What Does NAD+ Do in Your Body? Breaking Down the Aging-Energy Connection

by Goldman Labs Team

Here's a startling fact: NAD+ levels drop by up to 50% between ages 40 and 60. Why should this matter to you and your health as you age?

NAD+ (nicotinamide adenine dinucleotide) exists as a vital coenzyme in every cell of your body. This remarkable molecule acts as both a metabolic messenger and energy transfer system that supports hundreds of life-sustaining biological processes. NAD+ serves as your cells' delivery service by moving electrons between reactions. This powers everything from simple energy production to DNA repair.

Your body's natural NAD+ levels decrease steadily with age. This creates a domino effect of health problems that affect energy production, cellular repair, and metabolic function. Scientists have connected this decline to several signs of aging, including mitochondrial dysfunction, genomic instability, and increased inflammation. Research points to healthy NAD+ levels supporting better skin health, brain function, and cellular resilience.

This piece helps you find what NAD+ does in your body at the cellular level and why levels drop with age. You'll also learn about the benefits of supporting NAD+ production. On top of that, it gets into practical ways to restore NAD+ levels, such as supplementation options like liposomal NAD+ and precursor compounds. The latest research sheds light on how NAD+ therapies might affect health and aging.

What Does NAD+ Do in the Body? A Cellular Overview

Scientists found that there was NAD+ back in 1906. At the time, they saw it as something that boosted fermentation rates in yeast ^[1]. But this molecule's significance is way beyond this simple observation. NAD+ (nicotinamide adenine dinucleotide) works as the central hub of cellular metabolism. It orchestrates countless biochemical reactions that are the foundations of life.

NAD+ as a Metabolic Messenger

NAD+ does much more than act as a coenzyme. It serves as a vital metabolic messenger that communicates cellular energy status throughout the body. The estimated total intracellular content of NAD+ in mammals sits between 200 to 500 μM ^[2]. This makes it one of the most abundant metabolites in the human body ^[3]. Such high prevalence highlights its fundamental importance.

NAD+ influences many pathways through its interaction with three major classes of enzymes:

Sirtuins (SIRT1-7) – These NAD+-dependent deacetylases exist in different cellular compartments. You'll find them in the nucleus (SIRT1, SIRT6, SIRT7), cytoplasm (SIRT2), and mitochondria (SIRT3-5) ^[2]. Sirtuins use NAD+ as a cosubstrate to remove acetyl groups from proteins. This regulates gene expression, DNA repair, and metabolic function.
Poly(ADP-ribose) polymerases (PARPs) – These enzymes use NAD+ during DNA repair processes and chromatin remodeling ^[4].
Cyclic ADP-ribose synthases – Enzymes like CD38 and CD157 use NAD+ to create second messengers involved in calcium signaling ^[4].

These interactions help NAD+ connect cellular metabolism to changes in signaling and transcriptional events ^[2]. Yes, it is remarkable how this molecule affects biological processes from DNA repair and gene expression to stress response and inflammation ^[3]. Scientists report that SIRT1's Km for NAD+ ranges from 94-96 μM in mammals ^[2]. This shows that SIRT1 activity responds to changes in NAD+ levels.

Role in Redox Reactions and Energy Transfer

NAD+'s most basic role comes from knowing how to accept and donate electrons in redox reactions. The molecule acts as a hydride acceptor and forms its reduced version, NADH. This process is vital for metabolic reactions in any discipline ^[1].

During glycolysis, NAD+ changes to NADH when GAPDH enzyme oxidizes glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate ^[4]. Each glucose molecule creates two NADH molecules in this process ^[4]. Under aerobic conditions, pyruvate then enters the mitochondria. Here it transforms into acetyl-CoA while creating another NADH from NAD+ ^[3].

