Feeling run down, fuzzy brained, low on motivation? Restore youthful energy and brainpower with the phenomenal benefits of NAD+ supplements.
Nicotinamide adenine dinucleotide (NAD+) is a vital coenzyme involved in many cellular metabolism and energy production processes. As we age, our levels of NAD+ decline, leading to impaired mitochondrial function and reduced energy. This accelerates aging and increases disease risk.
NAD+ supplement use has emerged as an appealing anti-aging strategy to restore optimal NAD+ levels and reap associated health and longevity benefits. This comprehensive guide will examine the science behind NAD+ supplements and provide key information on their use.
What is NAD+ and Why Does it Decline?
NAD+ is the oxidized form of nicotinamide adenine dinucleotide - a dinucleotide composed of adenine and nicotinamide ribose.
It serves as an important redox cofactor used by all cells to carry electrons in metabolism pathways and energy (ATP) generation.
NAD+ accepts electrons in catabolic reactions and becomes NADH. NADH donates electrons for energy synthesis.
This perpetual interconversion between NAD+ ⇄ NADH occurs billions of times daily!
With advanced age, NAD+ levels decrease due to:
Inefficiency of salvage pathways:
One reason NAD+ levels decline with age is that the salvage pathways that recycle and reuse NAD+ become less efficient. There are a couple key salvage pathways that convert the NAD+ precursors nicotinamide and nicotinic acid back into usable NAD+ after it is consumed in cellular reactions. The predominant salvage pathway uses the enzyme nicotinamide phosphoribosyltransferase (NAMPT) to salvage nicotinamide back into NAD+.
However, the expression of NAMPT appears to decrease as we get older. This reduces the cell's ability to recycle nicotinamide into NAD+ through the salvage pathway, resulting in less NAD+ available. The activity of other enzymes involved in NAD+ salvage like NMNAT also appear to decline with age. Additionally, high cholesterol can inhibit NAMPT. Overall, these age-related changes lead to reduced efficiency of the NAD+ salvage cycles, which contributes to the gradual depletion of NAD+ levels over time. Restoring the function of salvage pathways is one target of anti-aging interventions.
Increased activity of consumer enzymes like CD38:
This transmembrane protein acts as a nicotinamide adenine dinucleotide glycohydrolase, essentially consuming NAD+ as its substrate. Activity of CD38 increases substantially as we get older. The higher CD38 activity facilitates the breakdown of NAD+ into intermediates like ADPR and cADPR. This constant increased consumption and degradation of NAD+ by CD38 reduces net levels over time. Compounds that can selectively inhibit CD38 are being investigated to block excessive NAD+ destruction and preserve NAD+ availability during aging.
Mitochondrial dysfunction and DNA damage:
Mitochondrial dysfunction and accumulation of DNA damage are cellular hallmarks of aging that also diminish NAD+ levels over time. Mitochondria require NAD+ to fuel energy production through oxidative phosphorylation and the electron transport chain. But with age, mitochondria become less efficient and dysfunctional, increasing reactive oxygen species and oxidative stress. This mitochondrial dysfunction itself depletes NAD+ stores. DNA damage also accumulates from reactive species and telomere shortening. PARP, an enzyme activated to repair DNA, consumes NAD+ in the process. Age-related mitochondrial dysfunction combined with increased NAD+ demand from DNA damage repair collectively drain NAD+ pools as we get older. Preserving mitochondrial and genome integrity helps maintain NAD+ longevity.
Cellular senescence and Inflammation:
Cellular senescence refers to aging cells that stop dividing and secrete proinflammatory factors. Senescent cell accumulation is a hallmark of aging. These damaged cells drive chronic low-grade inflammation through inflammatory cytokines like IL-1, IL-6, and TNF-alpha. Inflammation itself depletes NAD+ by activating poly-ADP ribose polymerases (PARPs) and CD38—two major NAD+-consuming enzymes. PARPs are activated by DNA damage while CD38 generates inflammatory calcium signaling molecules. This chronic activation of NAD+-depleting enzymes by increased cellular senescence and systemic inflammation over time contributes significantly to the age-associated decrease in NAD+ bioavailability.
