Pharmaceutical Companies

Pharmaceuticals drugs take between an average of 10 and 15 years to reach the market place

Pharmaceuticals drugs cost between $0.8 Billion to $2.6 Billion per drug with an average of $1.2 billion.

Only the large companies have this needed money, smaller companies will have to raise it from investors.

Pharmaceutical Companies’ business model is to develop drugs that they can have a protectable proprietary market position on. They can then use this monopoly to charge significantly more than a competitive product would allow. This monopoly also allows them to take the time and pay the development money needed to beneficially change the complexity seen in biological systems. This is what allows pharmaceutical companies to gain a profit with long and expensive product pipelines. The pharmaceutical industry interchanges (in their minds) protectable proprietary market position with having a patent on the component(s) of the therapy. Use-patents are very difficult to enforce and thus are normally of no economic value. Due to the difficulty of getting a multicomponent therapy through the FDA regulatory framework this therapy (for all intensive purposes) is a singular component therapy. The patent offices around the world do not allow for an effective defensible patent for a compound that is a natural compound. Thus therapies developed by pharmaceutical companies are almost exclusively singular molecules that are not found in nature. Putting a molecule that is not naturally found into an individual human is probabilistically overwhelmingly not going to have a beneficial effect on the individual and will most probably have a significant negative effect on the individual. This is in contrast to molecules that are naturally found in an individual and that the individual thus has the evolutionary mechanisms to deal with (use, degrade and eliminate). Note “natural” can mean, and often does mean, that the molecule(s) is found in nature but is not naturally found in human’s bodies or even in their diets (skin and gut are surfaces of their bodies). These “natural” molecules, too, would most likely have a negative effect since humans have not interacted with them in evolution. These factors leads to the long development time of pharmaceuticals, their high costs, and their need for government regulatory bodies to oversee their scientific results prior to having the public take their drugs.

Overlooked (or at least not embraced) by the pharmaceutical industry is that the complexity of biological entities often have pathways (especially the most important pathways) that are dependent on assessing multiple sub-pathways prior to making a decision on how to act. This is the case with the human repair pathways that underlie biological aging. Sirtuin enzymes which are at the apex of the repair systems need to assess the energy pathways, the oxidation/ reduction pathways and the DNA transcriptional regulation pathways (epigenetics) simultaneously prior to making a decision on how to proceed (to turn off or turn on).  In cases such as these it is possible to get a patent on the alteration of this decision mechanism even though each of the components are compounds naturally found in the individual. This is what Egaceutical Corporation did to obtain a protectable proprietary market position patent for EGA. Thus Egaceutical’s patent position is on par with a pharmaceutical’s patent position. In addition to the patent, Egaceutical Corporation then does not have to deal with the negative effects of non-natural (to humans) molecules and the difficulties of pleasing the FDA, since natural-to-the-human compounds are allowed to be marketed as food supplements, because they are in the food supply humans normally eat.  They are found in all animals and plants, only in very low amounts, so food by itself is not a sufficient therapy.

Examples of dominant drugs in use today with substantial side effects include Statins, ACE inhibitors and Anti- arthritis drugs. All of these drugs have some age reversal properties; although when tested by the National Institutes of Aging, in mice, Simvastatin did not elongate life, but their side effects are significantly too large to use for that purpose. See “History of Heart Disease” for specifics of Statins and ACE Inhibitors mechanism of action which differs from what was thought originally. Arthritis drugs such as Humira disrupt the TNF-α pathway with antibodies, thus removing the problem when this pathway is overactive (which it can be in aging) but causing a problem when this pathway is needed to combat attacking viruses and bacteria.

Egaceutical Therapy Compared to Big-Pharma’s Approach to Therapy

With Example from a 2017 New England Journal of Medicine (NEJM) Study
The NEJM is the journal most read by medical doctors.

