Losing Weight is Tough
You don’t need to have any personal experience with weight loss to know that this is true. The demoralizing statistics following the obesity epidemic make this painfully clear. Twenty years ago, the prevalence of obesity among Americans was around 30%. Now, according to the latest NHANES data, a staggering 42.4% of people in the United States have obesity. The proximal cause of obesity is not a mystery. On a population level, we are eating more. Research shows that the average food intake for adults in the US rose by an estimated 300-500 calories daily over the period of time when obesity increased exponentially.
So, the solution seems pretty straightforward, right? But in practice, it is obviously more complicated than that. For dieters, their own brain is their biggest saboteur. As our friend Stephan Guyenet has explained on previous podcasts, appetite regulation is based in the hypothalamus, which is the main link between the endocrine system and the nervous system. Sustaining a lower caloric intake becomes extraordinarily difficult because of how this part of the brain resists it, affecting hormones and other signals to boost energy intake and lower energy expenditure.
Weight Loss on GLP-1 Agonist Drugs (Semaglutide, Tizepatide, Liraglutide)
This is why GLP-1 receptor agonists, like semaglutide and others are the greatest game-changer in weight loss medicine yet. We have known for some time that activation of GLP-1 receptors in the hypothalamus acutely induces satiety. Long-acting GLP-1 analogs have even more impressive effects, dramatically lowering food intake and making it much easier to maintain weight loss (as long as you keep taking them). The results speak for themselves. A once-weekly dose of semaglutide resulted in a 16% reduction in body weight when combined with a low calorie diet (versus -5.7% for placebo). When subjects being treated with semaglutide were presented with a meal at which they were free to eat as much as they wanted, they voluntarily ate 35% fewer calories than participants taking placebo.
People on semaglutide are able to lose weight without exerting a ton of willpower because semaglutide supports a lower “set point” by amping up the signals on one side of the body-fat set point. This, in effect, allows the body to feel more comfortable at a lower level of body fatness. And at least as far as we know at this point, you can maintain this new weight if you stay on the medication (and of course keep a reasonably healthy lifestyle).
Can We Make The Body Fat Set Point Healthier?
But on semaglutide, the set point isn’t affected directly, leaving room for additional interventions that actually make the set point healthier, if you will. Indeed, finding therapies that affect the set point directly is arguably the holy grail when it comes to weight loss and more permanent weight loss maintenance. Our guest may have uncovered one such mechanism – as well as a potential solution.
On this episode of humanOS Radio, we welcome Pankaj Kapahi back to the show. Pankaj is a professor at the Buck Institute, an independent biomedical research institute that is devoted to research on aging. His lab has been exploring how nutrient status influences health and disease, and particularly how nutrients affect age-related changes in tissues and disease processes.
In our previous interview with Dr. Kapahi, we discussed his work examining how advanced glycation end products (also known as AGEs) drive 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. AGEs wreak havoc by binding with cell surface receptors and cross-linking with body proteins, warping their structure and function. As you can imagine, this leads to all kinds of problems, including many of the chronic diseases associated with aging.
The Creation of “Glylo”
Since we last spoke, Pankaj has been hard at work trying to identify compounds that can rein in the deleterious impact of AGEs, primarily by lowering levels of methylglyoxal. Methylglyoxal is formed as a side product of the breakdown of sugars, and is involved with the formation of AGEs, so it is a logical molecular target for this purpose.
In his screening process, he managed to find five compounds which, when combined, showed synergistic protective effects against methylglyoxal toxicity:
- Alpha lipoic acid
This powerful combo now makes up the commercial product GLYLO, which you can buy yourself. Preliminary testing of GLYLO in rodent models has been very encouraging. Pankaj and his team found that the formulation reduced glycolytic byproducts, improved insulin sensitivity, reduced caloric intake, promoted fat loss, and extended lifespan by 30-40% when administered late in life.
How Did Glylo Affect Body Fatness?
When Pankaj and his team tried to tease out why GLYLO was dampening their appetite, they found that the effect was independent of peripheral hormones like leptin and ghrelin. In fact, injecting ghrelin into the mice treated with GLYLO – which normally ramps up appetite in humans and other animals alike – did not result in increased energy intake. This is key because it suggests that GLYLO was changing how the hypothalamus responded to ghrelin. In other words, reducing methylglyoxal, through GLYLO, appeared to be lowering their set point.
