You published specifically that alpha-ketoglutarate extends lifespan and compresses morbidity in aging mice. How does alpha-ketoglutarate work to extend lifespan? And is there efficacy data in humans? This is the question that's keeping me awake at night, how alpha-ketoglutarate works. 

I mean, these natural products, like in NAD precursors that are talked about a lot in the aging field and alpha-ketoglutarate. They tend to go down with age, they're important metabolites. And so they reduce the sort of the metabolic flexibility of the cell with age. The problem with trying to understand what they're doing is they participate, like AKG, in over 500 enzymatic reactions in the cell.  Dr. Brian Kennedy. Dr. Anton Titov, MD. And so if you want to figure out what the proximal effects are that are linked to aging, you've got a challenge on your hands. And we've been struggling with that. We can show that it improves adult stem cell function. They hit these hallmarks, and pillars of aging and like a lot of other interventions do. But what we really want to know is what's the direct activity of AKG.  Dr. Brian Kennedy. Dr. Anton Titov, MD. 

And so we're trying to sort through that now, there are a few clues. Alpha-ketoglutarate doesn't easily get taken up by itself. So there are certain tissues like liver and kidney, which is red blood cells, which take it out. And that's it. And that gives us a target area to look at. So we think that one of the things AKG does is it improves glutathione production in red blood cells. This is important because they're carrying a lot of oxygen around and there's a lot of reactive oxygen damage in those cells. But we're also looking at different metabolic effects in the kidney and other things right now. So I don't really have the full answer is probably not just one thing that's relevant to aging. But we're still sorting among the possibilities. There interesting microbiome effects of AKG as well.  Dr. Brian Kennedy. Dr. Anton Titov, MD. 

We do have human data. We published a study clinical study a few months ago showing that which is a product made by PDL Health, that contains the Alpha-ketoglutarate Plus low dose vitamin A for men and low dose vitamin D for women, reverses biologic age by about seven years using one of these methylation clocks.  Dr. Brian Kennedy. Dr. Anton Titov, MD. Now, first of all, I'm affiliated with that company. So full disclosure. Second of all, we didn't have a placebo control, those are just people buying the product. So I don't think it's the final validation that it works in humans, but it's very encouraging. And now we have a clinical study performed in the state of Indiana, that we're analyzing the data from. And it looks like we might get signals for other aging clocks as well. And that trial is placebo-controled. 

So we're encouraged. And I think that we need to take these interventions that may affect aging and test more of them in the context of these biomarkers to see which ones work the best. But more specifically to find which individuals which interventions work.  Dr. Brian Kennedy. Dr. Anton Titov, MD. And I think that it's going to be a personalized approach to understand aging, not just give one thing to everybody. And we need to understand why some people respond to some interventions, and some people don't. 

You mentioned the Alpha Ketoglutarate with different vitamins for men and for women. What is the rationale for that? Vitamin D is apparently good for everybody? Yeah, I think you're probably right on that. We were doing animal studies looking at not just aging, lifespan, and frailty. And we found that vitamin A in low doses very beneficial for the male mice, but not the females in ways we were still trying to figure that one out.  Dr. Brian Kennedy. Dr. Anton Titov, MD. Vitamin D is probably beneficial for both so but the thing is that we also found that when you start combining multiple interventions, you get unpredictable outcomes. And so this is something I would caution people about. There are now products out there that have 14 different longevity molecules. You can buy them separately and take them yourself. 

When I do mouse aging studies, once I get even at two and certainly three molecules, I can't predict the outcome of combining interventions. That's something we're very focused on in the lab right now. So if people want to be early adopters, I would suggest picking one or two things you're that are your favorites and doing that. And not just picking everything because I don't want you to hit that point.  Dr. Brian Kennedy. Dr. Anton Titov, MD. Also, with the vitamins, these vitamins are in such widespread use, I think the optimal approach to that really is to know the levels of your vitamins and micronutrients in your body and try to optimize those to a recommended amount, which would be at the high normal range. If you're taking too much vitamin, it can be just as bad as too little, particularly something like vitamin A. And so a lot of people go buy vitamins and just take them on faith. But really, it is better if you knew what your vitamin D levels really are, before you go start taking things and only take the things that you need to be supplementing.