[00:02] it feels like another celebrity, influencer, or family member who used to after using them. But, I'm very surprised by how many normal-weight people are using GLP-1s as well. Like, you don't need it. You're 12% body fat.
[00:16] Why are you using it? The reason most of these people take GLP-1s is to make it easier for them to stay lean. But, there are others who do it for the proposed longevity benefits. The idea is that microdosing GLP-1s would help
[00:29] fat percentage even more, lower their lipids even more, and lower their inflammation even more. And in theory, that does make sense a little bit. You're just moving yourself from normal
[00:41] to even more optimal. So, the question is, are GLP-1s just weight-loss drugs, benefits? So, in this video, I'm going to look at whether or not microdosing GLP-1s makes sense for lean individuals, and whether or not using them for
[00:54] longevity is smart or completely unnecessary. GLP-1s are known for their large weight loss, up to 24% mean weight loss. A 2023 phase 2 clinical trial on retatrutide saw that it resulted in 24% mean weight loss at 48 weeks, compared
[01:09] to semaglutide's 15% weight loss at 68 weeks, and tirzepatide's 21% weight loss. Some people even lost over 30% on retatrutide. A weight loss of 14 to 16% already for an obese person can be life-changing, not to mention 24% or
[01:24] 30%. And by losing the weight, you're lowering your risk of heart disease, kidney disease, and overall mortality. So, GLP-1s for obese people are yes, longevity drugs, because they lower the weight. In the SELECT trial, semaglutide
[01:36] users were also seen to have a 20% reduction in major cardiovascular disease events and 15% reduction in heart disease deaths in overweight or obese people with existing heart disease, but not diabetes. Most of these
[01:48] effects are because of losing weight, as well as lowering blood sugar, because is very bad for your heart health and these effects can also be attributed to modest reductions in blood pressure,
[02:01] inflammation. This would also have protective effects on the liver and kidneys. In the SELECT trial, kidney analysis found semaglutide improved kidney outcomes and slowed some kidney disease risk markers. Those who were
[02:14] receiving 2.4 mg of semaglutide per day had a lower decline in eGFR, which is a marker of kidney function. Semaglutide users also had a 22% relative reduction kidney disease or chronic kidney replacement therapy. When it comes to
[02:30] clinical trials on people with Alzheimer's disease have failed to slow clinical disease progression, despite some beneficial changes in biomarkers. GLP-1s can lower inflammation and neuroinflammation by improving insulin
[02:43] resistance. However, GLP-1s also have direct effects on the brain through the insulin resistance. This lowers inflammatory cytokines and improves mitochondrial function. So, the benefits of GLP-1s aren't just weight loss and
[02:57] lower blood sugar. GLP-1s work systemically and they improve multiple organ systems. What about GLP-1s in healthy normal weight individuals? There are a few studies looking at this. They found that GLP-1s lead to weight loss
[03:09] and favorable blood sugar changes even in normal weight healthy individuals. studies on healthy people. The way microdosing GLP-1s would have longevity benefits in normal weight people is by mimicking calorie restriction or
[03:22] creating a small calorie deficit. We know from animal research that being to extend their lifespan. Just by having less energy substrate in the system, extends their lifespan and reduces the risk of chronic diseases. Calorie
[03:36] restriction for 2 years in humans has also been seen to slow down speed of biological aging by 15% as measured by the Dunedin PACE test. However, in this study, the participants were told to aim for 25% reduction in calorie intake, but
[03:49] in reality, they achieved only half of that, so 12 to 13%. The reason people weren't able to adhere to the full 25% calorie deficit is because calorie deficit is very hard and people like to eat. Microdosing GLP-1s would arguably
[04:02] make it a lot easier to adhere to a calorie deficit. So, in this particular study, if people had taken GLP-1s, they would have been able to adhere to the full 25% calorie deficit for the entire study, probably. And in the process,
[04:14] even better metabolic health because we're talking about the general population, not some ripped health optimizers. So, imagine this situation. Alfred is 15% body fat and his hemoglobin A1C is 5.4%. These are normal
[04:27] numbers and they're considered in the healthy range. If Alfred were to microdose GLP-1s, he could get to 12% body fat and 5% hemoglobin A1C without any significant effort. Those numbers would be slightly better and based on
