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  • The Impact of NMN, NAD+, and NR, on Longevity

    Nicotinamide adenine dinucleotide, or NAD+, is a crucial molecule found in every cell of our body. It’s like a spark plug that helps power various essential processes, such as fixing DNA damage, controlling gene activity, producing energy, and regulating calcium levels. NAD+ levels tend to increase when our energy levels are low, like during fasting, calorie restriction, or exercise.

    Let’s dive deeper into the role of NAD+ in our bodies, its decline with age and health issues, and the challenges of oral supplementation.

    Role of NAD+ in the body:
    NAD+ is a crucial molecule that acts as a cofactor and substrate for various cellular processes, including:

    1. DNA repair: NAD+ is essential for repairing damaged DNA, which helps maintain the stability of our genetic information.
    2. Epigenetic regulation: NAD+ plays a role in controlling the expression of genes by modifying their structure. This process is crucial for normal development and cellular function.
    3. Energy production: NAD+ is a key player in the process of oxidative phosphorylation, which generates ATP (the energy currency of our cells).
    4. Intracellular calcium signaling: NAD+ helps regulate calcium levels within our cells, which is important for cellular communication and function.
    5. Immune function: NAD+ is involved in the activation of immune cells, which helps our bodies fight off infections.

    Decline of NAD+ with age and health issues:
    As we age, our NAD+ levels tend to decrease, which can contribute to various age-related issues. Low NAD+ levels have been linked to:

    1. Aging: Reduced NAD+ levels may play a role in the aging process itself.
    2. Cellular senescence: Senescent cells, which are cells that have stopped dividing and are no longer functional, accumulate with age and contribute to tissue dysfunction. Low NAD+ levels may promote cellular senescence.
    3. Inflammation: Decreased NAD+ levels can lead to chronic inflammation, which is a major contributor to various age-related diseases.
    4. Metabolic dysfunction: Low NAD+ levels have been implicated in insulin resistance, type 2 diabetes, and other metabolic disorders.

    Challenges of oral NAD+ supplementation:
    Despite the potential benefits of boosting NAD+ levels, taking NAD+ orally is not a straightforward solution. This is because:

    1. Poor bioavailability: Oral NAD+ supplementation has poor bioavailability, meaning that only a small fraction of the ingested NAD+ is absorbed into the bloodstream.
    2. Gut metabolism: NAD+ is metabolized by enzymes in the gut, which further reduces its availability to the body.
    3. Inefficient conversion: When NAD+ is absorbed, it may be converted back to its inactive form, NAM, by the enzyme NADase.

    Alternative NAD+ precursors:
    Researchers are exploring alternative precursors of NAD+ that might be more effective in boosting NAD+ levels. These precursors include:

    1. Nicotinic acid (NA): NA is a direct precursor of NAD+ and has been shown to increase NAD+ levels in certain tissues.
    2. Nicotinamide riboside (NR): NR is a precursor of NAD+ that is more stable than NAD+ itself and has been shown to increase NAD+ levels in mice.
    3. Nicotinamide mononucleotide (NMN): NMN is another precursor of NAD+ that has been shown to increase NAD+ levels in mice and is currently being studied for its potential benefits in humans.
    4. Nicotinamide adenine dinucleotide ribose (NAR): NAR is a form of NAD+ that contains ribose instead of deoxyribose. It has been shown to increase NAD+ levels in certain tissues.

    These alternative precursors are being investigated for their potential to improve NAD+ levels and provide therapeutic benefits. However, more research is needed to understand their efficacy and safety in humans fully. Intravenous infusion of NAD+ remains the most effective way to boost NAD+ levels, but alternative precursors may offer a more convenient and effective option.

    The discovery of Sirtuins, a group of enzymes that depend on NAD and are linked to longevity, has opened up a new frontier in aging research. Recently, there has been a surge of interest in using the NAD/Sirtuin pathway to combat brain aging, and therapies based on this principle are expected to become available in the future.

    A breakthrough in this field is the identification of nicotinamide riboside (NR) as a vitamin precursor of NAD with excellent oral bioavailability in both mice and humans. Studies have shown that a single daily dose of NR (1000 mg) can increase blood NAD+ levels by 270% within seven days. Additionally, NMN, another NAD+ precursor, is metabolized into NR, which is then converted into NAD+ inside cells.

    In mice with metabolic impairments, NR supplementation has been linked to increased SIRT1 expression, reduced oxidative stress, and enhanced mitochondrial function. In a fly model of Parkinson’s disease, NR supplementation has been shown to reduce the loss of dopaminergic neurons and improve motor skills. Furthermore, NR supplementation has been found to reduce tau phosphorylation and enhance cognitive function in a mouse model of Alzheimer’s disease with DNA repair defects.

    Another study demonstrated that NMN supplementation promoted mitogenesis in nematode neurons and improved cognitive decline caused by Alzheimer’s disease. In a rat model of Alzheimer’s disease, NMN reduced Aβ aggregation, enhanced spatial memory, and increased neuronal survival, partly by reducing reactive oxygen species (ROS). These findings suggest that NAD+ precursors like NR and NMN may hold promise in treating age-related brain diseases and improving cognitive function.