The tricarboxylic acid (TCA) cycle produces more NADH through multiple enzymes:

Isocitrate dehydrogenase 3 (IDH3)
α-ketoglutarate dehydrogenase (KGDH)
Malate dehydrogenase (MDH2) ^[4]

The process creates eight NADH molecules from each glucose molecule that goes through the TCA cycle ^[3]. This NADH then gives electrons to Complex I (NADH:ubiquinone oxidoreductase) of the electron transport chain ^[2]. These electrons flow through other complexes. They create a proton gradient that powers ATP synthesis through oxidative phosphorylation ^[3].

The NAD+/NADH ratio plays a key role in cellular energy metabolism. NAD+ exists in amounts 600–1100 times higher than NADH ^[3]. The balance between these molecules remains vital for efficient mitochondrial function. This balance affects glycolysis, fatty acid oxidation, and the citric acid cycle ^[3].

NAD+ can also become NADP+ through phosphorylation. Along with its reduced form NADPH, it maintains redox balance and helps biosynthetic processes like fatty acid and nucleic acid synthesis ^[4]. NADH mainly fuels catabolic reactions like respiration. NADPH, on the other hand, works mostly in anabolic reactions ^[4].

Cells compartmentalize NAD+/NADH distribution because of specific NAD+ biosynthetic enzyme locations. The mitochondrial inner membrane's impermeability to these molecules also plays a role ^[4]. This compartmentalization needs various shuttle systems, like the malate–aspartate shuttle, to keep proper NAD+/NADH ratios across cellular compartments.

How NAD+ Influences the Hallmarks of Aging

NAD+ levels drop as we age, which links metabolism to biological aging processes. Studies show that less NAD+ speeds up how fast our cells break down, and this affects several key aspects of aging.

Genomic Instability and DNA Repair

DNA changes become more likely as we age. These changes include point mutations, deletions, and chromosomal rearrangements ^[5]. NAD+ helps keep our DNA stable in several ways.

NAD+ works as fuel for poly-ADP-ribose polymerase (PARP) enzymes, especially PARP1, which spots DNA damage. PARP1 jumps into action when it finds broken DNA and uses up to 90% of the cell's NAD+ ^[5]. This high NAD+ use helps PARP1 attach ADP-ribose molecules to broken DNA sites. This process brings in repair proteins like XRCC1, BRCA1, and Ligase V ^[5].

Our DNA repair ability gets substantially weaker when NAD+ levels drop with age. Research confirms that DNA damage builds up when NAD+ is low, but DNA repair improves when we boost NAD+ in cells ^[5]. Human DNA ligase IV, which we need to fix broken DNA ends, can also use NAD+ to join DNA pieces ^[5].

NAD+ does more than power PARP enzymes. It also turns on sirtuins (mainly SIRT1 and SIRT6) that help keep DNA stable. Studies show that adding NAD+ can reduce DNA damage markers like γH2AX in older cells ^[1] and lower DNA strand breaks ^[1].

Mitochondrial Dysfunction and Energy Decline

Our mitochondria's health also depends on NAD+. Less NAD+ as we age hurts mitochondrial function in several ways.

We need NAD+ and its reduced form NADH to make cellular energy. The balance between NAD+ and NADH controls many metabolic enzymes including pyruvate dehydrogenase, isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and malate dehydrogenase ^[2]. Mitochondria make less energy when this balance shifts with age.

NAD+ also activates mitochondrial sirtuins, especially SIRT3. This protein improves how well the energy-making machinery works by activating parts of Complexes I, II, and III ^[5]. SIRT3 also helps cells fight oxidative stress by:

Increasing NADPH, which lifts reduced glutathione levels
Making antioxidant enzymes like SOD2 and catalase work better ^[5]

Scientists have found that boosting NAD+ levels can fix age-related mitochondrial problems. To cite an instance, mice given nicotinamide riboside (NR) showed better mitochondrial function and energy production ^[2].

Cellular Senescence and Inflammation

Cells stop dividing as they age, which we call senescence. This process magnifies tissue aging and dysfunction. NAD+ affects both senescence and inflammation through many pathways.

