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

• Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine, 2018
• Fisetin reduces the impact of aging on behavior and physiology in the rapidly aging SAMP8 mouse. J Gerontol A Biol Sci Med Sci, 2018
• Fisetin Acts on Multiple Pathways to Reduce the Impact of Age and Disease on CNS Function. Front Biosci, 2015
• The Potential of Flavonoids for the Treatment of Neurodegenerative Diseases. Int J Mol Sci, 2019
• Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature, 2003
• How fisetin reduces the impact of age and disease on CNS function. Front Biosci, 2015
• Fisetin inhibits high-glucose-induced vascular inflammation in vitro and in vivo. Inflammation Research, 2014
• Fisetin lowers methylglyoxal dependent protein glycation and limits the complications of diabetes. PLoS One, 2011
• Fisetin regulates obesity by targeting mTORC1 signaling. The Journal of nutritional biochemistry, 2013

ALPHA-KETOGLUTARATE

• • Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice. Cell, 2020
  • The metabolite alpha-ketoglutarate extends lifespan by inhibiting the ATP synthase and TOR. Nature, 2014
  • Alpha-ketoglutarate extends Drosophila lifespan by inhibiting mTOR and activating AMPK. Aging, 2019
  • Alpha-ketoglutarate stabilizes redox homeostasis and elasticity in aged mice. J Physiol Pharmacol. 2011
  • Effects of alpha-ketoglutarate on lifespan and functional aging of Drosophila melanogaster flies. Ukr Biochem J, 2018
  • Dietary alpha-ketoglutarate partially prevents age-related decline in locomotor activity and cold tolerance in Drosophila melanogaster. Biologia, 2017
  • Dietary alphaketoglutarate increases cold tolerance in Drosophila melanogaster and enhances protein pool and antioxidant defense in sex-specific manner. J Therm Biol, 2016
  • Krebs cycle dysfunction shapes epigenetic landscape of chromatin: novel insights into mitochondrial regulation of aging process. Cell Signal, 2014
  • Anti-osteopenic effect of alpha-ketoglutarate. Journal of Bone and Mineral Metabolism, 2012
  • Alfa ketoglutarate (AKG) inhibit osteoporoses development in postmenopausal women. Journal of Bone and Mineral Research, 2003
  • Healthy ageing: the beneficial effect of dietary supplementation with alpha-ketoglutarate on arterial elasticity in elderly mice. Journal of Pre-clin and Clin research, 2009
  • Addition of a-ketoglutarate to blood cardioplegia improves cardioprotection. The Annals of Thoracic Surgery, 1997

• a-ketoglutarate for myocardial protection in heart surgery. The Lancet, 1995
• Dietary alpha-ketoglutarate promotes beige adipogenesis and prevents obesity in middle-aged mice. Aging Cell, 2019
• Alpha-Ketoglutarate: Physiological Functions and Applications. Biomol Therap, 2016

GLUCOSAMINE

• D-Glucosamine supplementation extends life span of nematodes and of ageing mice. Nature Communications, 2014
• Glucosamine Extends the Lifespan of Caenorhabditis elegans via Autophagy Induction. Journal of Applied Glycoscience, 2018
• Total mortality risk in relation to use of less-common dietary supplements. The American Journal of Clinical Nutrition, 2010
• Use of glucosamine and chondroitin in relation to mortality. European journal of epidemiology, 2012
• Association of habitual glucosamine use with risk of cardiovascular disease: prospective study in UK Biobank. British Medical Journal, 2019
• Association between use of specialty dietary supplements and C-reactive protein concentrations. American Journal of Epidemiology, 2012
• New functions of glucosamine as a scavenger of the lipid peroxidation product malondialdehyde. Chem Res Toxicol, 2007
• Glucosamine induces autophagy via an mTOR-independent pathway. Biochem Biophysic Research Comm, 2010
• Assessment of protective effects of glucosamine and N-acetyl glucosamine against DNA damage induced by hydrogen peroxide in human lymphocytes. Drug Chem Toxicol, 2014
• Associations of herbal and specialty supplements with lung and colorectal cancer risk in the VITamins and Lifestyle study. Cancer Epidemiol Biomarkers Prev, 2009
• Increased protein O-GlcNAc modification inhibits inflammatory and neointimal responses to acute endoluminal arterial injury. Am J Physiol Heart Circ Physiol, 2008
• Distinct effects of glucose and glucosamine on vascular endothelial and smooth muscle cells: evidence for a protective role for glucosamine in atherosclerosis. Cardiovasc Diabetol, 2005
• Effect of a high dose of glucosamine on systemic and tissue inflammation in an experimental model of atherosclerosis aggravated by chronic arthritis. Am J Physiol Heart Circ, 2009
• Glucosamine inhibits IL-1beta-induced NFkappaB activation in human osteoarthritic chondrocytes. Osteoarthritis Cartil, 2003

