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The Role of Advanced Glycation End Products in Aging and Disease. Podcast with Pankaj Kapahi

Have you ever wondered what makes cinnamon rolls so irresistible? I don’t know about you, but whenever I walk past a Cinnabon, I am bombarded by an unmistakable and mouth-watering aroma.

But what exactly makes them smell and taste so wonderful? The ingredients alone don’t explain it. Like, if I put white flour, hydrogenated oil, artificial flavors, cinnamon, and sugar (a lot of sugar) in a bowl, it wouldn’t produce that characteristic Cinnabon fragrance, nor would it taste particularly good.

You can see where I’m going with this. Obviously, the cooking process is the mediating factor here. More specifically, I am referring to the Maillard reaction. When amino acids and reducing sugars are exposed to high heat, hundreds of flavor compounds are generated. Food generally becomes browner, and it tastes and smells extra enticing. And this feature is obviously not exclusive to cinnamon rolls. The scent and flavor of roasted coffee, toasted marshmallows, fried bacon, grilled burgers, freshly baked bread, are all results of this chemical reaction.

Humans almost universally gravitate to foods that have been exposed to this process. However, our affinity for these compounds is a bit of a paradox, because of the negative long term effects that they seem to have on our health.

On this episode of humanOS Radio, we welcome Pankaj Kapahi to the show. Pankaj is a professor at the Buck Institute, an independent biomedical research institute that is devoted solely to research on aging. He and his team have also begun to investigate the role of advanced glycation end products (also known as AGEs) in the aging process. Advanced glycation end products are compounds that are formed when proteins or lipids become glycated, as a result of being exposed to sugars.

As I mentioned above, this has been carefully studied and exploited by the food industry for decades, because of its appealing effects on sensory qualities of food. However, it was only recognized comparatively recently that AGEs may impair our health and function over time.

Aptly enough, the formation and accumulation of AGEs is a hallmark of age. AGEs wreak havoc by binding with cell surface receptors and cross-linking with body proteins, altering their structure and function. This produces a range of deleterious effects throughout the body.

So, how can we reduce our exposure to advanced glycation end products in the food that we eat? And how can we control the formation of AGEs inside the body? To learn more, check out the interview below!

Interpersonal Neurobiology and the Power of Mindsight. Podcast with Dan Siegel

What is the mind? This is a question that has inspired intense debate for centuries.

We tend to think of the mind as being our thoughts, feelings, and other cognitive faculties. But some would argue that this is a relatively narrow view, in light of our history as social organisms. Our brain evolved, at least in part, as a processing system for social information.

The mind does not just encompass what is within us – it is also between us. And that brings me to our guest for this episode.

On this episode of humanOS Radio, Dan talks with Dan Siegel. Dr. Siegel is a clinical professor of psychiatry at the UCLA School of Medicine. He is a pioneer in a field known as interpersonal neurobiology (sometimes referred to as relational neuroscience). Interpersonal neurobiology characterizes human development and function as a product of interactions between the body, the mind, and relationships with one another.

Dan is also the executive director of the Mindsight Institute, a unique educational organization that provides online learning and in-person lectures that examines the interface of human relationships and basic biological processes, with the goal of cultivating mindsight in individuals, families, and communities. Mindsight is a theoretical construct that is closely related to theory of mind. However, mindsight goes beyond merely being able to conceive of one’s own mind and that of others. Mindsight refers to the capacity to sense patterns of shared communication of energy and information change within relationships.

It also captures the ability to recognize our emotions without being consumed by them. An illustration of this concept, commonly cited by Dr. Siegel, is the subtle difference between “I am sad,” as opposed to “I feel sad.” The latter implies recognition of a feeling you are experiencing in the moment – a state that isn’t permanent, and to which you can control your response.

As you might imagine, mindsight and the intricacies of interpersonal neurobiology are very challenging concepts to understand and research, at least using the tools currently available to biologists and scientists, which is why Dr. Siegel’s work in this area is so valuable. To learn more, check out the interview!

Sleep and DNA Repair. Podcast with Lior Appelbaum.

Sleep is a paradox – or at least it seems that way when examined from an evolutionary standpoint.

When we’re asleep, we have diminished awareness of our surroundings, leaving us vulnerable to predators and other threats in the environment. Lying down with your eyes closed for eight hours also seems like a frustratingly unproductive behavior.

Despite the obvious disadvantages, we spend about a third of our life in slumber. And not just us – some form of sleep seems to be just about universal in the animal kingdom. And as everyone knows all too well, disturbances to sleep can have a serious negative impact on our physical and mental health.

