Fueling Fertility: How NAD⁺ Shapes Ovarian Health and Egg Quality with Dr. Mark Ratner

Mark Ratner 

So NAD serves these two different roles. It’s for energy production and it’s also for enzyme activation. Both of those roles play very, very heavily into female fertility, into ovarian health, ovarian aging, and egg quality. So when we talk about female fertility and the OO side or the egg, we really have concerns about two different aspects, quantity and quality.

Lorne Brown

I’m your host, Dr. Lorne Brown, and today we’re diving deeper into a topic that’s become central in longevity science, and particularly today, what we’re talking about, fertility, reproductive health, NAD. I want to know what it really does, how to raise it, and why it matters for egg quality and ovarian aging. Now, if you’ve listened to my past episodes, you know we’ve explored NAD, in particular, NAD recycling, inflammaging, and why precursor supplements may not work optimally in everyone in a past episode. After that conversation, I had some correspondence with our guest today, Dr. Mark Ratner, and he provided a detailed response about maybe not dismissing the topic, but actually clarifying several key biochemical points in challenging some of the assumptions that have been popular in the NAD space. So my guest today is Dr. Mark Ratner. He’s a chief science officer of Theralogix. It’s a company that is well known for evidence-based fertility and women’s health formulations.

Mark is a medical doctor. He has decades of experience in clinical practice, nutritional biochemistry and supplementation formulations. Now, he did his undergraduate and graduate studies in nutrition at Cornell University. Why he’s such a good fit for the biochemistry around nutrition and supplement formulations. And as I remind you, he is an MD and he does residency and training at Tulane University School of Medicine. And he’s someone who does read the primary literature, understands the enzymatic pathways and builds products that reflect actual human data and not trends. And I’ve had Mark on the integrated facility symposium twice. He’s been in person in Vancouver when we’ve held it as a speaker. And also when we did it online, I think it was back in 2021. Now, Theralogix released a product called OvaNAD+, and it combines nicotinamide, riboside NR. And Mark, what’s the reserveratrol-like compound? How do you say it?

Mark Ratner

Analog. Yeah, it’s called Tericilbine

Lorne Brown 

Tericilbine, okay. Which supports NAD production, mitochondrial health, and ovarian function. So this is why I think this conversation’s going to matter and why I wanted Mercare to have this conversation. We’re always looking for ways, at least in my clinic and the people I work with and my colleagues, we want to help our patients try to conceive. And a lot of them are in their mid 30s to mid 40s. And in this demographic, we’re constantly talking about egg quality. We’re talking about mitochondrial function. We’re talking about ovarian reserve. We’re talking about biological versus chronological age and how all that’s impacted by inflammation and metabolic health. And it seems like NAD sits at the intersection of all of these. And at the same time, the NAD world has become confusing and honestly, a little bit contradictory. Do you use NR, NMM, NAM? Do you use a recycling formula?

Hey, should I do IV NADs? Maybe an NAD injection, or is an oral precursor enough? Is there such a thing as a precursor overload? This enzyme, CD38 and inflammation, does it make the precursors useless? What actually matters for egg quality? So as I mentioned, after hearing my previous episode, Mark sent me a thoughtful scientific clarification around which enzymes is truly rate limiting, why some precursors outperform others, what CD38 really does, and why suppressant it could be risky, and how NAD and SIRT1 specifically influence quality ovarian aging. So Mark, my aim today for having you in this conversation is to help me not be confused, but also the public. And I kind of want you to clarify the actual biochemistry behind NR and NM, NAM, NAD production. We’re going to connect it hopefully today to egg quality and ovarian aging using what we know from current research that you’ve been sharing, and how we integrate this with lifestyle and clinical support because NAD doesn’t operate in isolation.

So all that was my intro to say, Mark, I put a lot of pressure on you today, but maybe can you share a little bit about what NAD is and how this impacts egg quality? And then we can start looking at all the products on the market and what you’re offering and all the things people can do at the end to improve egg quality and the chances of having a healthy pregnancy and taking home a baby. Great.

Mark Ratner 

Okay. So what is NAD? NAD nicotinamide adenine dinucleotide, very long tongue twister there. It is a compound that is literally found in every cell of our body. It’s a derivative of vitamin B3, niacin, and it serves really, really important functions in the cell, both in two different ways. It’s got two main roles that it plays. NAD comes in two forms. It comes in an oxidized form, which we call NAD+, and it comes in a reduced form, NADH. The reduced form, NADH is actually what we call an electron donor. So it’s involved in a very important step in energy production in the cell. So NADH donates an electron in what’s called the electron transfer chain, which produces ATP. That’s the primary energy substrate of the cell. And when it does that, NADH becomes oxidized and it becomes NAD+. And so this is what we call a redox pair, and they switch back and forth between NAD and NAD8, NAD+ and NADH.

The other role that NAD plays besides this energy production role is in enzyme activation. NAD+ is what we call a D acetylase, another tongue twister, which is very important for activating certain key protective enzymes in our cells. What are those enzymes? Well, one of them is CD38.

CD38 is an enzyme that actually, when activated, helps to activate the immune response. Another one of the enzymes that NAD+ activates is called, or it’s a class of enzymes called the PARP enzymes. PARP is short for an even longer term that’s even harder to remember and pronounce, but basically the PARP enzymes, which are activated by NAD+, repair breaks in our DNA. So they’re important for DNA repair. The third class of enzymes that are so important that NAD+ activates are what we call sirtuins. And the sirtuins are seven different enzymes. We call them SIRT1, SIRT2, sirt the abbreviation. So SIRT1, SIRT2, all the way up through SIRT seven. These enzymes are the master metabolic regulators in our cells. So NAD serves these two different roles. It’s for energy production and it’s also for enzyme activation. Both of those roles play very, very heavily into female fertility, into ovarian health, ovarian aging, and egg quality.

