NMN Probably Won't Make You Live Forever
Niacin (vitamin B3) is essential for maintaining a healthy gut, skin, and mind. Its deficiency leads to early-stage depression and schizophrenia in later stages, alongside inflamed skin, especially when exposed to sunlight, and digestive issues from poor nutrient absorption. Niacin plays a vital role in the production of NAD+, a crucial coenzyme involved in energy metabolism. As we age or face certain diseases, the levels of NAD+ naturally decline. This decline is one of the key targets of popular longevity supplements like nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), which are widely believed to combat aging and potentially extend life expectancy. However, a recent study published in Nature Medicine raises significant questions about the safety and long-term effects of niacin and its derivatives, particularly with regard to cardiovascular health.
The Emerging Concerns: A New Study by Stanley Hazen’s Group
A new paper from Stanley Hazen’s group at the Cleveland Clinic suggests that a metabolite of niacin called 4PY might promote cardiovascular inflammation, potentially leading to early death. The paper’s authors propose that while niacin is beneficial for boosting NAD+ and its associated health benefits, its metabolism may also generate harmful compounds, such as 4PY, which contribute to vascular inflammation—a key factor in cardiovascular diseases. The paper presents evidence suggesting that individuals with high circulating levels of 2PY and 4PY have an increased risk of major cardiovascular events, including heart attacks and strokes. However, these findings are not entirely conclusive, as the study relied on observational data without establishing a direct cause-and-effect relationship.
Understanding Niacin Metabolism and Its Implications
Niacin, in its various forms, is metabolized into NAD+ (nicotinamide adenine dinucleotide) and NADPH, which are critical in cellular energy production. NAD+ plays a central role in numerous processes, including maintaining DNA integrity, supporting telomere length, and serving as a signaling molecule. However, niacin that exceeds the body’s need for NAD+ is further metabolized into byproducts like nicotinamide and, in some cases, methylated metabolites such as 2PY and 4PY. These byproducts, particularly 4PY, have been shown to increase vascular inflammation in animal models.
The liver, a primary organ in niacin metabolism, converts nicotinamide into various metabolites, including 2PY and 4PY. While 2PY is typically the dominant metabolite in humans, 4PY can accumulate in the blood when excessive amounts of niacin are ingested. In fact, high doses of nicotinamide riboside (NR) and NMN have been shown to significantly elevate circulating 4PY levels, which may be associated with cardiovascular inflammation. This raises concerns about the long-term use of NAD+ precursors, especially in high doses.
The Role of 4PY in Cardiovascular Inflammation
The Nature Medicine study specifically points to 4PY as the culprit in promoting vascular inflammation, which is a precursor to heart disease. It was found that elevated levels of 4PY led to increased expression of vascular cellular adhesion molecule-1 (VCAM-1), which facilitates the adhesion of white blood cells to the endothelial cells lining blood vessels. This process is a key component of inflammation and can eventually lead to the formation of plaques in the arteries, increasing the risk of cardiovascular events.
Interestingly, the study’s findings did not show a similar effect for 2PY, which suggests that the structural difference between 2PY and 4PY might explain their distinct biological effects. The presence of two closely positioned carbonyl groups in 4PY makes it more chemically reactive than 2PY, potentially contributing to its toxic effects. This structure is similar to methylglyoxal, a highly reactive compound known to cause cellular damage and contribute to the progression of diabetes. The authors of the study hypothesize that 4PY’s chemical properties may make it a key player in cardiovascular inflammation, although further research is needed to definitively confirm this.
Niacin, NR, and NMN: The Risks of Overuse
While niacin, NR, and NMN are commonly used to boost NAD+ levels and counteract aging-related declines in cellular function, the current research suggests that taking high doses of these supplements may not be as beneficial as once thought. The study indicates that supplements should be capped at a maximum of 250 milligrams per day to avoid unnecessary increases in 4PY levels. This dosage is considered safe for addressing specific health conditions or deficiencies, but using higher doses for general health maintenance or longevity purposes could potentially lead to adverse effects, including cardiovascular inflammation.
Supplementation with high doses of niacin has been historically linked to positive effects on lipid profiles and cardiovascular risk factors, particularly before the widespread use of statins. However, with the advent of statin therapy, the need for high-dose niacin in managing heart disease has diminished. Additionally, while high-dose niacin has been associated with a reduction in heart attacks and strokes in some studies, it has also been linked to an increased risk of developing diabetes, particularly in individuals with existing metabolic risk factors.
The new evidence surrounding 4PY emphasizes the need for caution when using NAD+-boosting supplements. The rise in 4PY levels caused by high doses of NR and NMN might offset the potential benefits of NAD+ supplementation by promoting vascular inflammation, thereby increasing the risk of cardiovascular events.
Conclusion: A Balanced Approach to Niacin and NAD+ Supplements
The findings of the Nature Medicine study underscore the importance of exercising caution with high doses of niacin, NR, and NMN, particularly for individuals without a clear deficiency or specific health condition. While these supplements may offer benefits in boosting NAD+ levels and promoting longevity, their overuse could have unintended consequences, including cardiovascular inflammation linked to elevated 4PY levels.
For individuals seeking to optimize their NAD+ levels, it is advisable to focus on meeting the recommended daily allowance (RDA) for niacin through diet and consider supplementing only when necessary to address deficiencies or specific health issues. Limiting niacin and its derivatives to a maximum of 250 milligrams per day, particularly for long-term use, is a prudent approach until further research clarifies the long-term safety and efficacy of these supplements. This balanced approach will help mitigate the risks associated with excessive 4PY accumulation while still allowing for the potential benefits of NAD+ optimization.
Update from Chris Masterjohn, on 2024-02-23Source