The Role of NAD⁺ in Regenerative Medicine and Addressing Cellular Aging

Introduction

Aging is a complex, multifactorial process that ultimately reduces the body’s ability to maintain homeostasis, repair damage, and regenerate tissues. Although its effects are visible at the tissue and organ levels, many of these changes originate from cellular and molecular dysfunction.

In recent years, the concept of the Hallmarks of Aging has become a major focus of research in aging biology and regenerative medicine. According to this framework, aging does not result from a single process. Instead, it reflects a combination of cellular changes, including genomic instability, cellular senescence, mitochondrial dysfunction, epigenetic alterations, altered intercellular communication, and declining stem cell function.

Within this framework, nicotinamide adenine dinucleotide (NAD⁺) has attracted particular attention as a key molecule involved in metabolism and the regulation of cellular function. The evidence discussed in the reviewed article indicates that NAD⁺ levels decline with age and that this decline may be associated with multiple processes involved in cellular aging.

The article The Role of NAD⁺ in Regenerative Medicine, by Nichola J. Conlon, examines the role of NAD⁺ in aging biology, skin health, and regenerative medicine. It was published in Plastic and Reconstructive Surgery in 2022.

What Is NAD⁺, and Why Does It Matter?

NAD⁺ is an essential intracellular coenzyme involved in a broad range of metabolic reactions and cellular signaling processes.

One of its best-known functions is its involvement in oxidation–reduction reactions and cellular energy production. These processes are important for generating ATP, the main form of energy used by cells.

However, the role of NAD⁺ extends beyond energy production. It is also required for the activity of several important groups of cellular enzymes, including:

• Sirtuins, or SIRTs: A family of NAD⁺-dependent enzymes involved in regulating cellular function and supporting cellular responses to stress. 
• Poly(ADP-ribose) polymerases, or PARPs: A group of enzymes involved in detecting and responding to DNA damage. 
• CD38: An important cell-surface protein and enzyme that can break down and consume NAD⁺. 

NAD⁺ can therefore be viewed as a link between a cell’s energy status and its responses to stress. In simple terms, cells need adequate NAD⁺ to produce energy, repair damage, and respond appropriately to different forms of stress.

Connecting NAD⁺ with the Hallmarks of Aging

The relationship between NAD⁺ and the hallmarks of aging illustrates an important shift in how aging is understood.

Historically, aging was primarily assessed through visible changes in tissues. In the skin, these include reduced thickness, increased wrinkles, reduced elasticity, and structural changes.

It is now understood that many of these visible changes arise from deeper disturbances at the cellular level.

These disturbances include DNA damage, mitochondrial dysfunction, cellular senescence, inflammation, and reduced regenerative capacity, all of which may interact with one another.

Addressing aging more effectively therefore requires attention to the cellular mechanisms underlying these changes as well as their visible consequences. NAD⁺ occupies an important position within these mechanisms because it is directly linked to several major aging-related pathways.

Age-Related Decline in NAD⁺

One of the key findings discussed in the article is that NAD⁺ levels decline with age. This decline has been reported in different tissues and biological samples, including:

•  Skin 
•  Liver 
•  Brain 
•  Skeletal muscle 
•  Plasma 
•  Immune cells 

Declining NAD⁺ is more than a simple consequence of aging; it may also impair the function of many NAD⁺-dependent pathways.

For example, NAD⁺ is required for the activity of SIRT and PARP enzymes. A reduction in its availability may therefore affect DNA repair, gene expression regulation, mitochondrial function, autophagy, and the regulation of cellular senescence.

NAD⁺ and the Hallmarks of Aging

An important section of the article examines the relationship between NAD⁺ and the Hallmarks of Aging. The following table outlines its connection with major cellular features of aging.

These relationships indicate that NAD⁺ is involved in a wide range of processes that influence cellular health and longevity, in addition to its role in energy production.

Cellular hallmark of agingRole of NAD⁺Genomic instability | NAD⁺ is required for the function of certain DNA repair pathways, including those involving PARP1 and SIRT1/SIRT6.
Cellular senescence | Reduced NAD⁺ is associated with increased cellular senescence, while restoring it may reduce senescent cell burden in research models.
Epigenetic alterations | NAD⁺-dependent sirtuins participate in epigenetic regulation and the maintenance of cellular function.
Mitochondrial dysfunction | Adequate NAD⁺ is important for proper mitochondrial function and the removal of damaged mitochondria.
Telomere shortening or dysfunction | Increased NAD⁺ has been associated with reduced telomere-related dysfunction in some studies.
Altered intercellular communication | Reduced NAD⁺ is associated with increased age-related inflammation.
Loss of proteostasis | NAD⁺ is important for activating SIRT1-dependent autophagy pathways and removing damaged proteins.
Deregulated nutrient and energy sensing | NAD⁺ contributes to sensing cellular energy status and responding to metabolic stress.
Declining stem cell function | Increased NAD⁺ has been associated with improved stem cell function in preclinical studies.