NAD+ levels affect what senescent cells release - a mix of inflammatory signals called SASP. Research shows that NAD+ metabolism controls how strong these inflammatory signals become ^[6]. Adding NAD+ precursors might increase inflammatory signals ^[6].

This creates a tough cycle. Senescent cells cause inflammation, which turns on CD38 - an enzyme that breaks down NAD+ faster ^[7]. Lower NAD+ levels then create more senescent cells ^[7]. Scientists call this "aging's vicious cycle."

NAD+ and SIRT1 work together to affect senescence. Low NAD+/NADH ratios make cells become senescent in part by limiting energy production ^[5]. Studies show that senescent cells have less NAD+ compared to NADH in their cytoplasm, and their energy balance is off ^[5].

Skin cell studies show this relationship clearly. Low NAD+ leads to senescence by reducing SIRT1 activity, which lowers p63 and slows cell growth ^[8]. But adding NAD+ back can reduce senescent cells in skin fibroblasts ^[8].

NAD+'s role in aging connects deeply with these three processes. Each mechanism reinforces the others in a complex network that determines how well cells survive and how long they live.

Why NAD+ Levels Drop as You Age

"By far the largest study (enrolling 10 times more people than the other studies combined) found a slight drop in NAD+ in the aging bloodstreams" — Dr. Michael Greger, Physician and founder of NutritionFacts.org

NAD+ levels steadily drop in almost all tissues as we age. Scientists have seen this decline in both animals and humans. Brain scans show older people have lower NAD+ concentrations than younger individuals ^[4]. Let's explore why keeping healthy NAD+ levels becomes harder with age.

Overactivation of PARPs and CD38

Two enzyme systems—PARPs and CD38—are big players that speed up NAD+ loss as we age.

PARP enzymes, especially PARP1, act like DNA damage detectors that help protect our genetic code. PARP1 activation is vital for protection, but it comes with a cost. When it spots DNA damage, PARP1 can use up to 90% of cellular NAD+ ^[9]. DNA damage builds up naturally over time, so PARP activity rises and uses more NAD+ ^[4].

Strong PARP activation from severe damage can drain NAD+ and kill cells ^[9]. Research shows DNA repair-deficient rat neurons and human neuroblastoma cells lose more than half their NAD+ when PARP1 stays active ^[10]. This creates an odd situation where DNA repair, meant to protect cells, can hurt energy production by depleting NAD+.

CD38 stands out as the biggest factor in age-related NAD+ loss ^[7]. This enzyme uses NAD+ to make calcium-signaling molecules like ADPR (its main product), 2dADPR, NAADP, and cADPR ^[9].

CD38 stays quiet when we're young but ramps up with age ^[9]. Scientists found CD38 increases in many tissues as time passes ^[4]. This matters because CD38 knockout mice don't show the typical age-related drops in NAD+ and mitochondrial function seen in normal mice ^[4].

Inflammation and CD38 create a troubling loop. Aging cells release inflammatory signals that turn on CD38, mostly in immune cells ^[7]. This speeds up NAD+ breakdown and makes more cells age, creating what scientists call "aging's vicious cycle" ^[7].

Decline in NAMPT and Salvage Pathway Efficiency

NAD+ levels don't just fall because of increased use. The body's ability to make NAD+—particularly through the salvage pathway—drops a lot with age.

The salvage pathway recycles nicotinamide (NAM) into NAD+ and serves as our main NAD+ production route ^[11]. NAMPT sits at this pathway's heart and controls the key step in making NAD+ from NAM ^[11].

NAMPT levels drop with age in fat tissue, muscles, eye cells, and parts of the brain ^[12]. One study of eye cells showed NAMPT matched the age-related NAD+ decline, suggesting it drives NAD+ production in these cells ^[11].

Several factors might cause NAMPT to decrease. NAMPT follows daily rhythms that weaken with age, which could affect its levels ^[4]. Both human and mouse tissues show natural NAMPT decreases over time ^[13].