This raises all kinds of questions. Does this mean that glycation contributes to the disease process of obesity? And could we achieve even greater results in weight loss by combining GLYLO with GLP-1 agonists like semaglutide?
To learn more, check out the interview below!
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Pankaj Kapahi — 00:04 : We have been pleasantly surprised to see almost a 30, 40 % increase in lifespan, even when given that late. We tested a lot of animals on this. It’s very rigorously done. With over 80 animals, we’re confident that this is the real anti-aging effect and very promising intervention.
Kendall — 00:24 : HumanOS: learn, master, achieve.
Dan Pardi — 00:31 : Hi everyone, we are back. It has been a while since we published our last show and I had to shift some priorities due to the pandemic and all, but I do appreciate all the kind messages letting us know you’ve missed the show and it certainly has reinspired us to get back in the saddle now. We will not be doing the show regularly at first, but we do plan to start publishing again and eventually get back into a good rhythm. I have to say that for all the projects in my work, the podcast is especially enriching. I get to speak with fascinating people about their fascinating work, and I get to share these discussions with the world, and I’m ever grateful for it. So, to kick things back off, we welcome back Pankaj Kapahi to the show. Pankaj is a professor at the Buck Institute on Aging. Back in 2019 I interviewed Pankaj about his lapse investigation into the role of advanced glycation end products, aptly known as ages in the aging process. Advanced glycation end products are responsible for many of the complications of diabetes and I have recently been implicated in other age-related diseases. Since we have published the last show, Pankaj and his colleagues have been hard at work to identify compounds that can fight AGEs. That work has led to the commercialization a formula called Glylo. Today we’re going to discuss the compound in a large series of experiments that have been done on it on Kash. Welcome back to humanOS radio.
Pankaj Kapahi — 01:58 : Thank you very much. It’s great to be on the show.
Dan Pardi — 02:01 : Could you please do a quick review of AGEs for those who missed the last show and how they impact our physiology?
Pankaj Kapahi — 02:08 : Yeah, so ages and short for advanced glycation end products. We’re actually all familiar with this because making advanced glycation products is the most commonly practiced chemistry reaction. Every time you’re cooking sugars and amino acids react, they form AGEs at high. Temperature for example, if you made a toast this morning, that toast created about 50 different AGEs and that’s what gave that very interesting flavor that we’re all addicted to. This was discovered in the early nineteen hundreds, but what’s been very important in terms of biology, that’s been this realization that the formation of advanced glycation end products is also taking place in our cells, though at a slower rate. But it’s quite appreciable and is now linked with several diseases, including diabetes, neurodegenerative diseases and aging. My lab studies a specific type of age, which we think is one of the most common ones. The precursor is methylglyoxal. So during glycolysis you make this byproduct called methylglyoxal and this reacts with protein DNA lipid non enzymatically and will then form a irreversible product. And that’s why it’s called an advanced glycation end products. The idea is that it can’t be reversed back, just like what would happen when you would make a toast. You can get back the bread or when you fry your egg. When it’s in this advanced form, it crosslinks different proteins and has impact on different cellular and tissue Physiology, leading to a breakdown of homeostasis.
Dan Pardi — 03:42 : So endogenously these are formed largely through carbohydrate metabolism, glycolysis in particular, and as a result methylglyoxal is formed. Now this toxic compound will interact non-enzymatically, with biomolecules like protein and DNA to form advanced glycation end products, which is an irreversible process. AGEs, once created, then form crosslinks that impair tissue function, which leads to disease. So, is there an endogenous system that prevents age formation?
Pankaj Kapahi — 04:12 : Absolutely that’s exactly what made me realize this is a very important system, because there are several enzymes in place that are trying to detoxify methylglyoxal. What’s interesting is that some of them are redundant, so it tells you how much you’re so devoted energy in terms of ensuring that. Don’t accumulate aging. And the second important point is this happens in every cell that’s using glucose. There’s no way So from bacteria to us all cells that use glucose make anything else. So even our microbiome is classically making AGEs or getting it from outside, and then on top of that, we’re endogenously producing it in every cell.
