134: Why Your Cells Age (And What You Can Do About It) with Dr. Ben Bikman

There are two master switches inside your cells that influence how fast you age. They're called AMPK and mtor. AMPK turns on when energy is low. It tells your cells stop building and start repairing. MTOR turns on when food is abundant. It tells your cells that it's time to grow, build and divide. Here's the problem. Modern life keeps MTOR turned on all day. Constant food, constant insulin, constant growth, time that crowds out repair. Aging slows when we periodically shift the balance back toward AMPK through things like time between meals, lower insulin exposure, and giving cells a break from constant growth. Longevity isn't about a magic pill. It's about knowing when to build and when to clean and aligning your habits with that natural rhythm. This is lecture 134 of the Metabolic Classroom. Welcome back to the metabolic classroom. I'm Dr. Ben Bickman, metabolic scientist and professor of cell biology. In this mini lecture, I want to teach you about two molecular master switches that control how your cells age, grow and even survive. These two signals are AMPK and mtor. And I guarantee that by the end of this episode, you'll understand why these two pathways may hold the key to extending not just lifespan, but more, I would say, health span. These two pathways are essentially opposites. They are like a cellular seesaw. When one is up, the other is going to be down. And the balance between them may determine whether your cells are building and growing, or cleaning house and repairing. Even if you've heard about the so called longevity drug rapamycin, or you've wondered why metformin keeps showing up in anti aging research, or even maybe you've heard me talk about all the benefits of ketones. All of these tie directly into AMPK and mtor. But I want to be clear from the start, understanding these pathways doesn't mean we have a magic pill. In fact, as we'll discuss, the pharmaceutical approach to manipulating MTOR comes with some serious concerns. So let's break all of this down. Let's start with ampk. Speaking of breaking things down, AMPK stands for AMP activated protein kinase. Think of AMPK as your cells fuel gauge or some kind of energy sensor when cellular energy is low. And by that I mean ATP. So I mean ATP levels have dropped and AMP levels rise. AMP is a product of breaking down ATP. I know nowadays a lot of people use the term cellular energy mostly because it sounds so cool, but I'm using it very deliberately. I mean ATP, which is the actual molecule that the cell is breaking in order to get work done. So when ATP is low, or back to what I said previously. Cellular energy is low. AMPK gets activated and it essentially sends a very clear message to the cell and all of its other metabolic machinery, which is we're running low on energy. It's time to stop building and start burning. When AMPK is activated, thus, several critical things will happen. First, it stimulates catabolic processes, the pathways that break things down to generate ATP, like for example, fatty acid oxidation. Your cells will start burning more fat for fuel. Second, AMPK will inhibit anabolic processes, the energy consuming pathways that aren't immediately necessary for the survival of the cell. So things like building new proteins or making new fats. But here's where it gets really interesting for aging. AMPK also activates autophagy, the cellular housekeeping process, where your cells clean up damaged proteins and dysfunctional mitochondria. This is absolutely critical. As demonstrated in a really clever 2012 paper. AMPK controls autophagy through direct regulation of MTOR and and another protein, ulk1 signaling, which augments the quality of what we might call cellular housekeeping. AMPK also improves the stress resistance within the cell through the activation of transcription factors like Fox O, NRF2, as well as SIRT1. SIRT1 is a big one when it comes to aging. It suppresses inflammation, also through inhibition of NF Kappa B signaling. That's a protein that we've talked about quite a bit in the metabolic classrooms in the past. In essence, AMPK is your cellular guardian of longevity. And here's the problem. Emerging studies indicate that AMPK responsiveness clearly declines with aging as we get older. In other words, our cellular fuel gauge becomes less sensitive. This impairs the metabolic regulation and increases oxidative stress and reduces that critical process of autophagy. Now let's get to the other side of what we could call the seesaw, which is mtor. MTOR stands for mechanistic target of rapamycin. If AMPK says it's time to burn or break things down and clean house, MTOR says it's time to build and clutter up the place with more molecules. MTOR is a serine threonine kinase. It and it integrates multiple signals from nutrients, so it can respond to nutrients when they come to a cell. Growth factors and energy status to control cell growth. Things like protein synthesis, fat synthesis, like I mentioned, and