“When compared to separate peer-reviewed studies using similar endpoints, the magnitude of change falls within ranges typically associated with intensive lifestyle interventions, like exercise (including High Intensity Interval Training), Mediterranean and DASH diets, and dramatic weight loss (>10% body weight loss), and exceeds what is commonly reported in most supplement studies. That’s not typical in nutrition research.“
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Link to paper and abstract https://papers.ssrn.com/sol3/papers.cfm?abstract_id=6241278. Kinda weird to see it published in ssrn, usually I see papers on economics and sociology published there
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Assuming the effect is real (and not somehow a doctored study to get the desired results), I asked Google search which ingredients most likely contributed to the cardiovascular effects, and it said:
Based on evidence for reducing mortality, preventing atherosclerosis, and reducing arterial stiffness, Glucosamine Sulfate and Fisetin likely have the biggest positive effect on cardiovascular health among the listed options. Studies show glucosamine reduces cardiovascular death risk by up to 22%, while Fisetin combats vascular aging and calcification.
Here is a breakdown of the top contenders based on cardiovascular impact:
- Glucosamine Sulfate Large studies link its use to significantly lower risks of cardiovascular disease and mortality, likely due to reduced inflammation and improved blood vessel health.
- Fisetin As a potent senolytic, it clears “zombie” cells, reduces arterial stiffness, and protects against heart damage.
- [Glycine] Associated with lower risks of cardiovascular disease and improved cardiometabolic function, including reduced blood pressure and improved blood lipids.
- [Calcium Alpha-Ketoglutarate] Known for protecting heart tissue from damage and improving mitochondrial health in the cardiovascular system.
- [Magnesium Malate]: Magnesium is crucial for blood pressure regulation, vascular tone, and heart function.
Conclusion: For direct, statistically significant, long-term cardiovascular mortality reduction, > Glucosamine Sulfate is a leading choice, followed closely by Fisetin for vascular anti-aging effects.
And it’s worth pointing out that Glucosamine is being tested by the Interventions Testing Program as part of their 2025 cohort.
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I don’t understand. Their product is a mix of supplements and they brag that the improvements are across all endpoints. That shouldn’t be surprising at all! I wouldn’t use that as “we are reversing aging itself” as the article seems to say.
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Hey guys,
Chris here – founder of NOVOS. Been a reader of your forum for years, and figured now was the time to sign up to respond to the points about the NOVOS Core clinical trial, and answer any questions you might have.
So, here are a few clarifications based on the comments:
- Why publish on SSRN?
We shared the manuscript as a scientific preprint so the data is publicly accessible immediately while formal peer review is happening. SSRN is operated by Elsevier and widely used. The paper is also being submitted through standard academic channels.
- Assuming it’s real / not doctored
The study was a randomized, double-blind, placebo-controlled human trial executed by Professor Christian Heiss, a cardiologist at the University of Surrey who has published more than 200 peer-reviewed papers. Objective vascular measurements (FMD, PWV, SBP) were prespecified endpoints on ClinicalTrials . gov. Being double blinded and placebo controlled materially reduces bias compared to typical supplement evidence. Additionally, the study was analyzed many ways, and the results remained statistically significant versus placebo across multiple sensitivity analyses.
- “It’s a mix of supplements — improvements across endpoints shouldn’t be surprising”
Combination biology is not trivial. In fact, aging research suggests the opposite: that combining compounds without proper evaluation more often than not cancels out benefits.
This has been shown in years past, but most recently in 2024, Dr. Ocampo at University of Lausanne, Switzerland (celebrated for his seminal work with Yamanaka factors) published this quote in his combinatorial lifespan screening paper:
“In our study, combining two compounds with a positive effect on lifespan rarely led to an additive effect and sometimes canceled the positive effect observed in the single compounds. These results highlight the importance of combinatorial screenings for the identification of combinations of compounds with additive or synergistic effects of lifespan, and strongly suggest against the consumption of multiple supplements and drugs, which combined effects on health and lifespan have yet to be evaluated.” (“Comprehensive evaluation of lifespan-extending molecules in C. elegans”)
That is exactly why we tested the entire finished formulation in a randomized, placebo-controlled human trial, rather than assuming individual ingredient data would translate.
Additionally, in vitro research we ran on NOVOS Core at the Salk Institute, and an in vivo mouse lifespan study from Dr. Satomi Miwa, both find unexpected synergistic outcomes from our formulation. Dr. Miwa stated the following about NOVOS Core’s effects after running in vitro senescence and in vivo mouse lifespan experiments: “The study demonstrates that this multi-ingredient formulation exhibits synergistic effects rarely achieved by a nutritional supplement.” While preclinical studies don’t establish human outcomes, they provide a plausible biological framework for the multi endpoint effects observed in the NOVOS randomized human trial.
