NMN Transporter Slc12a8 and the future of NMN clinical trials with Dr Alessia Grozio
The need for NMN Clinical trials
Dr Alessia Grozio is Chief Scientist at Elevant and a researcher at the Buck Institute, ‘insanely’ interested in all things NMN and longevity.
In a recent post, we discussed a key barrier in our knowledge of NMN supplementation in humans - namely the very limited clinical trial data.
However, this barrier is soon to be removed, thanks to high profile research + business collaborations which a directly confronting this lack of information.
With their execution and success, we will soon have a clear understanding of the benefits of NMN supplementation in human subjects (well beyond simpler experimental results, such as how NMN improved our Founder Nick’s biological age by 3.5 years).
Collaborations on NMN Clinical Research
One such collaboration we recently highlighted was the the work between aging research leader the Buck Institute, Elevant, and its parent company Seneque.
Together they have developed a healthy pipeline of NMN clinical trials in humans, which will focus on muscle recovery after exercise, potential benefits to skin health and much more (details in our interview).
Today, we host Elevant’s Chief Scientist and Buck Institute Researcher Dr. Alessia Grozio (PhD) for an exclusive interview on the future clinical trial outlook for NMN.
Interview with NMN researcher and expert Dr Alessia Grozio
A Longer Life contacted Dr. Grozio with a number of important questions on the topic of NMN supplementation in humans.
Seneque’s mission is to increase healthspan by 20% in the next decade.
One key topic area we addressed was Dr Grozio’s co-discovery of a transporter that delivers NMN directly into cells called slc12a8.
This discovery was the first time that a pathway for NMN to enter cells directly had been discovered. A key development which well renowned NMN expert Dr. David Sinclair was very quick to highlight in Nature Metabolism (read it here) .
This discovery has not been without controversy, as NAD biologist and researcher Dr. Charles Brenner was quick to criticise the study. This has led to a bit of a schism in the research community on whether or not slc12a8 does what Dr Grozio says it does.
So we wanted to hear it from the expert directly, asking Dr. Grozio to help us better understand the significance of slc12a8, particularly around how NMN enters the cell (which is critical for it to fulfil its NAD boosting function).
As always, we also ask her about her personal longevity strategy.
Without further delay - onwards!
This interview was conducted in written format over email correspondence during May 2021
A Longer Life (ALL): Dr Grozio, thanks for joining us here on A Longer Life.
To kick us off - you work diligently at both a research organisation and a commercial venture. Surely its hard work! Tell us - what drives you? What brings you into work each day?
Alessia Grozio (AG): Thanks for inviting me. The passion for my work and an “insane” curiosity for anything related to aging/longevity and NAD+ biology that brings me to work every day.
After earning my PhD in biochemistry, I started working on the enzymes (sirtuins, NAMPT, CD38/CD73 ecto-enzymes) involved in NAD+ metabolism.
NAD biology is quite complex. This is an area Dr. Grozio finds quite fascinating. We do too!
In a previous post with Dr Grozio’s college, Dr. Eric Verdin, we discuss this topics in further detail.
I have always been fascinated by the pivotal role that NAD+ plays in maintaining homeostasis in our body and the plethora of cellular processes in which it is involved.
Therefore, investigating the effects of NMN (nicotinamide mononucleotide), a critical endogenous compound for NAD+ biosynthesis, in different physio-pathological conditions where NAD+ levels are impaired, was a natural prosecution of my scientific interests.
More than “hard”, I would say that my job, as for many other scientists, is never boring!
What is NMN-C
ALL: Thank you for sharing those personal insights. One of the reasons we’re speaking with you today is to help introduce ‘Elevant’, and your efforts to make ‘NMN-C’ available to a broad audience.
Please introduce us to NMN-C. How does this formulation differ from other forms of NMN that our readership may already be taking?
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“What makes our NMN-C special is the extremely high level of safety and development that has gone into it. ”
AG: What makes our NMN-C special is the extremely high level of safety and development that has gone into it. We think what is most important is providing consumers with NMN-based products that have the highest levels of safety and quality possible.
NMN-C is exclusively available through Elevant in their “Prime” product (pictured)
What’s critical is, once NMN has been synthetized, to characterize the impurities, filter them as much as possible to reduce them to the minimum, and make sure that the few impurities remaining are safe.
