Humans have been searching for the magic pill for aging for eons. Thousands of years ago, it was the water of life that supposedly made you young again. But today, it's various supplements and pharmaceuticals that are touted as having longevity benefits.
How do you know if a supplement is going to make you live longer? Well, you can't, because it's virtually impossible to do that kind of an experiment in humans. However, we do have a bunch of animal studies on rodents, worms and flies that have found life extension effects with different compounds. In this video I'm going to go through the findings of the National Institute of Aging's Interventions Testing Program and see what supplements and molecules they've found to work in extending the lifespan of mice by 20, 30 and up to 60%. So what is the Interventions Testing Program or ITP for short?
It's considered the world's most rigorous peer-reviewed program for investigating longevity molecules and their effects on mice. They started in 2002 so the program has ran for over 20 years. and have tested dozens of different compounds. You can read all their supported interventions and publications at the National Institute of Aging's website. Over the 20 years, the ITP has identified 9 molecules that have extended lifespan in mice.
They are Acarbose, Aspirin, Canagliflozin, Captopril, Glycine, Nordihydro, Bioeretic Acid, Protadim, Rapamycin and 17-alpha-estradiol. That's not a very large amount of compounds from the dozens of compounds that have been tested. which kind of shows that most supplements don't have life extension effects even in animals.
This doesn't mean that the list is conclusive either, because the ITP is continuously testing new molecules. So let's take a look at these molecules more closely. The first one is Acarbose.
Acarbose is a diabetes drug that blocks glucose absorption. The ITP studies on Acarbose found that it extended median lifespan in male mice by 22% and by only 5% in female mice. Maximum lifespan increased by 11% in males, and 9% in females.
This is quite interesting and you would predict that these life extension effects were because of lowering blood sugar levels. However, the ITP studies done on metformin, which is another diabetes drug and also lowers blood sugar levels, have found that metformin doesn't extend lifespan unless it's paired with rapamycin. So it's rapamycin that does the extension effects, not metformin.
Metformin does reduce the risk of heart disease mortality in people with diabetes, but it hasn't been found to have any longevity effects in otherwise healthy humans either. So in my opinion, the life extension effects of ACARBOS might have to do more with the reduction in glucose absorption rather than lowering of the blood sugar levels. If you absorb less glucose, you also absorb fewer calories and we know that calorie restriction is the most proven non-genetic method of life extension in animals. Does this mean that taking ACARBOS is going to be beneficial for human longevity?
ACARBOS does reduce the risk of heart disease and hypertension in people with impaired glucose tolerance. ACARBOS also induces weight loss through reduced glucose absorption as well as by increasing the expression of GLP-1, which is the mechanism by which Ozempic works. The problem is that Acarbose also appears to have some negative side effects.
Type 2 diabetics who take Acarbose see a decrease in muscle mass, hand grip strength and walking speed. Metformin has also been seen to blunt the muscle growth signal in response to resistance training in older adults. Muscle mass and muscle strength are both very important for longevity.
and it appears that acarbose and metformin could be harmful for older people who have low muscle mass and low strength. It might be that with acarbose you can mitigate the negative effects on muscle mass by just lifting weights, because in these studies the patients didn't do any form of resistance training. However in the metformin study the people did lift weights and they still saw the reduction in the hypertrophy response from the training. So I would predict that it might happen the same with acarbose.
Metformin has been seen to decrease VO2max and aerobic capacity as well. which is a bad thing for cardiovascular function. A higher VO2max is linked to longevity. When it comes to acarbose, then acarbose hasn't been seen to reduce VO2max. And in one 2006 study, they found that exercise combined with acarbose treatment actually increased VO2max, whereas exercise alone didn't.
That is very interesting, but obviously we would need more studies to confirm that. So overall, acarbose as well as metformin can be life-saving for diabetics. If you're otherwise healthy, you don't have impaired glucose tolerance, then taking these medications. might have negative effects on your fitness.