Dan Pardi — 04:55 : Do you think then, since we have an endogenous system, that part of the pathology of modern life might be the overproduction of AGEs or even the under handling of them, given how we live and what we eat?
Pankaj Kapahi — 05:07 : That’s the idea under conditions of nutrient overconsumption or especially consumption of too much glucose. And with age, the system can’t cope with the amount of AGEs we make. And that’s why it’s becoming bigger and bigger problem as the epidemic of obesity and diabetes is crazy right now.
Dan Pardi — 05:24 : So you did a series of experiments. Looking at whether or not you could modify AGEs. Is that correct?
Pankaj Kapahi — 05:31 : Correct he actually had a very elegant model in C. elegans. So one of the challenges in the eighties field is that it takes decades to accumulate. So people have always thought of it as a biomarker, but necessarily a causal factor. And there haven’t been good drugs around to detoxify that previously. There were some very promising drugs, but they had the side effects, but they were made based on a chemistry approach that we’ll just trap the AGE and that will be the end of it. We are taking a different approach, we’re saying. The cell already has these endogenous defenses in place. Why not see how the cell can respond to natural compounds and if they can upregulate these defenses to toxify the agents? Ok, so we had an elegant system in C elegans where we could see the accumulation of AGEs within three four days, and what’s amazing is that we’ve shown that this accumulation of AGEs is sufficient to not only shorten lifespan, cause neuronal damage and essentially mimic diabetic neuropathy in C elegans. So given the C elegans worms level only 20 days, we were able to screen for about eight hundred nine hundred compounds to identify those that protected against AGEs. And one gratifying moment was that you can get a worm to have the same pathology like a diabetic would show with neuropathy. And the second moment of epiphany was that the identified lipoic acid is one of our top hits and probably supports paper and that was really interesting because. The boy got acid has already given in several countries for diabetic complications like neuropathy, and it helps lower sugar as well, and it’s one of the key components of Glylo.
Dan Pardi — 07:12 : Tell us what you did next. You now have an understanding of which compounds are most powerful to fight against ages. What was the next step then in terms of creating the formulation of Glylo
Pankaj Kapahi — 07:22 : Yeah, identified about 15 different hits from this screen. We knew lipoic acid was there and several other interesting compounds on which trials had been done, their protective. We asked if we could do better. Our approach was, let’s only take compounds that are known to be safe in humans. Most of them would come under supplement grade. We commonly take them. We know there’s going to be no risk of toxicity. That means we can translate it in humans much easier. So we took only those compounds and we tried hundreds of combinations because we had about 10 odd compounds. So we first tried doubles, then we tried triple, and like that. We essentially came up with a combination of five compounds that would be found have the best activity in reducing glycation. We moved from C elegans to mammalian neurons because we’re not neurons are very sensitive to the damage due to AGEs. So we did the combination screen in neurons. You take neurons and you put methylglyoxal already the eighth we found that would kill the cells or damage them or retract their processes. So the neuron can only function into ha s long processes. And then we were able to reverse all that by this combination.
Dan Pardi — 08:33 : Ok. So some of the earliest work was to identify the compounds that have the most potent effect on advanced glycation endproducts, combined those compounds into a formula that was additive slach synergistic, then first test the formulation in a sensitive marker which was neurite length retraction, and what you found was that the formula rescued the neurons that were exposed to the toxic methylglyoxal. That led to a series of other experiments. And from a high level, what were the types of outcomes that you were looking at with Glylo In this paper that was recently published?
