Watch the replay of the event held on May 6, 2021. (Transcript below.)

We all want to enjoy a satisfying old age. Happily, research is providing us with some pointers, ranging from understanding how to maintain psychological and physical health to insights into molecular changes in the aging brain and how they might be reversed.

Join Annual Reviews and Knowable Magazine for a discussion with three important contributors to different aspects of the topic at the 2021 Zare Science Forum: The Keys to Successful Aging.

The Zare Science Forum is an annual event designed to illustrate how progress in science impacts on a crucial societal issue.

The event will take the form of three one-to-one conversations, covering practical aspects of successful aging; a framework that explains how we adapt to aging and the conditions under which we don’t; and an exploration of new treatments that hold the promise of reversing age-related cognitive impairments. The unique circumstances of the Covid-19 pandemic will form a backdrop to the discussion.


Photo of Daniel Levitan

Daniel Levitin is a neuroscientist, cognitive psychologist, and bestselling author of many books, including Successful Aging. He is Founding Dean of Arts & Humanities at the Minerva Schools at Keck Graduate Institute in San Francisco, and Professor Emeritus of Psychology and Neuroscience at McGill University. He coauthored The Psychology of Music: Rhythm and Movement for the Annual Review of Psychology in 2018. 

Photo of Susan Turk Charles

Susan Turk Charles studies emotional processes across the adult life span at UC Irvine’s School of Social Ecology where she is Professor of Psychological Science and Nursing Science. Susan explores how subjective experience varies throughout life, and relates these differences to changes in cognitive processes. Susan coauthored Social and Emotional Aging for the Annual Review of Psychology in 2010.

Photo of Saul Villeda

Saul Villeda’s research interest is regenerative and cognitive impairments in the aging brain, and how these effects can be reversed. He is Assistant Professor of Anatomy at UCSF’s School of Medicine. Saul’s goal is to identify cellular and molecular mechanisms that promote brain rejuvenation. He coauthored Mechanisms of Hippocampal Aging and the Potential for Rejuvenation for the Annual Review of Neuroscience in 2017.


Richard Gallagher headshot

Richard Gallagher, President and Editor-in-Chief, Annual Reviews

Richard Gallagher has served as Senior Editor of Science, Chief Biology Editor of Nature and Editor-in-Chief of The Scientist. He has a PhD in cell biology, and spent 10 years in research, five as Wellcome Trust Lecturer in Immunology at Trinity College, University of Dublin, Ireland, working on the immunopathology of celiac disease.


The annual Zare Science Forum is named in honor of Professor Richard N. Zare, a distinguished chemist and former Chair of the Directors of Annual Reviews.

This event is also part of Reset: The Science of Crisis & Recovery, an ongoing series of live events and science journalism exploring how the world is navigating the coronavirus pandemic, its consequences and the way forward. Reset is supported by a grant from the Alfred P. Sloan Foundation. 

Knowable Magazine is a product of Annual Reviews, a nonprofit publisher dedicated to synthesizing and integrating knowledge for the progress of science and the benefit of society. Major funding for Knowable comes from the Gordon and Betty Moore Foundation.


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Richard Gallagher: Hello, everyone, and a very warm welcome to this event on Keys to Successful Aging. I’m Richard Gallagher from Annual Reviews. This is the annual Zare Science Forum co-sponsored by Knowable Magazine. The event is named in honor of Professor Richard Zare of Stanford University.

Dick is a distinguished researcher in physical and analytical chemistry. He’s an acclaimed teacher and mentor, a renowned science administrator, and an all-around good guy. He was chairperson of the board of directors of Annual Reviews for 23 years, and he continues to serve as a board member to this day. Thank you, Dick, and thank you to all of our wonderful board members.

Before I introduce the talent, a word about format today. This is a series of three short interviews that explore different aspects of successful aging. Person A interviews Person B. B interviews C. C interviews A. We’ve set aside time for questions at the end, and you’re welcome to submit these throughout and to use the chat function to talk to one another during the event.

Before I introduce the discussants, I see that the word cognition comes up each time. Cognition simply refers to intellectual activities such as thinking, reasoning or remembering. Cognitive impairment is a reduction in these functions.

Daniel Levitin is a neuroscientist and cognitive psychologist. He has written bestselling books, including one titled “Successful Aging.” Dan is the founding dean of arts and humanities at the Minerva Schools at Keck Graduate Institute in San Francisco. He’s also professor emeritus of psychology and neuroscience at McGill University in Montreal.

Susan Turk Charles studies emotional processes across the adult life span at the University of California Irvine School of Social Ecology, where she is professor of psychological science and nursing science. Susan explores how subjective experience varies throughout life. She relates these differences to changes in cognitive processes.

Saul Villeda’s research interest is in impairment of regeneration and cognition in the aging brain, and how this impairment can be reversed. He is assistant professor of anatomy at the University of California San Francisco School of Medicine. Saul’s goal is to identify cells and molecules that can promote rejuvenation of the aging brain.

I hope like me, you’re really looking forward to these discussions. The first pairing is Saul interviewing Dan. So take it away, Saul.

Saul Villeda: Thank you so much, Richard, for that introduction. Really looking forward to this conversation. Hi, Dan, good to see you again.