[04:40] greater likelihood of living longer and having less risk of diabetes or heart a slightly leaner and slightly lower blood sugar person would live longer than the otherwise normal person, but slightly higher body fat and higher
[04:54] So, there are reasons to believe that the slightly leaner and slightly lower blood sugar person would live longer. Almost all of the proven GLP-1 benefits come from pushing metabolically dysfunctional people into a normal range
[05:08] instead of pushing normal people into a super optimized territory. The key is to develop nutrient deficiencies, but this is easily prevented. Number one, you do muscle and strength. Number two, you eat whole foods nutrient-rich diet to avoid
[05:23] take some supplements if necessary to fill the nutrient gaps. And number four, you eat enough protein to minimize muscle loss. The idea that GLP-1s would you're not lifting weights or you're not eating enough protein. You will lose
[05:36] muscle on any diet that you lose weight with, but you can minimize it. But even then, the muscle loss from GLP-1s appears to be very over exaggerated. A A phase two clinical trial showed that in type 2 diabetics, retatrutide at a dose
[05:50] of 8 mg shifts weight loss more towards fat loss rather than muscle loss. It's loss treatments. Here's what the fat mass loss was like from baseline to week mass loss was like from baseline to week 36. Placebo group lost 4.5% as fat loss.
[06:03] 36. Placebo group lost 4.5% as fat loss. Retatrutide at 0.5 mg lost 4.9% fat loss. Retatrutide at 4 mg 15.1% at 8 mg 26.1% and 12 mg 23. 2%.
[06:16] at 8 mg 26.1% and 12 mg 23. 2%. Dulaglutide 1.5 mg resulted in 2.6% fat biggest fat loss was seen with retatrutide at 8 mg resulting in 26.1%. In terms of absolute values for fat loss, placebo group lost 1.7 kg, 0.5 mg
[06:32] loss, placebo group lost 1.7 kg, 0.5 mg of retatrutide 2.1 kilos, 4 mg 7.1 of retatrutide 2.1 kilos, 4 mg 7.1 kilos, 8 mg 10.9 kilos, 12 mg 10.5 kilos, 8 mg 10.9 kilos, 12 mg 10.5 kilos, and dulaglutide at 1.5 mg 1.4
[06:44] kilos. The interesting part is for muscle loss. Placebo group 0.6 kilos, muscle loss. Placebo group 0.6 kilos, retatrutide 0.5 mg 0.4 kilos, 4 mg 3.1 retatrutide 0.5 mg 0.4 kilos, 4 mg 3.1 kilos, 8 mg 6.5 kilos, 12 mg 6.5 kilos,
[06:57] and dulaglutide plus 0.4 kilos. The ratio of fat loss to muscle loss is quite favorable. 10.9 kilos of fat versus 6.5 kilos of muscle, which is a ratio of 1.7 to 1. That's nearly twice as much fat loss than muscle loss. This
[07:11] is to be expected during weight loss, especially without resistance exercise. GLP-1s that combine it with resistance exercise yet, so the muscle loss would be greatly reduced if you incorporated resistance training. But a fat loss
[07:24] ratio of 1.7 to 1 is already quite impressive, especially without resistance training. One of the major potentials for GLP-1s for healthy people is joint regeneration. There's some preclinical evidence that semaglutide
[07:37] the of joints independent of the weight loss and metabolic health benefits. Joint pain and osteoarthritis are debilitating so it might be an amazing progress in increasing people's quality of life. And
[07:52] could also exercise for longer and stay mobile, which helps them to stay them live longer. We should also talk GLP-1s, because there are some. Number one, reduced reward motivation. It
[08:06] basically reduces the food noise. Many people report less interest in food, alcohol, and even shopping. This is likely because GLP-1s act on dopamine reward circuits. This has been seen to reduce addictions like alcohol or
[08:18] over to other areas of life where you do draw enjoyment from. For some, this can be good because it improves their self-control, but for others, it can cause more apathy, or you just feel less enjoyment. Number two, apathy and
[08:31] emotional flattening. The evidence for this is anecdotal, but it is emerging. Some users describe less drive, and they don't care about things as much. Number three, depression and anxiety. Some observational reports suggest possible
[08:43] increased depressive symptoms due to the same down signaling of the dopamine pathway. Others show improvements in depression, likely due to the weight loss and improved metabolic health. Regulatory agencies like EMA and FDA
[08:55] thoughts, but there's no clear causal link. The reason I brought up these specific side effects is because someone is obese, they lose the weight, they can depression, and their just overall quality of life because they're not
[09:08] obese anymore. However, for a normal weight individual who is microdosing GLP-1s, those same side effects can be very detrimental. You might see a life, and you might experience a lot more apathy and less enjoyment from your
[09:21] life. We don't have enough data to know if it is true or how true it is, but it side effects are mainly gastrointestinal. The most commonly reported adverse effects are nausea, diarrhea, vomiting, and constipation.