On August 27, 2017, the New England Journal of Medicine published an article named “Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease” by first author Paul M. Ridker of Harvard Medical School. Canakinumab is drug made by the Novartis Pharmaceutical Company. It is an antibody that disrupts the interleukin-1β innate immunity pathway.

The Good for Novartis is that this antibody is a compound that is non-natural to the human body and nature so it is patentable which then allows Novartis to have a monopoly on the therapy thus able to charge as much as they wish and make a large profit if it is purchased. The fact that the therapy is a singular entity allows a far better chance at getting FDA approval, thus getting it on the market faster and cheaper. This study showed that lowering inflammation lowered heart disease and cancer deaths.

The Bad for Novartis is that this antibody takes away a large part of natural immunity. This is shown by the increase in serious adverse infection events when taking Canakinumab. The increase deaths due to this flaw made up for the lives saved from lowering inflammation which reduced heart disease and cancer deaths. So overall there was no statistical lowering of overall deaths in people who take Canakinumab. The above (seen in The Good) business-model considerations are key to the Big-Pharma business-model, and why GSK did not pursue treatment with Nicotinamide Mononucleotide (NMN) against the strong-advice to pursue from their consultants, knowledgeable in the field.

The conclusion of these study researchers is that this proves a point, which is that inflammation is important cause of heart disease and cancer in humans. Their suggestion is to wreck only a smaller portion of the immune system, example only the immunity under Interleukin-6 (IL-6), which is below the level destroyed by the Canakinumab therapy. 6 other large studies in humans have shown that IL-6 is predictive of all-cause mortality.

The Egaceutical Approach to Therapy is to reduce immunity naturally the way nature meant it to be lowered under conditions when it is not needed and allowing it to be better at its job when it is needed.

Egaceutical measures this response to its therapy in humans by measuring IL-6 as well as Tumor Necrosis Factor – Alpha (TNF-α) which EGA®  lowers considerably without any side effects seen to date. Research articles indicate that lowering these naturally will allow a better response to bacteria and viruses. Research also indicates that lowering these will decrease all-cause mortality and each of the diseases of aging (Heart disease, Stroke, Cancer, Alzheimer’s etc.) separately.

Egaceutical Corporation was able to apply for a patent because the therapy needs three ingredients, although these three are already found in the human cell, a combination of three necessary ingredients, which turn on and keep on the pattern recognizing Sirtuin enzymes, make the patent claims non-obvious and patentable. Because the FDA does not consider aging to be a disease, Egaceutical is able to market its product called EGA®, which is age spelled backward, to humans as long as the compounds are made in a “good manufacturing”  (cGMP) manner.

Egaceutical Corporation has shown its EGA® product lowered IL-6 and TNF-α in 20 males , and two females, with other wonderful age reversal effects without any negative effects seen to date. Five of the 20 males from 45 to 70 had arthritis which was eliminated with EGA® therapy. The arthritis market itself is over $30 billion annually.

Large Corporations

Calico (Google’s Age Reversal Company)

In 2013 the company was founded with $1.5 billion from Google as sort of a “Bell Labs” for aging research. In 2018 another $1.0 billion was pledged from Abbie Vie and Google, profits will be split for projects. Their CEO is Arthur Levinson (ex Genentech CEO). In 2017 the head of R&D (Hal Barron) left and in 2018 the head of Artificial Intelligence (Daphne Koller) left. Their, now 74 year old, Chief Scientific Officer, David Botstein, said “the best case scenario is that Calico has something profound in 10 years”.

Their first product concept, that they raised money from Goggle for, was for the NAMPT activator P7C3 to increase the NMN made in cells. This technology was from the University of Texas, Southwestern in 2014. Egaceutical Corporation included in its patent the use of drugs of this sort with the needed compounds to stop feedback loops which they believe will be needed for P7C3 to work effectively.