  • Spermidine May Increase Human Healthspan

    Spermidine is a polyamine that’s found in various human tissues, and its levels decrease as we age. It’s also abundant in sperm, which helps keep germ cells healthy and alive for a long time. Spermidine levels are influenced by our diet, gut bacteria, and our body’s own production and breakdown processes.

    You can find high levels of spermidine in foods like fresh peppers, wheat germ, broccoli, cauliflower, and cheese. Soy products like natto, shiitake, and durian also have high amounts of spermidine.

    Spermidine has been shown to have many benefits in animal studies. It can help protect the heart and brain and even fight cancer. It’s also been linked to a reduced risk of cancer and heart disease in human studies.

    Spermidine works by maintaining the health of our mitochondria, reducing inflammation, and helping stem cells stay healthy. It also helps by mimicking the effects of calorie restriction, which is when you eat fewer calories but still get all the nutrients your body needs.

    In animal studies, giving spermidine has been shown to increase the survival rate, improve memory, and even help with motor skills. In human studies, taking spermidine supplements is safe and effective in improving memory and reducing blood pressure.

    Here are some of the key details about spermidine and its benefits:

    1. Anti-aging effects: Spermidine has been shown to slow down the aging process by promoting autophagy, a process where cells clean up and recycle damaged components. This helps maintain cellular health and prevent age-related diseases.
    2. Cardioprotective effects: Spermidine has been found to protect the heart by reducing inflammation, oxidative stress, and blood pressure. It may also help prevent cardiovascular diseases like atherosclerosis and heart failure.
    3. Neuroprotective effects: Spermidine has been shown to improve memory, learning, and cognitive function in both animal and human studies. It may also help protect the brain from neurodegenerative diseases like Alzheimer’s and Parkinson’s.
    4. Anti-cancer effects: Spermidine has been found to inhibit cancer cell growth and promote cancer cell death. It may also help prevent cancer by reducing inflammation and oxidative stress.
    5. Mitochondrial health: Spermidine helps maintain the health of mitochondria, the energy-producing structures within cells. This is important for overall cellular health and may help prevent diseases like diabetes and neurodegenerative disorders.
    6. Caloric restriction mimic: Spermidine has been found to mimic the effects of caloric restriction, which is when you eat fewer calories but still get all the nutrients your body needs. This has been shown to have many health benefits, including increased lifespan.
    7. Safety and efficacy: Spermidine has been shown to be safe and well-tolerated in human studies, with no significant side effects. It has also been found to be effective in improving various health markers, such as blood pressure, memory, and cognitive function.

    In terms of dietary sources, spermidine is found in a variety of foods, including:

    • Fresh peppers
    • Wheat germ
    • Broccoli
    • Cauliflower
    • Cheese
    • Soy products like natto, shiitake, and durian

    It’s also available as a dietary supplement, which can be a convenient way to increase your spermidine intake if you’re having trouble getting enough from your diet alone.

    Overall, spermidine is a promising nutrient that has been shown to have many health benefits. Further research is needed to fully understand its effects, but current evidence suggests that it may be a valuable addition to a healthy Longevity Lifestyle.

  • Intermittent Fasting – The Impact on Autophagy, Inflammasome, and Senescence

    A recent study published in Human Nutrition & Metabolism explored the molecular effects of prolonged intermittent fasting on human health and longevity markers. The research revealed that fasting can alter the expression of genes linked to autophagy, the inflammasome, and senescence, which are all related to aging and age-related diseases.

    The study recruited 25 healthy young men who intended to fast for the entire month of Ramadan from dawn to dusk. The researchers measured gene expression levels one week before Ramadan, in the middle of Ramadan, in the last days of Ramadan, and one week after Ramadan.

    The study found that intermittent fasting activated autophagy, a cellular process that breaks down components within cells. Autophagy has been linked to longevity, and the researchers observed an increase in ULK1, a gene involved in autophagy, two weeks and one month after starting the fasting period. Another gene, ATG5, involved in autophagy induction, also showed a similar pattern. However, BECN1, a gene essential for autophagy, exhibited a different pattern, with an increase in expression two weeks after the start of fasting and a subsequent reduction in its levels.

    The researchers also measured inflammation and senescence markers, including the inflammasome and senescence mediator p16INK4a. They found that NLRP3 and IL-1β expression increased two weeks and one month after the start of fasting, but ASC levels were lower than basal levels one month after the start of fasting, suggesting that the inflammasome was not activated. The senescence marker p16INK4a did not show statistically significant changes until the end of the observation period, but p21 levels decreased during and after fasting.

    The study’s limitations include a lack of data on food intake, physical activity, and sleeping patterns, which could impact gene expression patterns. Additionally, only young males were included in the study, making the results questionable for other demographic groups. The authors emphasize the need for further research to confirm or refute their findings and to assess the levels of actual proteins rather than just gene expression levels.

    Overall, the study provides valuable insights into the molecular effects of prolonged intermittent fasting on human health and longevity markers. While more research is needed to understand the complex interplay between autophagy, the inflammasome, and senescence, the findings suggest that fasting may contribute to delaying the onset of age-related diseases and promoting overall health and longevity.