In our NMN-C the level of impurities is very low, complying with the pharmaceutical grade guidelines.
Our product is then tested at high dosage, pre-clinically and in human, to confirm it’s safe to use.
Is NMN Safe for Humans?
ALL: There was a recent study specifically looking into the ‘safe’ level of NMN supplementation, could you share some information on this work?
“NMN-C at doses up to 1500 mg/kg/d appears to be safe”
AG: Our NMN-C acquired self-affirmed GRAS (Generally Recognized as Safe) status in accordance with US FDA regulatory guidelines, performed by an independent panel of toxicology and nutrition experts.
Moreover, we have recently published the first OECD 408 toxicology study performed on NMN. This study analyses the No Observable Adverse Effect Level (NOAEL) of our NMN-C and demonstrated that repeated oral administration of NMN-C at doses up to 1500 mg/kg/d appears to be safe and did not promote adverse effects in rats up to 90 days.
Diagram showing the role of Slc12a8 and how it enables NMN to enter the cell. Source: Nature Metabolism
Does NMN enter the cell intact?
ALL: You made some waves in the research community with your published results on a NMN ‘transporter’ slc12a8.
This was a particularly exciting discovery, as the ‘doorway’ for NMN to enter the cell was previously unknown.
Could you briefly explain why this discovery is significant for the prospects of NMN supplementation?
AG: The identification of a novel NMN transporter, Slc12a8, further advances our knowledge regarding NAD+ metabolism by providing a new mechanistic insight through which the absorption and distribution of NMN is regulated to fuel the NAD+ biosynthesis in different tissue.
In the manuscript published in 2019 in Nature Metabolism, we employed several biochemical and in vivo (testing done in a whole organism) analyses to demonstrate that the Slc12a8 gene encodes a selective NMN transporter that facilitates the direct uptake of NMN into cells and intestinal tissue of mice.
We found that Slc12a8 is regulated by NAD+, specifically, Slc12a8 expression is increased when intracellular NAD+ levels are declined, as a compensatory mechanism, in order to maintain the cellular NAD+ homeostasis.
The Debate Around Slc12a8
ALL: Proponents of alternative NAD precursors (NAD biologist Dr. Charles Brenner amongst them) such a Nicotinamide Riboside have contested that slc12a8 is an ‘intestinal cation-calcium transporter’ and not an NMN transporter.
The NMN proponents predicted that NMN would still work as NMN in cells that don't have NR kinase but we and others showed that when NR kinase is knocked out, NMN can only raise NAD+ by acting as nicotinamide. That's because NMN works by conversion to NR and needs NR kinase /14
— Charles Brenner, PhD (@CharlesMBrenner) January 13, 2020
Surely the ‘devil in the details’, but what is your reply to such claims?
How can we trust that NMN is making it ‘into the cell’ intact, rather than only through the Nicotinamide Riboside Kinase pathway as NR?
AG: Slc12a8 is an orphan member of the SLC12 family of the electroneutral cation–chloride co-transporters, this means that so far, its function as cation–chloride co-transporter has not been demonstrated.
Indeed, Slc12a8 shares low level of similarity with its family members for what concerns amino acid sequence and predicted membrane topology.
As described in our Nature Metabolism paper, we have conducted isotopic tracing experiments using side by side isotopic NMN and nicotinamide riboside in Slc12a8-OE NIH3T3 cells (the cell line overexpressing Slc12a8 protein) and primary hepatocytes from Slc12a8 knockout mice (mice completely lacking the Slc12a8 protein).
Both experimental conditions demonstrate direct NMN uptake without any previous conversion of NMN to nicotinamide riboside outside of cells.
ALL: Thanks for answering that very important question.
NMN as a Topical Cream for Skin Health
ALL: Moving on from transporters, and onto Elevant’s impressive research efforts, you are engaging with some very significant topic areas - namely beauty and sports performance, which are very significant consumer markets.
Could you share with us the future of NMN based ‘creams’ for topical use? Is this a future development area for beauty products? And do we know if NMN can enter skin cells through a topical? (We are very interested in measuring & preserving aesthetic age)
AG: Yes, previous research has shown that NAD+ appears to play an enormous potential role in skin health.
Research has shown that NAD+ energizes aging skin cells to function more like young cells, counters transepidermal water loss and improves the moisture content of the outer layer of the skin, along with several other actions that support healthy skin.