So when we talk about female fertility and the oocyte or the egg, we really have concerns about two different aspects, quantity and quality. We know that as women age, they have fewer and fewer eggs left and we can get into that discussion a little bit more deeply. We also know that as women age, the quality of those eggs by which we mean the chromosomal quality, whether or not the proper number of chromosomes are present in the egg that they’ve produced that month, goes down as they age as well. And so there is a really growing body of evidence that by enhancing NAD activity in the ovary and sirtuin one activity, the first sirtuin enzyme, by improving both of those, we can improve both egg quality and egg quantity. And so some people will use the term that it can rescue ovarian aging. There is one paper that said it reverses ovarian aging, but I think that’s an overstatement.

To say that it actually reverses ovarian aging, meaning it produces new eggs that aren’t already there in the resting follicular state, that’s never been shown, but can it slow the process of ovarian aging? I think there’s a good reason to think that that is the case.

Lorne Brown 

Do you think though, this is just in the topic in general about this ovarian rejuvenation that you shared. If there’s a lot of noise in the system, inflammation, metabolic disorders, is there increased chance when the chromosomes, the eggs split and then when it gets seminated by the sperm and they start to divide, that if there’s noise in the system, mitochondrial health isn’t great that you have airs in these chromosomes dividing. And if you can clean up that noise like NAD, for example, then there’s the energy requirement and the ability to repair so you have less chance of those airs. So I’m not saying you’re making more eggs, but can you change the quality of the egg then if you give it the materials it needs so there’s less chance of those errors?

Mark Ratner 

So this is the same principle that underlies the use of CoQ10, Coenzyme Q10 in terms of improving egg quality. Each of the cells in our body contains 46 chromosomes, actually 23 pairs of chromosomes, a total of 46, except for the sperm and the egg. They each have 23. And obviously when they come together, you end up with an embryo that has 46 chromosomes in each cell. The process by which sperm and egg end up with 23 instead of 46, we call that myosis. And let’s focus on the egg for a second. That step where it divides from 46 down to 23, that last step of myosis requires those pairs of chromosomes. And let’s think of the pair as being two copies of chromosome one and two copies of chromosome two and two copies of chromosome three. Those two chromosomes need to split and they get pulled into one side becoming the egg and the other side becomes what we call the polar body and it gets discarded.

That process of splitting the chromosomes and dividing them, so you get 23 and 23 requires a huge amount of energy. Where does that energy get produced in the mitochondria? And the mitochondria uses this electron transfer chain to produce energy. One of the steps in that electron transfer chain is CoQ10, the transfer of electrons is done by CoQ10. And so if you have reduced levels of CoQ10, you’ve got less energy being produced by the mitochondria. And so that process of chromosomal splitting doesn’t happen with the same assurance. And instead of the chromosomes going one this way and one that way, you can end up with both chromosomes going this way. So now you’re going to end up with an egg that’s got an extra chromosome in it, and we call that aneuploidy. An egg that’s got the correct number of chromosomes, we call that a euploid egg or oocyte.

It’s got 23 chromosomes. But if the pear doesn’t split, if one of those pears doesn’t split and you get, because there isn’t enough energy being produced in the egg, then you end up with an egg that’s got the wrong number of chromosomes. Now, CoQ10 is important for that because it’s in the middle of that electron transfer chain, but the actual start of that chain, that process of electron transfer, it’s begun by NADH.

And so if you have lower levels of NADH in the egg, in the ovary, you’re not going to have that same energy production. So by improving … And it’s been very clearly shown in mouse models that as the female ovary ages, the level of Coke, I’m sorry, of NAD and NADH is diminished with aging. And if you can restore levels of NAD to better levels, to younger levels, you’re going to end up with better quality eggs, less aneuploidy, the right number of chromosomes, and those eggs will fertilize. Now you might say … So this concept of aneuploidy, most people are familiar with Down syndrome. Down syndrome is an extra copy of chromosome 21. It’s trisomy 21, meaning that embryo ends up with three copies of 21 instead of just two. So you might say, well, why does that happen just with chromosome 21? The answer is it happens with every chromosome.

That failure to divide properly can end up happening with any chromosome, but with the other chromosomes, you just end up with an egg that won’t fertilize. Chromosome 21 happens to have the fewest genes. It’s only got six or seven genes on it. And so an egg that’s got an extra copy of chromosome 21, it can fertilize and you end up with a baby that has Down syndrome. So infertility as women get older is primarily due to the fact that they’ve got abnormal chromosome content in their eggs. And so by improving energy production, not only with NAD supplementation, or I should say NAD boosting, but also something like coenzyme Q10, you’re going to reduce the risk of aneuploidy and improve egg quality in the aging ovary.

Lorne Brown

Thank you for that. And we’re going to get into supplementation. First, I want to stick with the biochemistry that you’re sharing. Unpack this. So as you shared, the aging ovary, just with aging, we have a reduction in NAD, and this can be part of the risk of infertility or egg quality, more antiploid abnormal embryos. And things that can accelerate the NAD loss, my understanding is it gets drained not just by aging, but it gets drained by chronic inflammation, oxidative stress, and metabolic dysregulation. So lifestyle and diet will- So

Mark Ratner 

This is where CD38 comes in.

Lorne Brown 

Okay.

Mark Ratner 

So the process by which NAD+ activates those enzymes, CD38, the PARP enzymes, the sirtuins, when it activates those enzymes, it actually destroys the NAD+. It breaks it down. And it turns out that there’s a pathway in our cells as a biochemical pathway to then regenerate NAD from those breakdown products. But it’s been very clearly shown that the greatest loss of NAD at the cellular level is from activation of CD38. So CD38 is a very interesting enzyme. It’s present on the surface of cells, and it’s primarily present on the surface of immune cells. And what happens is when there’s an initial immune reaction and cytokines are released, those are messages that come out of certain immune cells. They basically upregulate the amount of CD38 that’s present on these other immune cells, and the NAD then activates the CD38. Activation of CD38 then sends messages out to the rest of the immune system that says, let’s get going here.

