In this enlightening episode of Next Act Ninjas, join host Rachael Van Pelt as she delves into the intricacies of aging. Ever wondered why your body changes without your consent or why the fountain of youth remains elusive? Rachael breaks down the most widely accepted theories of aging, from evolutionary senescence to the DNA damage theory, and explores the 12 hallmarks of aging, providing a comprehensive understanding of the biological processes that drive age-related diseases. Discover the potential of emerging anti-aging therapies like NAD+ boosters, metformin, and rapamycin, and learn why lifestyle interventions such as exercise, caloric restriction, and quality sleep are crucial for slowing biological aging. Rachael also highlights the role of AI in accelerating aging research, offering a glimpse into the future of longevity science. Tune in to gain valuable insights into how you can take control of your aging process and improve your healthspan. Whether you're passionate about healthy aging or curious about the latest scientific advances, this episode is packed with practical advice and cutting-edge information. Don't miss out on this chance to empower your health and longevity!
Chapters
00:00 Introduction: WHY and HOW We Age
01:14 Theories of Aging
06:02 The 12 Hallmarks of Aging
12:12 Cellular Aging at the Root of All Age-related Diseases
13:57 Pharmacotherapy Treatments for Slowing Down Aging
19:50 Lifestyle Interventions for Slowing Down Aging
25:08 The Future of Aging Research
Welcome back to Next Act Ninjas, the number one podcast for becoming a master of your health and wealth longevity. I'm your host, Rachael Van Pelt, a retired healthspan scientist turned Realtor and coach. Today, I want to dive into why we age, how we age, and what, if anything, we can do to slow the aging process.
Do you ever wonder why your body keeps changing without your consent? And why the heck can't scientists find the fountain of youth already? It's frustrating, isn't it? As a scientist myself who studied the biology of aging for more than 25 years, I get a lot of questions about why it's so hard to solve the problem of rapid aging. So buckle up because today we're about to explore the science behind aging and what we can do to slow declines, delay disease, and add life to our years.
First, let's talk about WHY we age. Scientists have come up with several theories of aging over the years. These theories are each a piece of a puzzle that explain a part of why we age. Let's break a few of the most widely accepted theories down today.
The first is evolutionary senescence theory. It's one of the more widely accepted theories. This theory suggests that natural selection doesn't influence traits that appear late in life. It only impacts those genetic traits that help us survive and to reproduce while we're young. And this allows harmful genes that promote aging to be passed on to our kids and accumulate over many generations. It's as if your body is a car that's designed to be driven only during your reproductive years, but after that it becomes undrivable.
Now the second theory of aging is the DNA damage theory and/or the mitochondrial damage theory. Over time, our DNA accumulates damage and this leads to cellular deterioration and malfunction. Likewise, damage to mitochondrial DNA leads to cellular decay. You can think of DNA as the instruction manual for your cells. If pages in that manual get torn or smudged, the instructions become unclear and that leads to errors. And because mitochondria are the powerhouse of your cells, when their DNA gets damaged, it's like a power plant losing its efficiency and starts to cause energy shortages.
The third theory of aging I want to talk about is the free radical theory. If you can remember from high school chemistry, free radicals are those highly reactive molecules or atoms that have one or more unpaired electrons in their outer shell. And because of those unpaired electrons, they're highly unstable and they are reactive. Because of that reactivity, they cause a lot of damage to cells, proteins, DNA, and all of that contributes to the aging process. Some free radicals are just natural byproducts of physiologic processes, like your immune response, while others come from environmental pollutants and environmental toxins that put undue stress on your body. You can think of those free radicals as just these tiny little unstable bullies that damage anything they bump into and it wreaks havoc on your cells over time.
The fourth theory of aging I want to talk about is the cellular clock theory. This one is also very popular today. You've probably heard of telomeres. Telomeres are the end caps on your chromosomes and they shorten every time a cell divides. Because cells have a limited number of divisions, those telomeres act as a biological clock that determines cellular aging and lifespan. And when telomeres reach a critically short length, they signal the cell to stop dividing. They enter senescence or cell death. And that effectively marks the end of the cell's lifespan. This is why telomere length is commonly used as a biomarker of aging. You can think of telomeres as like the plastic tips on your shoelaces. As they wear down, the shoelaces, really our cells in this example, they start to fray and malfunction.