We have conducted clinical trials that have directly shown the beneficial effects of NMN on the skin.
The trials demonstrated improved skin moisturization, elasticity and brightness, and a reduction in skin roughness and visibility of wrinkles. The results are to be published soon and we will share them with you.
NMN for Exercise Recovery
A Longer Life is very interested in how anti-aging compounds might improve athletic performance and the benefits of exercise.
Another longevity supplement “Urolithin A”, which is derived from pomegranates, also has benefits on improving physical recovery, through the mitophagy pathway. Read more!
ALL: An ongoing clinical trial is now recruiting participants, which will analyse the benefits of NMN for ‘physical capacity and recovery’.
Looking forward, do you see a potential future role for NMN in human performance (i.e. sport)? If so, do you have any insights on how it might improve an athlete’s ability to compete in their sport of choice?
AG: We have preliminary results showing NMN is efficient on physical recovery, at any age. We will keep you informed, prior to the publication of our results.
Upcoming NMN Clinical Trials
ALL: Beyond these two clinical trial areas, Seneque are also ‘preparing’ several more clinical trials covering many areas with NMN-C: impact on NAD+ levels, NMN vs NR, sleep, cognitive function, immunity - each is a significant undertaking (self-titled ‘the world largest pipeline’).
What timeline do you expect for the results on these projects? They will each go quite a long ways toward demonstrating the efficacy of NMN supplementation.
Seneque has a very impressive pipeline of NMN based clinical trials at various stages of maturity. Find the latest on their website.
AG: Two more studies started this month (May 2021), a tolerance and a pharmacokinetic study with 20 participants each and dosage of 400mg per day. Preliminary results to be announced next July (2022).
The first results of further trials will be published Q3 2021 and several publications will occur until July 2022. You can see our extensive clinical research pipeline here.
Some additional confidential studies are being conducted at the moment, so pending the timing and results of those we hope to start communicating about them at the end of this year.
We are confident it won’t be long until we can demonstrate the efficacy of NMN supplementation in several clinical trials.
We aim to be able to share results sometime between Q3 and Q4 2021.
Research Business Partnerships for Longevity Research
“We are confident it won’t be long until we can demonstrate the efficacy of NMN supplementation in several clinical trials”
ALL: Some elements of these clinical trial efforts will occur in partnership with the Buck Institute, namely the pre-clinical studies and basic research efforts.
Could you describe the merits/value of private longevity technology companies collaborating with leading aging research institutions? What are the challenges for you personally, ‘wearing two hats, so to speak (as you’re also a scientist at the Buck Institute)?
AG: The main interest in collaborating with leading aging research institutions is to work and share knowledge with scientists coming from various backgrounds and expertise, foster new ideas and drive our research to constantly innovate.
This allows diverse new research leads and areas of study, all undertaken in line with scientific principles.
The powerful and high-end equipment and infrastructure at the Buck is of course a huge asset.
Finally, as you know, time is of the essence. These partnerships allow invaluable gains of time.
NMN-C is Manufactured to a High Standard
ALL: Elevant is now manufacturing NMN-C in Europe, which differentiates from other suppliers of NMN, who rely on manufacturing in China. This undoubtedly introduces additional costs, but likely as a trade-off for many benefits.
Could you comment on what ‘Made in Europe’ means for consumers?
AG: We strictly control every element of our proprietary manufacturing process, which we undertake at cGMP-certified facilities in France. Consumers receive what we believe are pharmaceutical grade and the highest levels of quality and safety available in an NAD+ booster today.
Dr Grozio’s Longevity Strategy
ALL: Dr Grozio, changing gears, as we close off the interview - could you share with our audience one or two items from your personal longevity strategy?
AG: I am Italian, therefore I am following a Mediterranean diet, rich in vegetables, legumes, fish and extra virgin olive oil.
Moreover, I am taking our NMN-C every morning to boost my physical and mental energy needed to go throughout the entire day.
ALL: Dr. Grozio, thank you such much for taking the time to answer our equations today!
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FDA & TGA DISCLAIMER
This information is intended for educational purposes only and is not meant to substitute for medical care or to prescribe treatment for any specific health condition. These blog posts are not intended to diagnose, treat, cure or prevent any disease, and only may become actionable through consultation with a medical professional.