And it upregulates the inflammatory response. So CD38’s not a bad guy. I mean, there’s this notion that somehow CD38 is a bad actor in our tissues, in our cells. It’s really, really important, especially in an acute immune response. If we’re exposed to a virus, if we’re exposed to a bacterial infection, in those initial stages of the immune response, CD38 is absolutely critical. Where it gets into trouble is in chronic inflammation.

And as we get older, there’s more and more inflammatory changes in our tissues. They call it inflammating. There’s this term that has been coined. I’m not sure you’d find it in the dictionary, but-

Lorne Brown 

I’ll share with the audience. We often say in my clinic, inflammating that in the play around definition we say it leads to accelerated biological aging, which leads to premature degenerative diseases. And I say premature fertility decline.

Mark Ratner 

What’d you call it? It’s self-perpetuating. It starts to get worse and worse. The more inflammation, the more aging, the more inflammation, it gets worse and worse and worse. And

Lorne Brown 

That’s why chronologically, all 40-year-olds aren’t equal because chronologically you have the same number of times the earth has gone around the sun per se, but somebody may be biologically 48, although they’re chronologically 40, and this is that inflammation. So a couple of things I wanted to hear again, hear myself say it for my audience and for my sake. So CD38, it’s part of that inflammatory response, but it’s not necessarily a bad actor. It’s the body’s self-preservation. Mark, I think in the same way when we see cholesterol and people freak out, “Oh, you have high cholesterol.” It’s the body cell preservation for the inflammation in the cardiovascular system. It’s trying to deal with the poor diet, poor lifestyle, everything else. It’s self-preservation, and if you don’t deal with that problem over time, it becomes its own problem, the cholesterol, right? But it came from a way of survival.

“Hey, you’re inflamed, your vessels are inflamed, we need to protect.” And it sounds like CD38 is the same thing. It’s a protection thing, but if it’s going on for years and years, the body basically is not getting the support it needs to deal with inflammation. And so I’m wondering if it is the CD38 that is the issue or it’s the chronic inflammation and it’s just that the body can’t handle it. And so all these breakdowns happen.

Mark Ratner 

So CD38, it’s funny because in a sense, it’s both partly a response to inflammation, but it’s also a cause of further inflammation. And so it’s when inflammation becomes chronic that the approach of saying, let’s downregulate CD38 a little bit, let’s tamp down how much CD38 is being expressed in our tissues becomes a potential approach. Unfortunately, the only … I mean, look, there are monoclonal antibodies. These are drugs that are used that target CD38 cariating cells, and they’re used for cancer treatment and things like that, but they end up causing immunosuppression. And so using a supplemental approach to try and reduce CD38, that’s been shown to be potentially effective in mouse studies. There are no human studies showing that that approach works in human tissues as well. But then again, if we go to the NAD literature, that’s also primarily mouse studies.

Lorne Brown 

If only our patients were mice.

Mark Ratner 

At least in the fertility world.

Look, there’s no question that the precursors, NR, NMN, to some degree NAM, which is nicotinamide or niacinamide, are capable of increasing NAD levels in human tissues. That’s been very clearly shown. The only problem is there’s no study that has looked at ovarian tissue in humans. They’ve looked at muscle, they’ve looked at fat, they’ve looked at the liver, and they’ve shown that you can take NR, you can take NMN. Those are the two best ones. There’s no question that they’re more effective than say NAM, which is niacinamide or nicotinic acid, which is actually the NIAIS in itself. But there’s no study that has yet looked at ovarian tissue levels that’s still waiting to happen. And we’re extrapolating to some degree from mouse models. And you might say, well, is that appropriate? Can we study female mice and see a benefit there in terms of preserving ovarian health and improving egg quality in mice?

And then say, well, this is going to work for people too. And it’s a very important question. You should understand though that there are some real interesting similarities between mice and human ovaries, mouse and ovarian human ovaries. The benefit of using mice is that mice live for two years. Okay, that’s it. They become fertile after a month. They’re like four weeks old and mice can start having babies. But just like women and women’s ovaries, they basically lose ovarian reserve very steadily. By 18 months, mice are no longer ovulating. They also have increasing levels of aneuploidy.

Lorne Brown 

Those are the abnormal embryos.

Mark Ratner 

The abnormal chromosome, the abnormal egg chromosomes, just like people do, just like women do. And they also have NAD and both NAD+ and NADH. They also have the same sirtuin enzymes. And we haven’t even talked about how sirtuin improves ovarian health and preserves ovarian reserve. So there are some real parallels between mouse ovarian physiology at the cellular level and human ovarian physiology. So there’s good reasons to think that …

Lorne Brown 

Yeah. And we do a lot of the non-invasive stuff supplements people will often start to do, although there’s no human trials yet on them, but that we would love to see those. So NAD, in general, we’re talking about the mitochondria, the battery of the cell. Every cell has the mitochondria. Most of our audience is very familiar with CoQ10. People are hearing about NAD, and NAD, from what we’ve shared so far, helps with energy production and DNA repair. Two important things that cells need. They need energy to function. We talked about how the egg cell needs a lot of energy for that myosis, for those chromosomes to go to either side. And then the embryo, which comes from the female line, those mitochondria are what allows the embryo to divide on its own energy in the fallopian tube or in the IVF lab growing out to blastocyst, and it requires that energy for implantation.