Taking these pharmaceuticals recreationally for longevity purposes is also somewhat of a mixed bag. On one hand we have the ITP results showing that the carbose works but on the other hand the human evidence suggests that a carbose can result in loss of muscle and strength. But honestly I think you can mitigate it with resistance training and a higher protein intake. It's the same with Ozempic. You lose muscle because of not lifting weights and you're under eating protein.
Personally I'm not taking a carbose I don't have any plans to take it in the future right now. but I do think that it's quite interesting. The next one is canagliflozin. Canagliflozin is another FDA-approved diabetes drug that supports kidney function and cardiovascular function. It also inhibits the sodium glucose transporter 2 by blocking renal uptake and intestinal absorption of glucose.
In the ITP study, canagliflozin Canagliflozin extended median survival of male mice by 14%. Cana also increased the age for 90th percentile survival by 9%. However, they found no effects in female mice, although their glucose tolerance still improved. This drug appears to be very similar to a carbose, it works through reduced glucose absorption, and it improves glucose tolerance. But does it have the same negative side effects on muscle growth?
There's no studies in humans, but in mice, canagliflozin does downregulate certain proteins in muscle stem cells. Next up we have aspirin, which is a non-steroidal anti-inflammatory drug or NSAID. You can get it over the counter, which makes it very easily found.
In the ITP study, aspirin treatment extended median survival in male mice by 8%, but it wasn't very significant. There are other animal studies as well that find how aspirin extends their lifespan. The effects are probably because of aspirin's anti-inflammatory effects.
However, in humans, daily intake of aspirin has been actually seen to be linked to a higher risk of all-cause mortality, primarily because of increased cancer-related deaths. This applies to elderly people who see an increased risk of cancer metastasis from aspirin treatment and accelerated cancer progression as shown by several randomized controlled trials. There have been previous studies that found that aspirin treatment reduces the risk of cancer, but those studies were mostly done on younger populations, whereas the recent clinical trials were done on the elderly people and in those people aspirin treatment appears to increase the risk of cancer.
The reason why there's a discrepancy between younger and older people might be because of the age-related decrease in the immune system. Older people have weaker immune systems, and aspirin might modulate the immune system in a negative way that enables the proliferation of cancer more easily. So it looks like aspirin isn't a good idea later in life.
Historically, aspirin has been used for primary prevention of cardiovascular disease, which means preventing a heart attack or preventing the onset of atherosclerosis. Taking baby aspirin or small amounts of 50-100mg of aspirin per day has been very common for decades for this reason. So the question is, does microdosing baby aspirin every day?
reduce the risk of heart disease. The American Heart Association says low dose aspirin could be considered for primary prevention of atherosclerotic cardiovascular disease in adults aged 40 to 70 who are at a high risk of atherosclerosis but with no increased risk of bleeding because aspirin increases the risk of bleeding. They don't recommend it for people over the age of 70 or for anyone who's at increased risk of bleeding. What about secondary prevention which means preventing getting a second heart attack?
Here, daily low-dose aspirin has more benefits and is generally recommended by the American Heart Association for people who aren't at increased risk of bleeding. Next supplement is glycine, which is an amino acid that supports collagen turnover, glutathione production, creatine synthesis and heme synthesis. The 2019 ITP study found that glycine supplementation increased maximum lifespan in both male and female mice by 4-6%. The mice consumed a diet comprising of 8% glycine, which is quite a large amount.
Another 2011 study found that a diet comprising of 8-12% glycine extended the median lifespan of rats by 28%. The rats lived 113 weeks instead of 88. Maximum lifespan also increased by 30%, from 91 to 119 weeks. The reason why glycine extends lifespan is thought to be because of mimicking methionine restriction.
Methionine is another amino acid you get primarily from animal protein, and methionine restriction has been often seen to extend lifespan in animals. Glycine counterbalances methionine toxicity and has been seen to have the same life extension effects as methionine restriction, without restricting methionine. That's why in these studies you see that a very large intake of glycine 8-12% of their diet extends lifespan. In humans the evidence is obviously more limited, but the average person's diet is very high in methionine and it doesn't contain that much glycine. Muscle meat, eggs, dairy, chicken, fish, etc. they're all very high in methionine and very low in glycine.
