Transcription
When scientists discovered one of the most counterintuitive dynamics related to aging back in 1935, it was thought that radical lifespan extension was just around the corner. So when the rats were starved in these experiments, they lived much longer.
Now, of course, starving humans isn't exactly ideal, but if we could figure out on a molecular level why calorie restriction helps to extend lifespan, then maybe we could mimic those effects without the calorie restriction. And this was the problem that scientists in Leonard Garanti's lab at MIT were wrestling with in the late 1990s. They were trying to gain a deeper understanding of the pathways linking calorie restriction to longevity benefits. They were working with a very simple organism, yeast. They meticulously tracked different lines of yeast cells throughout time, carefully noting the molecular pathways linked to a longer life.
As they poured through the data, they uncovered a subtle clue. It seemed that the increased longevity generated by calorie restriction, it required the activation of a specific protein called sir 2. But that activation in turn depended on another molecule called NAD. If you remove NAD then sir 2 isn't activated and without that activation there's no longevity gains. So this research suggested that NAD might be an essential player in the molecular processes related to aging and age related diseases.
Another clue dropped a few years later. So researchers took skin samples from newborn babies as well as from adults aged between 15 to 77. So they were exploring a link that had been found in rodents that NAD levels appear to decline with age and that decline was linked to age- related increases in cellular damage. So as they analyzed the human samples the same pattern emerged. DNA damage correlated strongly with age and crucially NAD levels also dropped as age increased. The researcher's conclusion was this: that as we get older NAD levels go down and without that NAD fuel then we don't have the DNA repair enzymes that are functioning correctly and that accumulates the DNA damage. So the decline in NAD might play a major role in the aging process. Again, as levels drop that could be limiting energy production, DNA repair and important other signaling pathways.
So this pointed to an obvious question. If we could boost NAD levels to counteract this natural decline, could we delay some of the processes of aging? Well, in a crucial study published in 2016, that theory was put to the test in mice. First, researchers needed to boost NAD levels. And scientists had discovered that this was possible by supplementing with nicotenomide ribocide or NR. So, NR is one of the precursors that the body uses to make NAD. And after increasing NAD levels in mice, the researchers looked specifically at how stem cells in their muscles behaved. And the results were exhilarating. The treatment indeed seemed to counteract some of the processes of aging. Cellular the function was restored to a more youthful state and the lifespans of the mice increased.
So at this point interest just took off. The story was compelling. NAD is central to cellular health. It declines with age and if we supplement with precursors, we can increase NAD levels. And that Mel study seemed to show us that this leads to meaningful rejuvenation at a cellular level that extends lifespan. And if it could work in mice, why not in humans? That was the next obvious question. But not everyone waited for the experimental evidence we needed to answer it.
>> So what NMN does and this other molecule called NR, which both you can get on the internet, they boost the body's levels of NAD back up to youthful levels again. And if we give them to mice, these molecules to to mice or even to worms or yeast, they live longer and they're super healthy. Nammen is is um something I I get from for myself and I'm not selling anything. So I take a gram of animemen in the morning based on clinical trials has been shown that that will raise NAD.
>> So that was David Sinclair on the Joe Rogan podcast in 2019. So he's describing the logic and his own use of Nmen supplements. So Nmen is another precursor to NAD. Now, of course, what Davis Sinclair does privately is his own business, but he gives a strong impression here that there's good scientific basis for what he's doing, and that's an impression that he's leaving with millions of viewers. There's just one problem. At the time that that episode aired, there wasn't a single human clinical trial on the claimed benefits of any men supplementation. Not one. And there's been some more recent data that cast doubt on that 2016 lifespan extension study in mice.
So, there's a dirty secret in scientific research that most people who aren't researchers don't know about, and that's the reproducibility crisis. It's a depressingly common story. So, the initial study surfaces some amazing new discovery, and that generates incredible hype. And you may have seen some of these headlines from studies like this, only to wonder years later, what ever happened to that amazing new cure that was supposedly found? Well, here's what's probably happened. After that initial excitement, other researchers tested out the findings of that first study and they didn't see the same results. So those early exciting findings are often not repeatable.
Instead, we have a far more robust program that tests different molecules to see if they will extend lifespan in mice and it's called the interventions testing program. It has reproducibility built in because the tests are performed by three different labs at the same time. So given the excitement, the scientists working for the interventions testing program. They turned their attention to NAD precursors and specifically they looked at NR. But what they found was a serious blow to the hype. NR failed to increase the lifespan of mice. NR did raise blood NAD levels in the mice, but again there was no lifespan benefit or any other functional improvement. Now given the rise in NAD levels that the interventions testing program saw, it's highly unlikely that a different NAD precursor such as NN would have a different outcome.
So to add to that disappointment, the theory that NAD levels decline with age has also been called into question. So muscle biopsies of old adults who exercised were taken and they had similar NAD levels compared to younger adults. And I go through all of the disappointing enemy human clinical trials in a video that I'll link to at the end. But I do want to look at one more new study that was just published because it's got profound implications for how we should think about Nmen and NR supplements. And to me, this is a nail in the coffin for Nmen and NR.
So the study looked at long CO. So what's the link here between Nmen or NR supplements and CO? Well, when the body fights infection, one of the many negative consequences is that the recovery process, it strains our NAD metabolism. So long co involves cognitive issues like brain fog, immune system problems and mitochondrial dysfunction which might be related to the strain on NAD metabolism. So researchers thought that NR supplements to support NAD metabolism might be a promising treatment option for long co and all of this connects to aging because as the original theory goes as we age our NAD metabolism is strained and if we support it then we should see functional improvements. So we can indirectly test that theory here with longco patients who who already have a strain on their NAD metabolism.
So the researchers recruited about 60 participants with longco and they placed them into two groups. So one of them took NR supplements for 20 weeks and the other took a placebo and then they also switched to NR later down the track. And during the course of the study NAD levels rose sharply with supplementation again just as we would expect. But here's the critical question. Did that actually help with any of the symptoms related to longco? Unfortunately, no. There were no differences between the groups for any metrics examined. And if we would ever see a positive functional outcome with NAD precursor supplementation, it's longco, but there wasn't.
Instead, all we have is a litany of failed human clinical trials of any men and n in humans. Yes, we see a rise in blood NAD levels, but that's about it. There is no functional improvement. And yet, I've seen plenty of anecdotal accounts online where people claim that they do feel better with Nmen or NR supplements. And yes, they might indeed. But it's always an open question about what's really going on here. It could just be the placebo effect, but there's also something else that might be going on here.
So many people who take NAD precursors such as Nmen or NR. They also take TMG supplements. And there is human clinical trial evidence that TMG improves muscle performance when combined with exercise. So for instance, there's a 2024 meta analysis that found that TMG supplements enhanced strength and jumping performance. It's also been found to boost testosterone levels. And those potential benefits are the reason why I included TMG in micro vitamin. But of course, just because I take a supplement does not in any way mean that you should as well. But coming back to Nmen and NR, it might be that those people who are taking Nmen and NR as well as TMG, they're seeing the benefits from TMG. Now again, we can't be sure, but that seems to line up with the clinical evidence that we have so far.
What we can be confident in at the moment is that we just don't have good evidence that NAD precursors help combat aging or age- related diseases in humans. And if you want to hear more about the story, including a thorough breakdown of the existing human enem clinical trials, make sure to check out this next video.