NOVOS Explains Its New Nutraceutical

NOVOS is a nutraceutical company focused on developing science-based nutraceuticals to slow down aging and will offer tests to track people’s aging processes to get a better picture of their health.

The company offers two nutraceutical products, NOVOS Core and NOVOS Boost. Core contains 12 ingredients that the company believes can slow down aging. Boost contains only one ingredient: Nicotinamide mononucleotide (NMN).

This is the conclusion of a two-part interview; the previous part of the interview explored why the founders of NOVOS believe that their product could shake up the nutraceutical industry.

Today, we are going to drill down into the science behind their two new products. CEO Chris Mirabile and CSO Dr. Kris Verburgh took the time to answer some questions we had about NOVOS.

Okay, so NOVOS Core contains a number of compounds that may be familiar to biohackers and people interested in supplements. Before we dive into the individual elements, can you explain your screening process and your selection criteria for a particular substance?

Kris: Currently, no golden standard test for a longevity drug or nutraceutical has ever been conducted, given that this would entail a clinical trial following thousands of people for 30 to 50 years to see if they actually live longer. Such a study would take decades and would cost tens of millions of dollars. So, to identify the most promising substances to slow down aging, we currently have to rely on other scientific evidence. We used specific guidelines and principles to select the most interesting substances to slow down aging. We specifically looked for substances that act on important aging mechanisms, such as epigenetic dysregulation, mitochondrial dysfunction, protein accumulation, senescent cells, DNA damage, and so on. Furthermore, the ingredients should work on not just one aging mechanism but on multiple aging mechanisms, enabling synergistic effects. For example, alpha-ketoglutarate can improve mitochondrial health but also has epigenetic effects, just like lithium, which can also improve autophagy – the digestion of proteins – while glycine is a chaperone protecting proteins, which enables further synergistic effects with lithium. Of course, the ingredients have to extend lifespan in well-conducted scientific studies, preferably in different species, hinting at conserved evolutionary pathways. The ingredients also need to have been associated with reduced risk of multiple aging-related diseases and symptoms in humans, which suggests that they act on an underlying process, namely aging itself or at least mechanisms of aging. Ideally, their use is also associated with reduced mortality in humans. For example, studies in the US and Europe showed that glucosamine was one of the very few supplements that was associated with reduced mortality – and also reduced cardiovascular disease, by the way.

How do you take the potential interactions of these substances into account?

Chris: We specifically focused on substances that have a very low side effect profile and

that have been recognised as safe by the FDA or EFSA, the European Food Safety Authority. Also, many substances have been taken for decades or even centuries without the risk of serious side effects. For example, alpha-ketoglutarate has been taken for decades by athletes and bodybuilders to improve strength and stamina with no serious side effects, while, only recently, studies showed that it also can extend lifespan in animals.

We also use doses that are not too high. For example, one of our ingredients is micro-dosed lithium amounting to 1 milligram per day. Lithium is used as a mood-stabilizing drug in psychiatric settings at doses up to a thousand times higher, chronically. Interestingly, very low doses of lithium have been associated with longer life spans and less risk of aging-related diseases.

For fisetin, we use a daily low dose of 100 mg instead of taking a very high one-off dose to kill senescent cells, which can be around 1,500 mg in one day. We did this after deliberation with one of our scientific advisors, Dr. Pamela Maher from the Salk Institute, who is one of the world’s leading authorities on fisetin. Continuous lower doses of fisetin can also extend lifespan.

Fisetin

Many substances are also naturally present in our body and decline with age, like glycine and alpha-ketoglutarate, the latter of which our blood levels can drop tenfold as we age. Using low “physiological” doses, often to restore declining levels to more youthful levels, and not using much higher “pharmaceutical” levels substantially reduces the risk of side effects. So, using combinations of safe, nature-based, tried-and-tested supplements in not too high doses substantially mitigates the risk of side effects.

Alpha-ketoglutarate

Our substances demonstrated beneficial lifespan effects and can reduce the risk of various aging-related diseases. We often see in medicine that combining beneficial substances or interventions leads to even stronger positive synergistic effects instead of drawbacks. And, of course, we ran our formulation with our scientific advisory board and consultants, consisting of top scientists in the aging field.

At a glance, a lot of these compounds in the Core product focus in one way or another on epigenetics. Is modulation of the epigenome a central focus of your design philosophy, and, if so, why do you think epigenetics plays such an important role in aging?

Kris: When creating our formulation, we focused not only on epigenetics but also on many other aging mechanisms, like protein accumulation, mitochondrial dysfunction, senescent cells, inflammation, and so on. But, we indeed believe that epigenetic alterations play a very important role in aging and could perhaps be one of the most important reasons why we age.

