about such and such leads to cognitive decline or by the time you're this age, your cognition is going to decline so much, these are the questions that we should be asking ourselves as consumers of science, which is I wonder when they measured that cognition. Is that representing what they're capable of or is that an artifact of how the study was conducted? Is it really measuring something slightly different? So it was just one of those things where science grows over time through this basic research to understand, oh, we need to be doing this in the morning, not in the afternoon.

Anthony Wagner:

Absolutely. That gets to another fundamental and maybe a critical point for our listeners to appreciate, which is we live in a culture, we understand what tends to happen to humans through time. One thing that we have associated with aging is cognitive decline. As we've discussed, many older adults do not show cognitive decline. That stereotype and with respect to at least particular diseases like Alzheimer's disease, one cognitive decline is memory decline. It creates a lot of potential psychological processes for an individual that can lead to underperformance for that individual, not because they actually have a true decline, but because they're worried about this stereotype about being an older adult.

Maybe my memory might be changing. If my memory changes, maybe it's a marker of, oh, maybe I'm in this early stage of slipping in towards Alzheimer's disease. That induces that psychological threat. So, what my colleague Claude Steele has described as a stereotype threat, that threat induces an anxiety response that we know actually degrades performance and can actually lead to underperformance. There's one study out there that you bring older adults in and you give them a standard cognitive task that's used on the front end in clinical assessment to see if there's in fact some cognitive decline. You prime that age-related stereotype that cognition might decline with age versus you don't prime it.

A significant percentage more of older adults underperform on that task leading to scores that might have you a little bit clinically worried about how well they're doing relative to if the stereotype isn't primed. So, this makes this just higher level point, which is what you want is a readout of what is your true capability, your true function, and that it's hard to get from a single measure. You can't really have confidence that you know what your ability is. You might underperform because you didn't sleep well that night. You might be stressed because you're worried about your performance and that could then create further worry that you might be showing cognitive change. It's a challenge for the field. It's a challenge for individuals when they think about they're trying to think about their own cognition.

Nicholas Weiler:

I remember I think you've told me that some of these results that Beth was telling us about with being able to see using PET imaging, that some people actually have subclinical levels of or maybe preclinical levels of amyloid and tau in their brains might say that, well, there are people who we've thought were "healthy aging" and their performance is actually lower because they have preclinical Alzheimer's. It was not clinically diagnosed, but they've got amyloid, they've got tau in their brains. So, that also might be lowering the expectation for the average person as they age. Is there anything else that you'd want to say about that? I thought that was a really interesting point.

Anthony Wagner:

So I will, and this builds on Beth's earlier comment about how much variance is explained by these variables. So, it's clear that it's really likely when we're trying to look at what happens with age in individuals who are as best as we can tell, cognitively unimpaired, we are enrolling these older adults who are cognitively unimpaired largely by assaying their cognition, their cognitive behavior. But as Beth noted, maybe 25% of them have elevated amyloid levels.

A subset of those individuals have elevated tau. In the SAMS study, in the literature, some of the differences between healthy older adults or putatively healthy, older adults relative to younger adults in terms of memory performance is likely due to those older adults who happen to be at this early stage perhaps of Alzheimer's disease. It's a small amount as Beth noted, and this is an important point, it's a small amount of that variance, right? Because these are cross-sectional studies rather than longitudinal studies.

But I do suspect the next direction, this is the direction we're taking in our work, is if you believe you're trying to understand cognitive and neural changes in individuals who you believe are not in the earliest stages of Alzheimer's disease, the strategy is going to be a combination of behavioral assay as well as probably blood plasma assay so that you can bring in individuals who appear to be cognitively healthy and who as best from these blood plasma measures appear to have low burdens in amyloid and tau.

Beth Mormino:

I want to make one comment on this too-

Nicholas Weiler:

Sure, please.

Beth Mormino:

... in terms of expectations for aging and what we're learning from SAMS about decline in general. So, I think what we've clearly learned is that it is certainly possible to remain cognitively stable and actually after a decent follow-up time too. But one, I think, criticism of our work is that we've really designed these studies to really get at very healthy aging. What I mean by that is our cohorts are not representative. When we enroll our participants, if they have significant comorbidities, medical conditions, they're excluded. If they have implants in their body that preclude MRI scanning, they're excluded. If they have complaints about their cognition, they're excluded. The reason we do this is because we're trying to get at healthy optimal aging.