Agreements that Calico has include: AbbVie (2014), C4 Therapeutics, Jackson Laboratories- for the genetics of health and longevity, California Institute for Quantitative Biosciences (QB3), UCSF- for integrated stress response related to cognitive decline, Broad Institute at MIT, Harvard, and the Buck Institute for Aging. All of Calico’s research and the research in their agreements are still in animal models.

Pharmaceutical Companies

Novartis (has a $200 billion market capitalization)

Worked on mTOR -> licensed with equity agreement to resTOR bio (see)

Glaxo SmithKline (purchased Sirtris for $720 million in 2008, then shut it down 5 years later)

They have a 12 person Sirtuin development unit headed by Jim Ellis, lead drug is for psoriasis

AbbVie

Working with Calico, in 2018 re-upped their involvement with a $½ billion investment

The $41,000 per year Humira drug of Abbvie “a TNF blocker” disrupts an immune pathway with an monoclonal antibody (adalimumab), which beneficially reduces inflammation when you do not need this TNF pathway, but detrimental when you need this TNF pathway to defend yourself from infections (viruses, bacteria, fungi). Egaceutical EGA’s product reduces TNF along with IL-6 by the natural human process for the same effect when beneficial but allows these pathways to work as nature intended them to work when they are needed to fight infection.

Stem Cell Companies

Stem cells age. Stem cells need to have their age reversed to have maximum effect before being used by these companies. Stem cell companies are not, in the true sense competitors, but customers.

International Stem Cell Corporation in Carlsbad California

Stem cells from unfertilized oocytes

Orchard Therapeutics in UK

Stem cells from patients own cells

US Stem Cell

Wnt Pathway Company

The Wnt pathway is a differentiation pathway for cells. The cells sent on this pathway age and their age needs to be reversed before use for optimum effect, so this company is not, in a true sense, a competitor but a customer.

Samumed

Wnt pathway (wingless integration site)

Possible use: for baldness, hair color, wrinkles, Alzheimer’s and osteoarthritis of the knee

$300 million has been raised from 5 investors in 2016 with a $12 billion valuation

Their research is still in mice.

Senescence Companies

Senolytic drugs: Senolytic drugs are drugs that preferentially kill, via apoptosis, senescent cells and cause the relevant youthful cells to replace them. Senescent cell can secrete deleterious cytokines and chemokines and extracellular matrix proteases. Examples are dasatinib, a cancer drug on the market, and quercetin, a natural flavonol. Each selectively kill a certain type of senescent cell. The thought is that a grouping of these senolytic drugs could kill a range of senescent cell types and stimulate the production of the youthful cell types killed.

Field of senolytic drugs was started by: Jan van Dearsen at Mayo Clinic, he wrote the proof of concept in 2011: the initial Journal article of field, then in 2016 he wrote a follow up journal article.

There is a problem of determination: which are senescent cells? James Kirkland stated “Not every cell that expresses P16 is senescent and not every senescent cell expresses P16”.

Is this a Re-Branding of The Oxidative Theory of Aging?

The initial senolytic drugs are Quercitin and Fisetin (has an additional hydroxyl group at position 5 of Quercitin). These are a subgroup of polyphenols called flavonoids. Flavonoids have been known for decades to have antioxidant properties. More recently the mechanism has been shown to be their turning on of Nrf2 (Malavolta M 2018) which in turn, turns on the transcription of a large number of anti-oxidant defense system enzymes. To sum up: in the field of senolytics, scientists cause cells to be senescent by oxidizing them (usually by irradiation) and then the scientists cure the problem by turning on the anti-oxidant enzyme defense system. This re-branding may not be a bad thing since in the start of the looking for a therapy for oxidation, researchers used small molecule anti-oxidants; these did not work and in the case of Beta-carotene in smokers actually tended to cause more cancer. The reason is that small molecule anti-oxidants only work once, then they are oxidized and there is no good way to re-reduce them into anti-oxidants again. Thus they stay in one’s body as oxidants, which is bad. In contrast to this, anti-oxidant enzymes continually work and do not need to be re-reduced, which is good. This may well be the reason humans lost the ability to make small molecule anti-oxidant vitamin C in evolution.