Daniel Levitin: Nice to see you, Saul.

Saul Villeda: Yeah. I’m excited. I’m very excited to ask these questions, and have a little chat with you about some of them. Let’s go ahead and start. We all tend to think that older age is this time of decline and decay. But you’ve argued that that isn’t necessarily true. I’m really interested in what exactly is your view.

Daniel Levitin: Well, I think it’s not just my view. It’s a view from science. I think that we’re dealing culturally with an outdated narrative. Yes, old age used to be a time of decline. But we’re living longer. We’re living healthier. We’ve eradicated most diseases that used to kill us before the age of 5, let alone before the age of 30.

Back in 1905, life expectancy was shorter, and life was harder. I think the new reality based on neuroscience, psychology, gerontology is that 80 really is the new 60. Now, it’s true, we do see some gradual slowing with every decade after 40; thought processes slowed down. There are neural structural changes, as you know, that cause things not to work quite as well as they used to.

But to say the old age is a time of decline, or irrelevance, I think is unfair and untrue to the science. Memory doesn’t necessarily have to go. I mean, in most of us, we can retain robust memories into our 80s and 90s, and other cognitive functions. I think the key point here, Saul, is that there are things we can do at any age to tilt the balance, to give us a fighting chance against the natural physiological processes of aging.

Saul Villeda: You bring up a really important point, which is you said in 1905 versus now, our life span is different. This idea of mortality, of course, is different. At least, for me, I often think about that decline and that decay. I think I have it associated a little bit with mortality, probably from my own perspective.

Why do you think so many of us hold this view of decay and decline that isn’t necessarily now true in the context of modern medicine, and how old we’re living now?

Daniel Levitin: Well, we hold a lot of views that are not true in terms of modern science and medicine. It adds a systemic problem. Particularly in the last few years, the increasing number of people say they don’t know who to trust, and you can’t trust the experts, because they keep changing their minds.

But I think without getting into the sociopolitical part of false beliefs, I think it’s ... (laughter)

Saul Villeda: (Laughter) We can go there a little bit.

Daniel Levitin: Well, you’re better to talk about this than I. But I think the situation is that increasingly people don’t trust science and scientists, because from their perspective, we change our minds all the time. First, they tell us to eat beef, and then they tell us not to, and then fat is good, and then fat’s not good.

The reality is the average person doesn’t know that science is an iterative and self-correcting process. We take in new evidence as it becomes available, and we adjust our views and so the story changes. Doesn’t mean we don’t know what we’re talking about. We’re basing it on the available evidence.

But I think the crux of the matter is that we’ve got these outdated societal narratives from the media, from cartoons and in any sitcom that you were to watch. The old person is usually the brunt of the joke, right? We’re now at a time of reckoning in our society where we’re facing head-on a lot of the “isms” that come from prejudice and bias, racism, genderism — and really, ageism is still with us. It’s not something that’s talked about.

But we make jokes about old people. They’re the doddering old ones that cause a laugh. That’s something that we can change.

Saul Villeda: I love how you said it’s science and what we do is self-corrective. I think that that’s a wonderful way of thinking about things. I think I’ve gotten a lot of questions over Covid and vaccinations and people, you know ... As the data comes in, we’re adjusting our hypothesis and our expectation all the time. I think this idea of aging and even aging research is often so linked, I think, to the diseases that we think of as age.

I think a lot of us maybe think one is the other. I’m wondering if you think that plays a role in this myth that we have, like you said, of that cartoon, the older person that’s the joke of it, or why do you think that failing memory that we think is such a myth, I guess.

Daniel Levitin: Yeah. It’s interesting. You’re talking about updating hypotheses and gathering data. I was just talking to your colleague, Jay Levy, recently at UCSF who discovered the HIV virus. This whole business with the coronavirus has been one of updating our understanding, and we still are.

Saul Villeda: Absolutely. Yeah.

Daniel Levitin: It’s often a long process. I think that we do confound, there are many people who think of aging as a disease and that it’s curable. Others think of it as a natural process, and maybe it isn’t curable, but some of the symptomatology, some of the side effects that we see of aging, like weak bones, or loss of a sense of balance, slowing, maybe those things are correctable.

That’s all on the horizon. I think it’s important to acknowledge that we haven’t had the opportunity to study aging until recently, because people didn’t live long enough.

Saul Villeda: Yeah.

Daniel Levitin: It also wasn’t considered a priority. Why should we as a society spend money studying 80-to-100-year-olds? How many people is that going to help — the reasoning might go with the granting agency — as opposed to studying younger people?

Saul Villeda: No. That’s a really great point. Something I’ve been thinking a lot lately is just in the news. You get all this news from census and everything, and birth rates are down in the United States. They’ve been down for long time in Japan, for example. And we know this elderly population is coming. I think for a lot of people, it’s this scary idea.

I love that from the perspective that you’re coming from, it’s not necessarily as scary a concept as we might think. I think people think, oh, my goodness, there’s going to be this huge population and it’s just decay like we said. Learning more about a different perspective coming into it, I think that there are a lot of good things that we may not be looking into that comes with that old age that comes with it.