Why Take an NAD+ Supplement?
Declining NAD+ has several detrimental effects, including:
Impaired mitochondrial function and reduced ATP energy:
The reduction in NAD+ availability decreases activity of complexes in the mitochondrial electron transport chain involved in oxidative phosphorylation for ATP synthesis. This impairs the mitochondria's ability to generate energy currency in the form of ATP. With less NAD+ to fuel respiration and carry electrons, mitochondrial energy output declines, negatively impacting cellular metabolism and function.Disruption of sirtuins and loss of gene regulatory activities:
Sirtuins are NAD+ dependent protein deacetylases that play vital roles in regulating gene expression. There are seven main sirtuin isoforms in humans that control important cellular processes related to metabolism, inflammation, DNA repair and more by modifying histones and deacetylating target proteins. Sirtuins require NAD+ as a cofactor for their enzymatic activities. Declining NAD+ availability during aging directly reduces sirtuin function. This disrupts normal gene regulatory activities of sirtuins, leading to transcriptional changes that drive aging phenotypes and related disorders. Maintaining NAD+ levels is critical for preserving sirtuin expression and their age-delaying epigenetic influence.
Accelerated aging across tissues along with associated diseases:
The reduction of NAD+ levels with age impairs normal cellular function and alters gene expression across tissues, accelerating the onset of age-related pathology. This NAD+ depletion leads to mitochondrial dysfunction, oxidative stress, inflammation, senescence, and telomere shortening characteristic of aging. The combination of these effects increases disease vulnerability in the brain, muscles, eyes, joints, liver, heart, and more, hastening overall functional decline.Neurodegeneration and loss of cognition:
The high metabolic demands of neurons make them especially vulnerable to mitochondrial dysfunction and bioenergetic deficits from NAD+ depletion. Without sufficient NAD+ to fuel neuronal mitochondria and DNA repair, oxidative damage accumulates, eventually leading to neuron death. Loss of NAD+ sirtuin activity also impairs cognition genes. This neurodegeneration manifests as impaired learning, memory, executive function, and processing speed. NAD+ decline is implicated in multiple age-related cognitive disorders like Alzheimer's. Maintaining neuronal NAD+ levels appears essential for healthy brain aging, supporting both neuron viability and optimal cognitive performance.Muscle deterioration, weakness and frailty:
The reduction of NAD+ availability during aging impairs mitochondrial function and energy production within muscle tissue. Without sufficient NAD+ to fuel muscular activity, muscles gradually weaken and waste away. This loss of muscle mass, strength and function is referred to as sarcopenia. NAD+ deficiency also reduces muscle stem cell regenerative capacity. Overall, lack of NAD+ accelerates loss of muscle fibers, leading to detrimental reductions in mobility, frailty, increased falls/fractures, and reduced independence with advanced age. Maintaining optimal NAD+ levels may help combat sarcopenia by energizing mitochondria and satellite cell repair within muscle.
This makes restoring NAD+ levels through supplementation enticing to counteract natural depletion over time. Potential benefits of increased NAD+ include:
Boosted mitochondrial biogenesis and energy
Activation of sirtuins that mimic calorie restriction
Enhanced neuronal health and cognitive function
Increased endurance, muscle growth and performance
Greater metabolic flexibility and obesity resistance
Extended lifespan and healthier aging
Different Types of NAD+ Supplements
There are several forms of oral NAD+ supplements currently available on the market, each with their own advantages and considerations when it comes to enhancing NAD+ levels efficiently. The main supplement types include:
Nicotinamide Riboside (NR)
Nicotinamide riboside is considered the most effective NAD+ precursor compound used in supplements. It has the highest oral bioavailability and ability to increase NAD+ levels compared to other precursors. NR is converted to NAD+ through a two-step process - first NR kinase converts it to nicotinamide mononucleotide (NMN), then NMN adenylyltransferase converts NMN to NAD+.
Human trials show doses of NR from 100-2000 mg/day effectively increase blood and tissue NAD+ levels safely. The predominant benefit of NR is it is highly bioavailable even at lower doses. It is widely available as a standalone supplement or bundled in anti-aging multivitamin formulas.
