NAD and Longevity: New Research Reveals Critical Role in Human Aging

by Goldman Labs Team

NAD and longevity share a deep biological connection that scientists have started to understand recently. NAD levels drop substantially as humans age—research shows a twofold decrease in older organisms, including multiple tissues of mice. This decline does more than just signal aging - it actively contributes to age-related cellular dysfunction.

NAD molecules play a vital role in cellular metabolic pathways, including glycolysis, mitochondrial oxidative phosphorylation, and protection against oxidative stress. The body's supply of this vital compound diminishes over time because of increased oxidative stress, DNA damage, inflammation, and cellular senescence. Scientists have found NAD metabolism's role in aging and longevity, which has sparked extensive research into possible interventions. Research shows that the enzyme CD38 acts as a major NADase that contributes to age-related NAD decline. CD38 knockout mice have shown NAD levels ten to twenty times higher than normal mice.

Scientists have found promising results in their research on NAD and NAD precursors for health and longevity. NMN supplementation has shown improved physiological functions and extended lifespan in aged mice. NAD therapy approaches that target the "NAD World" concept have emerged as potential strategies to curb age-related deterioration. The concept emphasizes how declining NAD+ levels drive aging systemically. Scientists have also found that eNAMPT, an enzyme from adipose tissue, helps maintain NAD levels across tissues and influences the aging process.

Molecular Structure and Redox Function of the NAD Molecule

Nicotinamide adenine dinucleotide (NAD) has a dinucleotide structure where two nucleotides connect through their phosphate groups. One nucleotide contains an adenine nucleobase while the other has nicotinamide ^[1]. This small molecule plays a huge role in cellular metabolism because it can participate in redox reactions, which makes it vital for life processes.

NAD+/NADH Interconversion in Energy Metabolism

NAD comes in two main forms: oxidized (NAD+) and reduced (NADH). These forms convert back and forth in one of the most basic processes of cellular energy metabolism. NAD+ accepts electron hydride ions from glycolysis, the tricarboxylic acid (TCA) cycle, and fatty acid oxidation to create NADH ^[2]. This cycle works both ways, letting NADH give electrons to other molecules while changing back to NAD+ ^[1].

NAD+ works as a vital cofactor during glycolysis's sixth step. Here, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) changes glyceraldehyde-3-phosphate into 1,3-bisphosphoglycerate and reduces NAD+ to NADH ^[2]. The glycolytic pathway stops without enough NAD+, even though many think phosphofructokinase limits the rate ^[1].

Pyruvate then moves into mitochondria where the pyruvate dehydrogenase complex turns it into acetyl-CoA and creates more NADH ^[2]. The mitochondrial TCA cycle has three NAD+-dependent enzymes that reduce NAD+ to NADH: isocitrate dehydrogenase 3 (IDH3), α-ketoglutarate dehydrogenase (KGDH), and malate dehydrogenase (MDH2) ^[2]. A single glucose molecule produces multiple NADH molecules through these pathways - two from glycolysis and eight from the TCA cycle when oxygen is present ^[2].

The inner mitochondrial membrane blocks NADH from passing through. Special shuttle systems - mainly the malate-aspartate shuttle and glycerol-3-phosphate shuttle - move reducing equivalents from cytosolic NADH into mitochondria ^[2]. Inside mitochondria, NADH gives electrons to Complex I (NADH:ubiquinone oxidoreductase) of the electron transport chain, which drives ATP synthesis through oxidative phosphorylation ^[3].

Comparison with ATP in Cellular Bioenergetics

NAD and ATP work together but serve different purposes in cellular bioenergetics. ATP stores and transfers energy through its high-energy phosphate bonds as the cell's main energy currency. NAD carries electrons and helps redox reactions throughout metabolism ^[4].

These molecules share a close relationship but work differently. NADH from various metabolic pathways gives electrons to the electron transport chain. This creates a proton gradient across the inner mitochondrial membrane that powers ATP synthesis through F0F1-ATP synthase ^[3]. NAD+ reduction to NADH captures metabolic energy that later becomes ATP.

ATP and NAD differ in how cells use them. ATP breaks down during energy use, but NAD+ and NADH switch forms without getting used up in redox reactions ^[1]. ATP mainly transfers energy, while NAD also helps with signaling through NAD+-dependent enzymes like sirtuins and PARPs ^[1].