And many embryologists I’ve spoken to share that the embryo early on cleans up stuff like when there’s sperms up so great, it does some repairs. So all that part of the mitochondria function. So the mitochondria is important for this and NAD is shown to help with that energy and repair, which is excellent to hear. Can we just highlight one thing for our listeners, because we’re going to talk about supplementation. That’s the focus today because people are looking at NAD and what’s the best form of it to support this energy production repair. But let’s remind people that it is inflammation, chronic inflammation, oxygenated stress and metabolic dysregulation that accelerates the draining of it unnecessarily. We’re going to have it with aging, but we’re accelerating. So NAD precursors, which is what OVA NAD is that you guys have created Theralogix, it’s a precursor. We should let people know that nobody’s getting the actual NAD molecule.

They’re getting precursors to it because it’s not something we need. Like COQ10, we can get it from our diet, but NAD is made inside. We don’t get it from food sources, my understanding, but you’ll correct that. The thing I want to highlight is that NAD precursors like your supplement Ova NAD, I’m assuming, work much more effectively when inflammation, sleep disruption, stress, and high blood sugars aren’t constantly draining the NAD toward damage control.

Mark Ratner 

I think that’s a valid assumption. Yeah. Have the studies been done to absolutely prove that? No, but mechanistically, it’s absolutely what you would expect to be the case because we- Our audience, just

Lorne Brown

Because you certainly wasn’t a study, because people go, some people shut off, no study, I’m out. There’s never been a study that says if you jump from a 30,000 plane without a parachute that you will survive or die on the ground. There’s never been a study, but I think it’s a pretty good assumption.

Mark Ratner  Lorne Brown 

No, that’s exactly right. So because of the mechanism of inflammation and sleep disruption, poor diet, stress, toxins, all that’s creating unnecessary inflammation, your body’s needing to deal with that and that will cause a loss of NAD. So basically what we’re saying is rather than NAD going towards that great energy production that it needs to give energy to the cell and repair the cell, it’s off putting out inflammation fires, so it’s distracted. So let’s just help the body, the cell, do what it needs to do and let’s supplement it. But I guess my point is, Mark, you can’t outsupplement bad diet, lifestyle, abusive relationships, smoking, et cetera. You can’t outsupplement it, in my opinion. It’s pretty hard.

Mark Ratner 

You have basically, it’s kind of like a sink that you’re trying to keep filled up. And if the drain is open and the NAD is just pouring out of you because it’s being chewed up by all that inflammation, you’re going to have a hard time keeping that NAD level at a proper good level. No question about that. Yeah.

Lorne Brown 

So supplementation, a couple questions. So I’ve had a guest on in the past and the theory went, which I thought sounded great. And then I’d done a deeper dive because of your email. There’s this idea that you don’t necessarily want to give necessarily the building blocks, the raw materials, like there’s a few on the market like yours that have NRN it. You also have that, what’s special about yours is you have a form of-

Mark Ratner 

pterostilbene

Lorne Brown 

Yeah, which is a cousin to resveratrol. My understanding from looking at it is that it’s a better cousin, seems to be more absorbable and stable and stuff. But in that discussion I had on that episode, they’re saying, “You got this recycling plant and you got this conveyor belt and you’re putting all these raw materials in, but if the recycling plant isn’t working, eventually you have a buildup on the conveyor belt and it makes a mess out of everything. The pathways get blocked and it actually causes a problem.” And so work on recycling. I’ve always thought when people ask me, “So should I take the supplement that works on the recycling or should I take the raw materials?” And I’ll say, “I guess both.” I’m curious though, your thoughts on the recycling pathways, because that’s what some people say, just you don’t need so much the precursors. I don’t know if that’s exactly how they said it, but they definitely said, “You got to work on the recycling.

That’s the issue.” And that’s where you thought differently. And the research wasn’t there necessarily to support it.

Mark Ratner

Okay. Getting back to one thing that you said a moment ago, and that is, you are right, you cannot take NAD as a supplement itself. There are companies out there that sell it. You can find it on Amazon, actual NAD. But the problem is it’s a molecule that gets broken down in the GI tract into its components. It gets broken down. You’re not going to absorb it as NAD. The second thing is even if you can get it into your bloodstream, if you can absorb it, you can get it into your bloodstream. And there are places out there that will give you an infusion of NAD. So the absorption issue is sort of bypassed. It’s just getting directly infused into you intravenously. The problem is NAD is what we call a hydrophilic molecule, a very large hydrophilic molecule, meaning it’s water loving. So to get through a cell membrane, which is lipid-based, it’s water, what we call hydrophobic.

NAD can’t get into the cells. Only the precursors could get in. And so you can’t really supplement with NAD and have any kind of significant benefit. You need to use a precursor. The two big precursors that are in use now are NMN, nicotinamide mononucleotide and NR, which is nicotinamide riboside. Up until about three months ago, nicotinamide mononucleotide was not allowed for sale in the United States. I’m not sure about Canada, but that wasn’t because it wasn’t effective or it was dangerous. It was because of a regulatory issue that a pharmaceutical company had that they sued the FDA to stop the sale of NMN and the FDA said, okay, fine, we’re not going to allow it to be sold. But they reversed that. So now you can get either one or both in the United States. The immediate precursor of NAD is NMN.

If you give NR, nicotinamide riboside, it has to first be converted to NMN, which is then converted into NAD. But the enzymes that do those conversions are not rate limiting. There is no rate limitation on either of those enzymes. There’s plenty of those enzymes available. Now, the other precursor that some people will suggest using is what’s called NAM, which is niacinamide or nicotinamide. That is actually also one step away. I’m sorry, two steps away. It gets converted to NMN, which then gets converted to NAD. The problem is that NAM into NMN requires an enzyme that is rate limiting. And so you have to basically pick your precursor to make sure that you’re not going to require the presence of a limited quantity enzyme to make it active. That’s the first issue. The second issue is this. There’s already some data that in some tissues, NR does a better job, and in other tissues, NMN does a better job.