Nicotinamide Mononucleotide (NMN)
Nicotinamide mononucleotide is a direct precursor to NAD+ that is converted by the enzyme NMNAT. NMN supplements have slightly lower bioavailability and conversion efficiency compared to NR. However, NMN follows the most direct natural pathway to replenishing NAD+. Doses around 100-500 mg/day have shown significant NAD+-boosting effects.
While not as common currently, NMN is gaining popularity as an alternative NAD+ booster. It pairs well with other activators like resveratrol. One downside is poorer stability and solubility compared to NR supplements. Overall, NMN remains a valid supplemental approach to raise NAD+ levels.
NADH
NADH stands for reduced nicotinamide adenine dinucleotide - the form produced when NAD+ accepts electrons. Technically, NADH easily converts back to NAD+ by giving up electrons. However, oral direct NADH supplements have very low bioavailability as the compound is quickly broken down. Thus, much higher dosages are required to achieve NAD+ boosting effects.
NADH can be taken sublingually for better absorption, but stability remains an issue. While NADH ultimately supports the NAD+ pool, nicotinamide riboside or NMN are more direct and efficient precursors.
NAD+ Intermediates
Some supplements provide NAD+ intermediate compounds the body can convert in a stepwise process to eventually synthesize NAD+. These include nicotinic acid riboside (NaR), nicotinic acid mononucleotide (NaMN) and nicotinic acid adenine dinucleotide (NaAD).
However, human data on the bioavailability and efficacy of these precursors is limited. Their multi-step conversion may be less efficient. But they do offer another route to provide cells with raw materials for manufacturing NAD+.
In summary, NR and NMN supplements are likely the most effective at directly raising NAD+ levels for anti-aging benefits. But exploring emerging alternatives may yield additional options tailored to specific needs.
Potential Anti-Aging Benefits of NAD+ Supplementation
Both animal studies and early clinical trials in humans have provided exciting evidence for the wide-ranging anti-aging benefits that boosting NAD+ levels may provide. While larger and longer-term human studies are still needed, initial findings show tremendous promise in using NAD+ supplements to help extend healthspan and counteract biological aging. Some of the key potential anti-aging effects emerging in early research include:
Increased Longevity
Studies in worms, mice and rats have shown increased lifespan of up to 30% with NR supplementation started even late in life. NAD+ appears to activate sirtuins and other longevity genes conserved across species. In humans, raised NAD+ may help prevent many age-related chronic diseases to prolong lifespan. Clinical trials are underway examining effects on human longevity.
Enhanced Cognition and Neuron Health
Supplementing NAD+ or precursors has demonstrated improved spatial memory, learning ability, and recognition in aged mice. It promotes neural stem cell proliferation for neurogenesis. NAD+ also protects neurons from DNA damage and oxidative stress for healthier brain aging. Human trials show increased blood flow signaling improved neuronal metabolism. Enhancing NAD+ shows real promise for maintaining optimal cognition into advanced age.
More Muscle and Strength
Animal studies reveal NAD+ supplementation augments mitochondrial content in muscle, increases endurance capacity, and guards against muscle deterioration. In human strength training studies, NAD+ boosting supported greater muscle size and performance gains. Preventing loss of mobility and frailty is a key anti-aging benefit.
Better Metabolism and Weight Control
NAD+ is vital for energy metabolism, insulin sensitivity, and mitochondrial fat burning capacity. Animal research demonstrates preventing obesity through dietary NAD+ boosting. Human trials also show increased resting metabolic rate. Maintaining a healthy metabolism promotes longevity and ideal body composition.
Cardiovascular Benefits
Rodent studies display improved blood flow, vascular reactivity, and cardiac function with NAD+ supplementation. The anti-inflammatory effects also benefit the cardiovascular system. Human studies are limited but show potential to reduce risk factors for heart disease like cholesterol. Protecting cardiovascular health is essential for longevity.
