Ginkgo Biloba And Recall — Does It Actually Work?
Quick Read Ginkgo biloba’s reputation as a memory supplement is more complicated than headlines suggest. Research shows it does not
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NAD+ is a molecule your cells need to produce energy. As you age, NAD+ levels drop significantly, partly because an enzyme called CD38 destroys it faster. This decline appears to explain why fatigue, muscle weakness and sluggish metabolism become more common with age. Research in mice shows that restoring NAD+ can improve energy production and even reverse some signs of aging, though these studies have not yet been replicated in large human trials.
One human study found that taking 250 mg daily of NMN, a precursor to NAD+, successfully raised blood NAD+ levels and produced modest improvements in walking speed and grip strength in healthy older men over 6-12 weeks. The supplement appears safe with no serious side effects reported. However, the trial was small and short, and we do not yet know whether these improvements continue long-term or how they translate to real-world energy and function.
If you want to try NAD+ supplementation, NMN and nicotinamide riboside (NR) have the most human research support. The biological case for why NAD+ matters is strong, the safety profile is reassuring, but the human evidence of lasting benefit is still early. The most important lifestyle factors remain sleep, regular exercise and reducing things that damage cells like excessive UV exposure.
Verdict: NAD+ supplementation is scientifically promising and appears safe, but long-term human evidence of meaningful benefit does not yet exist.
You wake up after eight hours of sleep and still feel like you haven’t rested. Your afternoon slump hits harder than it used to. The gym sessions that used to energise you now just exhaust you. Most people chalk this up to “getting older”, as if fatigue is simply the price of admission to your 50s. But what if the tiredness you feel isn’t inevitable? What if there’s a measurable, biological reason your cells are running out of fuel, and what if that reason has a name?
That name is NAD+. And the research around it is one of the most genuinely exciting areas in healthy ageing science right now.
NAD+ stands for nicotinamide adenine dinucleotide. That’s a mouthful, so let’s translate it into something useful: it’s a molecule found in every single cell in your body, and without it, your cells cannot produce energy [14].
Here’s how it works. When you eat food, your body converts those calories into ATP, adenosine triphosphate, the actual fuel that powers everything from your heartbeat to your thoughts. NAD+ is the essential middleman in that process. In its reduced form (NADH), it acts as the primary electron donor in the mitochondrial respiratory chain, the biological engine room where ATP is made through a process called oxidative phosphorylation [14]. Without enough NAD+, that engine sputters.
But NAD+ does far more than just help make energy. It’s a critical substrate, meaning it gets used up, by three major families of proteins [14]:
– Sirtuins, sometimes called “longevity proteins,” these regulate metabolism, stress responses and gene expression – PARPs (poly ADP-ribose polymerases), enzymes responsible for detecting and repairing DNA damage – CD38, an enzyme that, as we’ll see, turns out to be a key villain in the age-related NAD+ story
The NAD+/NADH ratio also regulates enzymes in glycolysis, the Krebs cycle, and fatty acid oxidation, in other words, it influences virtually every major metabolic pathway in your body [14]. Think of NAD+ as less of a single switch and more of the electrical wiring that runs through the entire house.
The problem? Your NAD+ levels decline significantly as you age [2]. And that decline appears to sit at the heart of why we feel progressively more fatigued, mentally foggy, and physically worn down as the decades pass.
This is where the story gets genuinely fascinating, and where the science has made a real leap forward.
For years, researchers knew that NAD+ declined with age. What they didn’t know was *why*. A landmark 2016 study published in *Cell Metabolism* identified a major mechanism: an enzyme called CD38 [8].
Here’s what the researchers found. CD38 is a NADase, essentially, an enzyme that destroys NAD+. The study demonstrated that CD38 expression and activity increase with ageing, and that CD38 is responsible for the age-related NAD+ decline and the mitochondrial dysfunction that follows [8]. When CD38 is absent in mice (knockout models), NAD+ levels are protected even as the animals age.
The study also found that CD38 is the main enzyme responsible for degrading NMN (nicotinamide mononucleotide), one of the key precursor molecules used in NAD+ supplementation, *in vivo* [8]. This has significant implications for why NAD+ replacement therapy works better for some people than others: if your CD38 activity is high, you may be burning through precursors faster before they can do their job.
The mechanism runs through a protein called SIRT3, a mitochondrial sirtuin. As CD38 rises, it depletes NAD+, which reduces SIRT3 activity, which impairs mitochondrial function [8]. The result is the kind of sluggish, low-energy cellular environment that feels very much like what most of us experience as “ageing fatigue.”