Now, one of the things I found really surprising, in learning more and going through what you’ve written, is the contribution or the role that personality factors play in how we age. I’m a biologist so I’m reductionist. I think of things as controlled, and almost try and take away certain aspects such as personality from the equation. That seems to be not the case. I just want to know if you can elaborate a little bit on the role that that plays.

Daniel Levitin: Well, I consider myself a reductionist, too. I mean, the fundamental tenet of neuroscience as I practice it and understand it is that all of our thoughts and hopes and desires, feelings and experiences are ultimately the products of a biological set of functions in the brain, that they have a physical basis. We call it materialism, that the material of the brain gives rise to all of this.

Personality may seem like this squishy thing. Some people are more generous than others, some are more outgoing. But these have a genetic basis, a biological basis, and basis in experience. The idea that genetics and brain development and environment interact is profound and now, I think, widely accepted.

And so I think the key argument that I’ve been trying to make for the last few years is that, yes, genetics will provide a kind of predisposition towards being a certain way. I mean, in your body, genetics can provide a predisposition towards being able to beat cancer or propensity to get it, or heart disease, as well as personality factors like conscientiousness and curiosity and resilience.

But in many cases, those personality factors, which have a genetic origin, the genes control as little as 7 percent of the variability and rarely more than 50 percent of the variability in outcomes. Meaning there’s a lot of wiggle room there for us to try and modify our lifestyles, to give us a fighting chance to do better.

Saul Villeda: Building on that a little bit, just with, I think, Covid, with vaccine rollouts, with just looking at how a pandemic affects an entire society. It reminds me that not all aspects of society are treated equally or impacted equally. There’s different cultures, for example, socioeconomic factors now that become almost a part of our culture in the American system.

For example, we have the educated, we have people that are well-off, we have people that are poor, people that are less educated. I’m wondering how you think of that, where you place those both cultural and that affects also personality responses in the context of aging. Is it something that you think, it’s a little bit different depending on where you’re from, is it one personality factor that really is the most important? Where do you see this?

Daniel Levitin: Well, you raise a lot of really crucial issues here. I’ll just try to tackle two of them. There is a single personality factor that has a genetic basis that more than anything else predicts how well we’re going to do at any phase of life — how happy we’ll be, how healthy we’ll be, how long we’ll live. That single factor is conscientiousness, which refers to a cluster of traits, such as stick-to-it-iveness, and reliability and dependability, following rules.

Conscientious kids don’t get hit by a bus because they don’t cross against the light.  Conscientious adults don’t end up in prison, which is bad for your health. I mean, there are mistakes made in some cases. But I’m talking statistically here. Yeah. I mean, you can get hit by a bus when you have the light. But I’m setting that aside.

Too much conscientiousness isn’t good either. It can lead to obsessive compulsive disorders. But there’s a kind of Aristotelian golden mean here, where the ideal amount of conscientiousness contributes to a happy, long and productive life. But, as you point out, conscientiousness and other traits are unevenly distributed throughout the population.

And due to socioeconomic conditions, not everyone in the population has equal access to being able to change themselves or act conscientiously. The biggest disparity is in health care in our country, where whether you’re conscientious or not, if you’re rich, you can afford better care than if you’re poor. The most conscientious poor person has difficulty accessing quality medical care.

We can talk all we want about this lofty ideal of, “Oh, yeah. I’m going to go out and become more conscientious. ” Tragically, that applies to a relatively thin slice of us in the world. I know people here in the US who are working two and three jobs. They’re overweight. They don’t have time to exercise. They don’t have time to eat well. They’re on the road. They’re traveling. They’ve got to get fast food. They’re trying to raise two kids as a single parent. This stuff, I mean, this is hard to pull yourself out of that and say, “Oh, yeah. I’m going to get healthy now. I’m going to lose some weight” with all this other stuff going on. I’m just using that as one example.

Saul Villeda: No. That’s a really, really good point. I think I had one more question to ask, but I think we might be out of time. I’ll come back to it, though, during the Q&A, if that’s OK. I know we have it. First in line for me.

Daniel Levitin: Well, thank you. Susan, I’ve been so looking forward to talking to you. You and I work in different areas and overlapping areas. I’m interested to learn more about your research and your views on this. To begin with, are there any life domains that get better as we age?

Susan Charles: Yes, and I’m happy to talk about this in addition to what you mentioned about remaining vibrant and cognitively active and engaged. I study two domains where we find age-related stability and often improvement across adulthood. That first domain is in the area of our social relationships. So those arguments, the contention that people often have in their daily lives, that decreases with age. People often report greater satisfaction with their relationships over time. We see continual improvement in the emotional meaningfulness and the satisfaction in relationships.

A second domain is our emotional experiences. Those emotions we experience on a daily basis. Older adults often report less distress than younger adults. They certainly have been during this time of the pandemic and in all the times before. We also see that older adults regulate their emotions as effectively and sometimes better than younger adults.

Daniel Levitin: So my image of the cantankerous old coot down the corner who’s yelling at people, that’s an anomaly, I suppose, because statistically people are regulating their emotions.

Susan Charles: Yes. Whenever I have a talk, I always get that hand raised in the back of the room says, “Let me tell you about my grandfather or my uncle.” I mean, there’s always that one person to dispel all the research that I’ve amassed across decades. And that’s where the personality context comes into play that you talk about.