The epigenome is the complex machinery that determines which genes are switched on or off. During aging, this process goes awry. Some genes that should protect our cells are switched off, such as housekeeping genes, while other genes that can damage our cells are switched on, like cancer genes. Various substances in NOVOS Core act on the epigenome, like alpha-ketoglutarate, lithium, glycine and fisetin, but the epigenome is only a part of our story. Other ingredients in our formulation target other hallmarks of aging. For example, fisetin can clear senescent cells, while pterostilbene reduces inflammation and malate improves mitochondrial health.

It is proposed that there are nine reasons we age called the Hallmarks of Aging. How is NOVOS designed to address some or even all of these hallmarks?

Chris: NOVOS is the first nutraceutical that specifically focuses on the nine hallmarks of aging. This makes NOVOS unique, given that most other “anti-aging” supplements focus on one or two aging mechanisms at best, such as the NAD+ pathway or free radicals. Aging is a complex process caused by multiple mechanisms.

Compare the aging body to a house in disrepair: only fixing the gutter is not going to help a lot if you don’t also fix the flooded basement, broken windows, leaky roof, and so on. You need to address all these at the same time to really make the house stay around for longer, but this is not what most supplement companies are doing, nor is pharma. Pharma mainly develops one drug for one pathway. Hopefully, NOVOS could be a wake-up call for them in the sense that the longevity pill of the future is likely not going to consist of one substance but of multiple substances acting on multiple aging pathways.

You opted to include NMN in your Boost product. Why choose NMN over other NAD+ precursors such as NR?

Kris: There are many reasons to believe that NMN is likely superior to NR. We explain this in depth on our website. For example, studies show that NR is very unstable and quickly broken down into nicotinamide, a B vitamin. This already happens in the gut lumen before NR is taken up into the body. In contrast, NMN is much more stable in the gut and blood.

Of course, if you take NR, you will also increase NAD+ levels, given that nicotinamide is also a precursor to NAD+. That is probably why many NR companies rightfully claim that NR increases NAD+ levels while they probably know you can do the same when taking nicotinamide. If we also look at the whole of scientific studies, NMN seems to have stronger effects than NR regarding improving various biomarkers of aging and aging-related diseases. There are good reasons why top experts on NR / NMN / NAD+ metabolism, like David Sinclair, take NMN themselves and not NR.

We also see that various biotech companies are currently developing analogues of NMN, not NR, to mitigate aging. Some websites claim that NMN is not well absorbed when taken orally, but that’s not the case. In fact, online NR is touted on many sites, mostly by NR companies. Some important reasons for this is that NMN was too expensive to produce and even study until recently and that the production of NR is patented, so various companies that have the licenses keep advocating NR and downplaying NMN, while NMN is probably significantly better. That is why we offer NMN and not NR.

A number of compounds included in the Core supplement are also associated with inflammation via differing pathways. Was tackling age-related inflammation part of your strategy and how important do you think inflammation is in the aging process as a whole?

Kris: We believe that inflammation plays an important role in aging. When we get older, our bodies become more and more inflamed. This inflammation stems from various sources, like senescent cells. These cells arise everywhere in our body and secrete pro-inflammatory substances. During aging, our gut also becomes more leaky, while the skin barrier becomes more permeable, causing pro-inflammatory substances to leak into our bloodstream, fanning systemic inflammation.

Abdominal fat, also called a beer belly, also secretes many inflammatory substances. Retrotransposons jumping around in our cells stir up inflammation. When we get older, the immune system becomes too overactivated in some ways, further fueling inflammation.

When we get older, our mitochondria become more damaged, making them secrete substances that fan inflammation, such as freely circulating mitochondrial DNA, DAMPs, and so on.

This increase in inflammation significantly contributes to the aging process. Therefore, we included various substances that reduce inflammation, like fisetin, glucosamine, glycine and pterostilbene.

What about cheap and readily available Niacin, which was recently shown to increase NAD+ in a human trial?

Chris: Niacin is a form of vitamin B3, which can increase NAD+ levels, as can another form of vitamin B3, namely nicotinamide. However, I would be careful with taking too high doses of vitamin B3. For example, nicotinamide could actually suppress the activity of sirtuins. Sirtuins are proteins that help to repair and maintain DNA, but some scientists believe that despite the fact that nicotinamide could inhibit sirtuins, it can have other beneficial effects. Nonetheless, studies like the one that Rafael de Cabo published in Cell Metabolism show that nicotinamide does not extend lifespan in mice. Some studies seem to suggest that niacin poses less of a problem than nicotinamide in that regard, but NMN is likely better than niacin and nicotinamide in improving NAD+ levels and in also exerting multiple other beneficial effects.