This creates a perfect storm: cells need more NAD+ to fight aging just when they're losing their ability to make it. Studies prove that low NAMPT leads to less NAD+ in tissues ^[14].

Fixing NAMPT helps—mice with extra NAMPT in fat tissue and those treated with young mouse cell particles showed better activity, sleep, blood sugar control, and lived longer ^[12]. This shows why keeping NAD+ production strong matters for healthy aging.

NAD+ Benefits for Energy, Skin, and Brain Health

Research shows that keeping optimal NAD+ levels brings many health benefits beyond simple cellular function. These benefits range from basic energy metabolism to visible improvements in skin and protection of brain health. Scientists continue to discover what NAD+ does when it returns to youthful levels through clinical studies.

Improved Mitochondrial Function and ATP Production

NAD+ supports cellular energy metabolism by taking part in redox reactions that create ATP ^[3]. This coenzyme works in both glycolysis and the electron transport chain, making the transfer of electrons possible for oxidative phosphorylation ^[15].

Studies show that bringing NAD+ back to normal levels creates remarkable benefits for energy metabolism:

Boosted mitochondrial function, more ATP production, and better quality muscle stem cells ^[3]
More activation of SIRT1 and SIRT3, which control mitochondrial biogenesis and recycling of damaged mitochondria ^[3]
Better cardiovascular markers including lower systolic blood pressure and less aortic stiffness ^[3]

On top of that, NAD+ helps cells defend against oxidative stress. Studies show NAD+ supplements can reduce high oxidative stress by up to 20.57% when combined with boosting compounds ^[16], which protects mitochondrial integrity.

Skin Rejuvenation via SIRT1 and SIRT6 Activation

NAD+ levels drop by about 50% every 20 years ^[5], making skin age faster. This reduction also affects sirtuins—especially SIRT1 and SIRT6—which are essential regulators of skin tissue's cellular health.

Studies show that applying NAD+ to skin can protect against both external aging (from UV exposure) and internal aging processes ^[16]. This protection happens through:

Skin stem cell rejuvenation ^[5]
Better autophagy from sirtuin activation ^[16]
More collagen production through increased fibroblast synthesis ^[5]

Clinical observations suggest that restoring NAD+ creates younger and healthier-looking skin by fixing DNA damage and reducing inflammation ^[5].

Cognitive Support and Neuroprotection

NAD+ plays vital roles beyond simple metabolism in the brain—an organ that needs lots of energy. Scientists have found neuroprotective effects in multiple studies when NAD+ levels are restored ^[17].

NAD+ helps fix cognitive problems and stops brain inflammation by protecting mitochondria and reducing reactive oxygen species ^[18]. This happens in part through the Sirt1/PGC-1α pathway, which creates more mitochondria in the brain ^[18].

Research shows NAD+ precursor supplements can:

Stop memory loss in test models ^[17]
Help with cognitive problems in neurodegenerative disease models ^[17]
Lower brain inflammation by changing microglial activity ^[18]

These brain benefits come from NAD+'s power to boost mitochondrial function, lower oxidative stress, and reduce inflammation ^[19]. These three connected mechanisms protect brain health as we age.

How to Restore NAD+ in the Body: Practical Approaches

NAD+ plays a vital role in cellular health. Scientists now prioritize finding ways to restore its declining levels in anti-aging research. Research has revealed several practical approaches that address NAD+'s functions in different contexts.