MICRO-DOSED LITHIUM

• • Low-dose lithium uptake promotes longevity in humans and metazoans. Eur J Nutr, 2011
  • Trace lithium in Texas tap water is negatively associated with all-cause mortality and premature death. Appl Physiol Nutr Metab, 2018
  • Pharmacogenetic analysis of lithium-induced delayed aging in Caenorhabditis elegans. J Biol Chem, 2009
  • Lithium Promotes Longevity through GSK3/NRF2-Dependent Hormesis Cell Rep, 2016
  • Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer’s disease. Curr Alzheimer Res, 2013
  • Association of Lithium in Drinking Water With the Incidence of Dementia. JAMA Psychiatry, 2017

• Effects of lithium on age-related decline in mitochondrial turnover and function in Caenorhabditis elegans. The Journals of Gerontology, 2014
• Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry, 2011
• Lithium treatment and risk for dementia in adults with bipolar disorder: population-based cohort study. Br J Psychiatry, 2015
• Is lithium a neuroprotective agent? Ann Clin Psychiatry, 2015
• Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer’s disease. Curr Alzheimer Res, 2013
• Chronic Treatment With a Low Dose of Lithium Protects the Brain Against Ischemic Injury by Reducing Apoptotic Death. Stroke, 2003
• Chronic lithium treatment decreases mutant tau protein aggregation in a transgenic mouse model. Journal of Alzheimer’s disease, 2003
• Standard and trace-dose lithium: a systematic review of dementia prevention and other behavioral benefits. Aust N Z J Psychiatry, 2014
• Neuroprotective Effects of Lithium: Implications for the Treatment of Alzheimer’s Disease and Related Neurodegenerative Disorders. ACS Chem Neurosci, 2014
• Influence of lithium treatment on GDNF serum and CSF concentrations in patients with early Alzheimer’s disease. Current Alzheimer Research, 2011
• Lithium-induced neuroprotection is associated with epigenetic modification of specific BDNF gene promoter and altered expression of apoptotic-regulatory proteins. Front Neurosci, 2015
• A new look at an old drug: neuroprotective effects and therapeutic potentials of lithium salts. Neuropsychiatr Dis Treat, 2016

GLYCINE

• Glycine supplementation extends lifespan of male and female mice. Aging Cell, 2019
• Dietary glycine supplementation mimics lifespan extension by dietary methionine restriction in Fisher 344 rats, FASEB, 2011
• Glycine promotes longevity in Caenorhabditis elegans in a methionine cycle-dependent fashion. PloS Genet, 2019
• Glycine treatment decreases proinflammatory cytokines and increases interferon-gamma in patients with type 2 diabetes. Journal of Endocrinological Investigation, 2008.
• Enhancing S-adenosyl-methionine catabolism extends Drosophila lifespan. Nature Communications, 2015
• Plasma Glycine and Risk of Acute Myocardial Infarction in Patients With Suspected Stable Angina Pectoris. J Am Heart Assoc, 2016
• Glycine intake decreases plasma free fatty acids, adipose cell size, and blood pressure in sucrose-fed rats. Am J Physiol Regul Integ Comp Physiol, 2004
• The metabolic response to ingested glycine. Am J Clin Nutr, 2002

NMN

• Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab, 2017
• Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice. Redox Biology, 2019
• Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell, 2016
• Impairment of an endothelial NAD(+)-H2S signaling network is a reversible cause of vascular aging. Cell, 2018
• Nicotinamide mononucleotide (NMN) supplementation promotes anti-aging miRNA expression profile in the aorta of aged mice, predicting epigenetic rejuvenation and anti-atherogenic effects. Geroscience, 2019
• NAD+ Repletion Rescues Female Fertility during Reproductive Aging. Cell, 2020
• NAD+ supplementation rejuvenates aged gut adult stem cells.Aging Cell, 2019
• NAD+ controls neural stem cell fate in the aging brain. EBJornal, 2014
• Impairment of an endothelial NAD(+)-H2S signaling network is a reversible cause of vascular aging. Cell, 2018
• Nicotinamide mononucleotide promotes osteogenesis and reduces adipogenesis by regulating mesenchymal stromal cells via the SIRT1 pathway in aged bone marrow. Cell Death & Disease, 2019

