Lessons in Lifespan Health

Francesca Falzarano is an assistant professor of gerontology at the USC Leonard Davis School. Her research is inspired by her personal experience as a caregiver to her parents and explores how to improve the mental health and well-being of family caregivers, including through the use of technology. On young caregivers “I think right now it's estimated that five and a half million individuals are under the age of 18 are caring for a parent or some family member with chronic illness, mental health issues, dementia-related illnesses, and other age-related impairments. So, this is something that's becoming more and more pervasive, and the needs of adolescents are going to vary extremely, and they're going to be extremely different compared to what my needs were as a caregiver versus what a spouse's needs are going to be.” “I talked to a ton of first-generation Gen Z caregivers who have really been at the forefront of their loved one's healthcare interactions since they were young teens, just translating and digesting information that a doctor is saying and communicating it to the rest of the family. So there's a lot of burden that we're placing on these individuals without simultaneously understanding what their unique needs are.” On dementia caregiving “If you think about dementia itself, it's got a very unpredictable disease course where most of that time is spent in dependency, and you have a variable lifespan anywhere from four to 20 years. So what we are learning is that there are so many things beyond just the caregiver's direct care tasks beyond what they're just doing in the care environment, like bathing or dressing or feeding that go into the caregiving role that individuals are not getting support for, whether that's managing finances, making end of life decisions, navigating the labyrinth that is Medicaid and Medicare, talking to healthcare professionals. It's essentially all of these roles and responsibilities that unfold over time is what we would dedicate one expert to take care of in our, in our school or department. And we're expecting caregivers to have learn on the fly and typically they're getting support and help in crisis.” “We learned that caregivers are expecting or anticipating the information, about what to expect about what the disease will look like and about how their responsibilities are going to unfold from the primary care physicians. But as our, my caregiver participants have said, it's a situation of diagnose and adios. So there's very little follow up, there's very little ongoing support that's provided.” On long-distance caregivers “Long-distance caregivers... their biggest challenges that they face is that intersection with the formal care system, being able to get adequate communication and information about their loved one's care. And really just feeling involved and being able to adequately manage all of the responsibilities involved in keeping someone safe, but also in terms of their doctor's appointments and their medications and the people that are physically providing care.” “I think we need to do a better job at educating the clinicians and the care providers that just because an individual is not in person does not mean they're not a caregiver and they're not really involved in all of the work that goes into that.” “The prevalence of dementia is just going to continue to increase and the likelihood that we'll have to provide care for somebody we love is very high. The likelihood that we'll have to do it more than once is also very high. And so really kind of my goal is to normalize caregiving the way we normalize parenting the way we provide all the resources and follow up for somebody who's going on maternity leave and about to give birth to a child. And that we need to start looking and viewing caregiving in a similar way and normalizing it and reducing the stigma as much as possible so we're not embarrassed or ashamed of our circumstances, but we can use it to empower...

Lauren Brown is an assistant professor at the USC Leonard Davis School. Her research uses publicly available data to uncover the unique difficulties Black Americans face in maintaining physical and psychological well-being as they age. Her lab both challenges the methods used to study older Black adults and strives to increase diversity in data science research with the goal of increasing the visibility of Black and Brown people via data and storytelling. Quotes from the episode On the role of racism in biomedical and statistical sciences and disease prediction If you think about the history of statistics and where it starts from, the earliest statisticians were actually also eugenicists. And a lot of it stemmed from the fact that Black people at the time that the census had started were property. And it was a way to count and keep up with property until we get to a point in the early 1900s when we start recording actual race in the census and colored being one of the options that you could check. And that being a way we kept track of Black populations, unfree, Black populations in particular, but also freed as well. And that transition of having Black people in the census started what was eventually used as studies that were confirming or trying to confirm biological and genetic inferiority among Black people. So once Black people were started to be included in the census and started included in medical research, clinical research, that research was usually often to compare Black people to white people with the innate goal to say Black people had more muscle mass biologically and genetically or smaller brain circumferences and justify it would a way to justify slavery by suggesting that the biological and genetic inferiority was a part of how Black people became slaves and would justify their continuation as slaves. So you fast forward to today that legacy of, of genetic and biological inferiority in medical, and statistical analyses has now manifested in things like race norming, where we're actually saying like, there are adjustments we use for Black patients in the clinic to justify whether they do or do not qualify for care strictly based on race. And a lot of it is based on false statistics that eugenicists had originally been pushing in the early 1900s. How injustice through data and storytelling affects the health and wellbeing of Black Americans When you think about like an individual, how this may affect one individual Black person, like for example, if we think about George Floyd's killing in 2020, his death originally was considered in the autopsy report performed by the medical examiners due to prior health conditions. They originally blamed his underlying health conditions and drug use as the cause of death. It was only after the family got an independent autopsy that they were able to show that the death was a homicide that then implicated Derek Chauvin and the Minneapolis Police Department, as responsible for the death and the knee on the neck. So this idea of blaming Black biology, is something that persists, I think, in larger society and that the biological inferiority is the cause and the precipice for Black death, and that it's not at all the function of society when actually now we know, you know, based on a lot of great research that the social environment is much more responsible for the fact that Black and Brown people often live shorter lives than white people or any other race and ethnic group in the US. We often live with more disease and disability at the end of life. And a lot of that we know is now it’s social conditions, it's discrimination, it's racism, those are at the forefront. But the research doesn't always follow that line of thinking because of the history and the legacy that still exists that we're still combating. And this new level of science is trying to push up against this idea. On diversity in population studies It’s been really obvious that a lot of the measurement...

Patrick Corbin is an associate professor of practice at the USC Gloria Kaufman School and an internationally renowned dance artist whose career has spanned over 30 years and bridged the worlds of classical ballet, modern and contemporary dance. He recently spoke to us about his work, exploring the positive effects that dance can have on neurology. On movement and movement therapy Well, on a neurological level movement is cognition. Movement stimulates cognition. So that's sort of the sciencey part. The other part is that dance is a multifaceted, multilingual way of movement, and we're actually in a duet from the time your mother becomes aware of you in the womb, you're already in a duet with her. So you're dancing before you're born. We come into this world dancing and we dance through life. So, it is intrinsic to our development. So why shouldn't it be also important to therapies and things? Movement therapy can range from anything from occupational therapy and living with different disorders to dance class or performative sort of therapies. Also, movement therapy can be sports anything obviously involving movements. Exercise can look like so many different things, and that's why we are getting in touch with each other and starting to work together. Because the more fun the exercise, the more people are going to do it. Dance is fun; therefore, people are going to do it and keep it going. On the benefits of dance in general There are a whole host of different areas where dance brings people together. We dance at parties; we dance at weddings we dance, and we don't even know that we're dancing. So, anybody who says, “ugh, you know, I'm not a dancer, I can't dance.” You know you don't even need two legs because that's even ableist going on. Do you move through space and do you like music? Then you dance and it's doing something good for your brain. Because of course, we focus on people maybe with disabilities or syndromes or some kind of situation that way, but actually dance is just really good for everybody, you know? It's all about community. You don't have to do dance in a group setting, but often we do. So, it's always keeping that active, curious, creative form of connection going with others. And also, it makes you feel a little sexy, right? So why shouldn't somebody who's 80 years old who has Parkinson's feel a little sexy? I think that's one of the best things that dance does, it puts us in touch with that sexier self, that sassy self, where you can express so many things through it. And I think that's one of the great gifts it can bring to anybody. On the benefits of dance for people with Parkinson’s disease and other conditions The anecdotal evidence is just massive, right? Everybody has stories about their family member who just started going to dance class and their quality of life changed. So, the scientific evidence is quite strong. Also, especially when you're talking motor skills, gait, and speed. When you're talking about the, the experiential evidence we want to talk about dance as, once again, this multifaceted art or form of exercise that brings together other domains other than just the motor. So, you have the sensory, you have the motor, you have cognitive, you have social, emotional, spiritual, rhythmic, and of course your creative process. So, what does that do to the whole person, right? What does that do for somebody who may be, have become isolated for whatever reasons? And, and I'm going to go across the board here with many different kinds of disabilities that this is, these are often invisibilized populations when you're talking about elders or when you're talking about, especially in the past, children with autism, or for instance. Now, one thing I did witness at one time is sometimes what happens the slowing happens so much, or the automaticity is so in decline that an actual freeze will happen. And so there are different ways that you can cue people out of a freeze. And this...