The universality of sleep, in the face of its costs, suggests that sleep is extremely important. But why precisely do we need it so much?

It has been suggested that sleep may play a role in DNA repair. For example, a study from earlier this year found that on-call doctors who were required to work overnight showed a decrease in DNA repair gene expression, compared to doctors who did not work overnight. Just a single night of sleep deprivation resulted in greater DNA damage, in the form of double-stranded DNA breaks.

In this episode of humanOS Radio, Dan speaks with Lior Appelbaum. Dr. Appelbaum is an associate professor of Life Sciences at Bar-Ilan University in Israel.

Lior and his team performed a series of elegant experiments using zebrafish to elucidate how sleep facilitates DNA repair. They genetically engineered zebrafish to express colorful chemical tags on chromosomes within their neurons, making it easier to identify and monitor them. Then, using a high-resolution microscope, they followed the activity of these chromosomes while the zebrafish were awake and asleep. What they found could reveal the fundamental purpose of sleep, and might explain why sleep is so crucial for cognitive performance and brain health. Check out the interview to learn more!

Does Metformin Block the Health Benefits of Exercise? Podcast with Ben Miller

Physical exercise is one of the best anti-aging interventions at our disposal. Research has shown, for instance, that cardiorespiratory fitness is one of the strongest predictive factors for survival into old age. In one study, men with the lowest exercise capacity were 4.5 times as likely to die within the follow-up time period, compared to those with the highest exercise capacity. And in men aged 75, exercise capacity was the most powerful predictor of survival to age 90, exceeding that of conventional risk factors like smoking, high blood pressure, total cholesterol, and obesity.

So if you want to live a long and healthy life – and who doesn’t? – exercise is a key tool to make that happen. But in order to further push the limits of lifespan and healthspan, it is thought that pharmaceutical drugs to target the aging process may be needed.

One well-elucidated candidate is the anti-hyperglycemic drug metformin. While it has classically been used to help control blood sugar in people diagnosed with diabetes, it has recently emerged as a possible anti-aging drug. This is largely because systematic reviews of the literature have found that patients with diabetes who take metformin have reduced risk of cardiovascular disease, cancer, and all-cause mortality – not just compared to other people with diabetes, but even in comparison to non-diabetics! It appears to extend lifespan and augment health independent of its effect on diabetes.

But some have wondered if metformin might come with some serious downsides, particularly with respect to the aforementioned health-promoting effects of exercise. Our guest today endeavored to answer that question with his latest study.

On this episode of humanOS Radio, we welcome Ben Miller to the show. Ben is a principal investigator in the aging and metabolism research program at the Oklahoma Medical Research Foundation.

In his study, Miller and his team randomly assigned 53 participants to consume either placebo or metformin for 12-weeks, while completing a supervised aerobic exercise program. This exercise regimen elicited measurable improvements in blood sugar control, insulin sensitivity, and aerobic fitness for the volunteers, as you would obviously expect. But when the groups were compared, some meaningful – and troubling – differences emerged. Check out the interview to learn more!

Optimizing Your Gut Microbiome with Personalized Probiotics. Podcast with Richard Lin

We like to think of ourselves as wholly distinct organisms – separate from the environment around us, and independent of other organisms.

But zoom in closer, and the truth is far more complicated.

We have vital symbiotic relationships with an unfathomable array and quantity of microorganisms on us, and within us. Perhaps the best known example of this phenomenon is the gut microbiome. The number of microorganisms inhabiting the gut has been estimated to be around 10 times more bacterial cells than human cells. Wow!

Given their staggering numerical superiority, it really shouldn’t be terribly surprising to learn that the amount and types of bugs you carry in your gut can make a big difference in how you feel and perform. But it is only in the last fifteen years or so that technology has enabled us to fully appreciate the far-reaching influence of the gut microbiome in human health. And as we’ve learned about ways to modulate the gut microbiota, this has become an area of tantalizing potential.

Consequently, many tools have emerged that purport to enhance the composition and functional properties of gut microbes. Commercial probiotics – live cultures meant to colonize the gut with “good” bugs” – have skyrocketed in popularity. At the same time, companies have also emerged that offer personalized analysis of the microbial content of fecal samples.

However, the human microbiome remains an enigma in many ways. For instance, by what criteria can we identify what is a “healthy” versus an “unhealthy” gut microbiome? And even if we are able to make such determinations, are we able to make lasting improvements?