The NAD+/NADH ratio shows how healthy cell metabolism is and affects many biochemical reactions' thermodynamics ^[5]. Research on brain tissue shows NAD and ATP levels rise and fall together, proving they work together in human metabolism ^[5].

These molecules also differ in where they concentrate in cells. Mouse skeletal muscle has twice as much NAD+ in mitochondria compared to the rest of the cell. Mouse cardiac myocytes have four times as much ^[3]. This arrangement lets cells control NAD+-dependent processes separately in different locations.

NADP+ and its reduced form NADPH help with different tasks. They support anabolic processes and fight oxidative stress rather than produce energy ^[4]. This split in duties - NAD+/NADH for breaking down molecules and making ATP versus NADP+/NADPH for building molecules and protecting against oxidation - shows a basic pattern in cell biochemistry.

NAD as a Substrate in Signaling and Protein Modification

NAD+ plays a vital role in redox reactions and acts as a substrate in many signaling and protein modification pathways. Unlike redox reactions where NAD+ transfers electrons without breaking down, these signaling pathways consume NAD+ molecules. These pathways are the foundations of cellular stress responses, gene expression regulation, and calcium mobilization that associate closely with aging and longevity.

ADP-Ribosylation by PARPs and SIRTUINS

The ADP-ribosylation process is a major NAD+-consuming pathway that transfers the ADP-ribose moiety from NAD+ to specific amino acid residues on target proteins. This post-translational modification substantially changes protein function through two main enzyme families: poly(ADP-ribose) polymerases (PARPs) and sirtuins (SIRTs).

PARPs use NAD+ to add ADP-ribose units to proteins, DNA, and RNA. Humans have 17 members in the PARP family with different functions ^[6]. The "polyenzymes" (PARP-1, PARP-2, PARP-5a, and PARP-5b) create branched or linear poly(ADP-ribose) chains. The "monoenzymes" (including PARP-3, PARP-4, PARP-6, and others) add single ADP-ribose units ^[6]. PARP-1 handles 85-90% of all DNA damage-induced PARP activity ^[7].

DNA damage can trigger continuous PARP activation that depletes cellular NAD+ levels by up to 80% ^[6]. This drop severely affects cellular metabolism because NAD+ is central to energy production. Aging tissues show increased PARP1 activation that links to higher DNA damage, which might lead to age-related NAD+ decline and metabolic problems ^[7].

Scientists first identified sirtuins as silent information regulators that work as NAD+-dependent deacetylases. Unlike regular histone deacetylases, sirtuins need NAD+ to remove acetyl groups from proteins. This process creates nicotinamide and O-acetyl-ADP-ribose ^[6]. Most sirtuins' Km values for NAD+ range from 100-300 μM, matching normal NAD+ concentration changes ^[6]. This makes sirtuins excellent cellular NAD+ sensors that connect their activity to the cell's metabolic state.

PARPs and sirtuins compete for the same limited NAD+ pool, which affects aging. Age-related DNA damage often increases PARP activity. The resulting NAD+ depletion can stop sirtuin activity ^[6]. Sirtuins help promote longevity by regulating mitochondrial function, stress responses, and genomic stability. This competition might speed up aging processes.

cADPR and NAADP in Calcium Signaling

NAD+ and its phosphorylated form NADP+ create two powerful calcium-mobilizing messengers: cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP).

Scientists first found cADPR, a cyclic nucleotide from NAD+, in sea urchin egg homogenates. Now we know it exists in many cell types including human T cells ^[2]. ADP-ribosyl cyclases and CD38 make this molecule ^[8]. cADPR helps release calcium by adjusting ryanodine receptors. This enables calcium-induced calcium release—a major calcium mobilization mechanism that works alongside the inositol trisphosphate (IP3) pathway ^[2].

The same enzymes that make cADPR also produce NAADP from NADP+ under different conditions ^[8]. Though structurally different from cADPR, NAADP powerfully mobilizes calcium from unique stores that don't respond to cADPR or IP3 ^[2]. Living cells show long-lasting calcium oscillations when scientists photoactivate caged NAADP, suggesting its role in creating rhythmic calcium signals ^[2].

These calcium signaling molecules help with fertilization, neurotransmitter release, T-cell activation, and plant gene expression ^[8]. The rise of multiple calcium mobilization pathways shows how precise calcium regulation matters for cellular processes that affect health and longevity.