Connie Cortes is an assistant professor of gerontology at the USC Leonard Davis School. Her work straddles the fields of neuroscience and exercise medicine, and she recently spoke to us about her research seeking to understand what is behind the beneficial effects of exercise on the brain with the goal of developing what she calls “exercise in a pill” therapies for cognitive decline associated with aging and neurodegenerative diseases. On brain plasticity and brain aging Brain plasticity we define as the ability of the brain to adapt to new conditions. And this can be mean something like a disease, it can mean something like stress, it can mean something like learning, and it can also mean something like aging. Our brain is actually quite plastic and can respond to a lot of these stimuli. Now, brain aging is a slightly different component to that where we think about what happens during the brain as we get older, the normal wear and tear. What are the differences and the similarities as well between a 75-year-old brain versus a two-year-old brain? What we've come to understand is like most other aging tissues, an aging brain begins to suffer from wear and tear just like a car would and that's where regular maintenance and regular checkups come in. … But essentially things at the biological level begin to slow down and as they slow down, that can affect the way our neurons fire and therefore we get age-associated decline in cognition and memory. On why exercise is good for the brain health That’s one of the questions that my lab is trying to answer, but in the field of exercise medicine, we've come to appreciate that exercise is very good for the brain, and it appears to do so in multiple ways. It can affect your cardiovascular health, which has a direct impact on the brain as far as blood flow and essentially clearing the brain out of things it doesn't need. The other way is delivering, metabolites and essential nutrients to the brain during exercise we make a lot of these things that get into our blood and eventually transfer through the blood-brain barrier into the brain. And so as far as the biological mechanisms of how exercise is good for the brain, we really, truly don't know yet. But that is why this field is so exciting and I think we're poised to answer these questions in the next five to 10 years. On whether exercise can prevent or slow cognitive decline or diseases like Alzheimer's that are associated with aging For actually many decades now, we have had anecdotal evidence from the clinics that aging populations that are active, physically active, and or exercise have significantly lower levels of age-associated neurodegeneration, as well as just age-associated cognitive decline. And it's only been in the past, I would say 10 years that we've come to appreciate that it is truly the exercise activity. And so what we find is that consistently, no matter what markers of brain health we look at, those aging populations that are sedentary tend to do worse than those that are physically active. And so the field now is extremely interested in trying to understand why this is happening and can we kind of use these mechanisms and these targets as new therapies down the road. On efforts to develop “exercise in a pill” therapies We all know a hope that exercise is good for us. However, the most at-risk populations that we are trying to help, especially here in the school of gerontology, are populations that usually cannot engage in the level of exercise required. Now in the field, we're still trying to define what an exercise prescription is, but you may have heard you know, three times a week, 90 minutes a day, uh, some sort of cardio. And something that raises your heartbeat, uh, that is, has come from exercise studies in young people. However, elderly populations are sometimes suffering from additional medical conditions or sometimes there's a financial constraint or even an accessibility constraint, and they just...

Dr. Roberto Vicinanza MD and PhD and instructional associate professor of gerontology at the USC Leonard Davis School, and a specialist in geriatric medicine, joins us for a conversation about healthy aging, including tips on how to keep the body and mind functioning for as long as possible. Quotes from this episode On the importance of setting small goals "People may have all the good intentions, but they might set up goals that are too ambitious and then when they don't reach that goal, they feel frustrated, and they quit… We have to let them understand that goals must be small…So, an apple a day. We have to eat the apple a day and be happy and recognize when we reach three or four days in a row that we are eating the apple, right? So celebrate the success even of small, very small goals." On keeping your diet simple "Diets cannot be too restrictive for a long period of time. The majority of people will give up. It is important that diet needs to be easy to follow, but at the same time needs to be healthy. When we talk about a simple diet, we are now referring on something that needs to be easy to follow, but also simple in terms of the way we make food. So we have to eat in a very simple way. So, avoiding ingredients that are maybe tasty, but not that healthy. And sometimes they also cover the, the real flavor of, of food. We have this tendency to add always sauces and creams and other things on food that actually cover the real flavor of food and also contain a lot of saturated fatty acids, heat and sodium, sometimes sugar. So, we increase these calories by adding something that we don't really need. Diet must be simple in terms of the type of diet that we have, but also in the way we cook and prepare dishes." On the benefits of the Mediterranean diet "So, the results that, that we have referred to the traditional Mediterranean diet, which is characterized by high consumptions of fruits and vegetables, cereals, legumes, extra virgin olive oil, nuts, and a moderate intake of fish, and a low intake of dairy products and meat products. So, we do have robust evidence suggesting that high adherence to these dietary patterns is linked to positive health outcomes, in particular for cardiovascular diseases, dyslipidemia and diabetes. But another important result was that the adherence to Mediterranean diet was inversely associated with a number of medications. So, patient who were more adherent to Mediterranean diet, they also used less medication. Another interesting observation that we found was related to depressive symptoms and comorbidity. When we analyze our data, we found out that the relationship between comorbidity and depressive symptom was high in older adults…In patients with higher adherence with Mediterranean diet, this correlation was weaker. When Mediterranean diet adherence declines, this relationship was stronger. So Mediterranean diet played seems to play a crucial role in mediating the relationship between the presence of comorbidity and depressive symptoms." On the importance of physical activity "Although we don't have big clinical trials on physical activity, we have small, randomized control trials showing that certain level of physical activity, may have some benefits in terms of improving the cardiovascular health and, utilization of glucose in the muscle in modulating inflammation, improved cognitive function and physical performance. Some of the benefits that we have from being active and also exercise regularly include an improvement in the cardiac output improving the health of the heart by improving cardiac contractility, oxygen uptake. And we know that we don't have to do long sessions of exercise or being extreme physically active. Already, if we walk between 45 to 75, 85 minutes a week, we can already see some benefits. Of course, the more we exercise, the more benefits we see, but at some point we reach a plateau." On sarcopenia "With the aging process, there is a decline in our...