There’s certain personality constellations that we’ve studied. For example, people who are high in neuroticism, that tendency to feel high levels of depression and anxiety, and to question your self-worth, that personality trait, we find a lot of these age-related improvements in our emotion regulation, or emotional experiences, we often don’t see these age-related benefits in people with certain personalities, such as those with high neuroticism. So not 100 percent of people get better with age, but the majority do.

Daniel Levitin: Getting back to this earlier thing that you said about how older adults experience less contentious relationships, and they experience better relationships. I’m now north of 60. I’m noticing that. I know what it is, I think, it’s helped me in that domain. But I’m wondering what the science says. Is it that older adults lose patience with so-called friends in their lives who make them miserable, and they weed them out? Or is it that older adults are more grateful and feeling more gratitude for the friends they do have? Or are there other factors?

Susan Charles: There’s quite a few factors. That’s a wonderful question. Some of the ones we’ve studied and found is that, as you grow older, that social networks get smaller. It’s not that they’re getting smaller as far as close friends and family members. But we see that older adults have fewer of those peripheral people that you don’t know very well.

We think that’s a proactive strategy on the part of older adults, even though they don’t really consciously realize they’re doing it all the time. But they are choosing to spend time with the people that mean the most to them, who are the closest to them. They prefer to spend time with their close friends to a higher degree than maybe younger people who like spending time with their close friends and family, don’t get me wrong, but also want to meet that person and that stranger. “Who is that person that we don’t know? Let’s get to know them.” Whereas older adults, if you ask them, “Would you like to interact with a stranger, or would you like to have coffee with your close friend?” They are more likely to say, “Yeah. I’d like to be with my close friend.” We know that interacting with those people that you love and feel closest to also helps your emotional wellbeing. Also... Go ahead.

Daniel Levitin: This goes by the name, if I’m not mistaken, this is called socioemotional selectivity theory.

Susan Charles: Yes, yes. Socioemotional selectivity theory that Laura Carstensen coined so many years ago that we’ve been studying. Also, older adults are more likely to ... when they’re having an argument with a friend or family member or even a stranger, they’re more likely to disengage from that argument. They will report that they do that and they’ll report that they’re fine doing that. They realize when something’s not going to be solved, or what’s the point of arguing, and they do this more quickly than younger adults.

Daniel Levitin: Just as a quick diversion, you and I were both at Stanford as undergrads, and later as postdocs, I think we overlapped. One of the things I remember about the Stanford psych department was how many older people were still working full-time, whether it was Al Bandura, or Ewart Thomas, many people who were beyond nominal retirement age.

I wonder if that influenced you, or what aspects of being in the department in those heady times influenced the course of your work?

Susan Charles: They were indeed some wonderful times, Al Hastorf and Al Bandura, and so many wonderful… Gordon Bower, who was close to retirement and continued decades after. Many academic departments around the country, you see people retiring very late in life. I think it has to do with just the joy of scientific discovery that you and Saul were talking about earlier that science is always new. It’s always unfolding. We’re always making these discoveries.

That’s one thing that I enjoyed so much about being there, and being among scientists is they want to know, “What is that answer?”       That joy of discovery, and it’s still is there and remains vibrant. You don’t want to stop that. At Stanford, there definitely was, I think, the desire to find what science is telling us, more so than the desire to be proven right, or the desire to hold fast old beliefs. It was the desire to see what’s coming next.

That’s what kept people so engaged, for so long.

Daniel Levitin: I was just thinking of my own experience at McGill, where Brenda Milner worked until … came into the MNI until she was 99. Peter Milner, who was in my department, well into his 90s, from Milner and Olds, the old pleasure centers studies in the ’50s. He was still going strong in 2010. It was great to see him and learn from him.

But moving back to the present, the pandemic has created persistent stress and trauma. I’ve come to believe that maybe the entire country, if not the world, are all suffering from some low-grade, chronic depression or traumatic stress. Course, older adults have been disproportionately affected by the physical effects of the disease, and by the isolation, particularly older adults who are in, well, in group-living situations or care homes of one kind or another.

What have you learned about the mental health effects? What do you predict will happen over the coming years?

Susan Charles: Yes, the pandemic, you’re absolutely right, has been devastating. The health effects have been disproportionately shouldered by older adults and with each decade of life that we see, the effects been so much worse. For mental health, actually the reverse is true. For each decade of life, the reports of the mental health wear and tear of not only having the health problems around, but the social distancing associated with that have been really borne on the shoulders of the younger adults.

We see rates of mental health and rates of distress, moderate and severe distress are greater for people of all ages. No one has escaped. But for people in their 20s, for example, it’s four times the rates of severe distress that we see among people who are over 60. People who are most distressed two months into the pandemic were those who had children under 18 at home.

These young families, these young adults have borne the mental health distress of not only Covid-19, but all of the economic and social fallouts of the pandemic. Also, those who live alone have been very socially isolated. But we also see that living alone is harder for younger adults than it is for older adults during this time.

Daniel Levitin: It’s going to be a problem for a while. The solution... Once we’re more or less back to normal, I think the psychological effects are going to play out for some time. But there’s something else I wanted to explore. I love this distinction that I just recently learned about between life span and health span. Can you walk us through that?