even metabolism. It exists in two distinct complexes. Mtorc. That's where the torc, t, o, r, c, now mtorc1 and mtorc2. And again, the the c stands for complexes mtorc1 and mtorC2. For our purposes today, I'm primarily focused on mtorC1, which is the nutrient sensing complex. When nutrients are abundant, particularly amino acids and glucose, MTORC1 is activated. It then promotes protein synthesis by phosphorylating or activating targets downstream, other downstream signals. The effects of that are, for example, one being that it can stimulate the synthesis of things like ribosomes and many, many other proteins. But the ribosome being very important for the growth and proliferation or multiplication of the cell, and importantly to bring back in an effect I mentioned a moment ago. When MTORC1 is turned on, it inhibits or suppresses autophagy. And there is within this then some key insight for aging. When MTOR activity is balanced and appropriately regulated, cells can maintain normal glucose and lipid levels. They're sensitive to insulin, they have reduced stress and toxicity, and they have a balanced cell cycle. So they know when it's time to grow and when it's time not to. The result is improved overall health and prolonged lifespan. But when MTOR becomes hyperactive, and this happens with chronic nutrient excess, we see elevated glucose and lipid levels. We see insulin resistance, increased cellular stress and disrupted cell cycles. These disruptions directly contribute to metabolic diseases like diabetes and obesity. And as the theory goes, it accelerates aging. Now, it does go beyond theory, depending on the model, which I'll get to in a moment, but the takeaway here is that MTOR is essential for growth and repair, but chronically elevated MTOR activity is a likely driver of aging and age related disease, at least in non human models. And this brings us to rapamycin as a good example. And I want to address this head on because there is a lot of hype in the longevity space about this drug. Rapamycin specifically inhibits MTORC1 in the animal. Research is genuinely impressive. I won't dismiss that. But I am very skeptical about translating that research and those findings to humans. And let me tell you why. First, let's acknowledge the animal data. In 2009, there was a very good paper published in Nature showing that rapamycin extends lifespan in mice even when it started later in life. Subsequent studies showed even larger effects at higher doses, with lifespan increasing up to 25% in some experiments. Those are significant findings in mice. But here's the critical point that often gets lost in the enthusiasm. We have no evidence that rapamycin extends lifespan in humans. None. Zero. The mouse findings have not translated to human longevity data. And there are good reasons to be Concerned they never will. We do have in humans a concerning picture of the side effects and one that troubles me greatly is the gonadal toxicity. Rapamycin and its analogs. These drugs that are cousins of rapamycin or siblings, to make it even closer, they cause significant damage to reproductive function in both men and women because of the direct damage to the gonads, of course, the gonads being testes in men, ovaries in women. This isn't a minor inconvenience, but rather a reflection of some very serious harm that I think anyone should admit is fundamental to biological systems. In men, MTOR inhibitors cause decreased testosterone levels and disrupted spermatogenesis. At the same time, there's increased LH and fsh. Those are signals that come from the brain that are kind of surveying. The brain is the higher order manager of all the things that are happening in the body. And when it comes even to processes like producing testosterone or adequately producing sperm, the brain is monitoring this and it will send signals down to the testes accordingly. So if you find that the testosterone levels, for example, are low, then the brain signals going down to the testes are really high. That indicates that the testes are not responding properly to the signals from the brain. In other words, the testes are broken, if you will. They've disrupted this axis or this signaling axis. Clinical reports have documented that these drugs, that there is an infertility in men associated with the use of these drugs, what's described as gonadal dysfunction. These drugs are used in humans, especially in transplant patients. But even further, rapamycin induces seminiferous tubule dystrophy and spermatogenesis blockade. We're talking about testicular atrophy and damage to the fundamental machinery of sperm production, not only producing it, but even getting it out. Those tubules, those little tubes that would be carrying it out, are all breaking down. Of course, women are not spared these effects in their own way. Studies have documented high incidence of ovarian cysts in women receiving MTOR inhibitors after transplantation. And what by that I mean tissue transplants, when they're on these rapamycin like drugs. Female