Dion Dickman, associate professor of neuroscience and gerontology, joins George Shannon to discuss how the nervous system processes and stabilizes the transfer of information in healthy brains, aging brains and after injury or disease. Quotes from the episode: On synaptic plasticity: “Synapses are essential, fundamental units of nervous system function and plasticity is this remarkable ability to change. And throughout early development into maturation and even into old age, synapses just have this amazing resilience to change and adapt to different situations and injury disease, things like that. So synaptic plasticity is really the essence of what it means to grow and mature and change throughout life. Things like learning and memory all depend on changes in synaptic function and structure and it's really a key area of research for many of us.” On challenges to maintaining nervous system stability: “You can imagine in the incredibly complex environment of your brain, where neurons are making synapses with thousands of other neurons, that itself is a big challenge to maintain stability. Sometimes I'm kind of amazed that we don't walk around like raving lunatics half the time and our brains remain stable. When you think of disorders of excitability or stability, things like seizures and various forms of defects in cognition ultimately come down to not being able to stabilize or maintain your neural circuit function. And this really just comes down to normal development that all of your nervous system has to stay stable and your synapses are the key substrates to maintain stability.” On the aging brain: “.. a lot of studies are showing is that this cognitive decline that happens in aging really is ultimately due some sort of a maladaptive reduction in plasticity. And it's kind of amazing, but, young humans, our brains are remarkably plastic and resilient, and that resiliency and plasticity seems to degrade over time and into old age… We think as old age happens .. people's memories start to lapse, even in the absence of any disease, they're not quite as sharp. We think this all ultimately comes down to some limitations imposed on neuroplasticity and that's a major area of the research. On studying diseases like schizophrenia, which cannot be seen in brain imaging: “There are no good biomarkers for neuropsychiatric diseases like schizophrenia and bipolar and things like that. So, there are basically two ways to study these kinds of diseases. One is through behavior where you try to get animals to model behaviors that mimic neuropsychiatric diseases. There's some good work happening rodent systems. Although I find it to be honest, very difficult to know whether a mouse is showing the defect in social interaction, for example, that are characteristic of autism or schizophrenia for that matter. So the alternative instead is not to actually model the disease in drosophila or mice, but to take humans in which we can mine their genetics to find genes highly associated with the disease in humans and find out what the fundamental function of these genes are. And that's kind of the strategy that we take. So we found about 30 genes now that when mutated in drosophila give rise to defects in this process of homeostatic plasticity at synapses, and the vast majority of these genes have links to human diseases that give rise to neuropsychiatric diseases like autism spectrum disorder, schizophrenia, seizure disorders and, bipolar disorder as well. And so I think by understanding the fundamental functions of individual genes, we can extrapolate what might be happening in humans when those genes aren't functioning properly.” On the importance of sleep: “…one of the most fascinating questions in neuroscience, or really science more generally is what is the function of sleep? What is the essential function of sleep and what role does synaptic homeostasis and disease play a role in sleep behavior? So, it's quite interesting that almost...

Kelvin Davies is a Distinguished Professor of gerontology, molecular and computational biology, and biochemistry and molecular medicine at USC. Over the course of his career, he has played a central role in defining the pathways and mechanisms by which the body is able to maintain balance under stress and in uncovering the role aging plays in disrupting this balancing act. He recently joined Professor George Shannon to discuss his research on how the body is able to maintain balance under stress and the implications it could have for preventing age-related disease and decline. Quotes from this episode On the concept of adaptive homeostasis “So every organism that we've looked at is able to adapt to stress. And I'm talking not about psychological adaptation, but adaptation at a cellular or molecular level. And we've been working on what are the pathways which that adaptation occurs. And what we came up with over a series of a number of years is the concept of adaptive homeostasis. “What we found with adaptation is that successful adaptation actually involves the turn-on of a number of genes, a key one being something called NRF2. And NRF is a sort of a master regulator that turns on about another 200 genes. When I say ‘turn on,’ what I mean is that those genes start making their protein products. So the code in that gene starts being read, turned into a protein product. Thousands of proteins are then made. Many of them at least are enzymes that have a job to do. And all of those enzymes have a role in enabling you to adapt.” On adaptive homeostasis and aging “As organisms age, the capacity for adaptive homeostasis declines. That's been true in everything we've looked at all the way from bacteria to yeast, to worms, to flies, to mice. “NRF2 activity is modified in aging. And so it doesn't work as well … And the reason we think that happens is that there's another gene that's turned on in aging that inhibits NRF2 responsiveness. It turns out that that gene might actually be helping to protect you against cancer. So one of the things that cancer cells are very good at is avoiding stress and adapting to stress. And in fact, NRF2 works really, really well in most cancer cells, better than in normal cells. So it looks as if the body is adapting to age by inhibiting its own NRF2 thus decreasing adaptive homeostasis in order to diminish the increase in cancer. We all know that cancer increases with age. Maybe it would increase twice as much if you didn't have this offset by inhibiting NRF2 in the cancer cells. And the price you pay is that you're also inhibiting NRF2 in your normal cells at the same time.” On understanding the role of enzymes and backup systems “What we've learned over the years is that the body treats important enzymes much more like the way that NASA treats important components in a space shuttle. In other words, if something is important, let's have a backup to it. And if it's really important, let's have a backup to the backup. And if it's life-threatening, let's have a backup to the backup to the backup. And the problem is when you knock out one enzyme if you don't know if there's a backup enzyme to that one, then, and that takes over, then you'll completely mask the effects you're seeing. “We had a great example of that in my lab several years ago where we found an enzyme that was induced during chemical stresses that stopped DNA being read. So basically protein RNA synthesis and protein synthesis were stopped by this particular enzyme that got turned on during stress situations. If you inhibited that enzyme, it didn't make any difference because there was a backup to that enzyme. And if you inhibited the backup, it didn't make any difference either because there was a backup to the backup. So it turned out what was really important in cells is that if you're being stressed to the point where it could be lethal for that cell, all of these things will get turned on simultaneously and any one of them...