Glycine you can get from tendon meats, collagen, fish skin, chicken skin and gelatin powder. This creates a scenario where most people could theoretically improve their longevity by balancing their methionine ratio with more glycine. They would either need to reduce their methionine intake or increase their glycine intake. But most people would benefit from both.
There are no hard outcomes observed from high methionine and low glycine intake, but there are a few benefits that have been seen in clinical trials. In older adults, they have found that low plasma glycine levels are a marker of visceral adiposity, independent of sex, age, body composition or chronic diseases. Serum glycine is also negatively associated with intramuscular adipose tissue, which is the fat inside the muscles.
Methionine restriction on the other hand appears to reduce visceral fat in both animals and humans. And glycine is also useful for other things, such as collagen production for the skin and joints, glutathione production for antioxidant defense and inflammation, sleep, blood sugar and creatine synthesis. So although we can't say whether or not glycine supplementation is going to extend lifespan in humans, we can be pretty sure that most people are eating too much methionine and not enough glycine. That's why I'm also taking 10 grams of glycine as a supplement every day, and I'm eating plenty of glycine-rich foods.
Next on the list is captopril. Captopril is an angiotensin converting enzyme ACE inhibitor used to treat high blood pressure. In the ITP study, captopril extended median lifespan of female mice by 4-5%. Hypertension is one of the most common comorbidities in the world and it's called the silent killer that increases the risk of heart disease, kidney disease and neurodegeneration.
If you have elevated blood pressure then you should try to normalize it as fast as possible because the longer your blood pressure stays elevated the more damage it can cause to your body. ACE inhibitors have some nasty side effects, which is why I think the recreational use of captopril is probably not worth it. Furthermore, the life extension benefits in the ITP study weren't that big.
It was only 4-5% and it was only observed in the female mice. So if you were ever going to take any pharmaceutical for recreational purposes to support your longevity, then you would be probably better off by taking something like a carbose or rapamycin instead of captopril. The next compound is Nordihydrohyaluronic acid, NDGA. It's a lignin found in creosote bush or grease wood.
In the ITP study, it resulted in 10% increase in lifespan in both sexes. NDGA is basically a herbal compound that's been seen to increase nrf2 activation and thus reduce inflammation. It's not a very common compound, although it's being investigated for clinical purposes at the moment.
And I haven't found any supplements that have NDGA in it, so that's pretty much all I have to say about this compound. Protandim is another herbal supplement that contains a patented mix of five herbal ingredients that support Nrf2 activation. It has turmeric root, green tea, milk thistle, bacopa monnieri, and ashwagandha.
In the ITP study, Protandim resulted in 7% increase in median survival of male mice, but there was no significant difference in survival at the age at 90% mortality. The company selling Protandim, LifeVantage, has gotten into some trouble with the FDA because of their misleading and illegal marketing claims. that claim protandim can help with different conditions like cancer and diabetes. There's no evidence that protandim or the specific ingredients in the supplement could help with those conditions. The ITP study did find that protandim resulted in 7% increase in median lifespan, but there was no difference at the end of life.
So in my opinion, taking the supplement isn't worth it. The problem is also that it's a patented proprietary blend, which means that you don't know exactly how much of each ingredient is in the blend. And it's also $66 for 30 capsules.
which is over $2 per day. Next up we have the most successful life extension molecule and the one with the greatest potential, rapamycin. It's been known to have life extension effects in animals for decades and in the ITP studies, it has done so by 14% in females and 9% in males, even if rapamycin was given late in life. Rapamycin increases median survival by 10% in males and 18% in females and it attenuates age-related decline in spontaneous activity in males, but not in females.