To that point, as you know, most “stacks” or multi ingredient supplements are never evaluated end to end in humans. NOVOS Core has been, mechanistically, pre-clinically, and now with this human clinical study.
- Which ingredient caused it?
This trial evaluated the complete formulation, not isolated compounds. Based on our review of published randomized, placebo-controlled human studies in generally healthy populations, individual ingredients such as those you mentioned (glucosamine, fisetin, magnesium, and others) have not consistently demonstrated simultaneous improvements across endothelial function, arterial stiffness, and systolic blood pressure within the same trial. They also haven’t achieved the effect sizes that NOVOS Core did as far as we’ve seen after a thorough review of the literature.
That’s why we tested the finished formulation clinically, rather than assuming single ingredient findings would translate to coordinated, multi-endpoint effects of this magnitude in humans (see point 3).
- Reversing aging itself
We are not claiming to reverse aging or treat disease. What we are reporting is that, in adults 40+ without established cardiovascular disease, the intervention group demonstrated statistically significant improvements versus placebo in validated markers commonly used in cardiovascular aging research over 6 months. These physiological systems are strongly associated with long term health outcomes. We are also noting that the formula we developed back in 2019 was designed to target the hallmarks of aging simultaneously, and that this study is potentially evidence of the downstream effects of this novel approach. We will do followup research to determine if the link between those hallmarks and these specific functional outcomes are strong.
I hope this helps clarify, guys!
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Glad you are officially here. Thank you for all of that!
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Would you ever consider updating the formula? It’s been the same since it was introduced.
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I’m assuming another formula would mean another clinical trial to show effectiveness.
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Hello, thank you for your response. I have a question I’d like to consult you on. Both a fellow anti-aging enthusiast and I have been taking your NOVOS Core, but why are we both experiencing an increase in bowel movements and diarrhea after taking it? These symptoms disappear once we stop. We are using the Orange flavor version. Is this a common reaction among users, and how should we avoid this situation?
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It’s a misconception that stacking the latest longevity ingredients leads to the best outcome. As the Ocampo animal study found, more often than not, combining two longevity ingredients together does not lead to a greater effect, and in many cases, they counteract each other.
Other researchers have found that the ingredients may not only do that, but counterintuitively can also shorten animal lifespan in some cases. If we take a hint from that, and knowing the complexity of aging, we should be careful when crafting a combination for humans.
The results that NOVOS Core has achieved, across mechanistic, preclinical lifespan, human epigenetic observational, and this latest double blind randomized placebo controlled study have been exceptional. When you compare our clinical study results to other supplements and lifestyle interventions similarly tested, our results really stand out. And that’s not accounting for the countless longevity mixes and blends that don’t have a shred of scientific research for their combined formula.
So ultimately, why fix what ain’t broke? With each study we run, we find increasing evidence of the formula’s impact. And to Ocampo’s and others’ research, we’d only be increasing the chances that the efficacy is reduced, and the millions of dollars that have supported our R&D over the last 7+ years would be scrapped.
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Hey! That is a rare side effect experienced by <2% of customers. It’s typically resolved by taking the product for a couple of weeks for the microbiome to adjust, or switching to unflavored or tropical passion flavor, both of which are erythritol free (orange will be as well shortly). If you get unflavored, just make sure you mix it with something flavored. I don’t recommend it in plain water.
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Been taking it for ~5 years, and was waiting for some confirmation it’s still worth the funds (when there has been some debate in the longevity community about the pertinence of some of its ingredients like fisetin/glucosamine/pterostilbene). Nice
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Do you have a link to the Ocampo study? I’m curious what exact combinations they saw cancel each other out.
In most other animal and human data, there is usually an additive effect where 1 + 1 =2 (rapamycin + Acarbose and glycine + NAC for example)
No, it’s the exact opposite of your statement. In most other animal and human data, there is usually a cancellation effect. Combinations perform worse than individual compounds. Rapamycin + acarbose is the exception to the rule. I can’t think of another example of a study that showed synergistic effect (the glycine, NAC studies have some issues that makes the results questionable).
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Hey LukeMV, I couldn’t link it but I included the name of it so you could easily search for it. Here it is again: “Comprehensive evaluation of lifespan-extending molecules in C. elegans”
I agree with @fasterfour on this. It’s a natural human tendency to expect more = better / stacking will work. I always thought that way, too. But with the complexity of biology, especially aging biology, more often than not experiments are showing that it doesn’t work out that way. That’s why Ocampo and colleagues specifically state, “[we] strongly suggest against the consumption of multiple supplements and drugs, which combined effects on health and lifespan have yet to be evaluated” in reference to human longevity supplement and Rx stacking.