NAD⁺ and Skin Health

The skin is one of the tissues in which the effects of aging are most clearly visible. With increasing age, it undergoes changes such as reduced repair capacity, increased cellular damage, reduced elasticity, and alterations in the structure of the extracellular matrix.

Accumulated DNA damage is an important contributor to this process. The skin is continuously exposed to damaging factors, particularly ultraviolet radiation. To respond to this damage, skin cells require effective DNA repair systems. Some of the key enzymes involved in these systems, including PARP1, SIRT1, and SIRT6, depend on NAD⁺.

A decline in NAD⁺ may therefore reduce the ability of cells to respond to DNA damage, allowing cellular damage to accumulate and contributing to other aging-related processes.

NAD⁺, Mitochondria, and Cellular Regeneration

Mitochondria are often described as the powerhouses of the cell. With age, mitochondrial function declines and damaged mitochondria become more abundant.

NAD⁺ plays a fundamental role in mitochondrial metabolism and energy production. In preclinical studies, increased NAD⁺ has also been associated with improved mitochondrial function and the activation of mitophagy, the process through which damaged mitochondria are removed.

In skin cells, maintaining proper mitochondrial function is likewise important for regeneration and appropriate responses to injury.

NAD⁺, Damaged Proteins, and Autophagy

Damaged and altered proteins accumulate in cells and tissues with age.

One of the natural cellular processes that helps address this problem is autophagy, through which damaged cellular components are identified, broken down, and recycled. The article describes the importance of NAD⁺ for the proper function of SIRT1-dependent autophagy pathways.

In the skin, disruption of this process may be associated with declining extracellular matrix quality and changes in components such as collagen, elastin, and hyaluronan. These changes may ultimately reduce skin integrity and elasticity.

Why Does NAD⁺ Decline with Age?

Declining NAD⁺ is not solely the result of reduced production. The article describes how aging disrupts the balance between NAD⁺ production, consumption, and recycling.

In simple terms, increased NAD⁺ consumption combined with reduced recycling can lead to lower intracellular NAD⁺ levels.

Important contributors to this process include:

•  Increased DNA damage 
•  Chronic inflammation 
•  Increased activity of NAD⁺-consuming enzymes 
•  Increased PARP activity 
•  Increased CD38 expression and activity 
•  Reduced activity of the NAD⁺ recycling pathway 
•  Reduced NAMPT levels 

Mechanisms of NAD⁺ Decline in Aging Cells

In young cells, NAD⁺ is continually produced, consumed, and recycled, with an appropriate balance between these processes.

With age, however, two changes occur simultaneously.

1. NAD⁺ consumption increases.

DNA damage and chronic inflammation increase the activation of enzymes such as PARP and CD38. These enzymes consume NAD⁺.

2. NAD⁺ recycling decreases.

One of the most important enzymes in the recycling pathway is NAMPT. Its levels decline with age, reducing the cell’s ability to recycle the products generated by NAD⁺ consumption.

Consequently, cells may reach a state in which NAD⁺ consumption exceeds its production and recycling. This imbalance leads to a gradual decline in intracellular NAD⁺.

Consequences of NAD⁺ Decline

Reduced NAD⁺ can contribute to a vicious cycle that progressively weakens the cell’s natural ability to respond to damage and maintain proper function.

Preclinical Evidence for NAD⁺ Restoration

Another section of the article focuses on studies conducted in animal models.

In preclinical studies, restoring NAD⁺ has been associated with a broad range of favorable effects, including:

•  Improved cardiovascular function 
•  Improvements in certain metabolic disorders 
•  Increased muscle function and endurance 
•  Improved mitochondrial function 
•  Increased ATP production 
•  Improved stem cell function 
•  Increased repair capacity in certain organs following injury 
•  Improvements in certain neurological disorders 
•  Improved oocyte quality in aged animal models 

These findings suggest that NAD⁺ may be an important target in regenerative medicine.

However, a substantial proportion of this evidence comes from preclinical studies, particularly animal models. These findings cannot be directly equated with established efficacy in humans.

Early Evidence from Human Studies

The article also discusses early human studies.

In some studies, increased NAD⁺ or interventions intended to raise its levels have been associated with:

•  Improvements in certain measures of cardiovascular function 
•  Reductions in certain inflammatory markers and factors 
•  Improved mitochondrial function 

However, at the time of the article’s publication, human evidence was still developing. Further clinical studies were needed to establish efficacy and support the widespread clinical use of NAD⁺-based therapies.