We now know that small amounts of oxidants [like H2O2 ,the least detrimental and longest lasting of cellular oxidants and the oxidant more-toxic-oxidants are broken down into before being turned into water and then assessed so that the cell knows how much oxidation it is under] turns on anti-oxidant enzymes through a mechanism centered on Nrf2.

The off-patent pharmaceutical drug Metformin is the drug companies “template” to get an age reversal drug through the FDA (before they put their own pharmaceutical through the FDA) since it has already shown to reverse signs of age in clinical trials for diabetes. Metformin’s mechanism of action is H2O2 in the gut as shown in fruit fly experiments where H2O2 was needed to be produced (otherwise it would not work) by Metformin in the fly gut, which would turn on Nrf2, and thus the antioxidant repair system (De Haes W 2014, Pickering AM 2013, Foislund K 2015)

Cells under oxidative stress (too much oxidation) either go on to kill themselves in an orderly way (called apoptosis) or if a molecule called Fox04 is present then they become senescent cells. Senescent cells spew out a grouping of molecules (called SASP that includes IL-6) that can be toxic to their neighbor cells. There can be heterogeneity of amount and constitution of SASP in these cells. Detrimental effects of this include osteoarthritis.

Quite often the scientists using senolytic drugs just measure IL-6 to see if their senolytic therapy is working. This is one of the molecules Egaceutical Corporation measures in humans to make sure EGA is working. Egaceutical’s triple therapy EGA’s third compound is specifically present to turn on Nrf2 and thus turn on the human anti-oxidant enzyme defense system and is therefore able (via turning off Nf-kB) to effectively reduce IL-6 in humans. EGA appears to do this more effectively and without the side effects of senolytic drugs.

Oisin Biotechnology

In Seattle, Started in 2016, raised $4 million, See: slide deck (below) from conference talk they gave

CEO Gary Hudson, Chief Science Officer is John Lewis. PhD

Proof of concept in 2016: to recognize senescent cell DNA expression and to kill all senescent cells in body at once.

SENS Research Foundation was a founder in company

https://www.oisinbio.com/s/Oisin-Slide-Deck-20180711c-ICSA20183.pdf

Senolytic Therapeutics

Barcelona Spain and 43 Newbrook Cir. Chestnut Hill MA 02467-2645

1 employee to get SBIR grants

CEO Marc Ramis Castelltort

David Sinclair is on the science board

Everon Biosciences of Buffalo NY

Cellular senescence

Unity Biotechnology

In San Francisco, Started in 2013, Public in 2018, value above $700 million, raised $385 Million

They are planning a clinical trial in 40 humans for arthritis of the knee. There are problems with getting the drug to location so they are using injection to local site. They have done a study of arthritis in the knees of 12 mice with their drug with limited success. In their initial experiment Unity Biotechnology’s drug killed 20 % of senescent cells and killed 5 % of good cells in mice. There are way more good cells so killing 5% of them is a significant side effect. See below: Comparison of Unity Biotechnology’s drug (in mice) to Egaceutical Corporation’s EGA (in humans).

Their claim to fame according to one of their investment bankers: Jeff Bezos is an investor.

CellAge Limited

Started in 2016, located at 272 Bath Street Glasgow Scotland G24JR raised 0.1 million in crowd funding

Mantas Matjusaitis CEO wants to use synthetic biology to specifically target senescent cells

Cleara Biotech

In Netherlands They use a peptide as their therapeutic. They have raised $3 million.

CEO James Peyes, PhD, the head science person is Peter de Keizer: he started in FOX0 research. He found Fox04 reacts with P53 under stress conditions. Their therapeutic is a peptide that disrupts this Fox04 and P53 interaction, called Fox04-DRI. Basically under oxidative stress cell goes to a senescent cell if Fox04 is on and to apoptosis (orderly cell death) if it is not.

