T-Mobile/US Cellular Advertiser (14:16)

Everyone deserves to be connected. That's why T Mobile and US Cellular are joining forces. Switch to T Mobile and save up to 20% versus Verizon by getting built in benefits they leave out. Check the math@t mobile.com and now T Mobile is in US cellular stores.

T-Mobile/US Cellular Plan Details Announcer (14:36)

Savings versus Comparable Verizon plans plus the cost of optional benefits, plan features and taxes and fees vary. Savings with three plus lines include third line free via monthly bill credits credit stop if you cancel any lines.

Capital One Bank Announcer (14:45)

Qualifying credit required with no fees or minimums on checking accounts. It's no wonder the Capital One bank guy is so passionate about banking with Capital One. If he were here, he wouldn't just tell you about no fees or minimums. He'd also talk about how most Capital One cafes are open seven days a week to assist with your banking needs. Yep, even on weekends it's pretty much all he talks about in a good way. What's in your wallet? Terms apply. See capitalone.com bank capital1NA member FDIC.

Dr. Ben Bickman (15:20)

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 overlooked. 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 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.

Verizon Advertiser (19:44)

In a world where January is supposed to be boring, one staple of the holidays refuses to end the great deals at Verizon, the joy just keeps on coming. Right now you can save on four new phones and four lines. Critics agree it's the deal that keeps on giving. Come into Verizon and save on four new phones and four lines on unlimited. Welcome. Additional terms apply@seeverizon.com for details.

Capital One Bank Announcer (20:13)

With no fees or minimums on checking accounts, it's no wonder the Capital One bank guy is so passionate about banking with Capital One. If he were here, he wouldn't just tell you about no fees or minimums. He'd also talk about how most Capital One cafes are open seven days a week to assist with your banking needs. Yep, even on weekends, it's pretty much all he talks about. In a good way. What's in your wallet? Terms apply. See capitalone.com bank Capital One NA member, FDIC.

Dr. Ben Bickman (20:47)

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 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. 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 worse, more recently, work that was again published in the journal Nature of 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 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 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 the metabolic classroom. Research has demonstrated the 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 pathway. 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. 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 have. 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.

T-Mobile/US Cellular Advertiser (26:47)

Everyone deserves to be connected. That's why T Mobile and US Cellular are joining forces. Switch to T Mobile and save up to 20% versus Verizon by getting built in benefits they leave out. Check the math@t mobile.com switch. And now T Mobile is in. US cellular stores savings versus comparable Verizon.

T-Mobile/US Cellular Plan Details Announcer (27:08)

Plans, plus the cost of optional benefits plan features in Texas and fees vary. Savings with three plus lines include third line free via monthly bill credits. Credit stop if you cancel any lines.

Capital One Bank Announcer (27:16)

Qualifying credit required with no fees or minimums on checking accounts. It's no wonder the Capital One bank guy is so passionate about banking with Capital One. If he were here, he wouldn't just tell you about no fees or minimums. He'd also talk about how most Capital One cafes are open seven days a week to assist with your banking needs. Yep, even on weekends, it's pretty much all he talks about in a good way. What's in your wallet? Terms apply. See capitalone.com bank capital1na member FDIC.

Dr. Ben Bickman (27:47)

My.

Skyrizi Advertisement Narrator (27:47)

Son loves to fly kites, but my active psoriatic arthritis can sometimes hold me back. Now with Skyrizi to treat my skin and joints, I'm ready to go. Skyrizi Risankizumab RZA A prescription only 150mg injection for adults helps with less joint pain, stiffness, swelling and fatigue. For those who also have plaque psoriasis, 90% clearer skin is possible with just four doses a year. After two starter doses.

Skyrizi Warning Announcer (28:14)

Don'T use if allergic to Skyrizi. Serious allergic reactions and an increased risk of infections or a lower ability to fight them may occur. Before treatment, your doctor should check for infection and tuberculosis. Tell your doctor if you have an infection or symptoms such as fever, sweats, chills, muscle aches or cough, or if you plan to or recently received a vaccine.

Skyrizi Advertisement Narrator (28:31)

With Skyrizi, there is nothing like clearer skin and better movement, and that means everything. Ask your doctor about Skyrizi today and visit skyrizi.com or call 1-866-Skyrizi to learn more.