In another 2016 study, treating middle-aged mice with rapamycin for only 3 months extended their life expectancy by 60% and improved healthspan. That's very interesting because they treated the mice with rapamycin for only 3 months. A mouse usually lives 12-18 months, so they got rapamycin only about a quarter of their life, and they still saw a large life extension effect.
For humans, the equivalent duration would be something like 20 years, which is a very long time. But it's still not your entire lifespan. But are there any longevity studies about rapamycin in humans?
If you don't know, then rapamycin is used for organ transplantation rejection as it suppresses the immune system if taken chronically. However, there are now several clinical trials showing that rapamycin actually enhances immune system function when used transiently. It appears that rather than using rapamycin daily, you would have to pulse it, something like once a week or once every two weeks, to avoid the immunosuppressive effects.
And by doing that, the elderly people actually see an improvement in their immune system function. Many longevity enthusiasts are taking rapamycin off-label in hopes of extending their lifespan. A 2023 study by Matt Kaberlein and colleagues looked at 333 such people. They found that at an average dose of 3-6 mg per week, rapamycin didn't have any adverse side effects on health, with the most common side effects being abdominal cramps and mouth ulcers. Most people also didn't know if the drug was working, but they did self-report improvements in their health, brain function, and youthfulness, coldness and general aches and pains.
The problem is that the placebo effect can be very big in these people who are taking rapamycin thinking that it's going to extend their lifespan. You can't just buy rapamycin from the pharmacy You need to go out of your way to get it And if you are doing that then you probably have some expectation that it's going to improve your health So it wasn't a placebo controlled study. Overall, I do think that out of all these compounds rapamycin is the most promising one I think it has the greatest potential of being the first geroprotective drug. We obviously need a lot more clinical trials on humans to see what the effects are, but many of the leading longevity experts do think that rapamycin does work in extending lifespan.
I'm personally not taking rapamycin at the moment, I don't have any plans in the near future either, I'm waiting for more of these clinical trials to come out in the next few years. The last compound is 17-alpha estradiol, which is also called non-feminizing estrogen. In the ITP study, it increased median male lifespan by 19% and by 11% when fed late in life.
This is quite interesting, and estrogens are known to have cardioprotective and neuroprotective effects. It's even thought that estrogen might be one of the reasons why women live on average 5-10 years longer than men. As you've seen repeatedly throughout this video, most of the compounds extend lifespan in male mice, more so than they do in female mice.
That's very interesting and it might be partly because of the sex differences between male and female animals. And in the ITP study, 17-alpha estradiol didn't extend female lifespan. What other studies have also found is that the life extension effects of 17-alpha estradiol go away in castrated male mice, which suggests that it works in the presence of elevated male hormones and androgens. Androgens and testosterone tend to shorten lifespan and they're associated with increased risk of heart disease, which is why it looks like 17-alpha estradiol counteracts those effects in males who have testicles. It doesn't do so in females who don't have testicles, and it doesn't do so in castrated males.
Interestingly, castrated males having also seemed to live longer than regular males in different human cohort studies. I'm pretty sure most men would like to keep their testicles, and they would much rather take something like 17-alpha estradiol rather than castrate themselves. 17-alpha estradiol is called non-feminizing estrogen because it doesn't have any of the feminizing effects of estrogen, such as breast tissue growth or other feminizing effects.
It's obviously very early to say if 17-alpha estradiol is going to extend lifespan or longevity in humans, especially in male humans, but I'll be interested to see the future clinical trials. There you go, these are the compounds that have been shown to extend lifespan in the ITP program. They've tested many other popular molecules like resveratrol, methylene blue, nicotinamide riboside, curcumin, and MCT oil.
and those compounds didn't increase lifespan. What's the practical takeaway from this? Well, personally me, I'm going to macrodose glycine and I might think about using rapamycin in a few years, but not right now.
If you want to know about the non-pharmacological evidence-based methods to slow down aging and add healthy years to your life, then check out my new book, The Longevity Leap, in the description. Thanks for watching this video. Make sure to click like and subscribe for future videos about living longer and staying healthier. My name is Siim. Stay optimized, stay empowered.