That brings me to our guest.

On this episode of humanOS Radio, Dan speaks with Richard Lin. Like all too many of us, Richard became personally invested in his health when he developed a problem that failed to respond to conventional medical interventions. He eventually realized that a disruption in the gut microbiota was the likely cause of his illness. This inspired him to start Thryve Inside.

Thryve helps consumers test and learn about their own microbiota by providing at-home microbiome test kits. But here’s what sets Thryve apart: they don’t just give you information, they also endeavor to provide solutions. Thryve offers monthly subscriptions of personalized probiotics to customers, which are formulated based on their microbiome and their individual health goals. To learn more about Thryve, and the future of microbiome testing and probiotics, please check out the interview!

Increasing Mitochondrial Autophagy for Better Aging. Podcast with Davide D’Amico

You probably associate getting older with a loss of energy. And on the molecular level, this is quite literally true, because one of the hallmarks of aging is mitochondrial dysfunction. Mitochondria are often referred to as “the powerhouse of the cell,” because they convert nutrients from the food we eat into usable energy, in the form of ATP. But as we age, mitochondria become less effective at generating the energy we need for various chemical processes.

So why does this happen? As with most things in biology, there are definitely multiple factors at work here. But one likely reason is a failure of quality control. As we age, mitochondrial autophagy (aka mitophagy) declines, and our body starts to accumulate broken and dysfunctional mitochondria. This becomes most obvious in tissues that consume a lot of energy, like skeletal muscle. Hence, mitochondrial dysfunction is linked to poor muscular strength in older people. If we could find a way to ramp up mitophagy, perhaps we could retain excellent mitochondrial function throughout our golden years.

That brings us to our guest. In this episode of humanOS Radio, we welcome Dr. Davide D’Amico to the show. Davide is a research scientist in the field of metabolism and aging. He was previously a post-doc at the Auwerx Laboratory of Integrative Systems Physiology at the École Polytechnique Fédérale de Lausanne (EPFL), where he investigated the role of mitochondrial function in health, disease, and the aging process.

In this interview, we discuss a recently published study from his team, which revealed one of the molecular mechanisms through which defective mitochondria accumulate in cells. Additionally, Davide is a scientific project manager at Amazentis, where he is investigating a naturally derived bioactive from pomegranate, that has been shown in a new clinical trial to reverse age-related decline in mitochondrial function in the muscles of older people. Please check out the interview to learn more about this exciting research!

The Epigenetic Clock: Are You Biologically Older or Younger Than Your Chronological Age? Podcast with Ken Raj

We tend to think of age in terms of the number of years we have been alive – meaning our chronological age. But the year that you were born is not necessarily an accurate measure of your health or your life expectancy. We are coming to realize that a better predictor is your biological age – and that can be quite different from your chronological age. So how do you learn your biological age? And what can you do with this information?

In this episode of humanOS Radio, I speak with Ken Raj. Ken is a Senior Scientific Group Leader at Public Health London, and has worked extensively with Dr. Steve Horvath of UCLA in developing and interpreting genomic biomarkers of aging. They are best known for developing the “epigenetic clock,” a tool that predicts life expectancy by examining age-related changes to DNA methylation, then using that information to calculate biological age in relation to chronological age. The epigenetic clock is able to predict life expectancy with remarkable accuracy, with a margin of error of plus or minus three years.

In this podcast, we discuss:

-How the epigenetic clock uses DNA methylation to compare biological to chronological age.
-Whether DNA methylation changes are the “drivers” or the “passengers” of biological aging, and how direct a role they play in the aging process.
-Whether or not epigenetic changes can be passed down from generation to generation.
-Whether or not someone with a biological age greater than their chronological age is more likely to develop certain pathologies.
-What diet and lifestyle factors have been researched to show an impact on epigenetic aging.

To learn more, check out the blog!

Is the Ketone beta-Hydroxybutyrate Good for Memory? Podcast with Professor John Newman from UCSF and The Buck Institute

Our memory is fundamental to us as humans. The remarkable capacity of the human brain defines us as a species. And variation in our minds is one major aspect of what makes each of us different from one another. Without a robustly functioning memory, our ability to interact with the world – and to relate to one another – is seriously impaired.

We can carry on relatively well if we lose a limb, or even certain organs. But if our memory is erased, we are erased, in a sense.

Everyone knows this on some level. This is likely one reason why large surveys of the public often find that dementia is the most feared disease – because our mind and our memory so profoundly defines us.