Kate Wilber is the Mary Pickford Chair in Gerontology and director of the Secure Old Age Lab at the USC Leonard Davis School. She's also the co-director of the National Center on Elder Abuse, which is housed at the Keck School of Medicine of USC. She recently spoke to George Shannon about her research, including her work exploring ways to provide long-term care services and supports that allow older adults to be as independent as possible and the challenges and opportunities that technology provides in this area. Quotes from this episode On building on lessons learned during the pandemic “I think a lot of what we saw were challenges that we already knew were there - how fragmented services are, how older adults can be at risk of isolation, how important the home community-based services and programs and opportunities to interact are for everybody. And I think showing the importance of community, which we didn't have during the pandemic, except a bit on social media and phone calls and maybe people getting together outside. So the key question is, how do we take the learning and the recognition of what we already knew into the future to build on these important lessons, to do better with our aging service delivery? I was going to say our aging service delivery system, but that's a huge problem. There isn't a system; there's just a lot of different components of a system.” On innovations in long-term care and supports “We have to prepare for an aging population. And until recently I felt like we didn't do that great a job preparing, but I see a lot of exciting innovations, which to some extent may have been jump-started a little bit because of the challenges of the pandemic. We have a variety of models of senior living and I think we're going to see more innovation there or the innovations that have been developed take off because they did better in the pandemic too. So if we look at what kind of care was best for older adults who maybe were isolated or need long term services and supports during the pandemic, how do we build on that? And how do we make sure that we translate what we know into reasonable programs and policies.” On barriers to implementing technology solutions “People not only need to have some kind of device. They need to have broadband, it needs to work. And we've seen that in some parts of the country, especially in rural areas, broadband it's not available. All the things we take for granted, electricity, water, et cetera, how much is this an essential service that we’ll do a better job providing across the nation in areas where it doesn't exist very effectively now. And then as I said, how do we help people learn? And what are the particular cultural competencies required for trainers? What are the different uses that people want? This gets back to being person-centered and engaging the people that will be the end-user users and understanding what's most effective for them. There are still a fairly large proportion of older adults who don't have access to any sort of computer; some have smartphones. And there is this notion, I guess, if we build it, they will come. Or if we give it to them, they'll use it, it would be the way of talking about that. But there's a variety of barriers. And if you hand somebody a box with a computer in it and say, ‘There you go, you're now going to go on the other side, the right side of the digital divide.’ They're not. So what can we learn about how to help people use technology in a way that is useful for them effective, meaningful?” On telehealth “So this will be a time saver. I think that's pretty clear, but the nursing facilities have to invest in it. The staff have to invest in it. They have to learn how to do it. And one of the things we're seeing is they thought the residents would be the most resistant and they're not. They're like, ’Okay, if I can see my doctor this way, fine.’ But I think the question is, how is it used, where is it most effective and...

Rong Lu is an associate professor of stem cell biology and regenerative medicine, biomedical engineering, medicine, and gerontology at USC. She joins George Shannon to discuss her research into the complex and surprising behavior of individual blood stem cells and what it could mean for treating diseases associated with aging. Quotes from this episode On stem cells and what makes them so promising for medical research Stem cells are the special cells in the body that can produce other type of cells. So in particular there are two type of stem cells, one called embryonic stem cells that only exist in the embryonic stages. And the other type of stem cells are called somatic stem cells that are also exist in adulthood. And these somatic stem cells can produce only a specific subset of the cell types in the body. For example, skin stem cells can only produce skin cells and blood stem cells can only produce blood and immune cells. But all the stem cells share the general special property called self-renewal and differentiation. So differentiation describes their ability to produce a different type of cells and self-renewal refers to their ability of making more of themselves over time and sustain the long-term differentiation and tissue regeneration. On the ability of stem cells to regenerate as we age …that's what makes stem cells super special because they are the only long-lasting cells in the body that continuously regenerate and sustain the tissue. But over time, stem cells capacity in terms of self-renewal are reducing and therefore the tissue as homeostasis decline when the body ages. On whether stem cells might offer protection against age-related immune decline Sure. So over aging stem cells become less and less competent in producing immune cells. And, the hope is if we can maintain the stem cells capacity over time then we could make the stem cells offer the protection. Again, this is very much a research in progress and many research labs are working on this important question, including my own lab. On the focus of research in her lab In our lab, we're interested in understanding how are individual stem cells different from each other and how different stem cells work together to maintain an overall balanced blood pool. And in particular, over aging, we want to understand how individual blood stem cells change during aging and how their change lead to the aging phenotype of the animal. And what we found is that there are a specific subset of blood stem cells that age, particularly faster than the others. And there's also another group of stem cells that actually can change in the opposite way during aging and provide more immune cells and their presence really correlate with the delayed aging phenotype of the animal. So we're very excited about this finding and we're following up on this study using our bar coding tool to track these anti-aging stem cells and study what make them so special. On the development and use of a tool to label individual cells with unique “barcodes” The barcoding tool was developed a couple of decades ago by several labs simultaneously. At that time they used the viral insertion site as a marker to track individual cells. So about 10 to 20 years ago, high throughput sequencing technology started to emerge. And at that time, I started to combine the new capacity of this high throughput sequencing to quantify the cellular behavior at a single cell level. So instead of using viral insertion site, I provide a particular DNA barcode sequence into the virus and use that as a marker to track individual cells. And what this allow us is a high precise quantification of the cellular behavior and also the high throughput that is needed to track hundreds and thousands of stem cells in the body. We can use this tool to study cancer cells and understand the heterogeneity among individual cancer cells. For example, a recent study from my group used it to track the primary acute lymphoblastic...

Assistant Professor of Gerontology Ryo Sanabria joins Professor George Shannon to discuss their research seeking to understand why stress response pathways break down as we grow older and whether there may be ways to delay that breakdown and potentially promote healthier lifespans. Quotes from this episode On the definition of stress: Stress can come in so many different forms and flavors. It can come in the form of something external, something like heat stress. For example, being out in the desert heat, it can be something as similar to cold stress of a winter storm, or even something like a bacterial or viral infection… Stress can also be internal though. It's not only external. When we think of humans, we can think of big things like mental stress, emotional stress, social and societal stressors. So really the definition of stress is pretty large. And just to say anything that causes some kind of adverse reaction to the body is a stress. And so we study all of these various types of stresses and how it impacts our bodies, our health, and of course aging. On how our cells respond to stress: The response to stress within the cell is simply to activate mechanisms that prevent damage. And the main way that this happens is to turn on genes. So genes encode specific types of proteins and processes and mechanisms that are important to mitigate the stress. So it's like essentially activating or turning on a switch that has some kind of functional output, similar to how you will just flip a switch to turn on a fan or an air conditioner. So you can cool down the house. Exactly in the same way, the cells will switch on jeans that can activate pathways that prevent or mitigate that is associated with exposure to stress. So for example, when we are under heat stress, our cells will turn on the mechanisms and pathways that will essentially alleviate damage associated with heat stress, such as damaging proteins or things like that, that happen under heat stress. So the cell is essentially trying to repair or discard damaged proteins that happen with exposure to heat. On efforts to give older person to have a younger person’s ability to deal with stress We know that the capacity to deal with stress declines during the aging process. So the question is if we give an older person, a younger person's capacity to deal with stress, would that actually combat aging? So if we go back to example again, before, if I give the grandmother her grandchild's capacity to deal with desert heat, we know that she'll be more resilient to the heat. She'll likely survive the desert, but generally, would she actually be healthier overall as well? Would she be in a sense younger? And the answer in most model organisms that we study is yes. When we give an old organism, a young organism's capacity to deal with stress, not only can they handle that specific stress better, but overall they're healthier and live longer. So when we think about model organisms, what we're doing is activating those genes that I talked about. So essentially turning on those switches that will then activate a specific pathway, like in the example I gave earlier where heat stress causes damaged proteins, you can turn on the switches that will essentially activate pathways that will remove or repair the damaged proteins. So what happens during the aging process is that the capacity to turn on these genes switch on these genes are impaired. So what do we do with this? We really try to increase the capacity of that gene to turn on. So it would be like increasing the electrical circuit's capacity to pump energy into your AC so we can increase the gene's output and in model organisms, this is easy. We can simply overexpress your gene. So what does that mean? If we think about the number of copies a gene has, usually one gene will have one copy, but if we give an organism 50 copies of the same gene, even if we decrease the output by half during aging, you're still having 25 times the...