Supplementing with NR, NMN, and NAM

Pure NAD+ supplements don't work well because they're unstable and the body can't absorb them properly ^[3]. The focus has shifted to precursor compounds that your body converts into NAD+:

Nicotinamide Riboside (NR) - This compound skips a step in the NAD+ biosynthetic pathway, making it highly efficient ^[20]. Studies show NR can boost NAD+ levels in blood by 40-90% based on dosage ^[21]. Clinical trials confirm that NR doses up to 2,000 mg/day are safe for humans ^[21].
Nicotinamide Mononucleotide (NMN) - Your body needs just one step to convert this into NAD+ ^[2]. Clinical studies showed oral NMN (300 mg daily for 60 days) increased the intracellular NAD+/NADH ratio ^[2] and made metabolic health better. Patients with high blood pressure saw reductions of 6.11 mmHg systolic and 3.56 mmHg diastolic ^[1].
Nicotinamide (NAM) - This vitamin B3 form uses the salvage pathway but stops at the rate-limiting step that NR bypasses ^[20].

Combining Precursors with CD38 Inhibitors

Precursor supplements alone might not fix the problem long-term because they don't address why NAD+ levels drop ^[3]. Scientists found better results by combining precursors with CD38 inhibitors (CD38 is a main NAD+ consuming enzyme).

Natural CD38 inhibitors include:

Apigenin - You'll find this in parsley, celery, and onions. It blocks CD38 with an IC50 of 10.3 μmol/L ^[22]. Research shows it raises intracellular NAD+ levels based on dose ^[22].
Quercetin - This flavonoid blocks CD38 with an IC50 of about 16.4 μmol/L in cells ^[22].
78c - This synthetic CD38 inhibitor almost doubled NAD+ in cells and helped aged mice process glucose better ^[23].

Topical, Injectable, and Oral Delivery Methods

You can restore NAD+ through different routes that serve unique purposes:

Oral supplementation - The most available and affordable option, though absorption takes longer. This works best to improve cellular health throughout your body ^[3].
Intravenous administration - NAD+ goes straight into your bloodstream for quick effects ^[24]. Doctors use this method before esthetic procedures to prepare cells ^[3].
Topical application - This targets specific areas and works great for skin rejuvenation ^[3].
Injectable delivery - This method works well with esthetic procedures like microneedling ^[3].
Nasal spray - This helps NAD+ reach brain cells faster and helps if you have serious health issues ^[25].

Each delivery method affects how well your body absorbs and uses NAD+. The best approach matches your health goals, and sometimes combining methods offers a complete solution to boost NAD+ throughout your body ^[3].

What Does the Research Say About NAD+ Therapy?

Research backing NAD+ supplementation keeps growing. Scientists have conducted studies on both animals and humans. NAD+ therapy has sparked keen interest among researchers and health enthusiasts alike.

Preclinical Results in Mice and Rats

Animal research shows promising results when NAD+ levels are restored through precursor supplements. NAD+ boosters extended lifespan in several model organisms ^[26]. The studies revealed better heart function, improved muscle repair, enhanced mitochondrial and stem-cell performance, and changes in how rodents process glucose ^[6]. Research with NAD+ or its precursor NMN showed less heart enlargement, reduced scarring, and better heart failure indicators in different mouse models ^[27]. The mice that received NMN treatment (500 mg/kg) showed improved heart contractions and better heart muscle energy production in a cardiomyopathy model ^[27].

Human Trials on Metabolic and Inflammatory Markers

Animal studies look promising, but human trials show more modest results. Clinical research showed varying increases in blood NAD+ levels with NR supplements. FDA-approved 300 mg/day doses led to moderate increases (40–59%), while bigger boosts needed much higher doses (1000–2000 mg/day) ^[28]. Three studies that measured NAD+ in skeletal muscle found no increase, even at high doses ^[28].

Looking at inflammation markers, two studies showed NR reduced IL-6 levels, but effects on other markers like MCP-1 and TNF-α varied ^[29]. One study found that NR treatment decreased IL-6 and IL-18 gene expression in peripheral blood mononuclear cells ^[29]. All the same, researchers point out that NAD+ precursors don't work as well in humans as predicted from animal studies ^[8].