How Can NAD⁺ Levels Be Increased?

One of the article’s main topics is how NAD⁺ levels might be restored.

The direct use of externally administered NAD⁺ faces limitations, including instability and limited bioavailability to many cells. For this reason, considerable attention has focused on NAD⁺ precursors, including:

• Nicotinamide (NAM)
• Nicotinamide riboside (NR)
• Nicotinamide mononucleotide (NMN)

These compounds can enter the biological pathways responsible for NAD⁺ production.

However, the author emphasizes that increasing the availability of NAD⁺ precursors alone may not address all the factors responsible for declining NAD⁺.

A Multitargeted Approach to NAD⁺ Restoration

The article emphasizes the idea that effective NAD⁺ restoration may require a multitargeted approach.

This approach consists of three main strategies.

1. Reducing NAD⁺ consumption

By reducing factors such as DNA damage and inhibiting pathways that contribute to excessive NAD⁺ consumption.

2. Increasing NAD⁺ recycling

By supporting the salvage pathway and increasing the activity of its key enzyme, NAMPT.

3. Reducing the loss of NAD⁺ breakdown products

The article also discusses NNMT, an enzyme that can divert nicotinamide metabolism toward a pathway that reduces its availability for recycling into NAD⁺.

The central concept is that increasing NAD⁺ requires attention to the balance between its production, consumption, and recycling, alongside the provision of NAD⁺ or its precursors.

Potential Routes of NAD⁺-Based Interventions

The article categorizes potential applications of different NAD⁺-raising approaches according to their route of administration and intended therapeutic purpose. The following are proposed applications rather than established clinical uses.

Route of administrationPotential applications discussed in the articleOral | Supporting cellular health throughout the body, with potential improvements in energy, cognitive function, general well-being, and sleep quality
Intravenous | Use before certain aesthetic procedures or surgeries with the aim of cellular preparation and support for repair and regeneration
Topical | Targeting specific areas to support skin repair and regeneration
Injectable | Potential use alongside certain aesthetic procedures, such as microneedling

The author introduces the concept of an Inside–Outside Approach to Aging. This involves addressing aging through cellular health within the body, together with topical or more localized approaches directed at the target tissue.

NAD⁺ and Aesthetic Medicine

One notable aspect of the article is the relationship between NAD⁺ and aesthetic medicine.

Many aesthetic treatments, including certain laser procedures and microneedling, work by inducing controlled stress in tissue. This stress activates cellular repair pathways and ultimately promotes tissue regeneration.

According to the perspective presented in the article, the proper function of many of these pathways depends on the metabolic state of the cell, with NAD⁺ representing an important contributing factor.

The author therefore proposes that optimizing cellular status before certain aesthetic treatments may, in the future, help improve tissue responses and repair processes.

The Future of NAD⁺ in Regenerative Medicine

Modern approaches to aging aim to address the cellular mechanisms that drive aging alongside its visible consequences.

NAD⁺ has become a target of interest in regenerative medicine research because of its involvement in:

•  Energy production 
•  Mitochondrial function 
•  DNA repair 
•  Epigenetic regulation 
•  Autophagy 
•  Inflammation 
•  Cellular senescence 
•  Stem cell function 

This is also relevant to aesthetic medicine, because the outcomes of many aesthetic procedures ultimately depend on the ability of cells to repair and regenerate.

This capacity declines with age. Supporting cellular function may therefore become an area of interest as a complementary approach in regenerative medicine.

Conclusion

NAD⁺ is a vital coenzyme that links energy metabolism, cellular signaling, DNA repair, mitochondrial function, and aging-related mechanisms.

The evidence discussed in the article indicates that NAD⁺ levels decline with age. This decline may be associated with increased DNA damage, mitochondrial dysfunction, inflammation, cellular senescence, and reduced regenerative capacity.

These relationships are particularly relevant to the skin, which is continuously exposed to damaging factors and depends on effective DNA repair, autophagy, mitochondrial function, and cellular regeneration to maintain its health.

Preclinical studies have shown that restoring NAD⁺ can improve many aging-related measures, while early human studies have also reported promising findings. However, larger and more rigorous human studies remain necessary to establish clinical efficacy and translate these findings into standard treatments.

NAD⁺ can therefore be considered a key molecule connecting cellular metabolism, aging, and tissue regenerative capacity. A better understanding of its production, consumption, and recycling pathways may support the development of new approaches in regenerative medicine, skin health, and aging-related interventions.

Prepared and compiled by:
Dr. Fahimeh Bahrami
Technical Manager, Behin Kara Darman Company

Source article:
Conlon, N. J. The Role of NAD⁺ in Regenerative Medicine. Plastic and Reconstructive Surgery, 2022