PTEROSTILBENE

• Effect of resveratrol and pterostilbene on aging and longevity. Biofactors, 2018
• Cellular and Behavioral Effects of Stilbene Resveratrol Analogues: Implications for Reducing the Deleterious Effects of Aging. Journ of Agricult Food Chemistry, 2008
• Pterostilbene Improves Cognitive Performance in Aged Rats: An in Vivo Study. Cell Phys & Biochem, 2019
• Low-dose Pterostilbene, but Not Resveratrol, Is a Potent Neuromodulator in Aging and Alzheimer’s Disease. Neurbiol Aging, 2012
• Biological actions and molecular effects of resveratrol, pterostilbene, and 3′-hydroxypterostilbene. J Food Drug Anal, 2017
• Effects of pterostilbene and resveratrol on brain and behavior. Neurochem Int, 2015
• Pterostilbene reduces oxidative stress, prevents hypertrophy and preserves systolic function of right ventricle in cor pulmonale model. Br J Pharmacol, 2017
• Neuroprotective effects of pterostilbene against oxidative stress injury: Involvement of nuclear factor erythroid 2-related factor 2 pathway. Brain Research, 2016
• Pterostilbene surpassed resveratrol for anti-inflammatory application: Potency consideration and pharmacokinetics perspective. Journal of Functional Foods, 2014
• Pterostilbene Ameliorates Streptozotocin-Induced Diabetes through Enhancing Antioxidant Signaling Pathways Mediated by Nrf2. Chem Res Toxicol, 2016
• Pterostilbene protects vascular endothelial cells against oxidized low-density lipoprotein-induced apoptosis in vitro and in vivo. Apoptosis, 2012
• Pterostilbene, a natural small-molecular compound, promotes cytoprotective macroautophagy in vascular endothelial cells. The Journal of nutritional biochemistry, 2013
• Cellular and behavioral effects of stilbene resveratrol analogues: implications for reducing the deleterious effects of aging. Journal of agricultural and food chemistry, 2008
• Cancer chemopreventive and antioxidant activities of pterostilbene, a naturally occurring analogue of resveratrol. Journal of agricultural and food chemistry. J Agric Food Chem, 2002
• Pterostilbene and cancer: current review. J Surg Res, 2012
• Pterostilbene alleviates polymicrobial sepsis-induced liver injury: Possible role of SIRT1 signaling. Int Immunopharmacol, 2017
• Promising therapeutic potential of pterostilbene and its mechanistic insight based on preclinical evidence. Eur J Pharmacol, 2016
• In vivo effect of pinosylvin and pterostilbene in the animal model of adjuvant arthritis. Neuro Endocrinology Letters, 2009

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

• Hexosamine Pathway Metabolites Enhance Protein Quality Control and Prolong Life. Cell, 2014
• Oral hyaluronan relieves wrinkles: a double-blinded, placebo-controlled study over a 12-week period. Clin Cosmet Investig Dermatol, 2017
• Ingested hyaluronan moisturizes dry skin. Nutr J, 2014
• Oral hyaluronan relieves knee pain: a review. Nutr J, 2016
• Oral hyaluronan for the treatment of knee osteoarthritis: a systematic review. Progress in Nutrition, 2018
• Oral administration of polymer hyaluronic acid alleviates symptoms of knee osteoarthritis: a double-blind, placebo-controlled study over a 12-month period. Scient Wo Journ, 2012

