The Role of NAD+ in Regenerative Medicine

NAD+ (Nicotinamide Adenine Dinucleotide) is a crucial molecule in the body’s biological processes, especially in energy metabolism and cell repair. In regenerative medicine, NAD+ plays a key role in maintaining cellular health and supporting tissue regeneration. Research on NAD+ is opening up new possibilities for treating age-related diseases and cellular damage.

The information below is referenced from the study “The Role of NAD+ in Regenerative Medicine” by Nichola J. Conlon, published in 2021 on PubMed Central.

1. NAD+ and Cellular Anti-Aging Targets

In cellular aging research, nicotinamide adenine dinucleotide (NAD+) has become a central focus. Metabolic analyses have identified NAD+ as a core metabolic mediator associated with numerous hallmarks of aging.

NAD+ is a cellular coenzyme essential for both metabolic and signaling reactions. In metabolism, NAD+ participates in redox reactions that lead to ATP formation. Beyond this, NAD+ is a vital regulator of several enzymes involved in post-translational protein modifications, altering their activity.

The combination of metabolic function and cellular signaling makes NAD+ a “metabolic messenger,” creating a critical link between the cell’s energy state and downstream signaling to appropriately adapt to bioenergetic stress. Therefore, maintaining adequate NAD+ levels is necessary for preserving tissue homeostasis and responding to stress.

Despite its vital role, age-dependent NAD+ decline has been observed across various organisms. In humans, age-related NAD+ reduction has been recorded in the liver, skin, brain, plasma, skeletal muscle, and monocyte-derived macrophages. Chronic low NAD+ levels have been noted in premature aging disorders and age-related pathological conditions and are linked with multiple aging markers.

Low NAD+ levels contribute to aging, as NAD+ serves as the exclusive substrate for two key enzyme families that impact cell repair and longevity—sirtuins (SIRTs) and poly (ADP-ribose) polymerases (PARPs). These enzyme families regulate many signaling processes crucial to cellular health and longevity, relying directly on NAD+ availability to function.

2. Clinical Benefits of Increasing and Restoring NAD+

2.1. Preclinical Benefits of NAD+ Restoration

In vivo restoration of NAD+ has been extensively studied, demonstrating numerous systemic benefits, which have recently been comprehensively reviewed. In summary, it has been observed in mice that NAD+ levels drop by half in middle age, correlating with the onset of many age-related issues. Successful restoration of NAD+ to youthful levels led to cardiovascular improvements and reversals of several metabolic conditions.

Enhanced muscle function and endurance, along with increased mitochondrial function, ATP production, and improved muscle stem cell quantity and quality, have also been noted. Organ protection and regeneration following injury were observed in the liver, heart, and kidneys, and NAD+ restoration was even found to rescue vision by reversing retinal degeneration.

Significant neurological benefits have been shown in animal models of Alzheimer’s disease when NAD+ levels were restored, including improved cognition and nerve regeneration. NAD+ availability also appears to impact fertility, with NAD+ boosting strategies shown to improve egg quality and restore fertility in older mice.

2.2. Clinical Benefits of NAD+ Restoration

These impressive preclinical findings have shifted focus to human clinical trials to explore the potential transfer of NAD+ restoration benefits to humans. Notable observations so far include a trend toward improved cardiovascular function indicators, such as lower systolic blood pressure and reduced aortic stiffness, significant reduction in circulating inflammatory cytokines in older men after just three weeks of NAD+ restoration, and increased NAD+-related mitochondrial function and reduced pro-inflammatory markers in heart failure patients.

The broad protective and regenerative capacity of NAD+ is attributed to its involvement in preventing many cellular aging hallmarks. Aging hallmarks are fundamental cellular changes underlying the chain of events leading to systemic age-related decline. NAD+ has been identified as a crucial metabolic mediator involved in numerous aging hallmarks, such as:

• Genomic instability: Adequate NAD+ is essential for activating DNA repair enzymes and pathways such as PARP1, SIRT1, and SIRT6.
• Cellular senescence: Low NAD+ promotes skin cell senescence, while NAD+ restoration reduces the burden of senescent cells.
• Epigenetic alterations: NAD+-dependent sirtuins are essential for youthful epigenetic regulation, and decreased NAD+ prevents sirtuins from performing this role.
• Mitochondrial dysfunction: Adequate NAD+ is crucial for healthy mitochondrial function and removal of damaged mitochondria.
• Telomere attrition: NAD+ restoration has been found to mitigate telomere dysfunction.
• Altered intercellular communication: Low NAD+ promotes age-related inflammation.
• Proteostasis imbalance: NAD+ is required for SIRT1-mediated autophagy to remove damaged cellular proteins.
• Nutrient sensing dysregulation: NAD+ levels are essential for sensing the cell’s energy state to adapt to energy stress.
• Stem cell exhaustion: NAD+ restoration leads to stem cell rejuvenation.

These findings reveal the tremendous potential of NAD+ in regenerative medicine. By boosting NAD+ in the body, we may activate self-repair and rejuvenation mechanisms at the cellular level, offering numerous comprehensive health benefits. The potential of NAD+ extends beyond merely slowing aging; it may even reverse some age- and disease-related effects.

However, boosting NAD+ is not as simple as directly supplementing NAD+ into the body. Researchers are focused on developing effective methods to enhance endogenous NAD+ production, improve NAD+ recycling, and reduce excessive NAD+ consumption. This includes using NAD+ precursors like nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN), in combination with NAD+ consumption enzyme inhibitors like CD38 and NAD+ synthesis enzyme activators like NAMPT.