@sunshine4 glad to hear that! The internet tends to look at the latest individual study and conclude in absolutes: good / bad, works / doesn’t work. When we designed NOVOS Core, we considered all of the literature per ingredient, the known bio pathways that each molecule impacts, and based on that, determined what to combine. So even if an ingredient in isolation doesn’t perform for a given metric in a study, when combined with the other molecules, we expect a synergistic effect. I feel that the combination of our mechanistic, preclinical, epigenetic, and now clinical studies, are demonstrative of the synergistic effects that the NOVOS Core formula is exerting.
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Yet, no one ever has any examples. They just say it over and over but can’t be specific about what interacts negatively. Meanwhile we have a lot of examples of things working better together. NOVOS Core is the latest example of this.
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I think it’s facially absurd. In fact, polypharmacy is the only route forward. Odds that a single molecule will fix all aging issues, where aging is an incredibly complex problem, is essentially zero. Sure, you might find a master regulator along the lines of a better rapamycin (not necessarily mTOR), but that’s still extremely limited. To get beyond that, you need combos, the same way rapa and acarbose extend the overall effect. Now, that doesn’t mean that every individual molecule in a stack has to be life extending. Hardly, and we have examples of drugs like metformin or simvastatin that failed LE on their own, but worked in combination with other drugs. Because any molecule that has enough power to affect LS it therefore follows that an unfortunate combination might indeed be deleterious. Polypharmacy absolutely can be detrimental (which is why it’s often such a problem in the elderly). But that’s why you need to carefully select your stack, to be additive and not subtractive.
But blanket warning against combining drugs is just stupid. It’s the only way forward. What do you think food is? It’s thousands upon thousands of molecules working together. Do you think we’re better off consuming all nutrients in isolation or in a matrix? The trick is not in trying to isolate every molecule, but to select better combinations - it’s called “diet”, and we have better and worse ones.
Same here. Until we get to genetic engineering, all we have is intelligent polypharmacy.
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Here is the paper
From Grok:
“The combinations that cancelled each other out (or were inferior/canceled the benefit) were:
• Resveratrol + GSK2126458
• Resveratrol + LY‐294002
No other combinations in the study were described as actively canceling or being inferior in this way — most simply failed to improve beyond the best single compound (i.e., neutral/no added benefit), while a few pairs showed additive or greater-than-additive benefits (e.g., GSK2126458 + doxycycline, GSK2126458 + LY‐294002, doxycycline + resveratrol in UV-killed conditions, and rifampicin + caffeine).”
So we are saying longevity interventions typically cancel each other out because something everyone here knows doesn’t work (Resveratrol) doesnt work well with two other things that aren’t actually drugs or supplements?
This study is hardly a smoking gun.
Like @CronosTempi articulated better than me, polypharmacy is the way forward
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I think we’re actually more in agreement than it might seem @CronosTempi & @LukeMV.
NOVOS Core is an example of polypharmacy: it’s 12 ingredients. So obviously I agree that aging is multifactorial and that combination approaches are likely necessary. I’m not arguing for “single molecule solves aging.” What I’m arguing against is the assumption that stacking = automatically better.
The Ocampo combinatorial screen wasn’t saying never combine. It showed something more nuanced:
- Most lifespan-positive compounds, when combined, did not outperform the best single ingredient.
- Some combinations were neutral.
- A few were additive or greater-than-additive.
- Some combinations canceled out benefit.
Specifically, looking at table S1, sheet “Figure3_combos” and only counting the unique combos, here’s what I arrive at:
- 15% produced negative outcomes
- 38% were inferior to the better of the 2 single ingredients
- 8% were neutral; no added benefit
- 31% were additive
- 8% were synergistic (greater than the sum)
So, in 53% of cases, the animals ended up worse off than the single ingredient, and in 15% of cases, they lived shorter lives.
LukeMV – your point about resveratrol is heard regarding the shorter lives, but it was also the only synergistic combo (Doxycycline + Resveratrol). In other words, resveratrol was an ingredient in both the best and worst combos. This just furthers my point: it’s complicated!
That isn’t anti-polypharmacy, it’s evidence that interactions are non-trivial and they’re unpredictable. The rate that 1+1=2 or 1+1=3 is much lower than intuition suggests. Most people don’t assume that more often it’s actually 1+1=0.5 or 1+1= –1
So, my point has not been that molecules should not be combined, it’s that we should test the combination.
That’s exactly why we ran the STAMINA DBRCT on NOVOS Core’s 12-ingredient formulation. Not because combinations are bad, but because combinations need to be empirically validated rather than assumed to be synergistic. I would argue that our research is demonstrating that NOVOS Core is likely part of that 8% of cases, where synergies are achieved.
And on the “food is thousands of molecules” analogy, sure. But food is low-dose, co-evolved, and matrix-buffered. High dose isolated actives, which is what supplements and Rx’s are, when stacked together, are pharmacologically very different than food. That’s why polypharmacy is not so simple even if each molecule individually makes sense.
So I’m fully aligned that rational polypharmacy is likely the way forward. I just think there’s a way to do it and a way not to: measure the stack, don’t assume synergy.
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