Evidence grade: Early stage, this specific mechanistic work was conducted in animal models, but it provides a compelling biological explanation for the human experience of age-related energy decline, and has shaped subsequent human research.
A 2014 paper in *Cell Metabolism* explored what happens to skeletal muscle, the tissue most directly responsible for physical energy and strength, when NAD+ levels drop [10].
The researchers described a biphasic model of muscle ageing. In the first phase, declining NAD+ reduces the activity of SIRT1 (a nuclear sirtuin), which triggers a cascade: a protein called HIF-1α accumulates, interfering with the transcription factor c-Myc, which in turn reduces levels of TFAM, the master regulator of mitochondrial gene expression [10]. The result is reduced oxidative phosphorylation, meaning less efficient energy production in muscle cells.
Here’s the striking part: when moderately old mice were treated with NMN (an NAD+ precursor) for just one week, oxidative phosphorylation activity was restored and markers of mitochondrial function improved in skeletal muscle [10]. The mitochondrial machinery, at least in this early phase, appeared partially reversible.
The caveat, and it’s an important one, is that muscle *strength* was not restored in this mouse study, and in very old animals with more advanced mitochondrial damage, the intervention had less effect [10]. There appear to be windows of opportunity in the ageing process where intervention is more likely to work.
Evidence grade: Early stage, mouse model, but mechanistically important for understanding how NAD+ decline translates into physical fatigue and muscle dysfunction.
The mouse data is compelling. But what about actual humans?
A 2022 placebo-controlled, randomised, double-blind parallel-group trial, the gold standard of clinical research, tested whether oral NMN supplementation could raise NAD+ levels and improve physical function in healthy older men [15].
Participants received 250 mg of NMN per day for either 6 or 12 weeks. Here’s what happened:
– Metabolomic analysis of whole blood confirmed that NMN supplementation significantly increased NAD+ and NAD+ metabolite concentrations, meaning the precursor was actually reaching the bloodstream and being converted [15] – There were nominally significant improvements in gait speed and performance in the left grip strength test [15] – NMN was well tolerated with no significant adverse effects [15] – Body composition did not significantly change [15]
The researchers were appropriately cautious: the improvements in gait speed and grip strength were described as “nominally significant” and the authors noted these need to be validated in larger studies [15]. This was a relatively small, short trial. But it provides real human evidence that oral NMN can raise NAD+ levels, which has been a question mark given CD38’s known activity in breaking down precursors.
Evidence grade: Promising, human RCT showing measurable increases in NAD+ levels and early signals of physical function improvement. Sample size was small and duration was short (6-12 weeks). More and larger trials are needed.
Energy isn’t the only story here. NAD+ is also the primary fuel for PARP enzymes, the molecular repair crews that fix damage to your DNA [1].
Every day, your DNA sustains thousands of small insults: from UV exposure, metabolic byproducts, environmental toxins. PARP1 detects this damage and coordinates the repair response. But PARP1 uses NAD+ to do its job. When NAD+ is low, DNA repair becomes compromised [1].
A 2026 review in *Aging Cell* explored this connection in detail, particularly in rare diseases characterised by defective DNA repair and premature ageing [1]. In these conditions, where PARP enzymes are chronically over-activated trying to manage high levels of DNA damage, NAD+ gets depleted rapidly, contributing to what the paper calls “hyperparylation” and mitochondrial dysfunction [1].
The researchers found that in model systems mimicking these disorders, and in emerging human studies, NAD+ supplementation demonstrated improved DNA repair capacity and improved mitochondrial function [1]. The authors conclude that NAD+ supplementation could serve as an effective intervention for these rare diseases, but also, importantly, that these insights “open new avenues for general ageing research” [1].
The implication for the rest of us: even without a rare disease, accumulated DNA damage and sub-optimal PARP activity may be part of why we age the way we do, and NAD+ may sit at the centre of that picture.
Evidence grade: Promising, some emerging human data, primarily from rare disease models. Mechanistic evidence for the role of NAD+ in DNA repair is strong; the translation to general healthy ageing supplementation is still developing.
Not all NAD+ supplements are the same, and a 2023 review in *Drugs & Aging* makes the distinctions clear [6].
The main precursors available are:
– Nicotinamide (NAM), a form of vitamin B3, widely available, cheapest option – Nicotinic acid (NA), another form of B3, used therapeutically for decades, associated with flushing at higher doses – Nicotinamide Riboside (NR), a newer form, better studied in humans, fewer side effects than NA – Nicotinamide Mononucleotide (NMN), a step closer to NAD+ in the biosynthesis pathway, the focus of most recent research
The review notes that these precursors “vary in their ability to promote NAD+ anabolism with differing adverse effects” [6]. NR and NMN are generally considered the most promising for raising NAD+ levels with a favourable safety profile, though the review emphasises that “careful evaluation” is still needed [6].