To keep costs down, you include NMN as a separate product called Boost. What makes NMN so costly, anyway; is it the manufacturing process?

Chris: The manufacturing of NMN is very complex. It was up until very recently that it was prohibitively expensive to manufacture, so even for scientific studies, scientists had to use NR instead of NMN. In recent years, the price of producing NMN has come down considerably, but it is still very expensive. This leads some unscrupulous sellers of NMN to adulterate it with flour, NR, or plain nicotinamide. Some “NMN” sold online is 100 percent nicotinamide!

Also, often producers claim that their NMN is high-purity. However, they do not measure absolute purity, but relative purity, by comparing their NMN supplement with one that is even more impure. There are a lot of bad-quality NMN products on the market, unfortunately, because the production process is so complex and expensive.

Vitamin C is somewhat of a surprise to see included given how common it is. What’s the rationale behind including a generic vitamin like this?

Kris: We added vitamin C because it works synergistically with alpha-ketoglutarate to improve the functioning of TET enzymes. TET enzymes are important epigenetic enzymes that play a role in stem cell-ness and overall methylation. TET enzymes ideally need both alpha ketoglutarate and vitamin C to work properly. Vitamin C also has other epigenetic functions. In fact, most people think of vitamin C as an antioxidant, but we like it much more for its epigenetic effects.

Why do you use pterostilbene and not resveratrol?

Kris: Pterostilbene and resveratrol look very similar as molecules, but the few extra methyl groups on pterostilbene provide it with multiple advantages over resveratrol. Pterostilbene is considerably more absorbable in the gut and is stable for much longer in the blood. Resveratrol has a very low half life in the body, meaning that it’s broken down very quickly after absorption. Pterostilbene stays around considerably longer. We also see in scientific studies that pterostilbene outperforms resveratrol, for example to treat brain aging.

Pterostilbene

Why do you use calcium alpha-ketoglutarate instead of alpha-ketoglutarate?

Chris: The most recent lifespan studies have been done with calcium alpha-ketoglutarate, not just plain alpha-ketoglutarate. The calcium form improves stability and transit time in the gut, enabling a slower release of the alpha ketoglutarate form in the gut, among other advantages.

Rhodiola Rosea is also not something I have seen discussed often in biohacking circles; while it has a traditional use for reducing stress, it isn’t something I see talked about in the context of life extension. What’s the reasoning behind this being part of the mix?

Kris: Rhodiola rosea is an interesting herb. It has been shown to extend lifespan in different organisms. Specific components of Rhodiola, like salidroside, can induce regeneration of nerves. It can also protect the brain of rodents against toxic insults. Rhodiola rosea has been used for centuries in people in northern Europe and Asia as an adaptogen to improve resilience against physical and mental stress. Its lifespan effects and abilities to improve cognition and reduce fatigue make it an interesting ingredient.

We find it important that people can also experience immediate benefits when taking NOVOS. Improved cognition is one of them, but we also used specific longevity ingredients that can improve skin health, like glucosamine, hyaluronic acid containing acetyl-glucosamine, and alpha-ketoglutarate.

What will the future bring for NOVOS?

Chris: We are planning to further improve on our formulation and release additional products focused on longevity. So, when novel studies appear in the coming years, it’s possible that we will change NOVOS Core’s ingredient formulation and add to the lineup. We will also offer tests on our website to measure biological age and health. NOVOS wants to empower people to take their health and aging process into their own hands. This is also because most physicians do not currently know a lot about aging, let alone how to mitigate or measure it.

We also want to advance the aging field, so we have elected to register as a Public Benefit Corporation (PBC), meaning that a part of our profits will be donated to aging research and for the public good.

Kris: There is a big need for more science-based supplements to address aging. In the last year, lots of research and insights have come about, paving the way for this kind of supplement. We want to create through NOVOS more awareness around the important need to address aging. Pharma is not focusing on it, because aging is not an official disease that can be reimbursed, while many interesting molecules cannot be patented by them. On the other hand, many food supplement companies have been selling antioxidants and multivitamins as “anti-aging” supplements with very little or no scientific evidence. It’s time that supplements like NOVOS advance the field and public perception, demonstrating that there are already very interesting substances available to address aging. By developing science-based nutraceuticals, we will bridge the no-man’s land between supplement companies and big pharma.

We would like to thank Chris and Kris for taking the time to answer our questions.

