GLP-1 Longevity Registry • West Coast Tour • NMN, NAD & Cardiovascular Health
Your sneak peek into the world of Longevity Docs.
Hey Docs,
A few weeks ago, I embarked on a West Coast journey that reshaped my perspective on longevity medicine. Beginning in Novato at the Longevity Clinics Roundtable Conference and culminating in the high-energy halls of A4M in Las Vegas, I traveled through San Francisco, Montecito, Los Angeles, and San Diego, before driving to Vegas (I loved it), and eventually ending up in New York. Along the way, I met so many incredible Longevity Docs—each one with a unique story, a shared passion, and honest reflections about the challenges they face.
What I learned on this trip was humbling and inspiring:
Longevity doctors often feel isolated in their practices. They want to connect with peers who truly understand their challenges and ambitions.
Education is their top priority. There’s a strong need for specialized certifications that reflect the fast-paced evolution of longevity science.
They respect the traditional system but see room for change. They want a model that fosters innovation and is more aligned with the realities of modern practice.
Growing a practice is hard. Beyond clinical skills, doctors are navigating business, leadership, and marketing. All areas they weren’t taught in medical school.
Independence is key. They want to build practices that allow them to serve patients on their own terms, but they need support to do it successfully.
Hearing these stories reminded me why this community matters so much. It’s not just about the science, it’s about creating a space where doctors can thrive together, share knowledge, and build practices that truly reflect their purpose.
To every doctor I met along the way: thank you. Your honesty and passion drive this movement. Together, we can bridge the gaps, foster innovation, and ensure that no doctor in this field ever feels alone.
Soon, I’ll be in London, Munich, and Zurich to meet more doctors, learn from their experiences, and continue building this incredible community.
Let’s grow and learn from one another. There’s so much more we can achieve—together.
Happy Sunday!
Dr. David Luu
This Week’s Highlights
Weekly Pulse
🧬 Longevity Docs Institute
Longevity Docs Launches Its First Research Project: GLP-1 Longevity Registry
The Longevity Docs Institute proudly unveils its inaugural research initiative: the GLP-1 Longevity Registry. This ambitious multicenter study aims to explore the transformative potential of GLP-1 agonists in longevity medicine.
With 30 leading Longevity Docs collaborating across multiple sites, the registry will collect real-world data on how GLP-1 therapies influence critical longevity biomarkers such as biological age, metabolic health, inflammation, and cellular senescence.
By combining cutting-edge diagnostics, patient-reported outcomes, and longitudinal analysis, the GLP-1 Longevity Registry seeks to establish a robust evidence base for integrating GLP-1 agonists into healthspan optimization strategies. This groundbreaking initiative represents a significant step forward in advancing longevity-focused clinical research.
Key objectives include:
Assessing longevity biomarkers like epigenetic clocks, inflammatory markers, and cellular senescence indicators.
Evaluating patient-reported outcomes to understand the broader impact on healthspan and quality of life.
Monitoring side effects and complications, including gastrointestinal symptoms, hypoglycemia, injection site reactions, and rare adverse events like pancreatitis or thyroid tumors.
Building a robust dataset to advance research in aging science and longevity medicine.
The study incorporates cutting-edge tools like epigenetic clocks, DEXA scans for body composition, imaging for visceral fat volume, and real-time data integration from wearable devices. By exploring the links between GLP-1 agonists and pathways related to aging, the registry aims to provide new insights into their role in optimizing healthspan and longevity.
💬 Buzz in the Chat
A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk (Nature Medicine). Do you believe that NMN/NR can increase 2PY and 4PY via MeNAM therefore increase vascular inflammation.
I do not use Niacin mainly because there is no positive outcome data. This may explain the mechanism behind lack of efficacy despite lowering LDL and Lp(a)
Agreed. I stopped Rx’ing Niacin (usually in form of FDA approved Niaspan) after AIM-HIGH. After HPS2-THRIVE I helped already established niacin patients get off niacin and move towards more supportable approaches.
Nice summary. A few caveats.. at the start you talk about 1 methylnicotinamide which is 1MNA being one of the bad metabolites. It is not. It's conversion to 4 pyridone is. 1MNA actually has many of the same properties as nad. When given exogenously(tested up to 6 grams )- 4 pyridone levels stabilize at a low level and the rest of it is eliminated in urine. If keep giving niacinamide or nr or nmn, the 4 pyr keeps going up.