A 2024 review in *Biochemical and Biophysical Research Communications* adds an interesting dimension: the gut microbiota plays a role in how NAD+ precursors are metabolised [12], which may partly explain why some people respond more strongly to supplementation than others. This is an emerging area of research and one to watch.
A 2020 systematic review in *Experimental Gerontology* that assessed 1,545 articles (of which 147 met inclusion criteria, 113 preclinical and 34 clinical) concluded that NAD+ precursors including NAM, NR, NMN and to a lesser extent NAD+ itself showed favourable outcomes across several age-related disorders [11]. However, the authors were clear: “evidence is still quite limited and long-term human clinical trials are still nascent” [11].
Evidence grade: Promising for NR and NMN specifically. Conflicted overall, results vary by precursor type, dose, population and duration.
It’s worth stepping back to appreciate just how central NAD+ is to the biology of ageing, not just fatigue, but the whole picture.
Sirtuins, the family of proteins sometimes called longevity enzymes, are entirely dependent on NAD+ as a substrate to function [2]. They regulate inflammation, stress responses, circadian rhythms, and metabolic efficiency. When NAD+ falls, sirtuin activity falls with it.
A 2025 review highlights that the NAD+/sirtuin axis is now recognised as one of the core nutrient-metabolic sensing pathways whose disruption is considered a hallmark of ageing [2]. This isn’t fringe science, it’s increasingly mainstream in ageing biology.
The 2024 mouse study on long-term NMN treatment found that NMN increased lifespan and healthspan, though the effects were sex-dependent, working more robustly in females than males in this particular model [7]. Again: animal data, but the sex-dependent finding is important and raises questions about whether human responses to NAD+ precursors might also vary by sex.
Evidence grade: Strong mechanistic evidence in animal models; early-to-promising in humans.
Let’s be honest, and this is where Vitacuity’s commitment to real, unfiltered science matters most. Our team reviewed over 1.77 million research papers to bring you only the most relevant findings, and that process also reveals the limits of what we currently know.
The human trial gap is real. The most compelling NAD+ research, including the CD38 mechanism, the mitochondrial restoration findings, and the lifespan extension data, comes from mouse studies [7, 8, 10]. The human RCTs that exist are small, short (weeks rather than years), and don’t yet tell us whether raising NAD+ levels in humans translates meaningfully into sustained improvements in energy, cognition or longevity [15].
We don’t fully understand why some people respond and others don’t. Multiple reviews acknowledge that “some studies show no observable advantages” from NAD+ supplementation [1]. The likely explanation involves individual variation in CD38 activity, gut microbiota composition, baseline NAD+ levels and the specific precursor used, but this hasn’t been systematically studied in large human cohorts [8, 12].
Long-term safety questions remain. The 2020 systematic review flagged potential risks worth knowing about: accumulation of metabolic byproducts, theoretical concerns around tumorigenesis, and possible promotion of cellular senescence at very high doses [11]. These risks appear low at normal supplemental doses, but long-term human data simply doesn’t exist yet. The authors conclude more long-term trials are needed before firm conclusions can be drawn.
The optimal dose, timing and form remain unclear. The human trial used 250 mg/day of NMN [15]. Other studies use different doses of NR, NAM or NMN. We don’t yet know the optimal dosing strategy, whether cycling on and off makes a difference, or how long supplementation needs to continue before meaningful benefits accrue.
The biphasic ageing window matters. The mouse muscle research suggests there may be a window, earlier in the ageing process, where NAD+ restoration is most effective, before irreversible mitochondrial DNA damage sets in [10]. Whether this window exists in humans, and how to identify it, is unknown.
So where does this leave you, as someone who wants to think clearly, move well and feel energised in your 40s, 50s and 60s?
Here’s how we’d reason through it as your trusted, well-read friend:
The biological case is genuinely compelling. NAD+ decline is real, measurable and mechanistically connected to the fatigue, mitochondrial inefficiency and DNA repair slowdown that characterise ageing [8, 14]. This isn’t speculation, it’s well-established biology.
The human evidence is promising but young. The RCT showing NMN raises blood NAD+ levels in older men is real and encouraging [15]. The physical function improvements were modest and need confirmation. What’s clearly established is that 250 mg/day of NMN appears safe and does raise NAD+ levels in the bloodstream.
NMN and NR are your best-evidenced options. Of the precursor forms available, NMN and NR have the most favourable research profiles and safety data [6, 11]. Plain nicotinamide (vitamin B3) is cheaper and also raises NAD+ via salvage pathways, though potentially less efficiently.