These NAD+-dependent signaling and modification pathways create a complex regulatory network. They influence cellular stress responses, metabolic adaptation, and calcium balance—processes tied to aging and longevity. As NAD+ levels drop with age, these pathways start to fail, which likely contributes to cellular dysfunction we see in aging.

NAD Biosynthesis Pathways in Mammals

Mammals have developed multiple distinct ways to blend NAD+, a vital molecule for cell function and longevity. Scientists group these biosynthetic routes into the de novo pathway that starts from tryptophan and several salvage pathways that reuse preformed pyridine compounds. These pathways join to create the same essential molecule but differ in their tissue distribution, regulation, and how much they contribute to cell NAD+ pools.

De Novo Pathway from Tryptophan

The de novo synthesis of NAD+ is unique because it creates the nicotinamide moiety from scratch. This process employs the essential amino acid tryptophan as its starting material. The multi-step process, known as the kynurenine pathway, happens mainly in the liver, kidney, and certain immune cells. The original step turns tryptophan into N-formylkynurenine. This reaction, which limits the rate of the entire pathway, is triggered by tryptophan-2,3-dioxygenase (TDO) in liver or indoleamine-2,3-dioxygenase (IDO) in extrahepatic tissues ^[3].

Several enzyme reactions lead to α-amino-β-carboxymuconate-ε-semialdehyde (ACMS), which marks a key turning point. ACMS can either turn into quinolinic acid (QA) through spontaneous cyclization or break down completely due to α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) ^[3]. ACMSD's activity determines how much tryptophan becomes NAD+. Studies show that blocking ACMSD lifts NAD+ levels 1.4 times in hepatocytes and makes mitochondria work better ^[3].

The last steps involve quinolinate phosphoribosyltransferase (QPRT) changing QA to nicotinic acid mononucleotide (NAMN). Nicotinamide mononucleotide adenylyltransferases (NMNATs) then change this into nicotinic acid adenine dinucleotide (NAAD). NAD+ synthetase (NADSYN) then changes NAAD to NAD+ using ATP ^[3].

NAMPT-Mediated Salvage Pathway

Most mammalian tissues make NAD+ by recycling nicotinamide (NAM) that comes from NAD+-consuming reactions. This two-step salvage pathway starts with nicotinamide phosphoribosyltransferase (NAMPT). This rate-limiting enzyme changes NAM and phosphoribosyl pyrophosphate (PRPP) into nicotinamide mononucleotide (NMN) ^[9].

NAMPT plays a key role in keeping cellular NAD+ levels stable, as many studies have shown. You can find NAMPT in almost every tissue and cell type, which shows how important it is for normal cell function ^[1]. The protein exists both inside and outside cells, with the internal form mainly in the cytosol and nucleus ^[1].

After NMN forms, nicotinamide mononucleotide adenylyltransferases (NMNATs) trigger the final adenylation reaction that creates NAD+ ^[10]. The NAD+ salvage pathway becomes more active in some diseases. Psoriatic skin, for example, shows higher NAD+ levels that associate with increased NAMPT transcription. These levels drop after treatment with anti-IL-17A biologics ^[11].

NRK Pathway for Nicotinamide Riboside

Scientists have found another way to make NAD+ that uses nicotinamide riboside (NR), a vitamin B3 found in milk. NR gets phosphorylated by nicotinamide riboside kinases (NRK1 and NRK2) to create NMN, which then becomes NAD+ through NMNAT activity ^[1].

NRK1 and NRK2 work differently in various tissues and bind to substrates with different strengths. NRK1 appears everywhere in the body and has a KM of 0.088 mM for NR. NRK2 mainly shows up in skeletal muscle and heart with a KM of 0.19 mM ^[1]. NRK1 can use both ATP and GTP as helpers, while NRK2 only works with ATP ^[1].

New research shows that NRK1 is crucial not just for making NAD+ from NR but also from NMN ^[12]. NMN must first lose its phosphate and become NR before cells can absorb it. This became clear when NRK1-knockout hepatocytes stopped responding to NMN but still worked with other NAD+ building blocks ^[12].

Finding these different ways to make NAD+ has changed how we think about metabolism in aging and longevity. Each pathway offers new ways to boost NAD+ levels and fight age-related decline. NR and NMN look particularly promising in early studies of age-related conditions.