Disclosure: A portion of the profits and equity from NOVOS are being donated to nonprofits working in the longevity science space, which includes us here at Lifespan.io.

Our Vice President, Dr. Oliver Medvedik, is also a scientific consultant, putting him in good company with Dr. Joao Pedro Magalhaes, Dr. Pamela Maher, Dr. Avi Rosenbaum, and Dr. Matt Kaeberlein, names with whom regular readers may be familiar.

Chris and Kris provided us with a non-exhaustive list of scientific studies to substantiate the ingredients used in NOVOS, which you can find below:

FISETIN

ALPHA-KETOGLUTARATE

GLUCOSAMINE

MICRO-DOSED LITHIUM

GLYCINE

NMN

PTEROSTILBENE

THEANINE

L-Theanine extends lifespan of adult Caenorhabditis elegans. Eur J Nutr, 2012
L-Theanine attenuates liver aging by inhibiting advanced glycation end products in d-galactose-induced rats and reversing an imbalance of oxidative stress and inflammation. Experimental Gerontology, 2020
Prevention of brain aging by green tea components: Role of catechins and theanine. Journ of Physic Fitness, 2016
l-Theanine, an amino acid in green tea, attenuates beta-amyloid-induced cognitive dysfunction and neurotoxicity: reduction in oxidative damage and inactivation of ERK/p38 kinase and NF-kappaB pathways. Free Radic Biol Med, 2009
Selective Upregulation by Theanine of Slc38a1 Expression in Neural Stem Cell for Brain Wellness. Molecules, 2020
Daily oral intake of L-theanine prevents the decline of 5-bromo-20 -deoxyuridine incorporation in hippocampal dentate gyrus with concomitant alleviation of behavioral abnormalities in adult mice with severe traumatic stress. J. Pharmacol. Sci, 2015
Facilitated neurogenesis in the developing hippocampus after intake of theanine, an amino acid in tea leaves, and object recognition memory. Cell Mol Neurobiol, 2011
Effects of L-Theanine Administration on Stress-Related Symptoms and Cognitive Functions in Healthy Adults: A Randomized Controlled Trial. Nutrients, 2019
Protective effect of the green tea component, L-theanine on environmental toxins-induced neuronal cell death. Neurotoxicology, 2008

HYALURONIC ACID & ITS COMPONENT ACETYL-GLUCOSAMINE

VITAMIN C (AND SYNERGY WITH ALPHA KETOGLUTARATE ON THE EPIGENOME INCLUDING TET ENZYMES)

RHODIOLA ROSEA (& SALIDROSIDE)

MALATE and MAGNESIUM

GINGER

Ginger extract extends the lifespan of Drosophila melanogaster through antioxidation and ameliorating metabolic dysfunction. Journal of Funct Foods, 2018
Zingiber officinale extends Drosophila melanogaster life span in xenobiotic-induced oxidative stress conditions. Frontiers in biology, 2018
Influence of ginger rhizome (Zingiber officinale Rosc) on survival, glutathione and lipid peroxidation in mice after whole-body exposure to gamma radiation. Radiat Res, 2003
Investigation of the effect of ginger on the lipid levels. A double blind controlled clinical trial. Saudi Med J, 2008
The effect of ginger supplementation on serum C-reactive protein, lipid profile and glycaemia: a systematic review and meta-analysis. Food Nutr Res, 2016
Anti-Oxidative and Anti-Inflammatory Effects of Ginger in Health and Physical Activity: Review of Current Evidence. Int J Prev Med, 2013
Effects of a ginger extract on knee pain in patients with osteoarthritis. Arthritis Rheum, 2001
Zingiber officinale ameliorates allergic asthma via suppression of Th2-mediated immune response. Pharm Biol, 2015
The Effects of Ginger on Fasting Blood Sugar, Hemoglobin A1c, and Lipid Profiles in Patients with Type 2 Diabetes. Int J Endocrinol Metab, 2017
The effect of ginger powder supplementation on insulin resistance and glycemic indices in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial. Complement Ther Med, 2014
Protective Effects of Ginger Root Extract on Alzheimer Disease-Induced Behavioral Dysfunction in Rats. Rejuven Research, 2012

Disclosure: A portion of the profits and equity from NOVOS are being donated to nonprofits working in the longevity science space, which includes us here at Lifespan.io.

CategoryInterviews, News

Tags: Chris Mirabile, Fisetin, Kris Verburgh, NMN, NOVOS, NR, Supplements

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NOVOS Explains Its New Nutraceutical

The company's founders explain the science behind the ingredients in their new product.