So yes blocking nnmt with 1 mna is helpful, if keep pounding the system with nad, it will still overwhelm. Use these intermittently and judiciously along with 1mna and apigenin to block cd38.
Also remember that there is a very interesting connection between p53 and nad. Nad modulate p53 positively...if too much it binds and reduces it which we do not want .
We just don't know the sweet spot! So I like nad precursors on and off after stress periods but use 1mna and apigenin to auto regulate levels . Let the cell do it
Here is the summary:
NAD+/NR/NMN Impact on CVD Prevention or Vascular Inflammation
Introduction
NAD+ (Nicotinamide Adenine Dinucleotide) is a critical coenzyme involved in energy metabolism, DNA repair, and cellular function. Supplementing NAD+ precursors like Nicotinamide Riboside (NR) and Nicotinamide Mononucleotide (NMN) is widely explored for their potential in cardiovascular disease (CVD) prevention and overall vascular health. However, recent evidence highlights the complex relationship between NAD+ turnover, downstream metabolites, and vascular inflammation. While NAD+ plays a beneficial role, excessive turnover can lead to unintended effects, raising concerns about its impact on CVD.
1. The Positive Role of NAD+ in Cardiovascular Health
Supplementation with NR and NMN can improve cardiovascular health through:
Improved Mitochondrial Function:
NAD+ is essential for mitochondrial energy production via the electron transport chain.
Sufficient NAD+ levels support ATP generation, reduce mitochondrial dysfunction, and enhance cardiomyocyte energy supply, which is critical for cardiac health.
Sirtuin Activation:
NAD+ activates sirtuins (SIRT1–7), a family of NAD+-dependent deacetylases that regulate inflammation, oxidative stress, and metabolism.
SIRT1 protects against endothelial dysfunction by reducing oxidative stress and inflammation while promoting nitric oxide (NO) production for vascular dilation.
PARP Regulation:
Poly(ADP-ribose) polymerase (PARP) consumes NAD+ during DNA repair in response to oxidative stress. Adequate NAD+ levels help regulate PARP activity, minimizing endothelial injury.
Conclusion: By improving mitochondrial function, activating sirtuins, and regulating oxidative stress, NR and NMN can positively influence endothelial health, inflammation, and cardiovascular outcomes.
2. Risks of Excess NAD+ Turnover and Its Impact on Vascular Inflammation
While NAD+ supplementation has potential benefits, excessive NAD+ turnover can result in the accumulation of harmful byproducts like N1-methyl-nicotinamide (MeNAM) and its oxidized metabolites:
N1-methyl-2-pyridone-5-carboxamide (2PY)
N1-methyl-4-pyridone-3-carboxamide (4PY)
Mechanism of Harmful Metabolite Accumulation
Excessive NAD+ Breakdown:
NR and NMN elevate NAD+ levels, but excessive breakdown (via sirtuins, PARPs, or CD38) generates high levels of nicotinamide (NAM).
NNMT (Nicotinamide N-Methyltransferase) methylates NAM to MeNAM, consuming methyl donors like SAMe (S-adenosylmethionine).
2PY and 4PY Formation:
MeNAM is further oxidized into 2PY and 4PY, which are terminal metabolites excreted in the urine.
The recent study identified both metabolites as biomarkers of residual cardiovascular risk.
Impact on Vascular Inflammation
VCAM-1 Induction:
Elevated 4PY levels directly induce the expression of vascular cell adhesion molecule-1 (VCAM-1) in endothelial cells.
VCAM-1 promotes leukocyte adhesion to the endothelium, triggering vascular inflammation and contributing to atherogenesis.
Genetic Correlation:
A genetic variant (rs10496731) linked to higher levels of 2PY and 4PY also correlated with elevated soluble VCAM-1 (sVCAM-1), further validating the role of these metabolites in vascular inflammation.
Residual CVD Risk:
In large validation cohorts, higher levels of 2PY and 4PY were associated with a 1.6–2.0-fold increase in the risk of major adverse cardiovascular events (MACE), suggesting their role as contributors to residual CVD risk.