Mechanisms of NAD Degradation and Turnover

NAD biosynthesis pathways restore cellular NAD pools, but cells constantly break down NAD through various enzymatic processes. Cells turn over NAD at a surprisingly fast rate. Some tissues show NAD half-lives of just minutes ^[13]. Learning about these breakdown pathways helps us understand NAD metabolism's role in aging and longevity.

CD38 as the Primary NADase in Tissues

CD38 (Cluster of Differentiation 38) emerges as the key NAD-degrading enzyme in mammalian tissues ^[14]. This versatile ectoenzyme works as both a glycohydrolase and ADP-ribosyl cyclase. The enzyme's main reaction breaks the high-energy β-glycosidic bond between nicotinamide and ribose parts in NAD ^[14]. CD38 produces nicotinamide and ADP-ribose, along with smaller amounts of cyclic ADP-ribose—a powerful calcium-mobilizing second messenger ^[14].

CD38's expression and activity rise high during aging. This age-related increase guides the steady NAD decline we see in older organisms ^[5]. Yes, it is worth noting that removing CD38 genes protects against age-related NAD decline and the resulting mitochondrial problems ^[14]. CD38 knockout mice keep their NAD levels stable as they age, unlike wild-type mice whose tissue NAD levels drop substantially ^[5].

CD38 not only consumes NAD but also serves as the main enzyme that breaks down nicotinamide mononucleotide (NMN) in vivo ^[5]. This dual role makes CD38 a vital regulator of both NAD levels and NAD precursor availability. Scientists now see it as a promising target for NAD restoration therapies.

PARP1 Activation in DNA Damage Response

PARP1 and its family members represent another major NAD consumer. DNA damage activates PARP1, which then builds poly(ADP-ribose) chains using NAD as raw material ^[15]. This process, called PARylation, plays a vital role in DNA repair but comes at a high metabolic price.

Heavy PARP1 activation from major DNA damage can drain 80-90% of cellular NAD within 8 hours ^[15]. This quick NAD depletion sets off a chain of metabolic problems that end up depleting ATP and disrupting cellular function ^[15]. Scientists found that blocking PARP1 prevents NAD loss, oxidative stress, and heart muscle cell dysfunction ^[15].

DNA damage, PARP1 activation, and NAD depletion create a dangerous cycle. Lower NAD levels cause more oxidative stress, leading to more DNA damage and PARP1 activation ^[15]. Breaking this cycle by blocking PARP or restoring NAD helps preserve cellular function in many aging and disease models ^[15].

SARM1 in Neuronal NAD Depletion

SARM1 (Sterile Alpha and TIR Motif containing 1) stands out as a key NAD-degrading enzyme in neurons. Scientists first found it as a crucial part of axon degeneration, and later discovered it works as a TIR domain NADase ^[4].

SARM1 activation causes remarkably fast NAD depletion. Neurons lose about 66% of their NAD just 15 minutes after SARM1 activates through TIR domain dimerization. This loss reaches 90% after 90 minutes ^[16]. ATP loss follows this sharp NAD decline and eventually destroys axons ^[4].

SARM1 breaks down NAD through direct chemical cleavage rather than blocking synthesis or pushing it out of cells ^[4]. Cells can fight this destructive activity by making more NAD—either by producing NAD synthetic enzymes NAMPT and NMNAT or by adding the NAD precursor nicotinamide riboside (NR) ^[4].

The balance between these breakdown pathways and NAD production determines cellular NAD levels, which shapes metabolic health, stress responses, and potential lifespan.

Age-Related Decline in NAD Levels Across Tissues

"I believe that aging is a disease. I believe it is treatable. I believe we can treat it within our lifetimes." — David A. Sinclair, Professor of Genetics at Harvard Medical School, longevity researcher

Research shows a clear pattern of NAD+ reduction across multiple tissues as we age. This pattern helps us understand the connection between nad and longevity. The decrease in NAD levels affects key metabolic processes and leads to various forms of cellular aging.

NAD Decline in Liver, Muscle, and Brain

NAD+ levels drop in tissues of all types as age advances, though some tissues show bigger drops than others. Aged rodents' skeletal muscle shows NAD+ drops between 15% and 65% ^[17]. This creates a major energy deficit in high-energy tissues. The liver shows a 10-50% decline ^[18]. Human liver samples from people over 60 have about 30% less NAD+ than those under 45 ^[18].