Susan Charles: Yes. That’s something that all of us know well, but I think the laypeople in our society are now focusing more and I’m thrilled to see this. Nowadays, science has told us that, at least in the United States, almost half of children born today will celebrate their 104th birthday. We see this in rich countries. It’s even greater in places like Japan, where it’s 107th birthday.

We see these incredible life spans ahead of us. Life span, which is the focus of how old we will live, has now given way to a lot of scientists and that’s why your book was so perfect to address this, which is health span. Let’s think of ways and study how to live this very long life span as healthy as we can. Health span are the number of very healthy years that we have.

Now, what is health in old age with a successful aging or healthy aging? We often define that as having high levels of cognitive functioning, our memory sharp, our problem-solving remains sharp, our thinking does, emotional wellbeing. Experiencing a lot of high levels of happiness and contentment and joy, and lower levels of anger and depression and anxiety.

Also physical functioning, that allows us to be healthy and not experience a lot of pain and be able to carry out the activities that make us happy and active and engaged.

Daniel Levitin: Well, if we’re all going to live to 107, and we’ve got children and grandchildren, and great-grandchildren, great-great-grandchildren, I’m going to need a bigger Thanksgiving table, that’s for sure.

Susan Charles: All right. So, Saul, I am now very excited to be talking to you because you are going to tell us about the molecules behind living to be older and older. Coming from the social science world, tell me what’s it about molecular biology that excited you and directed you to your current interest, and particularly studying aging?

Saul Villeda: Yeah. No. Thanks for that. I guess, I’m almost going to take off from where you ended, which is this idea of life span and health span. When I was just starting out as a graduate student, there were these amazing studies in animal organisms where they started manipulating individual genes. You could make these animals live longer.

It started first in things like worms and then in mice. But we started understanding that just tinkering with a molecule or with a protein or with a gene could somehow extend it. Now, when I was growing up, I was actually ... I never thought about doing research in aging. I loved development. I loved everything about the way that we come to be, how our personalities are formed, how our brain develops.

I thought it was just such an interesting approach, going from just a cell into a human. But I started to see a lot of parallels with aging, in terms of there’s some control to it. There’s some genetics to it. But it was a really weird field in that we were never really almost intended to live this long back in the day. …

Then what you said now that these children can look forward to 104. Where does the biology of aging fit into all this? If this is a new thing that we’re living so long, is there some sort of control? Is it something like development where there’s some exquisite interplay between cells and molecules that form your brain or your nose or your bone? Is that continuing on? Are those processes still happening, which is what’s maintaining function, which is what’s promoting cognition?

So I got into from this fascination of development, realizing there’s these parallels between regulation of life span and development. Now really thinking about, well, if we’re going to live 104 I want to be as sharp as possible. Can we leverage that idea behind development into old age? What can we do?

Susan Charles: I’m so glad you talked about that. That segues into my next question. Because we hear about how people can extend the life span of a worm twice as long and that’s amazing. But we want to have a cognitive ability to function a little higher than that worm. I’m walking the biology of aging. Tell us about cognitive integrity, maintaining that high level of cognitive functioning as long as we can.

Saul Villeda: Yeah. I mean, we’re all fascinated by the brain. That’s what we were asked to talk today. I have learned that the brain seems so almost unique compared to some of the other tissues or organs in our body in that even when we’re looking at just animal models, even if you look at a two-and-a-half-year-old mouse, which is the equivalent of someone close to their 90s, past their 90s.

We have this huge spread in terms of ability to learn and remember. We have a portion of those animals that will just act as if they’re still 25. I mean, they just naturally are aging, and their function stays sharp. Then we have a proportion of those animals that do show some decline. If you look over time, it may be because they had an injury, or there may be other problems with them or disease that caused that.

But when I look at that proportion of those animals that are just as sharp as before, that tells me that there’s a lot of plasticity still in the old brain, that there’s a lot of resilience. It brings me back to this idea of development. Something is happening in the brain, regardless of how old that brain is, that can still keep those connections, that can still maintain itself sharp.

What we’re learning now, there’s this new concept of the biology of aging — not disease, but really just this process of getting older. We’re focusing now more on this idea of health span. People are starting to think that the way your molecules and your cells are changing, the way the cells interact with each other, the way the organs interact with each other promotes some of what we think the aging phenotypes are. Let’s say gray hair or wrinkles that we’re all going to see.

That’s a combination of a lot of different mechanisms at play. But somehow there are aspects of the brain that are able to counteract that. Right now, that’s a big, big interest in the field is understanding the health span of the brain, because it seems like the brain ages almost a little bit different than some of the other things. Like I said, you get gray hair, and your hair stem cells are weakening, you get gray hair, you lose your hair, same thing, elasticity in your skin.

But somehow, something about the brain itself seems very unique and special. We’re trying to figure out what is it? Is it molecules? Is it the way that your cells are communicating? Are they getting signals from the rest of the body that are telling your brain, “Hey, promote cognitive function at all costs? ” We’re still learning about that. But I think there’s a lot to explore there.

Susan Charles: What do you think they are? I mean, what is it that might be able to help us maintain cognitive functioning or even reverse, if we start noticing decline? What on the molecular level or the cellular level is going on that you think will help us?