Research Assistant Professor Thalida Em Arpawong joins Professor George Shannon to discuss her research to better understand how our genes and environments influence how we respond to stress and adversity and impact how we age. On the definition of bioinformatics and its use in research “Bioinformatics is a science subfield, but really just refers to a set of tools that we use to collect, analyze, and interpret findings from large volumes of biological data. We use tools like super computers, biostatistical models, computer programming, and specific types of software, while at the same time, integrating biological concepts to guide how we use these tools. So the data we use—we call it “omics” data, for short—includes primarily genomics, transcriptomics, epigenomics, proteomics, metabolomics, that is, all the omics. Here in the school of gerontology, Dean Cohen had a vision of creating a core to help support researchers in their labs that want to use omics data but may not have the background to do so. So, relatedly, with the Genomic Translation Core, we also use bioinformatics to work with human data, to collaborate with biologists. So these biologists work on model organisms for their research, like worms, mice, or yeast, and the biologists who have been granted pilot awards through the Nathan Shock Center because they've made some important discoveries in their model organisms, we work with them to confirm what the relevance is of their findings for human aging processes. It’s an exciting time because through this work together, we have the potential to use the expertise across different disciplines to answer some bigger questions that we haven't been able to previously with regard to cross-species effects of genomics and health.” On her research on how experiences of stress and adversity throughout different developmental stages in life and genetic factors work together to influence emotional and cognitive health as we age “So we used to think that genetics was much more deterministic, but we now know there are much more complex and interrelated processes occurring. We found that social structures in which we can characterize groups, such as gender, race and ethnicity or social status, are very importantly related to how genes get expressed. Similarly, people's behaviors shape levels of gene regulation and expression, then have downstream effects on immune system health, development of chronic diseases—for example, obesity, heart disease, depression—and even lifespan. So it's becoming more critical to include these key social factors in human research when we evaluate the effects of genomic data on health.” On her research looking at how having early childhood adversity and adulthood adversities affect the level of depressive symptoms when older “What we found were two main things. First, that there was essentially a dosage effect, so that with each additional childhood adversity, there was an even greater risk for more later-life depressive symptoms, even after the age of 50. And second, the hypothesis that was supported was called stress proliferation, which is essentially the idea that stress begets stress. So therefore, earlier-life adversities are accompanied by more adulthood adversities, and that's how they work together to impact mental health later on.” On the mind-body connection, or the role of mental health in healthy aging “When we think of psychological factors, such as stress and adversity and socioeconomic hardships, compared to other factors that affect aging, we're finding that there are more influential compared to genetic or biological factors. And in a recent study by Eileen Crimmins, she found that, in particular with mortality and cognitive functioning, these factors explain 25 to 30% of the variance. So that's a significant amount and often much more variance explained than we can detect for something like genetics.” On epigenetics and how our social environment can affect our genetic...

Mireille Jacobson is an associate professor in the USC Leonard Davis School and the co-director of the Aging and Cognition Initiative at the USC Schaeffer Center for Health Policy and Economics, where she’s also a senior fellow. She joins Professor George Shannon to discuss her research using economic insights to better understand decision-making around vaccines, palliative care, Alzheimer’s disease and more. On health economics and the role it plays in healthy aging "Health economics really is just the application of economics to health and healthcare… So whether it's time or money or attention, we all have to kind of make what we call trade-offs. Health economics is really thinking about how to make choices in the context of healthcare and health. Economics isn't just relevant, but I think really critical to understanding things like how to incentivize healthcare providers to coordinate care or encourage people to save for retirement." On a recent study (with colleagues at USC, UCLA and Contra Costa Health Services) looking at whether financial incentives could increase vaccination rates among the vaccine-hesitant "What we did is we invited unvaccinated members of this health plan, this Medicaid plan, to participate in a survey. And some of the people who were in the survey were randomized to receive an offer of financial incentives, either $10 or $50, if they got vaccinated in the next two weeks. Some people saw public health messages several different kinds of public health messages that we used in the survey and others got access to kind of an easy vaccine scheduling link. And I should say all of these, what we call interventions, were crossed. So some people got none of them, and some people got financial incentives and a public health message and an easy vaccine scheduling link and kind of everything in between. And then after the fact, we kind of looked at both what people said they would do. So did they say they were going to get vaccinated after they saw our public health message? And then, more importantly, did they actually go get vaccinated? And unfortunately, none of our nudges actually moved the needle here. So we just found that unlike in other contexts, like flu vaccinations, where we know that financial incentives can really increase uptake, that didn't work in this context. In fact, when we kind of looked at the data more finely and tried to kind of see how different groups responded, we found something actually somewhat troubling, which was that while as a whole people didn't respond to the financial incentives, people who said that they supported Trump in the 2020 election, for example, were less likely to get vaccinated if we offered them a financial incentive. The same is true for the kind of older respondents in our survey. You know, the people 65 and over, most of them had gotten vaccinated, but if we look at the people 40 and over, if we offered them a financial incentive, they were also less likely to get vaccinated. ... This is how we interpret the data. They had very strong beliefs about COVID-19 vaccinations kind of not being a good thing, and offering money to them seemed to kind of reaffirm that for them and almost encourage them to dig in their heels further. The reason I'm so excited about this project is there's been so much discussion about how to move the needle on vaccinations but really very, very little data on actual vaccinations. So most of the work in this area … has been focused on what people would say they would do. So you'd say if I gave you $50, would that increase your likelihood of getting vaccinated? And we were able to both ask that question, as well as look at people's actual vaccinations. And in fact, the funny thing is that we found that often people said they would do things and that just didn't show up. When we looked at their actual vaccinations. So many of the public health messages, we used seemed to increase the likelihood that people said they would get...