Pankaj Kapahi — 09:09 : This was all done. That’s the elegance in neurons in vitro. We really wanted to now ask what happens when you give it to an intact animal and how the mammal is respond We started these experiments with mice before you tried in humans. We gave this to vice, and our hope was really to see protection against diabetes and maybe aging. There’s been remarkable to see the results that not only did we see a lot more interesting phenotypes, but all across the board it has such a strong protective effect that it’s led to the formation of the company. And I’ve been taking it for two years. The three major things we saw in my first of all, off the bat, we found it reduces calorie intake. Secondly, we found that it improves insulin sensitivity and that’s really remarkable because this idea in the field that methylglyoxal mightdrive diabetic pathologies and diabetes, but this was really very strong evidence to us that, well, you can take these compounds and significantly improve on the animal handles glucose. And thirdly, we saw the largest lifespan extension that’s been seen in animals where drug has been given after 24 months. I mean they’re already 2 year old, they’re equivalent to a 70 year old person and usually caloric restriction does not work that well when the animal is that old hmm we have been presently surprised to see it almost a 30, 40 % increase in lifespan, even when given that late. We tested a lot of animals and this that’s very rigorously done. With over 80 animals, we’re very confident that this is a real anti-aging effect and very promising intervention.
Dan Pardi — 10:51 : Lots of exciting stuff there. Let’s go a little deeper into some of these areas. The first thing that you mentioned is that you saw that there was a reduction in feeding. If they’re not eating as much, then it could be due to a couple of different things. So how did you then investigate what was potentially driving the effect of reduced consumption of food?
Pankaj Kapahi — 11:09 : Yeah so first of all, I want to say very specific effect on feeding here. We found that it specifically reduces carbohydrate consumption. If you remember how I told you we thought Lioresal is made from glycolysis. So it makes total sense that if you reduce methylglyoxal, we think it’s part of the sugar addiction mechanism. What makes you eat sugar? And once you eat sugar makes you want to eat more sugar? We think methylglyoxal could be driving this. And then you take this, it reduces specifically carbohydrate consumption which is good because you want to keep your healthy fats and proteins in it reducing the effects of carbohydrate toxicity. We found that the appetite was reduced but it goes to a new set point, the animal doesn’t get bound nutrition and we asked the major pathways that are known for appetite reduction of leptin and the other hormone. That’s very interesting. It’s called ghrelin. When you’re hungry, ghrelin goes up the animal eats more. So we ruled out that any of this is due to the effects of leptin. And this is a big advantage because we found that the gyro can overcome leptin resistance, which is commonly seen, which means people will overeat and even though they’re making leptin, the body does not recognize that signal keeps overheating. So Glylo would benefit in those animals. We tested this very. Earlier, and we even used a mouse model of leptin resistance, where the leptin receptor is knocked out. These animals become almost twice the size of a normal animal and we could bring it back to normal size and reverse all the phenotypes like fatty liver disease. That’s reverse. Most of these animals die quite fast because they overeat and after six months we lost half the animals, but not a single animal died which was eating the supplement.
Dan Pardi — 12:59 : Fascinating, So, it’s not uncommon to see changes and grow on after weight loss. In fact, that would be one of the physiological responses you do see. That then increases food consumption, getting weight back up to the point where it was before, which is really disheartening. And more specifically, you see. Increases in ghrelin higher levels of growing between meals and you also see a reduction in ghrelin after a meal has initiated. Both of those are going to be promoting more food intake. You saw ghrelin did not change. Was this also after weight loss?
Pankaj Kapahi — 13:32 : Yeah, exactly. So we injected crelin, which normally would make the animal eat more, but when the animals are fed with glylo, it had no impact on ghrelin. And what we have found is that title rewires the hypothalamus such that the animal thinks its fed even though it’s receiving 20, 30 % less calories. The brain is sending the signal we’re fed and what we have found, which is leading to lots of exciting projects in the lab, that client who seems to. Keep the hypothalamus young and in a better condition in the sense that it feels it’s fed. And we are now also pointing that it improves the whole hypothalamic gondal axis. It has positive impact on other systems as well, not just the hypothalamus, but we think hypothalamus is the key because that’s the seed of the brain, which you know it’s gonna controls all food intake. And we find that glylo seems to change that such that the animal thinks it’s in a healthy state and fed.