It's interesting, even with this very healthy sample, we still find evidence of early Alzheimer's, et cetera. We have our participants come for four visits to Stanford. They are just very committed and I think represents another sign of how healthy they are, the ability to do three imaging sessions and a lumbar puncture and blood draws. So, we have to be a little cautious in interpreting these results as this is what happens to everybody in the world as they age, because it could be possible that if we actually really did a random sample of 70-year-olds, we may or may not see more decline. I would suspect that we would.

Nicholas Weiler:

Right. I mean, how many of us get to go through our 70s, 80s, 90s without major surgery or some other life event that is going to add a lot of stress or cause some other insult that would probably preclude someone from being in your study. Not that those specific things are necessarily your determining factors. It reminds me a little bit of we have a story that should have come out by the time this airs, which we'll link to in the show notes about your colleague Martin Angst doing this long-term study of people post-surgery, supported by the Knight Initiative to see well, we know that after a major surgery, a lot of older adults do go into a decline following that surgery for one reason or another.

So, trying to follow people long-term and say, what are the factors again that determine whether someone is resilient to that stress or succumbs to whatever is going on that can be the trigger that leads to the decline? It reminded me, there's also this thing that I think a lot of people probably notice in their friends and family members that aging is not a linear process. It's not like we age the same amount every year. The Snyder Lab came out with a paper last year talking about aging spurts that got a lot of attention, and there's something going on biologically that we age in jumps. I'm sure everyone knows someone in their family and that you can see, maybe you don't see them for a year and you come back and you see, "Oh, wow, they've really aged."

Do we know anything about the biology of why someone might suddenly change their cognitive performance over the matter of a few years?

Beth Mormino:

So for neurodegenerative diseases, when that process is actually initiated, even though there's potentially a long asymptomatic phase and then maybe some subtle changes that are very difficult to dissociate from healthy changes, that's linking back to Anthony's conversation about the difficulties with measuring true performance. So, there's clearly this overlapping phase, but when somebody is actually progressing on this dementia cascade, there is going to be what might seem like out of nowhere a sharp rapid decline. I mean, that's the characteristic feature behaviorally of somebody as they're entering that AD dementia phase. We also know that that follows from what we know about the tau pathology as well.

So, I mentioned earlier that it's very uncommon to see distributed tau tangles throughout the brain in healthy older folks. If we see some tau signal with PET, it's usually quite focal within the medial temporal lobe. What we know from these longitudinal studies is that it does seem like there potentially is some trigger or spurt event where this pathology leaves the medial temporal lobe and spreads throughout the brain, and that trigger seems to be quite important for the actual clinical expression of Alzheimer's disease.

So, I think that is potentially one example of a process that might be a little bit linear, but then an event happens and then that person truly experiences decline that leaves this range of ambiguity and difficulty in terms of measurement.

Nicholas Weiler:

Well, to close us out, I'd love to go back to this idea of how do we live the dream of resilient aging? How can we all live like the Harry Tu who we talked about at the top of the episode? Are there any patterns that you're observing in the resilient aging cohort in the Stanford Aging and Memory Study or in the literature more broadly that can teach us something about the factors that are in our control or that we might be able to intervene and improve our chances of living independently into our 90s?

Anthony Wagner:

So there's constant discoveries happening, right? There's a paper out just this week about unexpected benefits of vaccines for shingles, and as we continue to accumulate more and more data from individuals and we follow larger and larger groups of individuals over time, I suspect there there'll be more and more discovery. We, of course, know many of the things or some of the things that matter in terms of remaining socially engaged, remaining cardiovascularly fit, remaining cognitively engaged, have a healthy diet, et cetera. That seemed to have some modest protective benefits and might increase the probability of you remaining resilient and having a very long neurocognitive health span. That's what we want.