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

• Vitamin C: An Epigenetic Regulator. Vitamin C – an Update on Current Uses and Functions, 2019
• Ascorbic Acid Promotes Functional Restoration after Spinal Cord Injury Partly by Epigenetic Modulation. Cells, 2020
• An epigenetic role for ascorbic acid in neurodegenerative diseases. CNS Neurosci Ther, 2018
• Ascorbic acid prevents loss of Dlk1-Dio3 imprinting and facilitates generation of all-iPS cell mice from terminally differentiated B cells. Nature Genetics, 2012
• Ascorbic Acid Enhances Tet-Mediated 5-Methylcytosine Oxidation and Promotes DNA Demethylation in Mammals. J Am Chem Soc, 2013
• Ascorbic Acid Promotes Plasma Cell Differentiation through Enhancing TET2/3-Mediated DNA Demethylation. Cell Reports, 2020
• Upregulation of TET Activity with Ascorbic Acid Induces Epigenetic Modulation of Lymphoma Cells. Clinic Lymph, Myel and Leukem, 2017
• Ascorbic acid–induced TET activation mitigates adverse hydroxymethylcytosine loss in renal cell carcinoma. Oncology, 2019
• Understanding and targeting epigenetic dysregulation, aberrant metabolism, and immune evasion in cancer with ascorbic acid. Doctoral thesis Niraj Shenoy, 2020
• Ascorbic Acid as an Epigenetic Therapy for Osteosarcoma. Stanford University thesis Shin Mei Chan, 2018
• The role of vitamin C in epigenetic regulation. Adv Hyg and Exper Medicine, 2017
• Breathing-in epigenetic change with vitamin C. EMBO Rep, 2013
• The role of a-ketoglutarate-dependent proteins in pluripotency acquisition and maintenance. J Biol CHem, 2019
• Alpha-Ketoglutarate as a Molecule with Pleiotropic Activity: Well-Known and Novel Possibilities of Therapeutic Use. Arch Immun Therap Exper, 2016
• Ascorbic Acid Mitigates D-galactose-Induced Brain Aging by Increasing Hippocampal Neurogenesis and Improving Memory Function. Nutrients, 2019

RHODIOLA ROSEA (& SALIDROSIDE)

• Extension of Drosophila lifespan by Rhodiola rosea through a mechanism independent from dietary restriction. PLoS One, 2013
• Plant adaptogens increase lifespan and stress resistance in C. elegans. Biogerontology. 2009
• The golden root, Rhodiola rosea, prolongs lifespan but decreases oxidative stress resistance in yeast Saccharomyces cerevisiae. Phytomedicine, 2011
• Rhodiola: a promising anti-aging Chinese herb. Rejuvenation Res, 2007
• Salidroside promotes peripheral nerve regeneration following crush injury to the sciatic nerve in rats. Neuroreport, 2013
• Salidroside promotes peripheral nerve regeneration based on tissue engineering strategy using Schwann cells and PLGA: in vitro and in vivo. Nature, 2017
• Pretreatment with Rhodiola Rosea Extract Reduces Cognitive Impairment Induced by Intracerebroventricular Streptozotocin in Rats: Implication of Anti-oxidative and Neuroprotective Effects. Biom & Environ Scien, 2009
• Protective effects of a Rhodiola crenulata extract and salidroside on hippocampal neurogenesis against streptozotocin-induced neural injury in the rat. PLoS ONE, 2012
• Decreased mitochondrial superoxide levels and enhanced protection against paraquat in Drosophila melanogaster supplemented with Rhodiola rosea. Free Radic Res, 2009
• Rhodiola rosea L. Improves Learning and Memory Function: Preclinical Evidence and Possible Mechanisms. Front Pharmacol, 2018
• Effects of chronic Rhodiola Rosea supplementation on sport performance and antioxidant capacity in trained male: preliminary results. J Sports Med Phys Fitness, 2010
• The effectiveness and efficacy of Rhodiola rosea L.: a systematic review of randomized clinical trials. Phytomedicine, 2011
• Rhodiola Rosea In Stress Induced Fatigue–a Double Blind Cross-over Study Of A Standardized Extract SHR-5 With A Repeated Low-dose Regimen On The Mental Performance Of Healthy Physicians During Night Duty. Phytomedicine, 2000

MALATE and MAGNESIUM

• Malate and Fumarate Extend Lifespan in Caenorhabditis elegans. PloS, 2013
• Magnesium Role in Health and Longevity. Trace Elements and Minerals in Health and Longevity. Healthy Ageing and Longevity, vol 8. Springer, 2018
• Role of magnesium in genomic stability. Mutat Res, 2001
• Association of dietary magnesium and DNA repair capacity with lung cancer risk. Cancer Epid. & Biomarkers & Prevention, 2006
• Dietary magnesium supplementation improves lifespan in a mouse model of progeria. EMBO Mol Med, 2020

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.

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.