Dan Pardi — 14:33 : I’ve come to think that obesity. Is really more of a problem of hypothalamic change than it is the expression of a higher body fatness. So, l et me say that again. My thinking is that obesity is not necessarily just a change in body fatness, but it is actually a change, or possibly a variety of changes in the brain. And the symptom of those change or changes in the brain is an elevation in body fatness. So in this situation, which is all too common, if a person loses weight, the brain thinks that it’s in a state of deprivation and makes a variety of changes to get a person back up to a level of body fatness that is unhealthy. Or undesirable. That is a disheartening situation for anybody who wants to lose weight. So really, in my mind, the Holy Grail for weight loss is some sort of compounded treatment that can re sensitize the hypothalamus. So that it is maintaining a body fat level against a lower set point, so the body feels comfortable when it loses weight. Because when people say I want to lose weight, what they’re really saying is I want to live at a lower body fatness level. So let’s say if a person wants to drop fifty pounds, whatever the weight number is. They really want to lose weight in a way where they their body feels more comfortable at that weight and not feel miserable and low energy et cetera. And we now have compounds these GLP one analogs like semaglutide and tirzepetide that can help the situation quite a bit. Do you think that Glylo might have an additive benefit on top of these drugs that are triggering the GLP one receptors?
Pankaj Kapahi — 16:06 : You’re absolutely right. What we are doing here is changing the set point and from what all the what we’re learning about what’s happening with glylo on the brain, it’s working through the changes of the hypothalamus, which is controlling the set point. So we think glycation has very strong impact on the hypothalamus whistle by reducing glycation. The Atom motors itself in a fit state and this impacted through the responsiveness of the hypothalamus to grab. We’re not changing peripheral. Hormones, but changing how hypothalamus is responding. So these other drugs should work in conjunction with glylo. There should be further positive effects that people wanted to use that in conjunction and we’ve got a very nice effect on insulin sensitivity, which is a big plus.
Dan Pardi — 16:52 : Let me say something more about GLP one analogs like semaglutide. The way that I imagine some magnetite and other types of compounds like it working is to imagine a seesaw. On one side of the seesaw, you have programs that are promoting and energy conservation, so lower physical activity, increased food consumption. And on the other side of the seesaw you have the opposite, you have increased activity and decreased food consumption. You can imagine if they’re balanced, then you’re at a healthy body weight and healthy set point. So, as the set point goes up, the seesaw starts to tilt towards the conservation side. How does GLP one work then? So imagine a finger coming into the picture and pushing down on the other side of the seesaw, the one that increases energy expenditure and decreases food consumption, particularly the food consumption part, semaglutide pushes that seesaw back into a state of better balance. And now with the weight loss that occurs, your body will feel more comfortable at that new weight, which is exactly what we would want if we lost So, semaglutide is an amazing advancement, but it’s still not the Holy Grail because we’re not actually changing the set point, we’re just reinforcing one side of the set point. So when I was reading your paper, I was thinking about the possibility of combining some magnetite with glylo to see if we could achieve. Levels of efficacy that go beyond what we see with Semacode alone, which have been really impressive. For the first time, we have a legitimate weight loss medication seeing 15, 20 % reductions in weight loss and as long as you stay on it, you can actually preserve that weight loss as though it appears so far. Can we go beyond that by adding in this complementary compound? Possibly i’d love to see more work in that area, but super exciting either way. Let’s go back to metabolism. You said that there was an improvement in insulin sensitivity. How did you measure that in the mice that were taking glyloidewell? .
Pankaj Kapahi — 18:56 : We’re finding. Very robustly that when we do a glucose challenge, for example, and this is not even in diabetic noise, even in normal mice, we compare how quickly does this animal essentially handles the glucose. So bring the brag to normal level, and we compare that with Glylo treated mice, and that Glylo treated mice do a much better job at helping the Organism bring back being close to manual. We’ve also done what’s called an insulin tolerance test. You give insulin and you ask how much? Does that bring down glucose? And what we’re finding is that globe and animals are fed with Glylo. The animal becomes more sensitive to insulin, so it with the same amount of insulin, it can bring down glucose further. So we think there are very profound referral effects, like for example, in the fat and the muscle, which are further contributing to this improvement. So this is where glycation is a very unique target because from the chemistry I’ve described, it’s in every cell, so you’re not working on something like a GLP. Which is in certain cell types in a very specific function, you’re actually working on glycation, which is modifying different cell types and different ways of generally in the negative direction. And So what you are doing here, we think you’re both improving insulin sensitivity while at the same time you’re telling the hypothalamus that the animal is fed. So that’s why I think it has such a profound effect on improvement of insulin sensitivity.