Increased Energy and Resilience
By enhancing mitochondrial capacity and efficiency throughout the body, NAD+ helps sustain daily energy and stamina. Animal studies show increased exercise endurance with NR supplementation. The cognitive and neuronal benefits also translate to staying sharper mentally long-term. Optimal NAD+ boosts whole-body resilience.
What is the Optimal NAD+ Supplement Dosage?
Most studies use dosages of NR between 100-2000 mg/day and NMN from 100-500 mg/day. Higher doses appear to increase NAD+ levels more substantially. However, there is likely an upper limit before toxicity occurs. Mild side effects like headaches or nausea may appear with over 1000 mg/day.
Due to the cost of supplements, smaller doses of around 100-300 mg/day in divided portions may provide benefits without breaking the bank. It's also wise to cycle on and off NAD+ supplements instead of taking them continuously.
Factors like your age, health status, and stack with other supplements can help determine the best NAD+ dosage and schedule. Start low and slowly increase based on your body's response. Work closely with your doctor to find your optimal dose.
Dietary Ways to Increase NAD+
In addition to direct NAD+ precursor supplements, certain dietary and nutritional strategies can also help support optimal NAD+ levels. Key ways to boost NAD+ through diet include:
Eat Foods High in Vitamin B3
Vitamin B3 in the form of niacin and nicotinamide provides the essential building blocks to synthesize NAD+. Excellent dietary sources of vitamin B3 include meat, poultry, fish, peanuts, mushrooms, sunflower seeds, green vegetables and 100% whole grains. Aim for at least 20 mg of B3 daily. Choosing B3-rich foods supplies raw materials for NAD+ production.
Fasting, Calorie Restriction, or Ketogenic Diets
Limiting food intake through intermittent fasting, calorie restriction, or ketogenic diets activates sirtuins and stimulates NAD+ salvage pathways. This recycling increases NAD+ production during fasting periods. Restricting calories may also limit NAD+ consumption pathways. Ketogenic diets favor mitochondrial NADH production.
Caution with High Niacin Doses
While vitamin B3 is beneficial, high supplemental doses of nicotinic acid can cause uncomfortable flushing. Doses above 35 mg/day of just the nicotinic acid form are not recommended. However, the nicotinamide form found in multivitamins and B complexes does not cause flushing even at higher doses. Get niacin primarily through food rather than single nutrient supplements.
Combining NAD+ with Exercise for Added Benefits
Engaging in aerobic and resistance exercise creates a higher demand for NAD+. Taking an NAD+ supplement before workouts may amplify certain benefits:
Augmented mitochondrial biogenesis and muscle cell adaptations
Better recovery by reducing exercise-induced muscle damage
Increased stamina, endurance and strength gains over time
Optimization of body composition with enhanced fat burning
However, appropriate rest and recovery are still vital to fully reap advantages. Don't overdo exercise intensity or duration. Optimize your workout regimen and combine smartly with NAD+.
Safety Considerations of NAD+ Supplements
Despite potential benefits, some precautions need to be kept in mind:
No long-term human safety studies yet, so prolonged high doses are unwise
May negatively interact with immunosuppressants, sirtuin inhibitors, diabetes meds
Side effects like stomach upset, headaches, insomnia at very high doses
Small risk of worsening autoimmune conditions or cancer
Those with medical conditions or on medication should consult a doctor first
Practicing moderation with dosing, cycling on and off, staying hydrated, and carefully tracking effects can help reduce risks when taking NAD+ supplements. Their long-term safety will become clearer over time.
Conclusion and Recommendations
In summary, evidence continues emerging on the anti-aging benefits of NAD+ supplements like NR and NMN that may extend lifespan, enhance neurons, muscle, metabolism and more. While extremely promising, they should be approached thoughtfully and with medical guidance.
To harness their potential, try these tips:
Choose quality NR or NMN supplements without added ingredients
Start with 100-300 mg/day and assess your response
Cycle between on and off periods of 1-3 months -Stack with B3, fasting, exercise, and a low-carb diet
Monitor for side effects like headache or nausea
Work closely with your healthcare provider, getting regular blood work
The future for NAD+ enhancement is bright. But being an informed, proactive consumer will help you actualize the longevity advantages safely and successfully.
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