Assistant Professor of Gerontology Joseph Saenz joins Professor George Shannon to discuss his ongoing work on rural-urban differences in cognitive ability among older adults in Mexico, as well as whether certain personality factors make people resilient to the negative effects of early-life disadvantage. Quotes from this episode On the focus of his work I focus my research on looking at how it's socioeconomic disadvantage throughout the life course relates with cognitive ability and late life. I'm interested in education. I'm interested in income, wealth and the resources that we have available to us throughout our lives and how this relates with better cognitive functioning, as well as lower dementia risk and the population of older adults of Latino origin here at the United States and also older adults in Mexico. On demographics and differences between rural and urban populations in Mexico One of the things that's very important about the Mexican population is we've seen a lot of demographic changes over the past century. In addition to seeing rapid population aging with the share of the Mexican population aged 60 and over increasing rapidly. We've also seen a large urbanization process where people are going from rural areas to urban areas. For example, back in 1920, only about 70% of the Mexican population lived in rural areas, but by 2010, this had declined to only about 20%. So a lot of people have been going from rural areas to urban areas. And this is important because in Mexico we see a lot of differences of a lot of disparities between urban areas and rural areas. Rural areas tend to be disadvantaged in several ways. They tend to have lower access to education. There's fewer schools for people to go to. And the educational quality that people got, especially if you look at several decades ago was significantly lower quality than their urban counterparts. Also in rural areas, we tend to see higher rates of poverty and various measures of SES. And we also see that the rural population tends to have less access to healthcare. This as the gap between the rural and urban areas in terms of healthcare access has shrunk a little bit over the past couple of decades, but there's still a disparity there. And so when you bring up the idea of the life course and where people live throughout life, I think this is especially important in Mexico, where we saw that rural to urban population shift, that many people who are living in urban areas now were living in rural areas as children. On his research looking at where people live throughout their lives In this more nuanced approach, what we see is that the people that had the lowest exposure to urban areas throughout life, those who lived in rural areas in early and late life, ended up doing the worst cognitively. And those who are doing the best are the people that lived in urban areas in early life and urban areas that late-life... And what we also see is that compared to people that stayed in rural areas throughout their entire lives, those who went from a rural to an urban area, also show advantages. So what it looks like we're finding in our current studies is that both early life, urban-dwelling and late-life urban dwelling are related with better cognitive ability. And there is an advantage that comes from moving to an urban area throughout life. On the negative impacts of indoor air pollution And then the other reason that we could expect to see these differences between rural and urban areas is that in urban areas, we know that people have high exposure to air pollution from the outdoor environment. When we look at pictures, for instance, say in Mexico City, we see the smoggy skies and we see this high level of air pollution that people are breathing in urban areas. However, in rural areas in Mexico, a significant portion of the population relies on solid cooking fuels. So this could be wood and coal and Mexico is primarily coal if people are using solid fuels...

Assistant Professor of Gerontology Andrei Irimia joins Professor George Shannon to discuss brain imaging and brain health, including his work to determine who is most at risk for Alzheimer’s disease after suffering a concussion or traumatic brain injury. Quotes from the episode On who is at risk for traumatic brain injury or TBI and adverse impacts from them Usually, injuries sustained early in life are the least likely to cause issues down the road during the aging process. And in fact, the brain is most robust to brain injuries in the first and second decades of life and injuries sustained during that period have typically the best outcomes and the best rates of recovery. And as we age, it becomes more and more difficult for the brain to recover after a traumatic brain injury. So, older adults, especially those over the age of 65, are at the highest risk for a poor outcome after a concussion or a more severe traumatic brain injury. After the age 40 or 45, there is a little bit of an increase in the risk for degenerative disease, including Alzheimer's disease. And that risk really increases after age 65. We have a preliminary study where we found that the biological age of the brain increases dramatically after a traumatic brain injury sustained after the age of 65, whereas for concussions sustained before that time, the biological age of the brain does not increase substantially at all. On sex differences in traumatic brain injury impacts It appears that in males, there is a higher risk for sequelae down the road up to about age 65, but for persons who are injured after the age of 65, there's actually a greater risk for atrophy of the brain in females, which is interesting because, as you already know, the risk for Alzheimer's disease is higher in females. And also the onset of Alzheimer's disease is typically after the age of 60 or 65. So one thing that my lab is very interested in is how exactly sex interacts with hormonal changes with the rates of biological brain aging and with other factors in determining the risk for Alzheimer's disease. There have been studies indicating without a doubt that there is an increase in the risk for Alzheimer's disease after traumatic brain injury, especially moderate to severe brain injuries. On identifying patients at risk for cognitive impairment after brain injury We’ve done a number of studies that have been funded by the National Institutes of Health and the Department of Defense on how we might be able to predict the risk for cognitive decline after traumatic brain injury. And we have studied cohorts of patients with Alzheimer's disease and compared them to healthy control adults who are age and sex match, who did not have a history of neurological disorders or have mental health disease. And, we found that it is actually possible using some tools that involve machine learning to predict the rate of cognitive decline based on acute imaging findings shortly after the injury. And we were able using these techniques to determine that the fact that we can actually identify the patients who are most likely to, uh, be at the highest risk for accelerated cognitive impairment six months or even one year or further after injury based on imaging scans. So this value, I believe is very valuable because it can identify patients who might benefit from additional monitoring and supervision by their clinicians and who might benefit from tailored therapies and from lifestyle changes that might decelerate the rate of cognitive impairment and might decrease the risk for Alzheimer's disease or other neurodegenerative diseases. On studying the brain and heart health of the Tsimane This is a very interesting and very important project that's been ongoing for essentially 20 years now. And I'm very fortunate to be part of a very large and talented group of interdisciplinary researchers who study the Tsimane people of the lowland Amazon basin in Bolivia. The Tsimane are a group of forager...

Instructional Associate Professor of Gerontology Paul Nash joins Professor George Shannon for a conversation on the impacts of ageism, intersectionality and LGBTQ+ issues in aging, and the importance of talking about sexual health with older adults. Quotes from the episode On stereotypes and the impacts of ageism Well, there are some huge implications when it comes to ageism. So when we look on an individual level, we know that those people who have internalized ageism, so when they've acquired ageist attitudes across the life course, and then they reach older age themselves and they start to internalize those negative perceptions. We know that people that do that tend to walk slower, they tend to be more unstable on their feet, more likely to fall. They also have reduced cognitive functioning. So we actually start to see these stereotypes as we call it embodied. So we call it the stereotype embodiment theory, and we know that older adults have this more negative opinion of aging and being older themselves also have an average life expectancy that is about seven and a half years, less than those people that have a positive attitude about aging. When we look at society, we know that older adults make a huge contribution to society. We talk about billions of dollars a year in things like informal caregiving, even in terms of paid work, but also within the volunteer sector as well. So older adults make a continued service to society and to the economy, but it's often something that is not really discussed this often. So it's not really met. And when we start to prejudice against old people, we actually discriminate against their engagement in society. And as such what we're doing is actually making things an awful lot worse for ourselves. So what we need to do is start to actively embrace older adults and their diversity and understand accurate perceptions of aging rather than these stereotype myths that are widely held. Ageism is essentially prejudice against your future selves. So if we set up an ageist society, now when we read later life for ourselves, then we're going to be living and growing old in that age of society. So we need to start to challenge that younger people need to appreciate that actually having no wrinkles having gray hair or whatever, having wrinkles and gray hair is not a bad thing. Being older is not a bad thing. When we start to see all these anti-aging serums, well, that's kind of a fallacy. It's not going to stop you from aging. Every moment that we're alive, we are aging. Therefore, really the alternative to aging is death. And I don't think many people would like to wish that upon themselves either. When it comes to the wider social problems and the stigmas and things that I think we need to try and do is we need to be very much aware of our own language. And language, as you know, is incredibly powerful. So for example, we might see ageist stereotypes in greeting cards, and we will have a bit of a giggle about that, but, well, that reinforces the stereotypes. That adds to the issues that older people think that well, okay, I'm 60, I'm 70 I'm 80 as well, I must have cognitive impairment. Well, indeed, what we need to do is start to challenge these stereotypes. We have this assumption, or we paint this mental image in our head that all older people are going to be frail. All older people are going to have cognitive impairment. That's just not true. The majority of older adults, even the age of 80 are not going to be living with cognitive impairment. It's a disease state. Yes. We understand that people who, as they age are more likely to develop dementia, but the majority still don't. On intersectionality and LGBT issues in aging We know that the majority of older adults within the LGBT community are likely to be single. They're also less likely to have a biological family, so children of their own. And they're also more likely to be estranged from their own family, which has led really to the...