Dan Pardi — 20:23 : So to recap, in your studies you saw a decrease in blood glucose following an IP injection of glucose. With the animal, so the body handled the glucose that came in better than another experiment. You saw decreased glucose after an injection of insulin so that it was more sensitive to insulin. We know that some carbohydrates are fine, but higher levels of glucose lead to further creation of AGEs. Is that correct?
Pankaj Kapahi — 20:48 : This is something that is so underappreciated, and as I’ve been studying this, I’m realizing more and more even we all know hyperglycemia causes diabetes and diabetes. When it’s a chronic state, this hyperglycemia is in sugar and serum is going to predispose you to several diabetic complications. It’s a lot. Biggest cause of blindness, diabetic retinopathy, neuropathy. You’re going to get peripheral neuropathy. Your whole autonomic nervous system falls apart due to diabetes. It’s the biggest risk factor for cardiomyopathy. Then you’ve got a big risk factor for stroke, chronic kidney disease, and then you’ve got neurodegeneration like Alzheimer’s and Parkinson’s. Diabetes doubles to quadruples. Risk of all these stages, but what do slight increases in glucose do in a normal person? And they’re found that there is ana inverse correlation with IQ, so cognition is affected even in normal people by increasing glucose. And I have an anecdote to share. I was doing continuous glucose monitoring because people respond differently to different carbs, and I was just observing myself and it was really remarkable to see that when the glucose hit the peak, like it was taking more sugar. I would fall sleepy when it would peak from that. Now I know when you start feeling cloudy after a meal, it’s that. So now I became much more vigilant after that. The intermittent fasting helps and that’s why we recommend that with Glylo. And secondly Glylo helps in reducing the meal size helps a lot. So all these things help you then not reach these points of sugar spikes, which essentially could be damaging in the long run. But even in the short run you seal cloudiness. So if you want to remain alert, it’s very important. Keep this homeostasis.
Dan Pardi — 22:32 : It’s interesting to think about this information, particularly in light of the paper that was recently from Valter Longo and Rosalind Anderson in the journal Cell. And in this paper, they looked at nutrition, longevity and disease from a basic science perspective all the way into interventions. And from theiranalysis, they’ve determined that a diet comprised of 60 % carbohydrate was the one that conferred the greatest longevity benefit. But they also made the point very clearly that this is only carbohydrates that are in the form of whole food plant types. So if you’re consuming carbohydrates that keep your blood glucose stable, if you’re taking in the right types of carbs that metabolize slowly, that have nutrients in them that affect the absorption, metabolism, excretion of the carbohydrates? Then is it really carbohydrates that are the problem or is it the form that they come in?
Pankaj Kapahi — 23:22 : Yeah, you’re absolutely right. It’s the ratio of fiber to carbs. So one is not taking simple carbs and if you take more fiber rich foods that helps the release of carbs to be more slow. And so you’re absolutely right that have been studies with thousands of individuals and people respond differently to different carbs. So it’s good to know what works for you or doesn’t work for you and because what everybody’s sugar apparently went up on white rice. So it’s good to understand these differences.
Dan Pardi — 23:51 : So these mice. On Glylo lost weight, you did DEXA scans on them. Were they losing lean mass, or was it mostly body fatness that they lost?
Pankaj Kapahi — 23:59 : This is a great question, and this is going to be the topic of our second paper. We found that it was impacting the fat mass, and it only just maintained lean mass, but actually helps increase muscle mass. And this fits very well with the idea that we’re finding that when we give Glylo, you increase glutathione. We’ve asked lots of questions, you know, using metabolomics, and we’ve found that it reduces glycolysis and it increases the pool of the antioxidants blue design, which also essentially help detoxify the ages and the combination of this is really good for the muscle. Diabetics don’t get the same benefits from exercise because the sugar seems to act as a brake on the benefits of muscle, but we’re finding the opposite with Glylo. Glylo the animals are more active and this is one of the common benefits people who are taking blias increase in energy into the muscle mass is also going up. And we’re finding increase in muscle strength based on a number of other measures.