We want to stretch health span to align with lifespan so that this spurt of maybe rapid decline that occurs may occur only at the very end of life and that we're healthy up until that particular moment. We're also discovering, and I can't say that I have anything specific to comment on here, but I did want to weigh in. There's other discovery science that's occurring over these same kinds of measures that we're collecting in SAMS, including these CSF and plasma measures where we're not only able to track these proteins related to, say, Alzheimer's disease or now with this new paper, potential resilience over a 7 to 10-year period.

You can also identify proteins that are differentially associated with aging of different organs, not just the brain, but other proteins that are associated with aging of other organs. So, organs aren't all aging at the same rate and the brain is not immune to what's happening in the rest of the body. As we go through time, we may actually find out that there's interactions and some of these spurts or changes in brain age might be coming about through interactions with aging and age-related processes or disease related processes in other systems. So, there are things that we think if you were going to give guidance to somebody, to a loved one, to a friend, stay neurovascularly fit, remain engaged socially, cognitively, have a good, healthy diet, et cetera.

But there's a lot of things that we just don't know. I'll turn to Beth on this in just a moment, but I want to take this moment to not only express my appreciation for the support we've received from the National Institute on Aging that's enabled SAMS and related studies, as well as the Wu Tsai Neurosciences Institute, but also the tremendous generosity of our participants in SAMS and the other aging studies that we're conducting. Because it's through this support both federally, privately, as well as from our participants that we're able to actually engage in this discovery science with the hope that we ultimately will have even more deliverables, more things we can say in response to this question about how can we stretch our health span to the latest periods of our lives.

Nicholas Weiler:

That's such an important point, Anthony. We need to stay curious and keep investing in understanding the fundamentals if we ever want to use these insights to improve human health and well-being. Beth, was there anything that you wanted to add to that?

Beth Mormino:

Yeah, I guess I would just add, I mean, I agree with everything, Anthony, you just listed and the importance of emphasizing the lifestyle choices we have. Anything that's good for the heart is good for the brain, it's good for all your organs. It also seems there's evidence that even strength training and things like this at older ages could be very beneficial. So, I think we have a better understanding of these exercise-related mechanisms too. But I think unfortunately, we actually don't know what the profiles and the factors are that predict this resilience, and it probably is quite heterogeneous.

Based on somebody's genetics and interactions with the environment and their lifestyle, it probably is quite complex. So, in a sense, I mean, I do think these longitudinal studies are so critical to continue and the deep phenotyping approaches, that's the only way we're going to have concrete answers to these questions is to continue doing this work.

Nicholas Weiler:

Right. There may not be one secret sauce or fountain of youth, but remembering that it is possible, right? Humans can live into their 90s and past 100 with their cognitive function intact, and in fact, probably more people do than we recognize either in the scientific literature or in our lives. Maybe we can all get there.

Beth Mormino:

Yeah, it's a reverse engineer problem that we have. So, definitely, we find the examples quite easily, so we know it's possible.

Anthony Wagner:

What's great is it really feels like we're on the cusp of real breakthroughs. The rate of discovery over the last 10, 15 years and the new methods we have, it really feels like we're on the cusp of figuring out some of the other critical processes that are going to essentially enable us to be resilient.

Nicholas Weiler:

Fantastic. Well, that's a perfect place to end. Thank you both so much for coming on the show and telling us about the cusp of discovery.

Beth Mormino:

Thanks, Nick. That was fun.

Anthony Wagner:

Yeah, thanks, Nick.

Nicholas Weiler:

Thanks again so much to our guests, Beth Mormino and Anthony Wagner. Beth is an associate professor of neurology and neurological sciences here at Stanford, and Anthony is a professor in the Department of Psychology and one of the deputy directors of the Wu Tsai Neurosciences Institute. You can read more about their work in the show notes. If you're enjoying the show, please subscribe and share with your friends. That's how we grow as a show and bring more listeners to the frontiers of neuroscience.

We'd also love to hear from you. Send us a note at neuronspodcast@stanford.edu with your thoughts on the show, suggestions for research topics, or just generally to say hello. From Our Neurons to Yours is produced by Michael Osborne at 14th Street Studios with sound design by Morgan Honaker. I'm Nicholas Weiler. Until next time.