Safety and Tolerability of NAD+ Precursors

NAD+ precursors have proven quite safe. The FDA has given NR its "Generally Recognized as Safe" status, and multiple regulatory bodies have approved it ^[6]. Human trials showed good tolerance to relatively high doses. Heart failure patients handled 1,000 mg twice daily well, taking 97% of their prescribed capsules ^[30]. Animal studies set the no-observed-adverse-effect level (NOAEL) for NR at 300 mg/kg/day ^[6]. Humans now have a 3-year-old upper limit of 3 mg/kg/day (about 180 mg/day for a 60 kg adult) ^[6].

Conclusion

The Future of NAD+ Research: Balancing Promise and Viewpoint

NAD+ plays a vital role as a cellular linchpin that influences energy production, DNA repair, and overall cellular resilience. This fundamental molecule was once viewed through the narrow lens of redox reactions. Now it stands at the center of aging biology research. Scientists have without doubt shown how declining NAD+ levels link to several hallmarks of aging, including mitochondrial dysfunction, genomic instability, and increased inflammation.

Multiple approaches can restore diminishing NAD+ levels. Precursor supplementation through compounds like NR, NMN, and NAM provides available interventions. Combination therapies that address both production and consumption pathways look particularly promising. People seeking to support their NAD+ levels can choose from delivery methods of all types, each offering specific advantages based on their health goals.

Clinical research on NAD+ therapy evolves with important nuances. Animal studies show remarkable benefits, while human trials reveal more modest outcomes. This difference emphasizes human metabolism's complexity and why individual-specific approaches to NAD+ restoration matter. Notwithstanding that, NAD+ precursors' favorable safety profile suggests they could work well for long-term use with proper guidance.

Scientists must tackle several unresolved questions. The optimal dosing protocols remain unclear, especially given how differently individuals respond to NAD+ precursors. Researchers need to identify which populations might benefit most from NAD+ interventions. The long-term effects of sustained NAD+ supplementation need further study to ensure both safety and efficacy.

NAD+'s story represents a fascinating mix of simple science and practical health applications. This coenzyme exists in every living cell and connects metabolic health, energy production, and cellular repair mechanisms in ways scientists continue to discover. While not a miracle solution to aging, NAD+ restoration helps support cellular resilience as the body ages. Learning about what NAD+ does throughout the body is a great way to get knowledge if you want to maintain optimal cellular function throughout life.

FAQs

Q1. How does NAD+ impact the aging process? NAD+ levels naturally decline with age, contributing to various age-related issues. Restoring NAD+ levels through supplementation has shown potential benefits in animal studies and some clinical trials, including improved cellular energy production, DNA repair, and metabolic function.

Q2. What are the primary functions of NAD+ in the body? NAD+ plays a crucial role in cellular metabolism, acting as a coenzyme in redox reactions and as a substrate for enzymes involved in DNA repair, gene expression, and stress response. It's essential for energy production in mitochondria and influences various cellular processes related to aging.

Q3. How does NAD+ contribute to energy production? NAD+ is vital for energy production through its role in the electron transport chain within mitochondria. It accepts and donates electrons, cycling between its oxidized (NAD+) and reduced (NADH) forms. This process is crucial for generating ATP, the primary energy currency of cells.

Q4. Can NAD+ supplementation improve skin health? NAD+ is involved in activating sirtuins, particularly SIRT1 and SIRT6, which play roles in skin health and rejuvenation. Some studies suggest that NAD+ supplementation may support collagen production, enhance DNA repair in skin cells, and potentially reduce visible signs of aging.

Q5. What are the most effective ways to boost NAD+ levels? Several approaches can help increase NAD+ levels, including supplementation with precursors like nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN). Combining these with natural CD38 inhibitors like apigenin or quercetin may enhance effectiveness. Additionally, lifestyle factors such as exercise and calorie restriction can naturally support NAD+ production.

References

Item added to your cart

What Does NAD+ Do in Your Body? Breaking Down the Aging-Energy Connection

What Does NAD+ Do in the Body? A Cellular Overview

NAD+ as a Metabolic Messenger

Role in Redox Reactions and Energy Transfer