Dan Pardi — 24:57 : Because Galileo is affecting ages, you’d expect tissues throughout the body to be affected positively, and when taking Glylo the mice kept more muscle mass, which is very desirable outcome. Among other things, lean muscle tissue is a sieve for caloric excess and society. In other words, when you have more muscle, your body can handle higher levels of calories and prevent high blood glucose, which is a good thing. There could very well be a positive influence on sarcopenia or age. Related loss of muscle tissue. I’d love to see more work on that specifically. Now, you mentioned that there was an increase in energy expenditure. When you’re looking at weight loss, you always want to consider both sides of the equation, both energy and energy. Out in your experiments, you saw that there was an increase in energy expenditure in these animals correct yeah.
Dan Pardi — 25:43 : Did you notice any effects on brown fat or thermogenic genes?
Pankaj Kapahi — 25:47 : Thermogenic genes were not altered that much. Not so much brown fat as well, but the animal engaged more increase breakdown of fat.
Dan Pardi — 25:54 : Let’s go back to lifespan. Obviously, it’s becoming an increasingly popular topic. Many companies now are trying to fight different aspects of aging and somewhere or another. You mentioned something earlier in the call, but this is the longest lifespan extension seen with any compound given in mice over 2 years old. Which would be equivalent to a human being 70. What was the previous champ in terms of longevity extension?
Pankaj Kapahi — 26:19 : We know rapamycin extends lifespan, and most of the experiments are done starting in 20 months. We did our experiments starting at 24 months, but the effect seems to be very strong even at 24 months, and we are now conducting more experiments head-to-head with rapamycin and also in combination with rapamycin to see what would happen under the same conditions. But from the percentage changes we are seeing, this is a striking of it even caloric restriction doesn’t work that well. At this age and on top of that, we’ve now done a comparison of changes in the gene expression in the hypothalamus and in the hippocampus, the part of the brain that’s important for memory information. And in both these parts of the brain, gene expression reverts to that of the younger. And so we’re seeing not only extension of lifespan, but actually a reversal of the pattern of gene expression in the brain.
Dan Pardi — 27:11 : So you started doing work in roundworms. You have now moved into mice andthere’s a product out there that is available for people to buy. Do you have any human studies planned?
Pankaj Kapahi — 27:22 : Absolutely we are working hard to raise funds to do clinical trials. Unfortunately that you may be aware like when you’re working with supplements because it’s not easy to get far more funding and private funding, it’s hard to raise money. So we are trying to raise money through philanthropy and also through the NIH to get funds to get human trials started. But we received the ID status from the FDA. So they’re good with us trying this in humans.
Dan Pardi — 27:48 : For the commercially available product. How did you determine dosage?
Pankaj Kapahi — 27:52 : That was a little tricky. Generally, you go 10X from what happens in mice. We tried to make it appropriate to what was seen in mice, but we also were mindful of what’s a good safety limit in humans and what have been tried in previous trials to see where it’s not too high. But I just want to remind everybody again, the five compounds are nicotinamide lipoic acid, tyramine per doxylamine and piperine. Now there are multiple clinical trials done with all of them. Individually and they’re all mostly beneficial, but we together this is going to be much more promising. And also if you use nicotinamide, the folic acid, none of these have lifespan extension effects in mice and what we are seeing with the combination is something synergistic and much more superior than a single supplement alone. So we’re excited about this. We all have them present in our body, three of them are B vitamins and one, the alpha lipoic acid is also found in body and piperine is a component of. Black pepper, but the dosage is such that it should be on the safe side. It is not a multivitamin pill. The doses are much higher than that in a multivitamin pill, but they’re on the same side but on the higher.
Dan Pardi — 29:01 : And so they’re within the upper tolerable limit that has been set by the FDA. exactly they’re within the safety limit set pioneer after. When I was looking at product originally, you have somewhat common ingredients, but in a specific combination and amounts that leads to results beyond what you would imagine seeing with those individual ingredients alone. When I looked at the B vitamins, they’re very high, but you put my worries at ease to show that it’s still within that uer limit of what is considered safe.
Pankaj Kapahi — 29:29 : I would like to other people recommend taking NMN or any kind of NR, but one advantage of taking the five together would then be you don’t need to take it at that height. If you’re taking a single call bond like your lipoic acid nicotine high levels. This actually allows you to reduce that dosage to get better effects.