[09:34] Higher doses generally cause more overall adverse effects than lower doses. Less common adverse effects include temporary ALT elevation, sensitivity. Based on the clinical trials, retatrutide causes
[09:47] dose-dependent heart rate increase, 5 to 10 beats per minute on average, peaking at 24 weeks, and then declining. About 20 to 30% of people are affected by this. Mild arrhythmias can also occur, but no major adverse cardiac events have
[10:00] been observed. These are just things to keep in mind if you have a history of arrhythmias or other cardiac problems. Consult your physician beforehand, even when microdosing. The overall message is that GLP-1s in obese people will be
[10:12] life-changing. There's no denying that. And it is also likely that an overweight person doesn't have to take GLP-1s forever. They might take it initially in and then gradually they can reduce their dose and eventually start microdosing
[10:25] GLP-1s. That's a likely scenario. Microdosing GLP-1s for the sake of longevity in already normal-weight individuals would work to the extent would work. It's going to make you eat less, you're going to be leaner, you
[10:37] lower blood pressure, lower lipids, better kidney markers, better liver markers. So, there's currently no evidence that they would slow down aging only make you a slightly healthier and leaner version of yourself. And the key
[10:50] healthier and leaner because of the reduced food noise, reduced dopamine signaling. But, that is still a valid mechanism of effect because we know virtually all animals. There's no direct human evidence for that, but it is very
[11:04] slightly lower blood sugar, slightly than the opposite. And if you bring in the example of Alfred again, it's likely that a 12% body fat Alfred with 5% hemoglobin A1C would live longer than
[11:17] Alfred with 15% body fat and 5.4% hemoglobin A1C. Will an 8% body fat and 4.5% hemoglobin A1C Alfred live longer? We don't know that. You don't necessarily need to microdose GLP-1s to reach 12% or even 8 to 10% body fat, but
[11:31] it's harder to rely solely on discipline or controlled lifestyle to do so. Whereas with GLP-1s, you can achieve it with less food noise and less effort. Me microdosing GLP-1s, at least not in the near future, because I would probably
[11:44] lose too much weight and I'm already lean. If I were to microdose GLP-1s, I would start eating less and I might lose too much weight. That's not my goal at muscle and strength. My blood markers related to insulin sensitivity and
[11:56] metabolic health are also all optimal. And aggressively pushing them lower would arguably have diminishing returns. For example, I'm already around 10% body fat and my hemoglobin A1c is 4.5 to 4.7%. My other biomarkers are also
[12:10] optimal. Will everyone start microdosing GLP-1s in the next few years? I think More and more people who aren't obese will start using them, because it's that six-pack. And that's what people want. So, GLP-1s make it easier for you
[12:24] calorie restriction, but they're not literal anti-aging drugs. At least there's no evidence for it yet. If you want to learn more about how to improve span without spending hours at the gym, without spending thousands on
[12:37] supplements, and get yourself to top 1% of health without obsessing about it, then check out my online community, Youthspan Society. It's where you can protocols from me. Link in the description.