Now there are more theories of aging, like the wear and tear theory, the rate of living theory. For the sake of time, I'm not going to cover all of those today, but the bottom line is simply that we have cells that are mutating, we have genes becoming damaged, we have harmful things accumulating and just general wear and tear, all of that adds up to general mayhem in your body. Now it's important to realize that no single one of these theories fully explains the aging process and many of these theories they interact in complex ways. Ongoing research continues to refine these theories of aging and computational advances in AI will eventually allow us to fully unravel the complexity. Maybe one day we'll even find a unifying theory that ties them all together in a useful way.
But in the meantime, even if we can't say precisely why we age, we can explore how our bodies age. Scientists have identified 12 hallmarks of aging. What do I mean by hallmark? What I mean by that is there are biological processes that characterize aging across a variety of organisms. Anything from yeast to flies to worms to rodents to primates. The full gamut. Why 12? Well, originally it was nine and the list just keeps growing. There's lots of overlap, but let's just say in science there are fewer people who are lumpers than there are splitters. Scientists tend towards reductionism. Nevertheless, I do think these 12 hallmarks do a good job of encompassing the many biological mechanisms of aging that we have to contend with if we ever hope to solve the problem of aging. You're going to recognize some of these mechanisms as being key components of the theories of aging that we just talked about.
Now the first hallmark is genomic instability. DNA damage accumulates over the years and this leads to errors in cell function across the board.
The second hallmark is telomere attrition, what we just talked about, those telomeres, they continue to shorten making cells more prone to malfunction.
The third hallmark is epigenetic alterations. We start to see changes in how our genes are expressed. That is, which ones are turned on and which ones are turned off. And this affects how we age. Even without any kind of changes in our DNA sequence itself, it's whether those genes are turned on and off.
The fourth hallmark is loss of proteostasis. We generally see declines in protein function and maintenance. Proteins misfold, they clump together, and that can lead to cellular dysfunction.
Fifth hallmark is deregulated nutrient sensing. Over time, our cells lose the ability to properly sense nutrients, to gauge and respond to nutrients like glucose and insulin, that sort of thing. And that can lead to misinformation. For example, cells start thinking they're starving amidst an abundance of sugar in the blood. We see that with diabetes, right?
Another hallmark of aging is mitochondrial dysfunction. Mitochondria, as we said before, are those powerhouses of the cell. When they start to fail, they become less efficient producing energy. And this leads to all sorts of downstream problems in energy metabolism.
Seventh hallmark of aging is cellular senescence. Senescent cells are old, they're dead cells. They accumulate and they clog up our cellular machinery. They're like zombies that are hard to get rid of.
Eighth hallmark of aging is stem cell exhaustion. Stem cells are highly valuable because they can become whatever cell that the body needs them to be. This is particularly important for regenerating tissue after injury. So when we begin to lose those stem cells, our body's ability to repair and renew goes down with time, it diminishes.
Another hallmark of aging is altered intercellular communication. Over time, our cells stop talking to each other. They stop signaling to each other. And that leads to all sorts of miscommunication. Kind of like some old married couples, right?
All right, the 10th hallmark of aging is chronic inflammation. A short rapid inflammatory response is important for a healthy immune function, for cellular repair, but when low grade inflammation persists over time, it's like a slow burning fire that causes lots of tissue damage over time. And that becomes a problem.
And the 11th hallmark of aging is disabled macro autophagy. Autophagy is the cell's self-cleaning process. When this process becomes impaired and cells can't clean up their mess, it leads to accumulation of more damage over time. Starting to see a theme, don't you?
The 12th hallmark of aging is dysbiosis. You've probably heard of gut dysbiosis. Your gut microbiome is made up of trillions of bacteria, some of them good, some of them not so good. And they impact everything in your body from your immune fit function to your brain function, to nutrient sensing, to epigenetics. When your microbiome is chronically out of balance, this negatively impacts your overall health and it accelerates many aging processes.
In short, there's just a lot of biological mechanisms of aging. And because there are many overlapping biological pathways, there's many redundancies in our body, many counterbalancing actions, these 12 hallmarks, they're hard to untangle. The overlap and the synergies are why our miraculous bodies works as well as they do. But it also gives you a bit of an idea of why solving for aging is not so easy.
WHY we age and HOW we age is incredibly complex. Now the good news is YOU don't need to solve the problem of aging. You can leave that to scientists to unravel. I have no doubt that AI is going to accelerate scientific progress in each of these areas separately and as a whole. The likelihood that we reach longevity escape velocity gets more and more real every day.
But I do want you to have a feel for the underlying biology of aging because it is these underlying mechanisms that DRIVE all age-related disease. That includes cancer, cardiovascular disease, heart disease, stroke, diabetes, neurodegenerative disease, dementia. Once you fully comprehend this, then it becomes obvious that the current medical approach is dealing with things far too little too late. It becomes a game of whack-a-mole, doesn't it? And we just try to knock each of those diseases down over time.