The brain's NAD+ decline follows a unique pattern. It starts between weaning and young adulthood and drops further by middle age (12 months in mice) ^[18]. This happens earlier than in most other tissues. Brain imaging studies of humans show a 10-25% drop in NAD+ from young adulthood to old age ^[18]. People over 45 have about 14% lower NAD(H) levels in their cerebrospinal fluid compared to younger people ^[18].

Human skin shows even more dramatic changes. NAD+ levels drop by at least 50% throughout adult aging. Adults have several times less NAD+ compared to newborns ^[18].

Circadian Oscillation and Nutritional Influence

NAD+ levels aren't fixed - they follow a strong 24-hour pattern in tissues of all types. These levels can change by 40-53% during daily cycles ^[19]. NAD+ works like a metabolic clock that controls core timing machinery through SIRT1 ^[19].

NAMPT controls this rhythm as the key enzyme in NAD+ production. Mouse liver and white fat tissue show strong daily patterns of NAMPT RNA, reaching its peak at dark period start (zeitgeber time 14) ^[19]. NAD+ levels match this pattern with two peaks that line up with NAMPT protein levels ^[19].

Diet has a big impact on this daily NAD+ cycle. Eating less increases NAD+ while lowering NADH levels ^[6]. This activates sirtuins that help with longevity. High-fat diets, obesity, and type 2 diabetes lower tissue NAD+ levels ^[6]. Moderate weight loss increases SIRT1 and NAMPT expression while PARP activity drops by a lot ^[6]. This shows how NAD+ metabolism adapts to changes in diet.

Subcellular Compartmentalization of NAD Pools

Cells don't distribute NAD+ evenly throughout their structure. Mitochondrial NAD+ concentrations are twice as high as the rest of mouse skeletal muscle cells and four times higher in mouse heart cells ^[18]. The mitochondrial NAD+ redox state has more reduction than cytosolic NAD+ ^[18].

This uneven distribution creates distinct metabolic zones that react differently to aging and stress. NAD+ pools inside cells connect to each other, with mitochondria helping maintain NAD+ levels during heavy use ^[7]. They do this by bringing in NAD+ through the SLC25A51 transporter and breaking it down into nicotinamide mononucleotide and ATP when NMNAT3 exists ^[7].

Changes in mitochondrial content with age can alter total tissue NAD+ without changing NAD+ levels in specific parts of the cell ^[18]. This explains why measuring total tissue NAD+ might not show the real metabolic situation in specific cellular compartments.

Consequences of NAD Decline on Aging Biology

NAD+ levels drop as we age, and this triggers many biological breakdowns. When NAD+ becomes less available, vital cell processes start to fail. This sets off a chain reaction that speeds up aging.

SIRT1 and SIRT3 Activity Reduction

The age-related NAD+ decline affects how sirtuins work, especially when you have SIRT1 and SIRT3. These NAD+-dependent deacetylases need enough NAD+ to work properly. NAD+ drops in aged tissues make sirtuins less active ^[8]. This creates a metabolic weak point because sirtuins control many pathways that keep cells healthy.

SIRT3, which mainly works in mitochondria, becomes much less active with age. It drops by about 38% in liver samples from high-fat diet-fed mice ^[2]. This SIRT3 slowdown leads to too much acetylation of its target proteins. The targets include key parts of the electron transport chain: NDUFA9 (Complex I), SDHA (Complex II), and core I subunit of Complex III ^[8]. On top of that, SIRT3 usually boosts cellular antioxidant capacity by activating SOD2 and catalase through deacetylation ^[8].

Mitochondrial Dysfunction and Oxidative Stress

NAD+ shortage causes serious mitochondrial breakdown as we age. Research shows disrupted breathing capacity in complexes III, IV, and V in mice without SIRT3 on high-fat diets ^[2]. These problems show up as increased protein oxidation in mitochondria and reduced oxidative phosphorylation enzyme activities ^[2].

Low NAD+ creates a "pseudohypoxic state" because SIRT1 slows down ^[20]. This condition makes HIF-1α stable, which then traps c-Myc. This prevents TFAM, a mitochondrial transcription factor, from getting activated ^[20]. This causes a big drop in mitochondrial gene expression, making metabolic problems worse in aged tissues.

