The Role of NAD+ in Anti-Aging Therapies

NAD+ plays a significant role in anti-aging therapies due to its ability to stimulate cellular repair and protect cells from oxidative stress damage. Maintaining or increasing NAD+ levels can help slow down natural aging processes, improve cellular function, and extend lifespan. Research on NAD+ opens new prospects for developing effective NAD+-based anti-aging therapies.

The aging process involves DNA damage accumulation, mitochondrial defects, progressive tissue degeneration and atrophy, as well as the development of metabolic dysfunction and frailty. Aging is also associated with decreased levels of nicotinamide adenine dinucleotide (NAD+), which can lead to cellular damage and even shorter lifespans. NAD+ acts as an enzyme cofactor in numerous essential biological pathways and serves as a substrate for certain regulatory proteins. Many studies have shown that upregulating NAD+ precursors can increase NAD+ levels in tissues or cells to slow aging. Clinical trials have been conducted to assess the safety and efficacy of NAD+. A 2019 study by Xuqian Liu and colleagues reviewed NAD+ metabolism and its role in aging-related therapies.

1. NAD+ Biosynthesis Pathways

NAD+ is a crucial molecule in living organisms, playing a central role in numerous biochemical reactions. It helps enzymes function and participates in cellular energy production. As we age, the body’s NAD+ synthesis declines, impacting the aging process across many species.

There are three ways the body synthesizes NAD+:

1. From an amino acid called tryptophan
2. From nicotinic acid
3. From nicotinamide (NAM) through the “recycling” pathway

This article focuses on the recycling pathway, which is the primary source of NAD+ in the body.

The NAD+ recycling pathway works as follows:

• Step 1: An enzyme called NAMPT converts nicotinamide into an intermediate called NMN.
• Step 2: Another enzyme, NMNAT, converts NMN into NAD+.

NAMPT is the rate-limiting enzyme in this process. As we age, NAMPT levels decrease, leading to reduced NAD+ synthesis. However, exercise can help increase NAMPT levels in muscle.

NAMPT exists in two forms: intracellular and extracellular. The intracellular form participates in NAD+ recycling, while the extracellular form acts as a signaling protein in the blood. NAMPT and another protein called SIRT1 are closely linked: SIRT1 regulates NAMPT secretion, and NAMPT affects SIRT1 activity through NAD+ regulation. Increasing NAMPT levels may help slow the aging process.

NAMPT is also crucial for bone health. It helps bone marrow stem cells develop into bone cells. A lack of NAMPT can increase the risk of osteoporosis and fractures.

Studies in mice show that increasing NAMPT can extend lifespan. Older mice with increased NAMPT levels had higher NAD+ levels in various tissues and lived longer.

NMNAT is the central enzyme in NAD+ synthesis. In mammals, there are three types of NMNAT located in different parts of the cell:

• NMNAT1 in the cell nucleus
• NMNAT2 in the Golgi apparatus
• NMNAT3 in mitochondria

Each type of NMNAT has an essential role:

• NMNAT1 is necessary for embryo survival.
• NMNAT2 is vital for nerve development and protection, particularly in the brain and nervous system.
• NMNAT3 regulates NAD+ production in mitochondria, affecting the cell’s energy-generating capacity.

In summary, the NAD+ recycling pathway is crucial for NAD+ synthesis and maintaining NAD+ levels in the body. Enzymes like NAMPT and NMNAT are key factors in this process. A deeper understanding of how they function may help us discover ways to slow aging and improve overall health.

2. Anti-Aging Effects of NAD+

NAD+ plays a crucial role in various cellular processes, such as energy production, DNA repair, gene expression, and managing oxidative stress. It does this by supporting the functions of key proteins like sirtuins, CD38, and PARP.

2.1. The Sirtuins Pathway

Sirtuins are proteins that require NAD+ to function. Increasing sirtuin levels can extend the lifespan of several organisms. In humans, the SIRT1 protein is especially significant. It enhances mitochondrial function, which is essential for cellular energy production. Research on mice shows that increased SIRT1 in the brain and heart can slow aging and extend lifespan. SIRT1 also helps protect heart and muscle stem cells from aging.

2.2. The PARP Pathway

PARP proteins play a role in detecting and repairing DNA damage. As we age, DNA accumulates more damage. However, if PARP activity is excessive, it can deplete NAD+, leading to reduced cellular energy, impaired mitochondrial function, and even cell death. Boosting NAD+ levels can help prevent this damage, particularly in heart cells.