kidney transplant patients that are on these drugs have developed amenorrhea, meaning they cessation of menstrual cycles and the drug stops normal ovarian function. Now, some will argue that these effects may be reversible after stopping the drug. That is partially true from what we can tell based on the best available data. But think about what we are being asked to accept here. Take a drug that damages your gonads potentially beyond repair. It disrupts your sex hormone production, it impairs your fertility, and you do it all on the hope that it might extend your lifespan. Based on some studies in mice. That to me is a terrible trade off, especially when we don't have. When we, when we have other approaches that a person can consider to leverage these same pathways, I would say in a more optimal way. Now, I'm not declaring that rapamycin research is invaluable for understanding MTOR biology when it comes to specifically wanting to understand MTOR leveraging and manipulation, rapamycin is as good as it gets. But I am saying that the causal adoption or looking at rapamycin as something that's causing an increased or enhanced longevity by these enthusiasts and influencers biohackers. It concerns me. We're experimenting on humans with a drug that has known serious side effects and unproven longevity benefits in humans. But back to something I've mentioned and touched on a bit. If rapamycin isn't the answer to promote longevity by optimally leveraging MTOR or turning it down, what is? I do think there's something valuable here, but let me shift to something that doesn't require a prescription and doesn't damage your gonads, that is namely dietary interventions. And here I want to address something that doesn't get enough attention in the longevity conversation. In fact, it's shocking that this isn't discussed more to me. The role of carbohydrates and insulin in MTOR activation. You'll often hear that protein restriction extends lifespan because amino acids activate mtor, and this is true. Studies have shown that reducing dietary protein, particularly branched chain amino acids like leucine, can extend lifespan in model organisms. In rodent models, reducing protein from typical levels to about 5 to 10% of calories can increase maximum lifespan by about 20%. Once again, however, I have reservations about the real world applications of this particular approach. To me, there is a clear harm in eating too little protein in an animal living in a safe environment of a warm cage isn't the same as a person in the real world who may need muscle to stop a fall to be less frail and similar. Regardless, here's what's Insulin is a potent activator of mtor, and insulin's effect on MTOR activation is more sustained than that of amino acids. Insulin activates mtor through the Pi3 Kinase Akt pathway. When you eat carbohydrates, you get and your blood glucose rises. Of course you're going to get A significant insulin response. When you eat a lot of carbohydrates, which of course most people do in modern society, you get repeated prolonged insulin spikes throughout the day. And here is, I think, the critical point. We eat far more carbohydrates in larger amounts and more frequently than we do protein. The average western diet is roughly 50% carbohydrates and it's only about 15% protein. So while people focus on proteins effects on MTOR, they are ignoring the elephant in the room. Chronic carbohydrate consumption driving chronic insulin elevation keeps MTOR chronically elevated. And this is of course, we have much longer periods. So if you directly treat a cell with leucine, the most mtor activating amino acid versus insulin, MTOR will go higher and stay higher for longer than it will in response with an insulin stimulus than it will with a leucine stimulus. And again, we eat so much more carbohydrate than we do protein. Research by Drummond's group demonstrated that amino acids are necessary for insulin stimulated activation of mtor. But the key word there is insulin stimulated or insulin induced. Insulin provides a sustained signal and amino acids provide an acute trigger. When you reduce insulin through carbohydrate restriction, you fundamentally change the MTOR landscape even without restricting protein, so to say all of this another way there is a modern push for restricting protein in an effort to reduce MTOR activation. I think that is mistaken because you do need some MTOR stimulation if you have any hope of maintaining muscle and bone mass. You need MTOR to be turned on in order to build a muscle. You want to keep that muscle. To me, amino acids are a perfect stimulus for this because it turns MTOR on and then it turns it off, and most especially at the muscle, especially if it's branched chain amino acids which are naturally enriched in muscle. Whereas insulin is going to turn MTOR on and turn it on for much higher and for much longer. And so if someone wants to leverage macronutrients in a way to optimize MTOR signaling, the focus on protein is, I think it's laughable. We should