Hibernation Companies

Fauna Bio Incorporated 4910 Croydon Place Newark CA 94560-1406

3 employee / founders (Ashley Zehnder, Katie Grabek, Linda Goodman)

They were funded by The Longevity Fund (Laura Deming, now 24 years old)

They are focused on: Manipulating metabolism, circadian rhythm and Insulin management by repurposed drugs, natural components and inventing drugs from mapping hibernator’s RNA and DNA to looking at mTOR, AMPK and therapeutic hypothermia using a combo treatment of beta-hydroxybutyrate and melatonin.

Genetics Companies

These are mainly medical diagnostic companies at this time searching for something of value.

Veritas Genetics $47 million raised

George Church, a Harvard Professor (he also started Egenesis for organs grown in animals)

$999 screening / analysis & genetic counseling

Human Longevity started in 2013 in San Diego, CA

Raised $80 million for founding and then $220 million

J. Craig Venter, PhD (Second person sequenced and founder was fired as CEO by the Board of Directors)

Calorie Restriction Companies

LifeGen

Richard Weindruch PhD U. of Wisconsin (He did calorie restriction studies on mice and monkeys)

DNA Microarrays to measure gene activity in Mammalian tissue from calorie restriction

They got $11.7 million from NuSkin

BiomX

They are a microbiome company wants to use bacterial viruses to kill bad bacteria in your gut.

mTOR Inhibition Companies

Rapalog:. Two rapalogs; rapamycin and everolimus, are clinically approved drugs for other indications that have anti-aging effects. Many that study aging, study the mTOR pathways. mTOR is the mechanistic target of rapamycin. Rapamycin was discovered in a soil sample from Easter Island, known locally as Rapa Nui, in the 1970s. The bacterium Streptomyces hygroscopicus, isolated from that sample, produces an antifungal that researchers named rapamycin after the island. The mTOR inhibitor rapamycin has been confirmed to increase lifespan in mice. In 2014, Xuan Ou in Hal Broxmeyer’s lab at the University of Indiana Medical School showed that Sirtuin 1 regulates the mTOR pathway. The NMN is thought to be a neutraceutical way to show this pharmaceutical effect along with NMN’s other effects.

In a phase II study in mice by the National Institutes of Aging (Miller RA 2011), Rapamycin (an FDA approved drug) was shown to elongate life in mice, but also shown to have a limited effect on aging (Neff F 2013). Study results in fish suggest the possible role of mTOR signal on GnRH1-mediated sexual behavior in males so inhibition would affect sexuality. Rapamycin also inhibits spermatogenesis by changing the autophagy status through suppressing mechanistic target of rapamycin-p70S6 kinase in male rats (Liu S 2017). Sirolimus is associated with decreased total testosterone levels (Lee S 2005). “There are Sex-specific Tradeoffs With Growth and Fitness Following Life-span Extension by Rapamycin” (Mi L 2016). Of note here is that human males without testicals live 9 to 13 years longer on average. This trade off with sexuality is a side effect of mTOR inhibition and also present with calorie restriction diets and this is one side effect that many want to avoid.

Navitor Pharma

Run by George Vlasuk (who ran Sirtris after GSK purchased it)

$100 million raised, so this is a well-funded mTOR inhibition company

Mount Tam Biotechnologies

This company is imbedded within Buck Institute

resTORbio a subsidiary of PureTech Health raises $40 million

Technology from Novartis

Orally active everolimus inhibition of mTORC1, Phase II report expected in 2018

CEO Chen Schor, CSO Joe Bolen, PhD

Mitochondria Company

Cohbar Inc. listed on Nasdaq as CWBR

Cohbar was started by Nir Barzilai. Therapies are based on peptides for mitochondria

Blood Component Company

Young blood: After the reports from Harvard Medical School by David Sinclair on NMN reversing age, a Stanford Professor, Tony Wyss-Coray, brought up in the press, an old observation that young blood (by heterochronic parabiosis – connecting the blood flow of a younger individual to an older individual) can decrease the age of an older adult (and increase the age of the younger individual). He has founded a company, Alkahest, to develop this concept. They will be looking at blood based ingredients that can be added to old blood and ingredients that can be taken away from old blood to reverse the age of an older individual. As previously stated, NAD+ is an ingredient that is in the blood of humans that can be made in the blood of humans and that has been seen to decrease 50% with age.