Associate Professor of Gerontology and Sociology Jennifer Ailshire joins Professor George Shannon to discuss the impacts of air pollution, global aging and how factors like location and education can influence the way we age. On the importance of place, or location, on aging Well, I think of place as one of the greatest supports and constraints on the way that we want to live our lives. So we envision a life for ourselves, our daily decisions, but it's really dependent on where we live. So for instance, I have a goal to be a very physically fit person and to engage in physical activity every day because I know that's one of the best ways to support my own health and aging. But if I live in a place where there aren't a lot of opportunities for me to exercise outdoors, maybe because I don't have access to good park space or other recreational spaces, maybe because of weather problems, it's going to have a constraining power on my individual choices. So a lot of people really want to eat healthy and exercise. And some people live in places that provide a lot of opportunity for that. And other people live in places where actualizing those wishes, those goals is really quite difficult. And then of course there are other factors about environments that really matter in terms of social stressors like crime or feeling safe in your neighborhood, and also more physical characteristics like, air pollution, which is one of the things that I've spent a lot of time studying while at the school of gerontology here at USC. On air pollution and aging We think of air as a physical characteristic. It's something that exists in the physical environment, but actually, maybe it's because I've been trained as a sociologist. I think of the air pollution as a social phenomenon because after all it's produced by humans for the most part. And so air pollution is located in places where we have a lot of industrial activity and where there's a lot of car traffic. So some people live in areas where they're closer to those sources of air pollution, and it usually is the case that those are lower income communities because throughout much of our kind of industrialized history in this country, people who could afford to live in a nicer area that was further away from sources of pollution would move and they would end up in a cleaner air environment. Now here in Los Angeles, we have poor air quality in a lot of places. On average, LA has worse air quality than a lot of cities in the rest of the United States, but there's also pockets of poor air quality here as well. So by the ports of Los Angeles and the ports of Long Beach, for instance, they have much worse air quality because a lot of that shipping and trucking activity, moving goods around. But living in California these days, particularly during fire season means that a lot of us are going to be exposed to poor air quality at some point during the year. And it doesn't at that point, it doesn't really matter what our own socioeconomic resources are. It's really just ways which way the wind blows and where the fires pop up around us. Most of the research had been conducted in younger populations in children and adolescents and in younger adults, but just in the past 10 years, it's become really clear that older adults are a vulnerable population and that they're more likely to suffer adverse consequences from chronic exposure to air pollution, and also from these acute episodes. So we've done a lot of work trying to grow that area of research in public health air pollution topics. And I think that it has really caught on, and there are a lot more people who will have been working in this area, trying to understand the negative impacts of air pollution on older adults. Our group was most interested in the aging brain. And so most of my research has been in trying to understand how air pollution might impact cognitive aging, increasing risk of cognitive decline or risk of cognitive impairment or the...

Julie Zissimopoulos is an associate professor in the USC Price School of Public Policy and the co-director of the Aging and Cognition Program at the USC Schaeffer Center for Health Policy and Economics, where she’s also a senior fellow and the director of two NIA-funded centers that support innovative social science research on dementia. She recently spoke to us about her research using economic insights to better understand the impact of Alzheimer’s disease on individuals, families, caregivers, and society. On the demographics of Alzheimer’s disease: “People are living longer than ever. So, for example, today about 50 million Americans are aged 65 and older. It was about half that in 1950. And by 2050, US census projects about 20% of the population will be 65 and older. And age is one of the foremost risk factors for Alzheimer's and other dementias. So what does this mean for our future? Well, it means that without new treatments or innovations or ways to prevent or delay Alzheimer's and dementia, the number of persons living with this disease will be about 12 million by 2050. The risk of Alzheimer's is really a risk at older ages and it rises dramatically with age. So for individuals 65 to 79, about 7% of them will have dementia. But in your eighties, the risk of dementia is about 20% prevalence. And by 85 and older, if you live that long, about 40% of those persons will have Alzheimer's. It's also much higher for women than men. And that difference is not explained just by the longer lifespans of women compared to men. It's also about one and a half to two times higher for Blacks, Hispanics, American Indians, and indigenous Americans compared to whites. And we know a little bit about what explains some of the differences by race. Some of its explained by education and prevalence of chronic conditions that are associated with higher risk of dementia, like hypertension and diabetes, but it does not explain it all.” On cognitive assessments at wellness visits “We collected data from a nationally representative sample of older Americans to understand better their use of annual wellness visit and the cognitive assessments. And what we found that was only about a quarter of them who received an annual visit also reported receiving a cognitive assessment. And this was higher for beneficiaries who were in Medicare Advantage-type plans versus those who were in the traditional Medicare plans. And this might have an important indication that these traditional benefit plans, the Medicare benefit plans, where there's direct service-related payment for a set of bundled services, like at the annual wellness visit, may not be a very efficient way to increase our cognitive assessments. We also, I think, have some opportunities to improve our policy around cognitive assessments. Right now there's no guidance about what constitutes a cognitive assessment or how it should be performed. So a clinician can use a structured tool, which we have many of, or they might just ask the beneficiary, the patient, if they're concerned about their memory. And so all of these factors may affect whether we are actually providing good early detection or not.” On the costs of Alzheimer’s “Along with the incredible health toll that Alzheimer's and dementia takes on a person and their families, it also takes an incredible, tremendous financial on the person who's living with dementia and their family. Alzheimer's disease leads to cognitive decline slowly destroying the brain functioning. It also leads for many to behavioral and psychiatric disorders and declines in ability to self-care, functional status. And all of this is extremely, extremely costly. So we estimated the costs for all the persons with Alzheimer's disease, other medical care costs in long-term care costs, and it's about $200 billion. But that's only a partial a portion of the costs. So as I mentioned persons with dementia need a lot of care and much of this care is provided by family...