Treating disease after the fact is being reactive rather than proactive. Age-related diseases are all downstream of the real problem. Even so-called disease prevention is what I would call secondary prevention. Catching someone with pre-diabetes and trying to keep them from converting to full-blown diabetes, that's great, right? But it's not going to slow the aging process. It's just reacting to one of the many symptoms of aging that's been percolating for decades. On the other hand, if we can address the root cause of cellular aging that underlie those so-called age-related diseases, now we're getting somewhere. Now we can truly move towards primary prevention. In other words, by slowing cellular aging, we can circumvent most age-related diseases altogether.
Now, how might we do that? I want to explore a few of the exciting pharmacotherapy treatments that we think might help slow down aging at the cellular level. But first, before we dig in, I do want to point out that most of these therapies I'm going to cover today are in the infancy phase. They're still in what we call pre-clinical trials, meaning they have only been tested in animal models so far. Clinical trials in humans have yet to be started. Or if they've been started, they're just in that safety and efficacy stage of study. That being said, let's talk about a few that you have probably already seen pop up on the internet. In fact, many are already being marketed as the latest and greatest anti-aging elixir despite lack of data in humans.
The first real promising pharmacotherapy intervention that's being tested are NAD+ boosters. NAD is short for nicotinamide adenine dinucleotide, it's a mouthful, isn't it? But cellular NAD+ is an essential metabolite and co-substrate for a number of metabolic reactions and it declines with aging. So by boosting NAD+, we think we might be able to improve a bunch of the hallmarks of aging that we just talked about, including genomic stability, mitochondrial function, and intercellular communication. Animal studies have shown promising results for extending lifespan and for brain health. But human studies are still limited. You may see products on the market already like NMN that can boost NAD +, but really there's little evidence so far in humans that it has much, if any, effect on many biomarkers of aging that we track. But stay tuned. The animal studies have been remarkable.
Metformin, that's another pharmacotherapy treatment that's being studied intensively right now. Metformin is an insulin sensitizing drug that's used to treat diabetes and it works through the AMPK pathway. This pathway is intimately involved in many aspects of cellular metabolism and autophagy. Cellular AMPK activity generally declines with aging across the board and studies in animals suggest that AMPK can impact longevity. That's why there's currently a large clinical trial underway called the TAME trial. You may have heard of it. It's testing whether metformin can be given to healthy, non-diabetic older adults to slow cellular aging. But, we're not going to know the results of those studies for a while yet, so don't run out and ask your doctor for metformin just yet.
Another class of drugs that's being studied intensively is senolytics. They're drugs that eliminate those senescent cells we talked about, the dead cells that are no longer able to divide. They clog up the machinery, right? There's a lot of evidence in animal models that eliminating those senescent cells may improve healthspan, improve cardiovascular fitness, a number of things. The initial studies, they've shown a lot of promise in reducing inflammation in patients as well, human patients who have lung disease, kidney disease, but there've been no long-term studies just yet, no clinical trials in otherwise healthy individuals. So the jury's out on that one yet.
Rapamycin is another drug that's being studied intensively. Rapamycin is an mTOR inhibitor that's been shown promise in delaying aging in animal models. mTOR is a protein kinase. It's involved in various aspects of cell function, metabolism, protein synthesis, and researchers are investigating the effects of rapamycin on a variety of biomarkers of aging in humans, including epigenetic markers, cellular senescent markers, inflammation, proteostasis, mitochondrial function, all of the hallmarks that we've just been talking about.
So you can imagine, given the benefits of each of these anti-aging therapies by themselves, it's probably not surprising that now studies are even exploring whether we can combine the effects of these things, combination therapies, because of the potential synergistic effect of these interventions. For example, there're studies that are combining rapamycin with metformin and/or NAD+ supplementation. But these kinds of cocktails are still very much in the experimental phase. So again, don't expect your doctor to prescribe them to you anytime soon.
Now there are other emerging technologies that are still in the experimental stage of testing and that are showing promise in animal models. They include things like growth hormone signaling inhibition, gene therapy, cellular reprogramming. You may have heard chatter about these on the internet, but they're again, not ready for prime time.
In a nutshell, there are lots of promising drugs therapies that are at various stages of research and development, but most of them are far from being ready for safe daily use in humans. But I don't want you to wait until we find the perfect anti-aging drug anyway, because lifestyle interventions such as exercise, nutrition, sleep, they improve the vast majority of the 12 hallmarks of aging we just covered. It's highly unlikely we're going to find a drug that hits all 12 hallmarks, and if anything, it's probably going to be a cocktail of things in combination with lifestyle that's going to be most effective. So you may as well tackle lifestyle now.