Alkahest

Tony Wyss-Corey

Propose to use TIMP2 for Alzheimer’s disease. In 2014, Tony reported that plasma from young mice, repeatedly injected into old mice, can increase memory function by targeting classical molecular pathways known to be involved in cognition and stimulate morphological processes in the hippocampus.

Ambrosia

Parabiosis; they pay donors under 25 for their blood and then they charge $8,000 to older adults to participate in clinical trial (one dose of young blood) see ClinicalTrials.gov Identifier:NCT02803554

Elevian in San Francisco

Seed round took in $5.5 million from Peter Diamandis’ Bold Capital

Giving people GDF11 (a blood) protein (lower in older individuals)

CEO Mark Allen (a software guy) Amy Wagers Cofounder was a Harvard Biologist

Others

Life Biosciences

Founded in 2016 by David Sinclair joined later by Adam Newmann a billionaire from WeWorks

Life Biosciences is an umbrella company for several daughter companies including: Spotlight Biosciences for novel peptides, Jumpstart Fertility for improving egg quality, Senolytic Therapeutics mentioned previously, Selphagy Therapeutics for autophagy improvements, Continuum Biosciences for mitochondrial improvement and Animal Biosciences for Veterinary drugs.

C4 Therapeutics $73 million raised in 2015 for Ubiquitin-proteasome based therapies they are working with Calico (see)

Non Profit Research Organization for Human Age Reversal

Academy for Health and Lifespan https://www.ahlresearch.org/

Clinical trial not connected to a company

The Metformin clinical trial: this is really a Trojan horse therapy to find the path through the FDA for other age-reversal therapeutics. The trial would cost $65 million for a 6 year 6000 person trial. Metformin an approved drug already has known side effects and the benefit is already known to be minimal (see above for further discussion).

NAD+ Companies

NAD+ IV companies, use NAD+ IV drip given to patients by MD’s

The object of NAD+ age–reversal methodologies is to increase NAD+ in cells. This can be done by making NAD+ from NMN (nicotinamide mononucleotide). This conversion of NMN to NAD+ is done by 3 separate enzymes in the three separate compartments of the cell. NMN is transformed by NMNAT (1,2,3) enzymes to make NAD+ in the nucleus (1), cytoplasm (2), and mitochondria (3). This allows each compartment of the cell to get the NAD+ concentration it needs; different concentrations are needed in each of the different cellular compartments.

“Why not just take NAD+ instead of NMN? “ First: NAD+ does not get through the stomach into the body. It is broken down into nicotinamide. Nicotinamide has a pro-aging effect unless the body methylates (adds a methyl group) it. This added methyl group physically stops the nicotinamide from fitting into a groove in the Sirtuins enzymes that would stop them from working. Second: If it were possible to get NAD+ into the blood stream, it is not thought that NAD+ is allowed to enter the cells with the exception maybe of nerve cells in the brain. NMN is the natural compound that is carried in the blood stream after it is made by the “e” form of the enzyme NAMPT the key regulatory enzyme in the NAD+ synthetic pathway. There is also an “i” form of this enzyme that is inside of cells as well. Third: If NAD+ were able to get into cells, this would take away from the cells ability to have different cellular concentrations of NAD+ in the different compartments of the cell.