Think about the risk/benefit honestly. NMN and NR at normal doses appear well-tolerated with a low risk profile [11, 15]. Deficiency or decline in NAD+ with age is essentially universal and is associated with real consequences for energy, repair capacity and metabolic health. The risk of supplementing at sensible doses is low. The potential benefit, if the human trials continue to develop in the direction the mechanistic science suggests, is meaningful.
Practical habits that matter alongside supplementation:
– Prioritise sleep. Circadian rhythm disruption is directly linked to reduced SIRT1 activity downstream of NAD+, the two systems are intertwined [10] – Exercise regularly. Muscle is where much of the NAD+/mitochondria story plays out, regular movement both demands and stimulates NAD+ metabolism [4] – Reduce unnecessary NAD+ drain. Chronic inflammation, excess alcohol and DNA-damaging exposures (like excessive UV) all accelerate PARP activation and deplete NAD+ faster [11] – Consider an NMN or NR supplement, 250-500 mg/day is the range used in human studies [15]. These are available without prescription, generally well-tolerated, and the human evidence, while still early, is moving in a promising direction
The honest truth is this: we don’t yet have the 10-year human RCT that proves NAD+ supplementation extends healthy human life. But we understand *why* it should, we have early evidence that it raises NAD+ levels and may improve physical function, and the safety profile at normal doses is reassuring. A sensible, informed person wouldn’t wait for certainty that may be a decade away. They’d pay attention to the direction of travel.
Watch this space. The NAD+ story is still being written, and the next chapter will be in humans.
[1] Promising Results With NAD Supplementation in Rare Diseases With Premature Aging and DNA Damage (2026). DOI: 10.1111/acel.70319 | https://pubmed.ncbi.nlm.nih.gov/41436848/ | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12727671/
[2] NAD+ and Aging: Nutritional-Metabolic Sensing Pathway Disruption as a Hallmark of Ageing (2025). https://pubmed.ncbi.nlm.nih.gov/40603033/
[3] NAD+ and CD38 as Anti-Aging Regulatory Targets (2025). DOI: 10.1016/j.bcp.2025.117050 | https://pubmed.ncbi.nlm.nih.gov/40516760/
[4] Effects of Aging on Glucose and Lipid Metabolism in Mice (2025). DOI: 10.1111/acel.14462 | https://pubmed.ncbi.nlm.nih.gov/39731205/ | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11984682/
[6] Importance of NAD+ Anabolism in Metabolic, Cardiovascular and Neurodegenerative Disorders (2023). DOI: 10.1007/s40266-022-00989-0 | https://pubmed.ncbi.nlm.nih.gov/36510042/
[7] Long-term NMN Treatment Increases Lifespan and Healthspan in Mice in a Sex Dependent Manner (2024). DOI: 10.1101/2024.06.21.599604 | https://pubmed.ncbi.nlm.nih.gov/38979132/ | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11230277/
[8] CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism (2016). https://pubmed.ncbi.nlm.nih.gov/27304511/
[10] Partial Reversal of Skeletal Muscle Aging by Restoration of Normal NAD+ Levels (2014). https://pubmed.ncbi.nlm.nih.gov/24410488/
[11] NAD+ Therapy in Age-Related Degenerative Disorders: A Benefit/Risk Analysis (2020). DOI: 10.1016/j.exger.2020.110831 | https://pubmed.ncbi.nlm.nih.gov/31917996/
[12] The Therapeutic Perspective of NAD+ and Its Precursors in Ageing and Gut Microbiota (2024). DOI: 10.1016/j.bbrc.2024.149590 | https://pubmed.ncbi.nlm.nih.gov/38340651/
[14] Emerging Therapeutic Roles for NAD+ Metabolism in Mitochondrial and Age-Related Disorders (2016). DOI: 10.1186/s40169-016-0104-7 | https://pubmed.ncbi.nlm.nih.gov/27465020/ | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963347/
[15] Chronic Nicotinamide Mononucleotide Supplementation Elevates Blood NAD+ Levels and Alters Muscle Function in Healthy Older Men (2022). https://pubmed.ncbi.nlm.nih.gov/35927255/
This article is for informational purposes only and does not constitute medical advice. Food supplements should not be used as a substitute for a varied and balanced diet and healthy lifestyle. If you are pregnant, breastfeeding, taking medication or have a medical condition, consult your doctor before taking any supplement. These statements have not been evaluated by the Food and Drug Administration (FDA) or the Medicines and Healthcare products Regulatory Agency (MHRA). This product is not intended to diagnose, treat, cure, or prevent any disease.
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