Alpha-Ketoglutarate for Longevity: Mechanisms, Human Data, and Vitamin Synergy

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• Alpha-Ketoglutarate Mechanisms in Aging
• Human Clinical Trial Data on Aging
• Personalized Aging Interventions
• Vitamin A and D Rationale
• Combination Supplementation Risks
• Vitamin Level Optimization
• Full Transcript

Alpha-Ketoglutarate Mechanisms in Aging

Alpha-ketoglutarate is a crucial metabolite that declines with age. Dr. Brian Kennedy, MD, explains that this decline reduces the metabolic flexibility of cells. The challenge in understanding AKG's anti-aging effects lies in its participation in over 500 enzymatic reactions within the cell.

Dr. Kennedy's research indicates that alpha-ketoglutarate improves adult stem cell function. It targets specific tissues like the liver, kidney, and red blood cells. One key mechanism appears to be the enhancement of glutathione production in red blood cells, which helps combat reactive oxygen damage. Dr. Kennedy and Dr. Anton Titov, MD, also discuss potential microbiome effects and other metabolic impacts currently under investigation.

Human Clinical Trial Data on Aging

Recent human data on alpha-ketoglutarate supplementation shows promising results. Dr. Brian Kennedy, MD, published a clinical study showing a product containing AKG plus low-dose vitamins reversed biological age by approximately seven years using methylation clocks. This initial study involved people purchasing the product directly rather than a placebo-controlled trial.

Dr. Kennedy discloses his affiliation with the company behind this product. A more rigorous, placebo-controlled clinical trial conducted in Indiana is currently being analyzed. This trial may provide additional validation through multiple aging clocks. Dr. Anton Titov, MD, explores these findings as part of the broader conversation on aging biomarkers.

Personalized Aging Interventions

The future of anti-aging interventions lies in personalization. Dr. Brian Kennedy, MD, emphasizes that not all interventions work for everyone. The goal is to understand which specific interventions work for which individuals, moving beyond a one-size-fits-all approach to aging.

This personalized approach requires understanding why some people respond to certain interventions while others do not. Dr. Kennedy's research focuses on identifying these response patterns. The conversation between Dr. Kennedy and Dr. Anton Titov, MD, highlights the need for targeted aging interventions based on individual biological profiles.

Vitamin A and D Rationale

The combination of alpha-ketoglutarate with specific vitamins follows careful research. Dr. Brian Kennedy, MD, explains that animal studies showed low-dose vitamin A benefits male mice but not females. Vitamin D appears beneficial for both sexes, though the research specifically paired AKG with vitamin A for men and vitamin D for women.

These gender-specific combinations emerged from studies examining both lifespan and frailty metrics. Dr. Brian Kennedy, MD, notes the complexity of these interactions, which researchers are still working to fully understand. Dr. Anton Titov, MD, explores this rationale during their discussion on optimized supplementation protocols.

Combination Supplementation Risks

Combining multiple longevity supplements carries significant risks. Dr. Brian Kennedy, MD, cautions against products containing numerous different longevity molecules. His laboratory research shows that combining even two or three interventions produces unpredictable outcomes that cannot be easily forecast.

Dr. Kennedy advises early adopters to select only one or two carefully chosen interventions rather than taking everything available. This cautious approach helps avoid potential negative interactions between compounds. Dr. Anton Titov, MD, discusses these risks as part of the broader safety conversation around anti-aging supplementation.

Vitamin Level Optimization

Optimal vitamin supplementation requires knowing your actual levels. Dr. Brian Kennedy, MD, emphasizes that widespread vitamin use should be based on individual needs rather than assumptions. The goal should be achieving high normal range levels through targeted supplementation.

Taking excessive vitamins can be as harmful as deficiency, particularly with fat-soluble vitamins like vitamin A. Dr. Kennedy recommends testing vitamin D levels before beginning supplementation. This personalized approach ensures people only supplement what they actually need, as discussed with Dr. Anton Titov, MD, during their conversation on responsible longevity practices.

Full Transcript

Dr. Anton Titov, MD: 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.

Dr. Brian Kennedy, MD: These natural products, like NAD precursors that are talked about a lot in the aging field and alpha-ketoglutarate, tend to go down with age. They're important metabolites, and so they reduce 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. 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.

We've been struggling with that. We can show that it improves adult stem cell function. They hit these hallmarks and pillars of aging, like a lot of other interventions do. But what we really want to know is what's the direct activity of AKG.

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, and red blood cells, which take it up, and that's it.

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; it's probably not just one thing that's relevant to aging. But we're still sorting among the possibilities.

There are interesting microbiome effects of AKG as well.

We do have human data. We published a clinical study a few months ago showing that a product made by PDL Health, which contains 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.

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. It looks like we might get signals for other aging clocks as well, and that trial is placebo-controlled.

So we're encouraged. 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 interventions work for which individuals.

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.

Dr. Anton Titov, MD: 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?

Dr. Brian Kennedy, MD: 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 is very beneficial for the male mice but not the females, in ways we're still trying to figure out.

Vitamin D is probably beneficial for both. 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 to 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 that are your favorites and doing that, and not just picking everything because I don't want you to hit that point.

Also, with the vitamins, these vitamins are in such widespread use. I think the optimal approach 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 start taking things, and only take the things that you need to be supplementing.