Why would that possibly be? It’s because in order, and when I say does a better job, I mean raising NAD levels in those tissues. So it’s like NR does a better job in the kidneys and NMN seems to do a better job in the liver and muscle. Why could that possibly be? It’s because to get from the precursor to NAD requires two things. It requires transport proteins to bring the precursor into the cell, and then it requires those enzymes to do the conversion. And there’s evidence that different tissues have different levels of those transport proteins and different levels of those enzymes. So the question is, since we’re really focusing back on ovarian benefits, which of those NMN or NR is better for the ovary? And the answer is we don’t know. All right, not in humans. In mice, it doesn’t seem to matter. There are studies both with NMN and NR, and both of them in the mouse models do the same good job of raising NAD levels in mouse ovaries.

So he’s done the studies yet, NP

Lorne Brown 

So with NMN, it seems to be one step closer, precursor to NAD. I know it used to not be available, but now it is. If you could reformulate, would you use NMN over NR? Is one more expensive than the other? Is one more stable in a supplement form? Since we don’t know tissue-wise, one is one step closer as a precursor.

Mark Ratner

So let me say that we are in the process of evaluating the changes that we want to make, but I think the best approach at this point, until there’s a study or studies that clarify which of those precursors does a better job in the ovary, I would say that if I was to start from scratch, I might want to go with both. Okay.

Lorne Brown 

I want to just highlight something because I’ve known Mark for several years now. We met pre- COVID. It’s funny how we date things now, right? So pre- COVID. And that was one thing. At our conference, we have many, which I think are excellent. We always vet excellent supplement companies. We’re always looking for good supplement companies that would sponsor. When I met you guys, your line wasn’t huge selection-wise, like all the other ones. And I remember our discussion, you’re like, I got to have research. We do science, not hype here. So until there’s science, we won’t do it. So I appreciate your answer and saying that right now you’re using NR and you’re looking at the idea of maybe having both in there, NMM and NR in

Mark Ratner 

Your- Yeah. I mean, look, we are what we call a practitioner line. In the supplement world, we’re a practitioner line. And we’ve been around 23 years. We started this company 23 years ago, but after 23 years, we only have 40 products. Now that might sound like a lot, but other companies like Metagenics and Thorn and Pure Encapsulations, these other practitioner lines, have 300 products or more. So our process is slow and our process is … We set the bar relatively high, just like you said. Unless there’s good science, we’re not going to chase these products and we’re constantly looking at our products to reformulate as the science evolves.

Lorne Brown 

I got some rapid-fire questions here that some we’ve answered. We’ll go through them again and get some yes and nos. But I had one other thing. We’re not done here, by the way, everybody. So the other ingredient, because there’s other NAD supplementation, supplements, and again, they’re not NAD, by the way, everybody. Again, like Dr. Mark Ranner said, they’re precursors because you can’t get NAD outside the body. But you did add another pterostilbene. Is that how you say it?

Mark Ratner 

Paracstilbine is an analog of resveratrol. And the reason we added that is because we want to both increase NAD levels and sirtuin one level. The sirtuins play a really crucial role in ovarian reserve, and this is a significant issue. As more and more women have delayed starting a family, whether it’s for professional reasons or whatever, the whole egg freezing world has taken off. Many, many women come in and they have consultations about egg freezing. But interestingly, only 20% of women, this is a survey that was done and looked at women across the United States. Only about 20% of women who go through a consultation actually then follow through and do the actual egg freezing. So there’s a lot more women out there that are concerned about preserving their fertility than actually are ending up doing egg freezing. And so the point is that if there are steps that can be taken to help slow the loss of ovarian reserve, then we think that’s a great backup strategy for those women who are concerned about future fertility.

And so that’s why we added the pterostilbene. By the way, pterostilbene, it’s PTERO, pterostilbene. The stillbeans are a class of polyphenols that are found in peanuts and blueberries. They’re found in certain plant foods and grapes. And the most well-known of the stillbeans is resveratrol, which is something that was first isolated from grape skins. And it’s been the source of a ton of research that’s been studied extensively. The problem with resveratrol as a supplement is that it is poorly absorbed. It’s got very low bioavailability. Why are we interested in resveratrol? Because it seems to improve sirtuin levels. It increases sirtuin levels, especially sirtuin one. Remember there’s seven sirtuins and sirtuin one is the sirtuin that’s intimately involved in ovarian aging. How does that work? So I think everybody’s familiar, at least people who are focused on fertility are familiar with the fact that women are born with all of their eggs that they’re ever going to be able to make already in their ovaries.

And at birth, it’s been estimated to be between one and a half and two million eggs. Now, as soon as the baby’s born, those eggs start to degenerate. I’m sorry. And they’re not really eggs at that point. They’re what we call follicles, primordial follicles. And then once a woman goes through puberty and starts to have monthly cycles, what happens is each month, about a thousand of those resting primordial follicles, these are sort of hibernating follicles. About a thousand of those get recruited each month and become what we call primary follicles. And then over the course of the following year, those follicles gradually develop and they develop under the influence of hormones, FSH and LH, which are familiar hormones to anybody in the fertility world until gradually at the end of that one year, you’re left with one follicle that spits out an egg. So you go from a thousand primordial follicles that are recruited to become primary follicles, and then those primary follicles gradually over the course of the year, they mature, but you lose 99.99% of them until you end up with just that one.

And so what happens

Lorne Brown 

And just except if you do an IVF, they’ll rescue in a sense several of those follicles versus one because you’ll have a group in that last bit. And we always talk about the hundred days before ovulation or IVF retrieval, because you talked about that one year, but it seems like those last hundred days, 120 days seem to be the most impactful of the environment in that the follicle is maturing and containing that oversight.