Saul Villeda: Yeah. It’s interesting. I teach a class to graduate students, to medical students, where we talk about the biology of aging. I start the class by saying, “What is aging?” People take pause with that question. “What is aging?” Then they’ll oftentimes say, “Well, I know it when I see it.” They’ll say, “Well, there’s gray hair, or there’s injury, or inflammation comes up a lot.”

Then I tell them, “OK. Well, why don’t we try and reduce this a little bit? Can you give me hallmark of aging? Maybe we were not sure about the whole aging process, but what about hallmarks of aging?” It took these biologists of aging researchers a long, long time to even define a series of hallmarks at a cellular level. We have them now.

Some of these are going to be buzzwords. Some things we think about are telomeres — the little caps of your chromosomes that shorten as you get older. We think telomeres might be important. We have things like stem cells. We think, “Oh, stem cells over time, they just get a little bit more quiet. They get quiescent.” Something like your gray hair, loss of hair. Maybe your stem cells on the top of your head just aren’t working as well. You’re going to get this balding.

There’s other things like senescence, which is basically when a cell just flattens out and just starts creating inflammatory molecules. Another hallmark we came up with was the way the cells communicate with each other; the best way to think about that is inflammation. Inflammation is your immune cells communicating to your whole body, especially things like infection or a virus. We need that immune system, but it is different as we get older.

We’re thinking collectively, all of these things, whether it be DNA damage, whether it be senescence, whether it be stem cells. We’re thinking about it holistically now in terms of, “OK. All of these changes promote aging in individual tissues.” Now, the idea now is, “Well, what if we can somehow block those changes or if we can maintain youth? What happens if we find a way of just activating your stem cells in your body?”

If we can maintain your stem cells going the whole time, will we no longer have gray hair? Will we not have wrinkles? Will we have much better improvement? Let’s say, when you’re running and maybe you have an injury to your muscle, will it just recover much, much faster? Will we be able to suppress inflammation? So that’s where the research is right now, trying to figure out which hallmarks of aging can we target?

If we can target enough of them, can we maintain a youthful state? Could we actually take an 80-year-old and it looks more like a 30-year-old? Is that actually possible? Not life span, but like you said, health span, can we keep things healthy or longer?

Susan Charles: Some of us are aging, closer to those times when dementia starts becoming a real thought. We only see it in about 5 percent of the population under 65. But as we know, in this law of doubling and 70-year-olds hitting 10 percent. It’s something that we think a lot about. When we think about studies like yours, we think, “How can it help us against things like dementia or neurodegenerative diseases such as dementia?”

Now, we know there’s been millions and hundreds of millions of dollars poured into develop therapies, and they haven’t always been successful. In fact, we don’t have a successful treatment for the declines that we are seeing. I’m wondering what your thoughts are about these targeting, this geroscience that you’re talking about, these mechanisms of aging? Maybe the Metformin, the interventions that we’re seeing in these trials. What do you think of those and how they might help us?

Saul Villeda: Yeah, it’s interesting, because there are now... I think it’s becoming more known. There are trials that are trying to ... some people say, “Extend life.” Some people are like, “OK, rejuvenation.” They get a lot of buzz. There was the red wine study. In red wine, there’s resveratrol, and what does that do now? There are these antifungal drugs like Metformin that are known to be really, really beneficial in, again, animal models, can they do something in humans?

There’s still this idea of dementia or disease like Alzheimer’s, and then there’s the idea of aging. Some people think, “Oh, it’s one thing. You age and eventually get the disease.” Some people think, “No, really, there’s a clear distinction between the disease and the aging process.” When we go to these conferences, these are still points of contention and discussion.

What I do know is that there is a link. As we get older, 80, 90, there is an increased prevalence of these diseases. We can’t untangle the two, I think. But the idea is our body, like you said before 55, if we look at 40, I mean, it’s a small fraction of the people that have dementia. That means that even with people that have genetic predispositions to them, they still don’t show those signs when they’re young.

The idea is something about youth, staying cognitively healthy, resilient, can counteract some of those effects. The idea is, “What can we do to maintain that as long as possible?” We’ve tried a lot of things. They’ve targeted A-beta for Alzheimer’s. They’ve done antibodies, and it just doesn’t seem to work. This new idea is, “Well, why don’t we just try and maintain youthfulness.”

A lot of it, I mean, there’s social things we can do. There’s the interventions like exercise. Some people think caloric restriction is also really beneficial. Other things that we can do that we know are targeting those hallmarks of aging. Can we just maintain function for as long as possible? As an alternative, let’s say, to finding that drug that takes away the plaques from your brain. That’s an idea.

I think some of these trials, like the ones on Metformin, the ones that are pursuing some of these molecules that have been identified. I think that’s what they’re trying to do. I think they’re trying to catch it before it starts and just maintain natural physiology. I think especially in any space where there’s no answers, why not try different things? Why not try a different atoms?   

For me personally, right now we’re studying exercise in my lab. Exercise is great. It’s been shown to be so beneficial even in patients. It’s conserved even when we look at it in little animals, like our mice or rats. It’s just beneficial. They have enhancements in cognition even when you’re young.

