NADIS 1.0 Interview: Rubén Zapata-Pérez
Rubén, what was your personal path into science? What made you decide to focus on metabolism and ageing?
Rubén: At that time, I realized that although I was focused on producing these compounds, they might have therapeutic potential. This was around 2012, when the first studies on NR and NMN appeared. So, after finishing my PhD, I thought that since I could produce some of these precursors — including a few new ones — I should test them in vitro or in vivo to see if they actually worked.
That decision shifted my research toward metabolism and ageing. During my postdoc, I left behind the enzymology side and began focusing on how NAD⁺ precursors function and whether they could have therapeutic effects. That’s how I became interested in metabolism and ageing.
I think that’s a beautiful story of curiosity-driven path into metabolism. And it sounds like you’re hinting at a particular type of precursor — reduced nicotinamide mononucleotide, or NMNH — as a new and potent NAD⁺ precursor.What makes NMNH different from other precursors, and do you see real potential in it?
Rubén: The NMNH story is interesting because we actually stumbled upon this compound by sheer chance. We were producing NMN from NAD, and then we thought — what if we give NADH to the enzyme that normally produces NMN from NAD? It turned out that the enzyme was much more active toward NADH, and it produced a compound we didn’t recognize at first. We wondered, is there something called NMNH? Does it even exist?
At the time, NMNH had only been mentioned in a few very old papers as a product of NADH degradation. So we asked ourselves — could this be a real NAD⁺ precursor like NMN? We tested it, and it worked — in fact, it worked much better than NMN.
The difference between NMN and NMNH is actually very small — just one hydrogen atom — yet their properties are dramatically different. Their stabilities and biological activities differ significantly, even though chemically they’re almost identical.
When we realized that NMNH was such a potent NAD⁺ precursor, we were amazed — it felt like finding the “holy grail” of NAD⁺ precursors. But, of course, as we continued studying it over the past few years, we discovered its limitations too. For example, it’s very unstable under acidic conditions, which means it can’t be given orally because it gets degraded — something we confirmed in our studies.
We also found that NMNH triggers different patterns of gene expression, and not all of those changes are beneficial. So we still need to study this compound carefully — in cells, in animal models, and eventually in humans — to fully understand its effects and therapeutic potential.
I feel like that’s a really solid foundation for your research as a young PI. Especially this early in your career, what has been the most valuable aspect of being part of the NADIS consortium — particularly working alongside more senior PIs?
Ruben: Having the opportunity to collaborate with — and get to know — the researchers whose papers I used to read during my PhD has been the most valuable part for me. I’m now regularly meeting and working with some of the leading scientists in the NAD⁺ field, and that’s incredibly inspiring. I’ve learned so much from them — really a lot.
Through the consortium, we also have access to various training opportunities — even for PIs. One of the most valuable ones for me was a leadership course we had a couple of years ago in Genova, hosted by Santina. At that time, I didn’t yet have any PhD students, but just a few months later, I did. During that course, I learned from colleagues who already had years of experience supervising students. Listening to their stories and advice was invaluable.
Now that I lead my own group and supervise PhD students, I find myself applying much of what I learned back then. It really helped me grow as a young PI and shaped the way I try to lead — to be the best PI I can be.
I can certainly say, speaking as a PhD student, that we really value that — that you’re doing your best as a mentor and PI.
Turning back to the NAD⁺ field for a moment: what do you think is one of the biggest unanswered questions in NAD⁺ metabolism that you’re most excited to tackle in the coming years?
Rubén: I would say the most exciting question I’d like to see answered in the NAD⁺ field is: do NAD⁺ precursors really work?
In humans.
Rubén: Exactly — in humans. Because we know that in mice and other model organisms, they work like a charm. They seem to cure every disease you can think of — from muscular dystrophies to ageing, obesity, and diabetes. It’s like a panacea in preclinical studies.
But in humans, the results so far have been quite modest across the studies that have been done. So that’s the key question I’d really like to answer: do these precursors work in humans as well?
I think one major limitation has been the duration of treatment. In animal models, we can give these compounds throughout the animal’s entire life, but in human studies, treatment durations are much shorter — just a small fraction of a person’s lifespan. That’s a big challenge we need to address going forward.
I see. So now that the biological direction is becoming clearer — that we should focus more on humans — you already touched a bit on the duration of treatment. Could you elaborate a little more on what new research directions or technologies we should focus on? For example, what approaches within NADIS 2.0 could help push the boundaries of our understanding of NAD⁺ metabolism?
Rubén: That’s a very good question. I often think about how much data we generate — it’s enormous — and for me, that sometimes becomes a real hurdle when it comes to analysis. When we apply multi-omics techniques, we produce huge amounts of information, and making sense of it all is challenging.
One promising direction for the consortium — and something we’re already working on — is incorporating AI into our research. I think that’s going to be a very important step, because AI can help us integrate and interpret all the data we generate and extract meaningful insights from it. This could help us identify new mechanisms by which small molecules regulate metabolism, and also reveal new potential therapeutic targets.
So, the integration of AI into our research is one of the developments I’m most excited about for the next phase of the consortium.
Thank you so much for participating in this interview.