2.3. CD38 and NAD+

CD38 is a multifunctional protein but is also a primary contributor to NAD+ reduction as we age. Aging cells release factors that stimulate healthy cells to produce CD38, causing an imbalance in cellular NAD+ levels. Recently, scientists have discovered a CD38 inhibitor that may reverse age-related NAD+ decline and activate genes associated with extended lifespan.

2.4. NAD+ Supplementation and Anti-Aging

One of the main causes of aging is the declining function of stem cells, which are essential for maintaining and regenerating tissues in the body. Supplementing with NR (a precursor to NAD+) has been shown to improve muscle and neural stem cell function in older mice, extending their lifespan. NR also helps restore the ability of older mice to repair gut damage and reduces DNA damage in neural and muscle cells.

Another NAD+ precursor, NMN, can improve blood flow in older mice by increasing capillary density. It also helps alleviate metabolic disorders and slows age-related physiological decline. In mouse models of Alzheimer’s disease, NMN restores mitochondrial function, prevents neuronal cell death, and slows cognitive decline.

Anti-aging NAD+ supplementation, or the use of its precursors, can improve mitochondrial function in stem cells, promote bone formation, and protect bones from aging. In older mice, NMN supplementation increases capillary density, improves blood flow, and enhances endurance.

Besides direct supplementation, inhibiting enzymes that degrade NAD+, such as CD38, PARP, and SARM1, can also increase NAD+ levels. Scientists are studying CD38 and PARP1 inhibitors as potential methods to boost NAD+ in cells, improve mitochondrial function, and serve as an effective anti-aging approach.

In conclusion, NAD+ plays a vital role in maintaining cellular health. Boosting NAD+ through supplementation or inhibiting enzymes that break it down is viewed as a promising anti-aging strategy to slow aging and improve overall health.

3. Measuring Biological Age

To date, the anti-aging effects of NAD+ have primarily been studied through analysis of related genes and biological pathways. However, there is still no gold standard for evaluating aging processes. A new method known as the “DNA clock” could provide a more objective indicator for aging research.

DNA methylation is an important chemical process that regulates gene activity. Scientists have found that the level of DNA methylation changes with age, which can be used to estimate an organism’s biological age. This process is independent of sex or tissue type, making it a reliable tool for assessing aging.

These anti-aging measures, also known as the Horvath clock (or DNA clock), are based on measuring methylation levels at specific sites on DNA. Initially, researchers compared thousands of sites on human DNA and identified those that changed with age. From this, they selected 353 unique sites capable of accurately predicting biological age.

For mice, scientists have developed similar models. One research group created a tool to predict the biological age of mice based on 90 DNA sites from blood samples. Another group developed a tool that could estimate age based on 329 unique sites from various tissues of mice. Remarkably, one study suggested that just three specific methylation sites might be sufficient to predict biological age in mice, although further validation is needed.

These studies show that the DNA clock can provide an objective indicator for aging research. Recently, a study revealed that metformin could reverse participants’ biological age, based on the Horvath clock’s assessment. Utilizing this tool will allow us to evaluate the anti-aging effects of NAD+ and its precursors in a more objective and accurate manner.

4. Clinical Studies

NAD+ precursors can be administered to humans or animals orally to alter the NAD+/NADH balance in the body. Preliminary human studies have shown that supplementation with NR (a precursor of NAD+) can improve NAD+ metabolism in muscle tissue in older adults.

In one study, healthy volunteers were given NR for 8 days, with doses gradually increased from 250 mg to 1000 mg. Results showed an increase in blood NAD+ levels with no adverse effects reported. Another study found that NR supplementation raised levels of NADH and NADPH, while also enhancing exercise capacity in older adults.

NMN, another NAD+ precursor, has also been shown to be safe in clinical trials. However, scientists caution that high doses of NAD+ precursors could accelerate glucose breakdown and mitochondrial activity, potentially prompting the release of pro-inflammatory substances within cells. Therefore, supplementation should be carefully monitored to maintain a balance between anti-aging benefits and potential side effects.

5. Conclusion

While NAD+ precursor supplementation has shown anti-aging effects in mice, the anti-aging potential of NAD+ in humans remains inconclusive. Using a more precise biological marker for aging, such as the DNA methylation clock, could significantly advance this field of study.

Recently, numerous human clinical trials have been launched to further investigate the effects of NAD+ and its precursors. These studies aim to provide deeper insights into NAD+’s potential as an anti-aging therapy for humans.

In summary, although there is still much to learn, NAD+ and its precursors show considerable promise in the field of anti-aging. With advancements in accurate biological age measurement tools like the DNA clock and the progression of more clinical trials, we may soon gain a deeper understanding of how to use NAD+ to enhance health and extend lifespan in humans.