Mark Ratner 

No, that’s exactly right. And so what happens is in that one-year process, towards the last two or three months, you end up with what we call pre-antral follicles and then antral follicles as they’re getting larger and larger. And when they do IVF, under normal circumstances, non- IVF, only one follicle becomes what we call the dominant follicle, and it makes one egg a month. But when they do IVF, by giving all of these extra hormone injections, they rescue, as you said, all of the preantral and antral follicles so that instead of just making one egg that month, you might make 15 or 20 because all of those antral follicles are pushed to mature and become full dominant follicles. Anyway, the point here is that the process by which primordial follicles get recruited each month to become primary follicles is controlled by SIRT1, SIRT2 and one.

Lorne Brown 

And if we can- So theoretically, can we pull out … You know how we prime to get more follicles in an IVF stim? Not that we make more eggs, but pull more out of that pool because of this-

Mark Ratner 

That’s exactly what the goal of sirtuin-1 is. And when they do this in mice and they elevate sirtuin levels in mice, they end up with doubling the number of follicles and antral follicles and eggs that get retrieved.

Lorne Brown 

Has this resveratrol cousin, the pterostilbene shown to do that as well in the mite studies?

Mark Ratner 

Well, it raises SIRT1.

Lorne Brown 

Okay. And by doing that, you get more out in the pool.

Mark Ratner 

Exactly. So the point is that you’re looking for a synergistic benefit here between NAD levels going up and SIRT-1 levels going up. And you have both a short-term benefit in that the chromosomal separation is done in a better way and you end up with a healthier egg that’s got the right number of chromosomes. So that’s a short-term benefit. And that really only takes maybe six or eight weeks of NAD boosting prior to the egg retrieval or conception to improve that egg’s quality. But if you want the long-term benefit, it’s potentially possible to start slowing down the loss of those follicles and keeping more in reserve by using supplementation that’ll improve NAD and SIRT-1 levels chronically. So that’s the goal.

Lorne Brown 

So in the literature, patients, we hear it, we’ve looked into it, resveratrol in general. So first of all, as you mentioned, pterostilbene, it’s a cousin of resveratrol, but my understanding, first of all, is stronger, as in it’s more bioavailable, which is why you want this and seems to stay a little bit active longer. So you’re going to get more benefit compared to resveratrol. People talk about resveratrol and it could interfere with implantation. Have you seen anything in the literature on that? A lot of times, because it’s out there, people have discussed it, that we just tell people to take it, but they stop close to if they’re doing a frozen embryo transfer or they’re trying to conceive around ovulation, we would stop it. So you have a product that has that in there. Have you done any literature review on resveratrol and implantation? Because that is definitely-

Mark Ratner 

Actually, it’s a great question. There’s actually a paper that was published a year ago, looking at women who have a condition that’s called recurrent implantation failure. So this is something that’s seen in IVF practices and fertility practices where women who have good quality embryos, they’ve tested the embryos, they know that they’re chromosomally healthy, and yet every time they implant one of these good embryos, it fails to implant. So they call this recurrent implantation failure. So they studied a hundred women with recurrent implantation failure, and they actually biopsied their endometrium. And what they found was that, and they compared them to women who had normal implantation. And what they found was that women who had recurrent implantation failure had CERT-1 levels that were 40% lower.

And so if your CERT-1 levels are too low, it appears that it impairs what’s called decidualization. Now that’s a real tongue twister, but decidualization is basically the process by which the embryo and the endometrium, the lining of the uterus attach themselves. And so you potentially, by raising CERT-1 levels, can improve implantation rather than be happy to send you the article. It’s an interesting study. So it’s actually, I’m not sure whether there’s a difference between resveratrol and pterostilbene in terms of that benefit. You wouldn’t expect it because resveratrol, the difference between pterostilbene and resveratrol, it’s almost the same molecule. It’s just that the pterostilbene substitutes a couple of methyl groups for hydroxyl groups on resveratrol, which makes it easier to absorb and less readily broken down by the body. So it’s more bioavailable. It’s basically doing the same thing as resveratrol

Lorne Brown

Though. As we’re chatting, I’m going to do a little search, and if anything comes up, I’ll ask you about it. But basically from what you’ve come across, it’s the opposite. You’re not seeing it as an interference with implantation. You’re actually saying that if SIRT1s are low, we see implantation failure and this product, this supplementation will increase it, which in theory should help with implantation.

Mark Ratner 

Yeah. I mean, here’s the thing, just improving NAD levels

Will increase the activation of SIRT1. But for SIRT1 activity to be optimized, to be increased, you need to do two things. First, you need the transcription. SIRT1, it’s an enzyme, it’s a protein. How do proteins get made through DNA transcription? So you want to increase the transcription of DNA to lead to more SIRT1 being produced, and then you need the NAD to activate the SIRT1. And so the pterostilbene is there to help improve transcription and what we would say expression of SIRT1, how much SIRT1 the cell is expressing, and then the NAD is there to help activate it.

Lorne Brown 

All right. In real time, everybody, where’s I got? Reservertrol appears to have anti-decidualization effects on the uterine line in endometrium. It can inhibit the transformation of endometrial stromal cells into the decidua and specialized uterine tissue that support embryo implantation. That was in a nature article. A clinical study of embryo transfer cycles in vitro IVF found that women who took 200 milligrams per day of resveratrol continuously had lower clinical pregnancy rates and higher miscarriage rates compared with controls. That’s in a pubmed. Because decidualization and endometrial receptivity are critical for embryo implantation, the anti-dissiguation effect of resveratrol is a strong biological concern even if it improves ag quality. So that’s what I’ve seen. So the consensus research, if used before ovulation stimulation to increase egg quality, especially if there’s diminished ovarian reserve or even PCOS, it’s probably wise to start resveratrol at least before embryotransfer ovulation and avoid it during the luteal phase.