Epigenetic Drift and DNA Repair Impairment

NAD+ decline weakens genomic stability at its core. Cells with low NAD+ can't fix DNA damage well, which leads to more genomic instability ^[8]. DNA damage-activated PARPs use up to 90% of cell NAD+, so repair heavily depends on NAD+ availability ^[8]. Low NAD+ lets DNA damage build up, but adding more NAD+ gets repair going again ^[8].

Beyond direct DNA damage, low NAD+ changes how genes get controlled. NAD+ shortage raises methylation of specific gene promoters. This pushes away DNA methylation-sensitive factors and changes histone methylation and acetylation ^[8]. These changes pack chromatin tighter and silence genes. Scientists call this "epigenetic drift" - a key sign of aging where epigenetic patterns keep moving away from their youthful state ^[21].

Evaluating NAD and NAD Precursors for Health and Longevity

"The science of aging is advancing rapidly, and we are on the verge of breakthroughs that will change the way we age." — Joon Yun, Managing Partner at Palo Alto Investors, longevity advocate

Scientists are working faster to combat age-related NAD+ decline. Their research centers on using nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) supplements to improve health and extend lifespan.

NMN and NR Supplementation in Animal Models

Mice fed with NMN in regular chow for 12 months showed remarkable benefits with no toxic effects. The supplements reduced age-related decline and body weight dropped by 4-9%. The mice's energy metabolism and physical activity improved ^[22]. Their bodies turned oral NMN into NAD+ in tissues within minutes ^[22].

Mice on high-fat diets didn't gain weight when given NR supplements ^[23]. NR also helped yeast live longer by more than 10 generations ^[24]. Even older mice lived 5% longer when given NR late in life ^[24].

Impact on Insulin Sensitivity and Muscle Function

NMN treatment worked well to improve insulin action and secretion in mice with diet and age-induced diabetes ^[22]. The treatment made older mice more sensitive to insulin without changing their muscle NAD+ levels. Instead, it sped up NAD+ turnover ^[25].

A 10-week study of postmenopausal women with prediabetes showed promising results. Daily NMN supplements (250mg) made their muscles 25% more sensitive to insulin ^[25]. Their insulin signaling improved as shown by increased insulin-stimulated phosphorylation of AKT and mTOR in muscle tissue ^[25].

Human Trials and Pharmacokinetics

The human body absorbs NMN quickly. It moves from gut to blood in 2-3 minutes and reaches tissues within 15 minutes ^[22]. NR supplements also increase blood NAD+ metabolome based on dose. Scientists tested single doses of 100, 300, and 1,000 mg ^[23].

Clinical trials proved NR safe at doses up to 2000mg daily ^[26]. Results varied across studies though. Some patients with premature aging showed better motor coordination ^[26]. Other older diabetic patients showed no improvement in grip strength or walking speed ^[26].

Both supplements show potential but work differently in various tissues. Animal and human studies often yield different results.

Targeting NAD Metabolism: Inhibitors and Transporters

Scientists have discovered promising targets beyond simple precursor supplementation through their research on NAD metabolism. Their work now centers on enzymes and transporters that control NAD levels, which opens new therapeutic possibilities to address age-related NAD decline.

CD38 Inhibitors and eNAMPT-EVs

CD38 is the main NAD-degrading enzyme found in mammalian tissues, and its expression grows as we age ^[27]. Scientists have found that thiazoloquin(az)olin(on)e compounds, particularly 78c, act as powerful CD38 inhibitors with excellent specificity ^[27]. This small molecule raises tissue NAD+ levels through a reversible uncompetitive mechanism ^[27]. Older mice showed improved glucose tolerance and reversed NAD+ decline when treated with 78c, without changes in their food intake or weight ^[27].

Scientists also use antibody-based approaches like isatuximab to target CD38's ectoenzymatic activity ^[28]. CD38 inhibition not only preserves NAD+ but also improves NMN availability, which addresses multiple aspects of NAD metabolism ^[28].

Extracellular vesicles containing extracellular NAMPT (eNAMPT-EVs) show great promise too. Adipose tissue produces these vesicles that deliver active NAMPT to target tissues ^[29]. Aged mice received weekly supplements of eNAMPT-EVs from young mice, which extended their median and maximal lifespan by 10.5% and 16.3% respectively ^[29].