Now I was thinking about what Dan said. He said, “I know someone that works two jobs, and they overeat and they’re just stressed.” That’s just not going to be conducive to the healthiest of aging, to maintain that resilience at a cognitive level. What we’re trying to do is we’re trying to understand what is it about your body that’s changing when you’re exercising? What’s so good about it? Is it hormones? Is it things in your blood? Is it your muscle? Is it the way your neurons are firing?

We’re trying to distill it down to molecules. Once you get molecules, you can make therapeutics. You can make things that can actually be injected or ingested as well. Right now we’re trying to figure out, “Is there a way of distilling that benefit of something like exercise down to something that can be introduced?” That’s in our animal studies what we’ve done, which is we identified some blood factors that just go up, their liver factors that go up naturally when you exercise.

Then when you give it to an older animal, you can actually enhance, you can boost cognition, even in the context of some of these disease models. That’s what we’re pursuing — taking interventions that we know are beneficial, and trying to give that benefit to a group of people that won’t be able to do it, either because they’re frail, because lifestyle just ... their life just doesn’t allow it. But we know they can benefit from it.

That’s where we’re targeting health span. We’re trying to take known health span interventions, and be able to apply it to people that just will not be able to do the intervention themselves.

Susan Charles: My last question for you, since I know our time is running out for the two of us together, how soon do you think these interventions will become commonplace that I’ll be able to go to my doctor and get an intervention of what you’re doing in your lab?

Saul Villeda: It’s such a good question. My answer today will be different than my answer would have been last October. How fast we managed to come up with a vaccine to Covid that was based on brand-new technology around mRNA that completely blew scientists minds, because it normally takes years to get there. Yet somehow by putting resources, opening borders, facilitating communication, interaction, crosstalk, I mean, we just transformed that.

Then my feeling right now is if we just talk together a little bit more, so if we have the molecular biologists talking to the people that are actually talking to the geriatricians or psychologists. We understand more about what is the need? What do we mean by saying, “I want a drug that maintains X?”

I think from where I stand and I’m doing these preclinical studies in a mouse, I mean, I wasn’t even thinking about personality traits and factors the way that Dan is, because I’m looking at a little mouse that I don’t really attribute too much of that for. I now think within the next 10 years, I think it’s absolutely feasible to do something to improve cognition, at least to maybe slow down the onset of something like dementia and Alzheimer’s.

But I think that because of what I saw is possible through things like this mRNA vaccine. That’s changed my perspective on speed.

Susan Charles: Thank you.

Richard Gallagher: Great. Well, thanks very much all three of you for a fascinating discussion. We’ve had a number of questions. I’d like to get right into them. The first one is drawing on all of your research experience and all of your reading. Can you provide us with a hit list of do’s and don’ts? What are the keys to successful aging? What are you doing?

Let’s say, what should someone in late middle age be doing right now and not doing right now? What should someone who is already old? I don’t know what age, 70, let’s say. What should they be doing and what should they not be doing?

Susan Charles: I’ll go ahead and start. I think it’s wonderful to have that list. There are many I know that Saul and Daniel will have additions to this. But they’re the usual items that have become very well-known in the popular literature now. So sleep — we know sleep is related to our physical, our cognitive, our emotional regulation. We need our sleep and we need high-quality sleep.

We need to exercise. Exercise is vitally important to our cognition, also our emotional regulation and our physical health. And we need to eat a healthy diet. I just want to add two more then I’ll let others add things, or three more.

Social relationships, having strong social relationships predict who’s going to die, as well as knowing their cholesterol levels, or their smoking history. It is huge. Yet people don’t often include that on their list of health behaviors. But your friends are as important, as predictive, in our research as cholesterol levels.

Another one is the emotions that you have every single day that responds to work deadline or an argument with a friend, how much you react to that. We see that that predicts whether the incident of chronic condition and mental health disorders 10 years later. When you think about regulating your emotions, no, it’s the small things. These small bumps that every day cause wear and tear, and they accumulate over time.

But just one more and then... Learning novelty, novelty seeking to stimulate the hippocampus and get the mind going and your memory. So learning, being exposed to novel activities and learning these activities. In our research, we found that if you engage in varied activities, a lot of different activities every day, we find that that is related to your cognitive functioning and predictive 10 years later.

Richard Gallagher: Dan?

Daniel Levitin: … I agree with that, but I don’t think I would have said them as well. I’ll just drill down on a couple with respect to sleep. We’ve seen now many, many cases of Alzheimer’s that was misdiagnosed. It was just sleep deprivation, particularly among older adults, after a certain age, whatever that age is, it’s different for everybody.

But it becomes more difficult to get the sleep you need, because the suprachiasmatic nucleus, the part of the brain that’s regulating your sleep wake cycles, doesn’t function as well. Melatonin signaling is not as good. There are a number of reasons. Those are just two. Doesn’t mean you need less sleep.

One night of impaired sleep, particularly over the age of 60 or 70, can disrupt your memory function for a couple of weeks, because one of the primary functions of ... besides cellular housekeeping, cellular cleaning is to help encode memories. The other thing I just want to drill down on quickly is that, yes, exercise is important. But many of us find the notion of exercise off-putting or intimidating.

Really, based on what our colleague at UC Santa Barbara, Scott Grafton, writes in his book, “Physical Intelligence,” exercise is perhaps the imprisoned corollary of movement, just getting up off the couch and moving, and as Susan says, exploring, in general helps the hippocampus which improves memory. Exploring the environment is very important.