There have been an estimated 30,000 drug and alcohol abusers that have been given NAD+ in an IV drip by physicians in South Africa as well as 1000 in Louisiana and many in San Diego, California. Egaceutical has visited the Louisiana and San Diego facilities to learn from this medical experience of NAD+ use in humans. The drug or alcohol abusers sit for 8 hours a day with the IV drip in their arms for 8 to 12 days straight. The total additive dose of NAD+ given over 10 days to these individuals is about 6 grams. The cost to the drug or alcohol abuser customer for the 6 grams of NAD+ taken is $10,000. NAD+ had twice the molecular weight as the NAD+ precursor NMN, so 1 gram of IV NAD+ is about equivalent to 1/2 gram of oral NMN, but you need to add to this equation that oral NMN has probably a low absorption rate (this still needs to be better quantified). Egaceutical dosage for age-reversal in human is 6 grams per day for an average sized human (165 lbs.) which is the total 10 day ($10,000) dosage for the IV NAD+ drug abuse users. It appears that the dosage used is correlated with what the suppliers think is the maximum their customers will (or is able) pay.

Despite the low dose, the physical and mental experience of the NAD+ IV customers has been extremely positive and without any negative side effects. The Company has met with individuals that have taken this IV NAD+ and their enthusiasm for this therapy is extremely positive. The only side effect noted by the participants and clinicians was caused by administering the NAD+ too quickly. When this side effect occurred, it was quickly and effectively dealt with by lowering the dose rate of the NAD+ IV. One scientific journal article indicates that NAD+ breaks down in the blood into NMN and AMP. AMP is known to drop blood pressure, which is probably the reason NAD+ IV has a maximum infusion rate in humans limiting the daily dosage to 1.5 grams in an 8 hour session. This history of low dose NAD+ administration in humans and that NMN had not had side effects in mice after one year added initial assurances prior to subsequent initial human studies that NMN would not have side effects in humans, which it did not.

There are also several companies that sell NAD+ tablets. These have never been shown to have believable beneficial effects, most likely for the above reasons.

NADH (tablets)

Age-reversal therapy is trying to change not only the level of NAD+ (which goes down to half in older adults) but also the NAD+/NADH ratio. Adding NADH to the body would change this ratio in the wrong direction and would thus have a pro-aging effect. Early studies in dogs did show that taking NADH did not produce any noticeable side effects or toxicity (Birkmayer JG 2004). NADH is sold on the internet, although there are no credible scientists that advocate taking this molecule.

NR companies

NR (tablets)

Nicotinamide Riboside (NR), Nicotinamide mononucleotide NMN and NAD+ are found in human mother’s milk, so they are all natural nutrients supplied by mothers to their babies (Ummarino S 2016). NR lacks a phosphate group that is on NMN so is one synthetic step away from NMN (thus two steps away from NAD+). There are two human enzymes (Nrk 1 and Nrk 2) that phosphorylate nicotinamide riboside and make it into NMN (nicotinamide mononucleotide). NR increased NAD+ levels in some tissues and is especially liked by muscle but not others cells nearly as well. This indicates that NR will not make NAD+ in some tissues where NMN will. Anthony Sauve of Cornell Medical School has researched this compound and patented (8,106,184) some synthetic methods to make the molecule. His patent was sold to Chromadex of Irvine, California. Professor Sauve chose not to be a consultant to Chromadex instead choosing to stay as a consultant for Glaxo SmithKline. In 2014 Professor Anthony Sauve said he had been taking a 250 mg dose of NR for some time and says it is great although he did not go into the effects on himself. This quantity is in line with dosages of niacin that lots of people have taken for some time. Niacin (Vitamin B-3) is farther up the synthesis pathway of NAD+, but niacin has the opposite regulatory effect as NMN on Sirtuins in regards to activation of the anti-aging effects of Sirtuins. Professor Sauve agrees that to get to the dosage that has shown beneficial effect of NR in mice he would have to take close to 10 grams a day. He thought that NR was an equivalent method of getting NAD+ into the body (now an exclusive NMN transporter has been found that does not take NR in Grozio A 2019) and that his results were telling the same story as David Sinclair’s (of Harvard Medical School) paper in the journal Cell (now NMN has been shown to be better that NR as a heart disease therapy: from Stam AR 2017, de Picciotto NE 2016). He admits that NR is an extra step away from NAD+, but says the advantage is that NR can be made in kilogram quantities, thus the price would be lower. NMN is now being made in KG amounts as well, so the price of it is dropping. Anthony Sauve declined to be a consultant to Chromadex because he thought it would interfere with his consulting to the pharmaceutical giant GSK. GSK is interested in increasing NAD+ in cells but not via precursors to NAD+. As previously mentioned, a pharmaceutical would have deleterious effects since it would disrupt normal pathways. Suave agreed but indicated GSK needed a proprietary position that adding precursors to NAD+ could not give. This means that pharmaceuticals will probably not be effective competition in this anti-aging market. Professor Sauve was convinced by three different scientific arguments that high quantities of NAD+ would not be dangerous in humans. He thought it was up to NMN proponents (the Harvard group) to show NMN was superior to NR.