Dan Pardi — 29:46 : When did it become commercially available?
Pankaj Kapahi — 29:48 : We started last August, now it’s almost been there.
Dan Pardi — 29:51 : Alright, so we’ll take this for what they are, but since it’s been on the market, we’ll kind of anecdotes. Have you heard from people that have been taking it?
Pankaj Kapahi — 29:58 : It’s been largely positive and especially people in the scientific community or people who know us, they have been more mindful of the changes. Not everybody sees the effects on appetite suppression, but a lot of people are seeing that. I see them myself, but I think one need to sort of awareness to observe this. You have to be mindful of what your daily practices are. But what’s been more exciting is the few people who are doing it long-term are seeing benefits. Like for example on the two friends, one of them keeps very close record of his swim time. He’s seeing almost 10 % improvement in how well he’s been swimming. He has data from the last seven-eight years. He’s been taking it now for almost a year. I feel an increase in stamina. So at the long-term effects which start of the three to six months, you can expect to see other benefits.
Dan Pardi — 30:45 : It’s always an advantage in the supplement world where you can feel the effects. So how is it taken?
Pankaj Kapahi — 30:50 : That that interesting point B vitamins at high doses should not be taken during the day because they can keep people active and so we recommend that you take it early in the day. Some people are taking 2 pills a day early in the morning, two to three pills a day. Or you can take one pill before lunch and one pill before breakfast or whatever. Works for people, but generally during early part of the day is when I recommend.
Dan Pardi — 31:13 : Do you plan to work on any new formulations or you feel like you’ve got the formulation that you are going to go with? At this point.
Pankaj Kapahi — 31:19 : This has been very exciting to see that components can work together. We’ll be trying other things in the lab to workout which ones work well together because some also can be detrimental. So we are going to go one by one. It’s going to be labor intensive, but to see which other things could be added further.
Dan Pardi — 31:37 : Do you have a road map of the future research work?
Pankaj Kapahi — 31:40 : We were counting our studio 10 studies planned in our lab and also a lot of collaborations have been trying this out with promising results. So just want to mention a couple of things that are coming. We will be doing a study on the improvement on muscle and the second, we’re finding that this can overcome the effects of menopause in mouse where you take out the ovaries and leads to a drastic decline in health. That can’t be reversed with this, which is exciting because the potential side effects of hormone therapy in humans after menopause. Related to cancer to have a safer alternative that can protect you from the aging effects of menopause would be promising. So during menopause or ovaries removal, but there’s a decrease in estrogen and an increase in FSH, follicle-stimulating hormone, and that’s been recently implicated not only in muscle loss and bone loss but also driving Alzheimer’s disease. We can reverse that with glycol, which is exciting and we’re building on that work.
Dan Pardi — 32:38 : You would imagine that if a compound had a positive effect. On an aging factor that has system-wide influence, then you would potentially see many different aging and lower health-related conditions improve if you were able to modify that factor robustly enough and early enough in the pathogenic process. I’d be curious to hear what improvements people report when taking Lilo, and I can see this becoming another source of new research ideas for your lab and collaborators.
Pankaj Kapahi — 33:06 : Exactly what other I just want to mention is that we seem dramatic improvements in the aging of the eye and the animals. As well, but nobody. You’re absolutely right. I think given glycation is something that ends up affecting different tissues, we do expect this to work on multiple tissues, but we have to go one by one. So hard eye and the brain seem to be protective right now, and we are working on papers around those.
Dan Pardi — 33:29 : Pankaj, thank you so much for coming back on the show and explaining ages to us and all the work that you’ve been doing, screening over 800 compounds to identify the ones that have the most impact on methyl glyoxalase reduction. And then all the subsequent experiments that you’ve been doing to test efficacy of this formulation on different systems and tissues, you’ve been very busy?
Pankaj Kapahi — 33:51 : My lab is wonderful and we’re very excited about what we’re doing here and especially now thinking more about how to translate this further. Thank you so much for having me on the show. It’s been a pleasure.
Kendall — 34:04 : Thanks for listening and come visit us soon at humanOS dot me.