3. Balancing NAD+ Supplementation to Mitigate Risks
To achieve the cardiovascular benefits of NAD+ while avoiding excessive turnover, the following strategies are recommended:
Moderate NAD+ Precursor Supplementation:
Avoid excessive doses of NR or NMN (>500 mg/day) to prevent overwhelming the NAD+ salvage pathway and excessive NAM production.
Inhibit NNMT Activity:
NNMT inhibition can reduce methylation of NAM into MeNAM and subsequent 2PY/4PY production:
1-Methylnicotinamide (1MNA) acts as a feedback inhibitor of NNMT.
Natural NNMT inhibitors like quercetin and metformin may also help regulate this pathway.
Support Methylation Balance:
Supplement methyl donors such as B6, B9 (folate), B12, and betaine to maintain SAMe levels and prevent methylation depletion.
Manage Oxidative Stress:
Reduce NAD+ consumption via PARP activation by addressing oxidative stress with antioxidants like resveratrol, vitamin C, and glutathione.
Natural NAD+ Optimization:
Encourage NAD+ synthesis through caloric restriction, exercise, and circadian rhythm alignment, which improve NAD+ production without excessive turnover.
Conclusion
While NR and NMN supplementation can support cardiovascular health by improving mitochondrial function, sirtuin activation, and endothelial repair, excessive NAD+ turnover can generate harmful downstream metabolites (2PY and 4PY). These metabolites are associated with vascular inflammation (via VCAM-1 expression) and increased residual CVD risk.
To maximize the cardiovascular benefits of NAD+ precursors and avoid risks:
Supplement with NR/NMN in moderate doses.
Inhibit NNMT activity using compounds like 1MNA and support methylation pathways with B vitamins.
Prioritize natural NAD+ optimization through lifestyle interventions like exercise and caloric restriction.
Further clinical trials are essential to confirm the long-term safety and efficacy of NR/NMN supplementation for CVD prevention.
🩺 Publications
Intermittent fasting triggers interorgan communication to suppress hair follicle regeneration
A randomized clinical trial (NCT05800730) indicates that intermittent fasting inhibits human hair growth. Our study uncovers an inhibitory effect of intermittent fasting on tissue regeneration and identifies interorgan communication that eliminates activated HFSCs and halts tissue regeneration during periods of unstable nutrient supply.
Cell - Recommended by Dr. David Lipman
Stem cells head to the clinic: treatments for cancer, diabetes and Parkinson’s disease could soon be here
More than 100 clinical trials put stem cells for regenerative medicine to the test. It’s a turning point for a field beset with ethical and political controversy.
Nature - Recommended by Dr. David Luu
Hyperglycemia and Metformin Use Are Associated With B Vitamin Deficiency and Cognitive Dysfunction in Older Adults
In this pooled analysis of cohort studies, the association between PA and mortality risk remained consistent across the adult lifespan, which contrasts with other modifiable health factors, for which associations with mortality risk diminished with age. Given these findings, the promotion of regular PA is essential at all stages of adult life.
The Journal of Clinical Endocrinology & Metabolism - Recommended by Dr. Tom Rifai
🌐 In the Media
ARPA-H launches new program aimed at extending the healthspan of Americans
US FDA warns online vendors selling unapproved weight-loss drugs
Scientists Unravel the Secrets of 37 Key Genes Linked to Reproductive Health and Longevity
Vitalist Bay: A new beacon for longevity innovation and collaboration
🗓️ Upcoming Events
Zurich: Jan 2025
Munich: Jan 2025
London: Jan 2025
Founders Longevity Forum - Singapore, February 27-28, 2025
Vitalist Bay - Berkely, CA, Apr 4 - May 29, 2025
The Longevity Med Summit - Lisbon, May 6-8, 2025
Life Summit - Berlin, May 27-28, 2025
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Newsletter Disclaimer:
The content shared in this newsletter, including the "Buzz in the Chat" section, is for educational purposes only. It is derived from peer-to-peer conversations among physicians within the Longevity Docs community and is intended to inform and engage our network of doctors.
Please note that these discussions do not reflect the official position of Longevity Docs and are not to be interpreted as medical advice or recommendations. The insights and opinions shared are those of individual physicians and are provided as part of our mission to foster collaborative learning and dialogue among healthcare professionals.
We encourage all readers to consult qualified healthcare professionals for personalized medical advice and to evaluate any medical information in the context of their clinical expertise and patient needs.
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