Even if you don’t exercise, just get out, walk around, especially in nature is good advice at any age. In wheelchairs, people who do this in wheelchairs show great benefits, too.

Saul Villeda: Maybe just to add one little thing as to the why. From our perspective and the molecular biology, we’re starting to understand the why. For example, sleep. Sleep is so big, even in the animal models. If you disrupt sleep, you decrease life span. In the brain, why is that? We’re finding out now that your blood brain barrier, what restricts the rest of your body from your brain, it actually opens up a little bit when you sleep.

It actually gets rid of some of the trash, some of the some of the protein aggregates that are in there are released into your blood when you sleep. We know that because we’ve been able to manipulate these things in animal models. That’s one of the main reasons. You’re clearing your brain at night.

Social isolation, we see the same thing in these little animal models. Why, when you socially isolate them, again, you shorten their life span. What ends up happening is you increase all these stress hormones that hyper-activate your immune system. It’s almost as if you were sick, but not because you did something, because you’re isolated. I think this social isolation, new novel environments, and things like sleep, we understand now why. We understand exactly what we’re impacting that’s causing the benefits. I think those are fantastic.

Richard Gallagher: Just a final quick question on this before we move on, Linda Rudnick asks about sufficient hydration. Obviously very important. She asks about water-only fasting and if you know whether that has any effect on brain health. I think at some other point someone asked about the positive and negative impacts of cannabis, if you want to comment on any other effect. You can avoid that if you’d like to.

Daniel Levitin: I’m happy to jump in on the fasting. I’ll leave the cannabis question to others. There’s mixed evidence on fasting. We’ve spoken in this hour about caloric restriction. It certainly works with C. elegans, the worm, it works with mice. But I was talking to a director at the NIH, in doing the research for my book, “Successful Aging.” He said, “The problem is that 95 percent of the stuff that works in mice, and really should work for humans just doesn’t work for humans.”

So we don’t know. It doesn’t seem to hurt. It doesn’t seem to matter how you do your intermittent fasting, whether you just skip dinner every day, or skip an entire meal once a week, or just go out on a water fast for a day a week or something like that. None of that seems to matter, yet, we don’t know. Science has entered it, we hope to know.

But the crucial thing here about hydration shouldn’t be lost. Hydration is a serious stressor on the body. Just drinking more water when you’re hydrated typically doesn’t help, because your cells aren’t ready to receive the water, which is why we have things like Gatorade and oral rehydration solutions that bring in the electrolytes and the salts that your body needs to actually use the water.

There are a number of hospital cases where somebody was dehydrated, and they kept drinking and drinking and drinking water. It actually damaged the physiology, because the water wasn’t getting in. There’s a medical term for being overwatered. I forget what it is.

Richard Gallagher: Let me move on, because we only have another couple of minutes. As we live longer, I wanted to ask you whether the societal role of the elderly should change and is changing. Maybe there’s something to learn from other cultures here. You talk about academics continuing to work into their old age. But what about the rest of us? I mean, where do we find meaning? How important is meaningful contribution to successful old age?

Susan Charles: That’s a wonderful question. I think that as healthier people are living into their 80s and 90s, we will see their roles changing and growing. We have the oldest president that we’ve ever had in the United States serving the country. We are seeing these wonderful, healthy examples. I think that it will also make the 20-year-olds and 30-year-olds realize with such a long life ahead of them that they also have freedom.

It creates freedom at every decade of life to realize we have this time. We can really use it and be productive at every decade in our lives. As far as the physical aspect of that, I don’t know.

Saul Villeda: I think one really interesting that I’ve been seeing, especially here, at least in the Bay Area, and at the university where I am, a lot of us are becoming multi-generational homes. A lot of my colleagues, a lot of my family members now, it’s the grandparents and the parents and the children. The grandparents are a huge critical component of it. They’re actually part of even the child development.

I think we’re going to have to just re-imagine a little bit how we interact across generations. The older population is so important. I think for us, we would not be able to work here the way that we do if it weren’t for the fact that we have three generations in one house.

Richard Gallagher: One final comment, Dan?

Daniel Levitin: Getting back to Richard’s first comment, I think, if you have to retire — many countries still have mandatory retirement — I say if you retire from something, make sure you retire to something else. It could be volunteer work, community organizing, political work, mentoring, tutoring, anything that gives you a reason to get up in the morning and demand that you actually face with and interact with other people. Particularly, as Susan was saying, people who are new to you.

Richard Gallagher: Great, fantastic. Well, being respectful of everyone’s time, I’m going to call a halt at this point. Susan, Saul, Dan, thank you so much. We could have gone on for another hour. Perhaps we’ll revisit the topic again in the not too distant future. Just to let everyone know that we have another event on the 26th of April. It will be about wearable devices and the health values of those devices.

Please join us for that. You can find out more information about Knowable. This event will be available on the Knowable website along with a lot of other supportive materials. We would love to hear from you. We’d love your suggestions and your feedback. Please join us again for future events.

Once more, thanks so much to our panel of experts for such an engaging and really valuable hour. I look forward to seeing everyone again in a future event. Enjoy the rest of your day.