Mark Ratner 

All right. So more real-time research is being done here. So this is a paper that was published in biological reproduction 2022 out of, I believe this is China. Actually, no, Michigan State University. And basically, here’s what it says. SIRT1 plays an important role in implantation and decidualization during mice in early pregnancy. That was the mouse study, but let me see if I could find the other one, which is the human study. Yeah. I mean, the human study, which I’m happy to share with you, basically showed exactly the opposite that women with recurrent implantation failure had SIRT1 levels that were significantly lower. And when was that published? Here, SIRT1 levels in recurrent implantation failure. Yeah. So this was in the European Journal several years back. All

Lorne Brown 

Right. And I just emailed you the 2019 study for the other one.

Mark Ratner

Yeah.

Lorne Brown 

I may get you to send me more information. Maybe we’ll add it before we put it out. Just let’s look at some of the research out there so we can let people know. For now, still in our clinic, we’re telling people for your OVANAD, which we like and recommend now as well, because you’re on the podcast, I think your company’s given us a discount to give to our patients as well. So we’ll put that in the show notes so you guys can order directly from Theralogix and save some money. But we’re still telling patients, take it up to ovulation or close to ovulation and then stop until … But that may change based on our discussion, Mark, that we may do post this, post-recording. And also we tell them not to do it the days before or after the transfer. So at this stage, when we’re working on egg quality, we want them to take it while we’re working on AG quality.

I got some rapid fire questions and some of these you can say we’ve covered it because I think we have covered everything. So this is what I wanted to talk to you about, and I think we’ve covered most of it. Let’s see if I missed anything. How does NAD decline impact mitochondrial function inside the OCYT, the egg, and what downstream effects does that have on egg quality ovarian reserve? You nailed that. You did that at the beginning.

Mark Ratner

Okay.

Lorne Brown 

Precursors, compare NAM versus NR versus NMN, and yours has the NR in it. From a biochemical standpoint, how do NAM, NR, and NNM differ from once inside the cell? And why does NR bypass rate limiting steps that NAM based products depend on? You discussed that too, right? There you go. You talked about NR and NM, both being those precursors. NAM takes a little bit more work and it becomes rate limiting. So you had no recycling concern with NR or NMN as your precursors. Some argue that precursors hit a wall because the recycling pathways become saturated and you said that isn’t supported by the literature. And one of the questions I had, what do human studies say now? And I think you’ve cleared that up as well with the other question we had, but is there anything to add to that that I missed? The rate limiting steps.

That’s the big thing out there now. There’s some saying there’s recycling issues. Pathways get gunked up, and I think you said there’s no real literature science on that when it comes to NR or NMN.

Mark Ratner 

Yeah. So basically there’s three different ways that the cells can make NAD. It can start with nicotinic acid, which is the vitamin form that niacin, which is actually, that’s the one that causes facial flushing. And it can actually start even before that with tryptophan. Then there’s another way of making it, which is called the price handler pathway. And the third way is the salvage pathway, which is by far the most important. The salvage pathway is a way … Remember we said that when NAD+ activates any of those enzymes, PARP enzymes, sirtuins, CD38, and others, whenever it activates one of those enzymes, the NAD+ gets broken down. And so the salvage pathway takes those breakdown products and reconstitutes them into NAD. And that’s by far the most important way of keeping NAD levels high in our cells. So what you’re doing when you use a precursor is you’re basically feeding the salvage pathway with more raw material.

And the rate limiting steps are potentially tissue-based. Like I said, it may be that either one of those precursors is better in the ovary than the other. We still don’t know. So it’s not only getting into the tissues by the transport proteins that have to bring them into the cells, the precursors, but it’s also those enzymes that then do the conversion. And although we pretty much know that the only one that’s generally rate limiting is the one that converts NAM into NMN, the enzymes that convert NR into NMN, not rate limited. The ones that convert NMN into NAD, not rate limited, not a problem with either of those.

Lorne Brown 

And can we revisit the IVNAD injections? Because that’s another popular thing. I know it’s quite expensive and time-consuming. You have to sit sometimes for four hours to receive one of those. Some people find them uncomfortable as well. Can it have any benefit? And because you’re bypassing the gut, as you talked about, there’s a lot of breakdown going right into the blood, but because it’s a large molecule, is there benefit to it? Because some people claim there’s a benefit. I just don’t know if there’s research about the benefits.

Mark Ratner 

Yeah. So you’re getting blood levels of NAD by doing an infusion, but the question is, are you getting intracellular NAD? Is the NAD that you get by infusion getting into the cells? It may not, because there’s a lot of evidence to show that because it’s a large hydrophilic molecule, it has trouble getting across cell membranes. There’s no specific transporter protein to bring actual NAD from an extracellular to an intracellular location. So what does that mean? What’s the implication there? From a purely theoretical perspective, CD38 is extracellular. It’s on the outside of the cell membrane. So it’s quite possible that some of the benefits of NAD just being in the blood level being up could be realized because some of the benefits, you don’t necessarily need the NAD to be intracellular, but the energy benefits in order to improve mitochondrial energy production and ATP production, you clearly need the NAD to be intracellular.

And if it has trouble getting intracellular as NAD as opposed to being a precursor, which can be transported into the cells easily, then there are theoretical reasons why NAD infusions might have some benefits, but not the ones that people are looking for in terms of energy production.

Lorne Brown 

Okay. Thank you. And then since inflammation, I call this noise, since inflammation can accelerate NAD consumption, do you have lifestyles or clinical interventions you believe would help reduce that metabolic noise so the NAD support like the Ova NAD that you offer at Their Logics can work optimally?

Mark Ratner 

Do I have lifestyle interventions? I mean, generally speaking, the things that are considered to be heart healthy and metabolically healthy are going to reduce inflammation. And so keeping your insulin levels down, more and more people are using continuous glucose monitors to monitor their metabolic health, the kinds of things that-

Lorne Brown 

The typical pillars then, we always go on a diet, anti-inflammatory, low glycemic index. No

Mark Ratner

Question.