Marc Vermulst is an assistant professor of gerontology at the USC Leonard Davis School, who focuses on the role of genetic mutations in human aging and disease. He recently spoke to us about how his research into transcription errors, essentially copying mistakes, aims to strengthen vaccines and delay or prevent diseases. On transcription errors …when you go from DNA to a protein, there's a short intermediate molecule that needs to be created, and that is an RNA molecule. And so conceivably you can make the wrong proteins … if a mistake occurs in the process of making an RNA molecule and that process is called transcription. So we study how frequently mistakes occur when RNA molecules are generated and what type of impact that has on aging and disease. When I first started this project the reason why it hadn't been studied much was because there was no technique capable of actually finding them, so it was something that we just could not see. So what my lab did is was we designed a novel tool, a molecular biology tool, that allowed us to find these transcript errors across the entire genome. So it was this massive improvement, and suddenly we could observe things that were previously unobservable and what we discovered with it was that these errors are really, really frequent and when they happen, there are a couple of impacts that they have. The most important one probably is that they result in incorrect proteins and those proteins tend to fold in the wrong way. Proteins are large 3d molecules. In order to function, this long molecule needs to fold in a particular structure. And when you make a mistake in the generation of that protein, because of a transcript error, the protein tends to misfold and as it turns out, misfolded proteins are a key component of numerous age-related diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis. All of these diseases are caused by misfolded proteins. So, what I think that we really found is a new component of the etiology, the origin of all of these diseases. … transcription errors occur a hundred to a thousandfold more frequently than genetic changes. So most of the mistakes that occur in proteins are not due to genetic changes, they are due to these transcript errors. One of the things I'm really interested in is the occurrence of age-related diseases for example Alzheimer's and Parkinson's disease. And one of the major questions is why do people get these diseases? There are families that have a mutation that makes them more predisposed to getting these diseases, but that really only explains five to maybe 15% of all of the cases. The remaining 85 to 95%. We really have no clue why these people get these diseases. So what I'm trying to do is I'm trying to explain these remaining 85%. Because all of these diseases are caused by misfolded proteins, and transcription errors cause these misfolded proteins, I think that we have found a new mechanism that can cause these diseases. And if the mechanism is indeed correct that means we can now do something about it. So it's really about finding the origin of the disease itself in order to be able to design medicine for it. That's one of the major goals. We're also asking when aging actually happens. We have reason to believe that the events that lead to aging can occur many, many years earlier, probably decades. And perhaps in certain cases, the pace of aging is actually set in our twenties or thirties. And that's one of the things we're trying to prove as well, On COVID-19 … one of the reasons why viruses become resistant to vaccines or to drugs is because there is always one viral particle that happens to get a mutation that allows it to be resistant. So one of the major things people want to know about viral particles and different kinds of viruses is how fast do mutations accumulate in the genome of these viruses. And they want to do that for two different reasons. First of all, they want to...

Hussein Yassine is a professor of medicine at the Keck School of Medicine at USC and is uncovering links between nutrition, genes, and risk for Alzheimer's disease. He spoke to us about his research on APOE4, omega-3s and inflammation in the brain. On APOE4 and Alzheimer’s risk So APOE is a gene on chromosome 19. It exists in the population in three different forms. The two form, not very common, the three form, the most common and the four form, which makes about 20% of the population. The four form, if you get one copy from your parents, your chances of getting Alzheimer's disease increased two to four times. If you inherit two copies, meaning you get one copy from mom and one copy from dad, your chances of getting Alzheimer's, or the odds ratio, goes to 12 times, meaning an APOE4 E4 homozygote, uh, 50% of those homozygotes by the age of 80 will have Alzheimer's disease. On the work of his lab My lab is working to understand whether omega-3s can slow down cognitive decline in people at high risk of Alzheimer's disease, based on APOE4. We are working on three different fronts. One, we have basic science models where we study the brains of APOE4 targeted replacement mice. We use brain imaging to study labeled DHA brain uptake in the human brain, and we do clinical trials where we give people omega-3 supplementation and look at outcomes. On omega-3 supplements versus dietary interventions At this point in time, we do not have high quality evidence to suggest that supplements make a difference. But we know from landmark observational cohorts, for example, the Framingham in the US, the Triple C in France, the Rotterdam in the Netherlands, and many others that people who consume at least one serving of fatty fish per week have lower risk of developing Alzheimer's disease. In contrast trials that have involved omega-3 supplements have not panned out. And as we discussed, omega-3 supplements might be too late to be given to patients with neurodegeneration because they may not reverse neuronal death. Giving omega-3s to the general population may prove to be very difficult because the majority of people do not develop Alzheimer's. So we need more research before we can recommend supplements. In addition, we don't know exactly what kind of supplements we should be providing, the exact dose, the composition that duration. More research is needed to figure out those questions. On what can people do to reduce Alzheimer's disease risk I think timing is key. I think if you know that you are at increased risk based on family history or APOE4 genotype nutritional and lifestyle interventions during middle age will provide you likely the most benefit. Our research and others suggest that between the ages of 45 and 65, those at risk individuals should be on certain lifestyle modifications, whether it is at least one serving of fatty fish per week, or some good exercise regimen. We're not talking about marathon running, maybe three times a week, 15 minutes per day is good enough. Lifestyle modifications, no smoking, reduced consumption of simple sugars to avoid complications of diabetes and obesity, increased intake of green leafy vegetables, which are enriched in polyphenols and antioxidants, good sleep, listening to music, certain forms of meditation, or in some individuals praying. And, uh, all of these factors, we know that have positive effect on mitigating or decreasing the chances of getting Alzheimer's. One additional factor that I did not discuss is hypertension or blood pressure control. Blood pressure is known as a silent killer, because people have blood pressure, but they don't know that they do so. Blood pressure control, diabetes control, cholesterol control in middle age together with these lifestyle changes can really pay dividends decades later. Once people start having symptoms and we're talking now 60 to 80, they often come to us and they're talking to us about omega-3 intake, about all these changes. And...

John Tower is a professor of biology and gerontology. He spoke to us about his research on the roles of sex differences and mitochondria in aging. Highlights from our conversation: As you may know, in humans, women live longer than men. And the reason for that is not entirely understood and also malfunction of the mitochondria, which is also called the powerhouse of the cell is, directly implicated in aging and multiple aging-related diseases, including Parkinson's disease and Alzheimer's disease and cancer. And so we'd like to understand at a very basic level, why does the mitochondria malfunction during aging and does this, or does this not have, uh, is this related to, or a result of sexual differentiation of the male and female? While there's no consensus in the aging field on pretty much anything. But, I would say at this point, antagonistic pleiotropy is the most favored model for how the genetics of aging works across species. And the idea is that genes can be beneficial in one context, but detrimental in another context. Specifically they're likely to be beneficial early in life, promoting things like differentiation and growth and sexual reproduction and in the long term, the same genes are detrimental and have a cost during aging. I've made a complete about face, from thinking that sexual differentiation was not important, to thinking that well, maybe sexual differentiation is actually causative to a large part in the aging process. In other words, in differentiating the male and the female, you set up the situation for sex specific trade-offs between reproduction and aging, and some aspects of these trade-offs are common between the male and the female. And some of them are unique to either the male or the female in that there are pathways that promote a reproduction, but then have a cost for the long-term maintenance of the animal. That's the kind of antagonistic pleiotropy my lab is focusing on right now which is the idea that a gene can be beneficial to one sex, but detrimental to the other, or a gene could be detrimental to each sex in different ways Across species, we see a decrease in mitochondrial gene expression and mitochondrial gene function during aging and the relevance to sex is that the mitochondria is transmitted to offspring only through the mother. And so this means natural selection can only optimize mitochondrial gene function for the female. This means that the male inherits a mitochondria that is less optimal for his physiology than, than it might be. And so what we see is that mitochondria isolated from female mammal tissues function better than mitochondria isolated from males consistent with this hypothesis. And so this may be one reason why females tend to live longer than males I think what I would expect is we're going to see sex-specific interventions in aging and aging-related diseases, even diseases common to the male and the female, like Parkinson's and Alzheimer's, that having an intervention that's tailored, to the male or the female will be more efficacious.