But another reason why diseases associated with aging and the brain are so feared is because they are recalcitrant to treatment. For example, drugs developed to address Alzheimer’s disease have the highest failure rate of any disease area (99.6%). And the situation isn’t much better for other neurodegenerative conditions, or for age-related cognitive decline in general. We need a new approach.

In this episode of humanOS Radio, I speak with John Newman. Dr. Newman is a geriatrician (a physician who specializes in the care of older people) at UCSF, as well as a professor at the Buck Institute for Research on Aging. He is chief investigator at the Newman Lab, where he is exploring ways to harness metabolic signals to promote health and resilience, particularly in older adults.

Dr. Newman’s research focuses predominantly on ketone bodies – molecules produced in the liver when glucose is scarce, either due to restricted intake or prolonged physical activity. So we tend to think of them primarily as an alternative source of fuel, particularly in the context of a low carb diet. However, they are also intriguing with respect to aging, because of how they function as molecular signals, and how they influence gene expression.

In this podcast, we discuss:

-How ketones are generated in the body

-Why most medical doctors tend to think of ketones as being harmful

-How beta-hydroxybutyrate influences gene expression – turning on or off genes

-How gene expression goes awry in the aging process

-How BHB functions as a signaling molecule to regulate inflammation

-Why animals on ketogenic diets live longer and exhibit better memory as they age

-Ketogenic diets and aging/longevity

-Why exogenous ketones are exciting but there is much yet to learn about them before we fully understand their therapeutic potential

Is the Paleo Diet Good or Bad for Aging? Podcast with Professor Michael Rose

Why do we age? The fundamental causes of aging at the molecular level are relatively well established. But the question of why aging happens in the first place is a more challenging one, one which has bedeviled evolutionary biologists and philosophers for years.

You might think, intuitively, that the process of natural selection would gradually eliminate senescence. Aging increases mortality, and organisms that experience impaired function and ultimately die would not be able to produce as many offspring as one that was able to live (and to reproduce) indefinitely, or at least for a much longer timespan. So, you would assume that this would result in selection for organisms that live much longer, generate more offspring, and ultimately the causes of age-related deterioration would fade from the genome.

Yet aging is very commonly observed. Why is that?

Natural selection is strongest in early life. This makes sense – the natural environment is full of predators, disease, and other perils that often kill organisms when they are young and vulnerable. Consequently, genes and pathways that enhance survival and reproduction in early life are likely to be favored – even if they come at the cost of problems later in life, when selection is comparatively weak.

But is aging inevitable? Can it be slowed, or postponed, or stopped altogether?

In this installment of humanOS, Dan talks with Michael Rose. Dr. Rose is a Distinguished Professor of Ecology and Evolutionary Biology at UC Irvine. He is a prolific biologist whose research into the evolution of aging has effectively transformed that field. Rose’s laboratory has been testing the theory of antagonistic pleiotropy for nearly forty years, through artificial selection experiments in fruit flies.

In what was perhaps his most famous experiment, Rose allowed flies to only reproduce successfully if they laid their eggs late in life. He discarded the eggs of any flies that laid eggs before they reached fifty years of age. Over a few generations, this population of flies evolved longer lifespans. Why might this be? Remember that natural selection is strongest early in life, and becomes weak later on. In theory, if adults reproduce when they are older, natural selection is apt to favor genes that enhance resilience (and reproduction) later into the lifespan.

Dr. Rose’s research into aging has also drawn him to some interesting (and possibly controversial) notions about evolutionary changes in the human diet, and how our age may influence how adapted we are to modern agricultural foods. To learn what that means, and its potential implications, check out the interview!

Studying Preindustrial Societies Informs us About How to Be Healthy. Podcast with Professor Herman Pontzer

For the vast majority of human history, our species lived hunter-gatherer lifestyles. We can therefore learn much about how humans probably once lived by studying preindustrial societies.

Research on preindustrial societies has consistently shown that these people have exemplary health. And when we consider that modern humans are succumbing to chronic diseases at an alarming rate, we clearly have much to learn from preindustrial people.

In this episode of humanOS Radio, I speak with Professor Herman Pontzer about what he has learned from his research on hunter-gatherers. Herman’s findings led him to develop the counterintuitive hypothesis that how physically active we are each day may scarcely affect how many calories we burn in the long term…

… no, I’m not kidding.

As he explains in the podcast, however, this hypothesis in no way discounts the importance of being physically active – far from it!

Tune in for more on Herman’s fascinating research on physical activity, diet, and more.