And one of the lifestyle things that I'd like to tackle first is caloric restriction. That's been studied the most over the years. In fact, we've known for more than 70 years that caloric restriction increases lifespan in many organisms, yeasts, flies, rodents, you name it. When you feed organisms and animals 20-30% less food throughout their life, they simply live longer. Caloric restriction has a dramatic impact on nearly all of the hallmarks of aging that we just talked about through a variety of molecular mechanisms.
Does it work in humans? We don't know because we can't exactly take someone when they're young and make them eat 20-30% less food their entire lifetime, can we? So it's hard to replicate the animal studies. In fact, I was one of a handful of scientists who tried to come up with a solution for this. We tried to figure out a good way to study caloric restriction in humans short term. Unfortunately, the best we could do was essentially just a prolonged weight loss intervention, something we already knew would improve many biomarkers of aging. So we don't really know if a lifelong caloric restriction would extend human lifespan. But what we do know is that many centenarians living in Blue Zones naturally have a lifelong practice of eating less. For example, Okinawans. Okinawa is a hot spot in the world for centenarians, for people who live to 100 and beyond, right? For Okinawans, they have a practice of stopping eating when they're about 70-80% full. It's called hari hachi bu. I'm sure I butchered that! But we think this natural practice of caloric restriction is likely one of the reasons they live so long.
But even if you haven't restricted your calories your whole life, the science does suggest that there's probably a benefit to starting late in life because we do see many of those hallmarks of aging improved when you cut back on your calorie intake. So if you want to slow your own biological aging, you might consider caloric restriction. But I want you to be aware that maintaining muscle mass is critical to your healthspan and your long-term mobility, something that most of those animal studies don't consider, right? And unfortunately, caloric restriction can accelerate muscle loss if you aren't actively working to preserve it. That's where exercise comes in.
Exercise is the other important lifestyle factor that's been studied extensively when it comes to lifespan and healthspan. Interestingly, when you compare exercise with caloric restriction, lifelong exercise doesn't seem to have the same impact on lifespan in animal models at least. But we do know that regular physical activity does improve most of the hallmarks of aging and through a wide variety of molecular pathways, again, like caloric restriction. It also helps to preserve muscle mass and it prevents, or slows the progression of, nearly all age-related diseases. So while it may not increase the number of years you live, we have lots of data in humans that it improves the quality of your years. So you're improving healthspan more than you're improving lifespan with exercise.
Sleep quality, that's the other aspect of lifestyle that we want to talk about. It's newer to the study of longevity. Deep sleep, also known as slow-wave sleep, it's crucial for cellular repair and regeneration. And enhancing deep sleep can potentially improve things like genomic stability, proteostasis, mitochondrial function. Better sleep also improves circadian rhythms and hormones that are known to impact pathways related to nutrient sensing and intercellular communication. In fact, a recent large study in about 172,000 men and women found that those who adhered to healthy sleep habits were significantly less likely to die prematurely from various causes like cancer or cardiovascular disease. And they had increased life expectancy of about two to five years, depending on whether you're looking at men or women. That's pretty remarkable. And I think we're going to see more data emerge in the coming years about the importance of high quality sleep for longevity.
The bottom line is chronological aging may be inevitable, but biological aging is not, it's modifiable. We may not have discovered the fountain of youth just yet, but the more you understand why we age and how we age, the more power you have. The scientific advances are coming, but don't fall for the snake oil sales pitch just yet. Focus on healthy lifestyle changes for now, because we know they work. They're low risk. Then when the good science emerges for a specific pharmacotherapy, it's going to just be icing on the cake, won't it? Is it going to happen in our lifetime? I don't know, but I think so.
Current advances in AI are poised to massively disrupt aging research. There may be too much complexity for traditional scientific methods to tease apart, but I believe that the sophistication of algorithms and the incredibly powerful compute, they're going to allow us to detect patterns in the data we never would have imagined. Stay tuned. It's going to be a wild ride.
Thanks for joining me today on Next Act Ninjas. Remember to stay curious, stay active, and stay young at heart. If you enjoyed this episode, please be sure to share, like, and subscribe. Leave a review as well. Share with someone you know who's passionate about healthy aging. If you're ready to massively reboot your health longevity, let's chat. Use the link in the show notes below to hop on my calendar and let's see if I can help. In the meantime, live well, love more, age less, my friends.