The potential of NAD+ in regenerative medicine also extends to skincare and aesthetics. Research shows that NAD+ enhancement can improve skin health and appearance by promoting collagen production, reducing inflammation, and providing protection against UV damage. This opens up possibilities for developing new NAD+-based anti-aging therapies, applicable both internally (through oral supplementation) and externally (through topical products).

In summary, NAD+ is emerging as a promising target in regenerative medicine, with enormous potential for slowing aging, preventing and treating age-related diseases, and enhancing overall health and appearance.

3. The Role of NAD+ in Skin Health

NAD+ plays a crucial role in maintaining the health and function of the skin, particularly during the aging process. The decline of NAD+ with age contributes to reduced DNA repair capabilities and the accumulation of DNA damage, which is one of the primary factors leading to skin aging. Enzymes such as PARP1, SIRT1, and SIRT6, which rely on NAD+ for DNA repair, are all affected when NAD+ levels drop, resulting in diminished tissue regeneration and the emergence of aging signs, such as cellular senescence.

Cellular senescence not only impairs a cell’s ability to divide but also produces inflammatory factors that negatively impact the surrounding environment, leading to a decline in skin quality, such as collagen degradation and reduced skin barrier function.

The reduction of NAD+ not only weakens the normal physiological processes of the skin but also promotes genetic instability and epigenetic drift, altering gene expression. NAD+-dependent sirtuins, such as SIRT1 and SIRT6, play important roles in regulating gene expression related to collagen preservation and skin regeneration, but their levels also decline with age, resulting in the degradation of supportive skin structures.

Moreover, mitochondrial function—a significant indicator of aging—also deteriorates due to NAD+ deficiency. However, boosting NAD+ can improve mitochondrial function, enhance cellular regeneration, and repair damage, offering great potential in slowing the aging process of the skin.

4. Causes of NAD+ Decline, Ways to Increase NAD+, and the Future of NAD+

4.1. Causes of NAD+ Decline

There is clear evidence of the role of declining NAD+ levels in the development of aging signs in the skin, leading to significant interest in understanding the root causes of NAD+ decline to identify successful strategies for restoring cellular NAD+ levels.

It is known that the metabolism of NAD+ involves multiple precursors, production pathways, recycling pathways, and numerous consuming enzymes. Current evidence suggests that the primary cause of NAD+ decline is the disruption of this tightly regulated network. Specifically, it has been found that the consumption of NAD+ begins to exceed its production and recycling with age.

The age-related and disease-related overactivation of NAD+-consuming pathways can severely impair the availability of NAD+ within cells, thereby limiting its utilization by other critical NAD+-dependent enzymes that promote good health, such as sirtuins.

Although the demand for NAD+ increases throughout life, in theory, NAD+ levels should be self-sustaining because cells can quickly recycle the byproducts of NAD+ consumption to replenish NAD+. This occurs through the salvage pathway, which plays a key role in NAD+ restoration. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in this recycling process, and it is now known that NAMPT levels decrease with age, paralleling the decline of NAD+ in aged tissues.

The reduced synthesis of NAD+ through the salvage pathway is a significant factor in older cells, as the increased consumption of NAD+ alongside aging and the rising demand for replenishment and recycling results in ineffective recycling of depleted NAD+, exacerbating the decline in NAD+ levels.

4.2. Ways to Increase NAD+

The biology behind NAD+ decline is complex. Restoring NAD+ through exogenous NAD+ supplementation is often impractical due to its unstable nature and poor bioavailability for most cell types. Thus, efforts have focused on oral supplementation with NAD+ precursor compounds, including nicotinamide (NAM), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN). These precursors are utilized by NAD+ biosynthetic pathways and converted into NAD+ within cells.

However, it is now clear that this popular approach overlooks the root causes of NAD+ decline, meaning that merely supplementing with precursors like NR or NMN does not provide an effective long-term solution for restoring NAD+. Instead, strategies that simultaneously address multiple root causes of NAD+ decline, such as combining a NAD+ precursor with a CD38 inhibitor and a NAMPT activator, have the potential to restore NAD+ with greater measurable benefits.

Furthermore, there is substantial evidence supporting these targets as interventions to successfully restore cellular NAD+ levels, and many safe and well-tolerated active components against these targets already exist. This presents opportunities to develop oral formulations, topical applications, and injectables that allow for both systemic NAD+ restoration benefits and more targeted use, leading to an optimal inside-outside approach to aging.

4.3. The Future of NAD+

The potential of NAD+ in regenerative medicine and anti-aging is increasingly recognized. Strategies to enhance NAD+ can be applied in various ways in clinical practice, from oral supplementation to improve overall health to local use in cosmetic procedures.

Oral NAD+ supplementation can provide systemic benefits such as increased energy, cognitive function, and an overall sense of well-being. Using intravenous NAD+ prior to procedures may help optimize cellular response and enhance recovery/regeneration capabilities. Local applications, such as topical NAD+ or injections, can target specific problem areas or be combined with cosmetic procedures like microneedling.

The future of NAD+ in regenerative medicine is promising, with the potential to improve various aspects of health and aging from both inside and outside the body. Further clinical research is needed to identify optimal methods for enhancing NAD+ and fully evaluate the long-term benefits. However, with the growing understanding of NAD+’s role in aging biology, it may become an essential tool in anti-aging and regenerative medicine in the future.