be focused on carbohydrates and of course the more refined carbohydrates because of their more exaggerated response with insulin or effect on insulin response. Alright, so if chronically elevated MTOR accelerates aging and AMPK responsiveness declines with age, we should ask the question, well, how can we restore the balance without resorting to drugs that damage our reproductive systems and more. I just happen to focus on the gonads because it's so obvious. But, but there are other tissues that are affected with these rapamycin drugs. But this is where speaking of drugs, compounds like metformin and then the ketone beta hydroxybutyrate become relevant. Metformin is the most widely prescribed anti diabetic drug on the planet and it is now understood to work primarily through AMPK activation. This has been demonstrated in many, many papers now. But it's been shown that metformin activates AMPK in tissues throughout the body, most especially the liver. And when AMPK is activated in the liver, acetyl COA carboxylase activity is reduced. And that means we are not making new fats. Fatty acid oxidation is turned on and lipogenic enzyme expression. That's like I just said, with acetyl Coa carboxylase is going to be turned down. So obviously there's an effect at improving liver fat levels and reversing fatty liver disease. But more recently, work that was again published in the journal Nature identified that metformin can bind to a protein called Pen2. And Pen2 inhibits ATPase, which can lead to AMPK activation through a pathway that doesn't require changes in cellular AMP levels. So, so that means it can activate AMPK without depriving the cell of ATP. So this explains why metformin can activate AMPK at clinically relevant doses without dramatically affecting cellular energy status. But perhaps even more exciting, and this you can do without any prescription, is the research on beta hydroxybutyrate or bhb, the primary ketone body produced during fasting or carbohydrate restriction or, or when needed or preferred, just supplemented with GO bhb. BHB is not just an energy source, but it is also a signaling molecule. I've discussed this, I think abundantly and will more in the future in the metabolic classroom, research has demonstrated that BHB activates AMPK and stimulates autophagy. A paper published in the journal Cells just a couple years ago showed that beta hydroxybutyrate stimulates the autophagic lysosomal path. So the lysosome is an important part of autophagy because it's a part of the cell that will actually erode the other organelles. It's essential for breaking stuff down and it does so through AMPK activation. And this has been confirmed even in the brains of rodent models that are on ketogenic diets. You have more autophagy and again, remember, that's cleaning out the cell. So I think there is a profound implication here when you Restrict carbohydrates and enter ketosis and or you are eating smart and supplementing with Go bhb. You're not just changing your fuel source. You're sending a powerful signal to shift the AMPK MTOR balance toward longevity pathways. You're lowering insulin, which reduces chronic MTOR activation, while simultaneously producing bhb, which activates AMPK and then promotes autophagy. And you're doing this without any of the potential gonadal toxicity or the immunosuppression that comes from taking rapamycin and its analogs. Let me bring this all together. Your cells are constantly receiving signals that push them toward growth and building, which is mtor, or conservation and repair and burning, which is ampk. In our modern environment of constant food availability and constant carbohydrate consumption, we've shifted this balance heavily toward MTOR activation. The research, I think, is quite obvious. Interventions that reduce MTOR activity can extend lifespan and health span in various used model organisms. Of course, you cannot really do longevity research in humans. Similarly, interventions that activate AMPK promote the cellular housekeeping that appears to keep cells young. But remember, you do not need some powerful, toxic drug to achieve this. In fact, I'd argue you shouldn't use rapamycin for longevity, given its unproven longevity benefits in humans and its proven documented harm to things like the gonads in both men and women. What you can do is leverage the natural tools we fasting, carbohydrate restriction, the production of ketones, or supplementing with ketones. These strategies activate favorable metabolic signaling. They shift the balance from chronic growth signaling toward periodic cleaning and repair. And they do it without damaging your gonads or suppressing your immune system. Remember, it's not just about how long you live, but how well you live. AMPK and MTOR are central to both of these things. But the path to optimizing these pathways, I think, runs more through your kitchen and your lifestyle than it does through the pharmacy. Thanks for joining me on the metabolic classroom. Remember, more knowledge, better health.