According to Professor Imai, at Washington University in Saint Louis, NR is a “gooey” substance a neutral PH, and was made into a solid by making it as a salt. The problem with this is that the quantity of NR that needs to be taken by the customer would make the salt intake with the NR a serious health problem for the NR customer. He also said that NR at a neutral PH is unstable (it is stable as an acid) and reiterated that NR does not get into all tissues. NR is sold in 125 mg tablets with a recommendation of taking 2 tablets a day. These dosage recommendations show the distributor is not selling NR as an age–reversal product. It is sold as a replacement for Niacin, because it does not cause the niacin flush. There are additional components in these 125 mg pills manufactured by Chromadex (these are the same as those sold by Elysium Health) that would make taking these pills to achieve multiple gram quantities of NR in the blood prohibited.

Presently active NR studies (a large number of which came up) in humans are listed on the government’s website

Past studies using NR:

A study on 120 individuals has been done using NR. Professor Leonard Guarente of MIT and the founding scientist of Elysium Health told Egaceutical Corporation founder in October of 2015 that they planned a two month human test of “Basis” to look at safety issues. The results of that study of NR for two months showed an increase of NAD+ in the subjects but no age reversal for results of this company run study paper website below as well as comments on paper.

Nature Journal article November 26, 2017

This 2017 article about using Elysium’s product for 8 weeks had results measurements at week 0, 4, and 8 on placebo, 1X and 2X product dosages.

Good things about study:

They did a study on NR in humans and say the study was done by a third party

Bad things about study:

NMN Companies

Nicotinamide Mononucleotide (NMN) is the only compound that has been shown to reverse aging in any mammals. Egaceutical Corporation initiated clinical trials to show that it patented EGA® reverses aging in humans. It uses NMN with two other molecules to control feedback loops that otherwise turnoff Sirtuin enzymes thus the human repair system thus age reversal. Egaceutical Corporation is agnostic between the use of NMN and NR since both are included in its patent.

NMN was shown in a December 19, 2013 Cell article to reverse aging in mice. Ana Gomes, the lead author of the paper from David Sinclair’s lab at Harvard Medical School, said other researchers had shown that mice will take up NMN when it is in their water supply. The reason they used NMN instead of NR (nicotinamide riboside) was because of the extra enzymatic step needed to get synthesis of NAD+ from NR. Because the necessary enzymes are not in all tissues, NR would not be made into NAD+ in these tissues. They did see excess NAD+ in lots of other tissue outside of the muscle tissue where it was injected. There is evidence now that the one cell type that may prefer NR to NMN is the muscle cell. Other cell types seem to prefer NMN to NR (now an exclusive NMN transporter has been found that does not take NR in Grozio A 2019). Of note is that it is important to be aware of circadian rhythm of cells when you measure NAD+, NMN and NR. Harvard used NMN from Sigma.