Lorne Brown 

Shout out for that, by the way, free Acubalance diet with 21 days of recipes you guys can download for the Acubalance website, movement, sleep, stress reduction, Sure. Stray away from unnecessary chemicals. That’s the pillars of life, right?

Mark Ratner

Absolutely. Yeah. Peter Attia, plenty of people writing about this stuff. 

Lorne Brown 

I got this book on my shelf over there.

Mark Ratner 

Yeah, it’s a good book. It’s a good book.

Lorne Brown 

And then any ideal candidates for this NAD support that would want to focus on foundational changes for this? Is it anybody? From

Mark Ratner 

Fertility, you were saying from a fertility perspective, we’re generally speaking. I mean, look, all of the buzz and the reason why there are dozens and dozens of NAD boosters being sold on Amazon and elsewhere really started with lifespan, with the concept that somehow this is going to extend lifespan. And the data just doesn’t really support that at this point. I mean, not in people. If you’re a fruit fly or a roundworm, yes, increasing your NAD levels will have you live longer, but it just hasn’t been shown in vertebrates, not even in mice. However, there’s a concept of health span. And I think there’s an accumulating body of evidence that improving your NAD and ascension levels can improve health span, meaning you’re going to stay healthier longer.That’s, I think, if not as sexy as lifespan, it’s certainly as important.

Lorne Brown 

I always enjoy meeting with you and talking with you. And there’s a lot of information out there and we want to offer what we think will help our patients the best at Acubalance. And for my listeners, I want them to get educated so they can go talk to their healthcare provider. And I like that you’re there and you got the science behind your supplements. In our clinic, we’re always doing things from the Chinese proverb, Mike, it nourishes the soul before you plant the seed. We’re looking at this environment. You were talking about the one-year, 100 days. We’re looking for that environment to support myosis, to support mitochondrial health. And so we just mentioned the pillars, everybody. There’s a diet. Download that diet for free from our website. There’s movement and sleep and stress reduction. We use low-level laser therapy in our practice to help with blood flow and regulate inflammation, and it’s been shown to help mitochondrial function, acupuncture for blood flow, stress reduction, and herb supplements.

And just to share, this is the supplement now that we’ve added also as one of the recommendations. We do CoQ10 and there’s fish oil. You have a really good inositol d-chiro product, which is great for the metabolic risk factors and issues. And I’m so happy that you’ve created this NAD product because there’s lots out there. And as I started this sentence, run on sentence, Theralogix puts the science behind it. And that’s why I wanted to have this conversation. And once I saw that you put out the product, we started having this conversation. I wanted to bring it to the public. Is there anything you want to share? Otherwise, I want to just summarize a little bit of what we talked about today.

Mark Ratner

No, I think this has been great. We covered the whole gamut of topics here. It’s a fascinating area. It’s one that … Listen, at this point, there are studies ongoing in China, in Australia, and there’s a couple of them gearing up here in the States looking at specifically different precursors in fertility outcomes. And so I think over the next several years, we’re going to have more and more certainty about what the best approach is. But those studies are … They’re hard to do. They’re tough to do, especially in fertility patients because nobody wants to get placebo. So I just think that it’s an exciting area, and it’s certainly one that is going to be evolving in the next several years.

Lorne Brown 

Perfect. So everybody, today’s conversation, hopefully with Dr. Mark Ratner, helped clarify several key points about NAD biology and how it relates to ag quality ovarian reserve, and just basically overall reproductive aging. First, NAD isn’t a wellness fad. It’s a central molecule for mitochondrial function, DNA repair, and the enzymes that protect cellular longevity, including the oocytes, the AG. Second, how you raise NAD matters. So we’ve explored why NR, nicotinamide, riboside, NR is a highly efficient precursor and why claims about precursor overload aren’t backed by human studies and why suppressant enzymes like CD38 may carry unintended consequences. Thirdly, supplements work best because they’re supplements. They’re there to supplement work best when the foundations are strong. And so my clinic at Acubalance, before we layer in anything advanced, we always start with just lowering systemic inflammation, reducing that internal noise. So anti-inflammatory eating, check out the diet, movement, exercise, restorative sleep, and stress reduction.

We also provide acupuncture, low level laser therapy, herbal medicine, and targeted nutritional support, including the Ova NAD by Atherologics. So once these pillars are in place, NAD support can be a meaningful tool for improving mitochondrial health and optimizing ag quality. And obviously, if you haven’t put those tools into place, you really want those supplements to counter as much of the negative lifestyle as you can. So in today’s episode, or I should say, if today’s episode brought up questions about how NAD fits into your fertility plan, you can reach out to us at AccuBalance or message me on Instagram at Lorne Brownofficial or at our AccuBalance Instagram channel or our podcast channel. Mark, I want to thank you again for bringing clarity to this complex topic. I really do. And thanks to all of our listeners for tuning in. And remember, your biology is adaptable and when you create the right environment, the body often responds in remarkable ways.

So thank you, Mark

Mark Ratner 

My pleasure, Lorne. Thank you for having me.

Lorne Brown 

I want to let you know that this is several weeks after I recorded this episode with Dr. Mark Ratner on NAD. And what we’ve done is we recorded another episode just on resveratrol because in this episode on NAD, we had that discussion about, is it safe or not based on the papers that are out there to take resveratrol after ovulation or leading up to a transfer, like a frozen embryo transfer or even a fresh transfer. So he sent me several papers that I got to review and I brought him back and we recorded a whole other episode on resveratrol, on the research, whether it can be used not just for egg quality, but for implantation failure and leading up to a transfer or post-ovulation. And he went through all the research right up to the most recent paper at the time of our recording of the 2025 paper.

We recorded it in early 2026, but the last research he could find was in 2025. So inviting you to go look for that next episode with Dr. Mark Ratner, where we talk about resveratrol on our podcast.