Slc12a8 Transporter in NMN Uptake

Scientists made a breakthrough when they identified Slc12a8 as the first specific NMN transporter, which helped them understand NAD precursor utilization better ^[3]. Slc12a8 helps with sodium-dependent NMN transport, especially in the small intestine where we find its highest expression ^[3]. Research shows that NMN uptake stopped completely both in vitro and in vivo when Slc12a8 was knocked down ^[3].

The aged ileum shows increased Slc12a8 expression as it tries to compensate for declining NAD+ levels ^[3]. This natural increase helps maintain intestinal NAD+ balance during aging, which makes Slc12a8 a valuable therapeutic target.

Combination Therapies with NAD Precursors

Research now points to combining NAD precursors with compounds that target metabolism. To name just one example, see how giving NMN with resveratrol increased NAD+ levels in heart and skeletal muscle more than NMN alone ^[30]. AMPK activators like metformin also improve NAMPT activity and might work well with NAD precursors ^[31].

Conclusion

NAD metabolism research is 20 years old and shows this molecule's crucial role in cellular health and longevity. NAD decline forms the foundations of aging biology. It affects multiple tissues and cellular compartments through various metabolic and signaling pathways. NAD levels drop and cause mitochondrial function, genomic stability, and epigenetic regulation to deteriorate. This creates a cascade of cellular dysfunction that marks aging.

Animal studies show that targeting NAD metabolism improves healthspan and could extend lifespan by a lot. NMN and NR supplements have become promising strategies that benefit insulin sensitivity, muscle function, and metabolic health. Clinical trials now confirm these compounds' safety while showing tissue-specific effects that need more research.

Scientists can now tap into the full potential of NAD beyond simple precursor supplements through targeted approaches on NAD degradation pathways. CD38 inhibitors reverse age-related NAD decline effectively. Researchers found that manipulating eNAMPT-containing extracellular vesicles extends lifespan in aged mice. The Slc12a8 transporter's discovery gave an explanation about cellular NMN uptake mechanisms.

NAD's relationship with longevity goes beyond our current knowledge. Research must tackle questions about optimal dosing, intervention timing, and possible synergies between different approaches. The largest longitudinal study in humans will determine if NAD-boosting strategies can lead to meaningful extensions of healthy human lifespan.

NAD metabolism connects simple aging biology with translational geroscience. Scientists see NAD as more than just a coenzyme - it's a central regulator of cellular aging processes. This new understanding has revolutionized how researchers develop interventions for healthy aging. NAD metabolism research continues to uncover novel strategies that could extend human healthspan and longevity.

FAQs

Q1. How does NAD+ impact the aging process? NAD+ plays a crucial role in cellular energy production and mitochondrial function. As NAD+ levels naturally decline with age, it can contribute to various age-related issues. Maintaining adequate NAD+ levels may help support overall cellular health and potentially slow certain aspects of the aging process.

Q2. Can increasing NAD+ levels extend lifespan? Research in various organisms, including yeast, worms, and mice, has shown promising results where boosting NAD+ levels extended lifespan. However, more studies are needed to determine if these effects translate to humans and to what extent NAD+ supplementation might impact human longevity.

Q3. What are the potential benefits of NAD+ therapy for skin health? NAD+ therapy may help improve skin health by supporting cellular repair processes. It could potentially help reduce damage caused by UV rays and decrease skin sensitivity to sun exposure. However, it's important to note that while NAD+ may support skin health, it should not replace proper sun protection measures.

Q4. At what age should someone consider NAD+ supplementation? There's no specific age requirement for NAD+ supplementation. While NAD+ levels naturally decline with age, individuals of any age might benefit from supplementation, especially if they have specific health concerns related to energy, cognition, or overall wellness. It's always best to consult with a healthcare professional before starting any new supplement regimen.

Q5. What are the most effective ways to boost NAD+ levels? Several strategies can help boost NAD+ levels, including supplementation with precursors like NMN (Nicotinamide Mononucleotide) or NR (Nicotinamide Riboside), regular exercise, maintaining a healthy diet rich in NAD+ precursors, and practicing calorie restriction or intermittent fasting. The effectiveness may vary among individuals, and a combination of approaches might be most beneficial.

References

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