May 1, 20267 min read
NAD+ is one of the most studied molecules in longevity research. Here is what it is, what the science actually shows, and why the midlife transition makes this topic particularly relevant for women.
Few compounds in cellular aging research have attracted as much attention in the past decade as NAD+. It has been covered in major scientific journals, discussed at academic conferences on aging, and studied in clinical trials across multiple institutions.
It has also attracted considerable marketing noise, which makes separating the science from the hype worth doing carefully.
This article covers what NAD+ is, what it does at the cellular level, what the research currently shows about supplementation, and why the hormonal transition in midlife creates particular relevance for this topic.
NAD+ stands for nicotinamide adenine dinucleotide. It is a coenzyme, a molecule that supports the function of enzymes, present in every living cell. It participates in hundreds of metabolic reactions and is particularly central to two categories of cellular function: energy production and cellular repair.
NAD+ is essential to the electron transport chain, the process by which mitochondria convert nutrients into ATP, the energy currency of the cell. When NAD+ levels are adequate, this process runs efficiently. When they are reduced, mitochondrial function may be affected and cells can produce less energy.
This connection to mitochondrial function is one factor researchers have explored in relation to the fatigue and reduced energy tolerance that many women report during perimenopause. Estrogen also plays a role in mitochondrial function, and the hormonal shifts of menopause occur at the same time that NAD+ levels naturally decline with age.
NAD+ is a fuel for a family of enzymes called sirtuins (SIRT1 through SIRT7), which regulate a range of cellular processes including DNA repair, inflammation control, mitochondrial biogenesis, and cellular senescence. Sirtuins are sometimes described as longevity proteins because of their role in the biological processes associated with healthy aging.
NAD+ is also consumed by PARP enzymes, which detect and repair DNA strand breaks. Every time a cell repairs damaged DNA, it uses NAD+. As cellular damage accumulates with age, PARP activity increases, which uses up more NAD+.
Studies of human tissue have observed that NAD+ levels generally decline with age. Research using magnetic resonance to measure NAD+ in the brain, and other studies measuring NAD+ in skin and skeletal muscle, have observed lower levels in older adults compared to younger adults.
Several mechanisms appear to drive this decline:
The result is a gradual reduction that may affect cellular energy, repair capacity, and the activity of sirtuin-dependent pathways.
Because NAD+ cannot be taken directly as an oral supplement in a form that reaches cells effectively, research has focused on precursor molecules that the body converts to NAD+. The two most studied are:
Both have been studied in animal models, and human clinical research has been expanding.
A 2018 randomized clinical trial of NR supplementation in healthy middle-aged and older adults found that chronic NR supplementation was well tolerated and effectively increased NAD+ levels in whole blood. The trial also reported preliminary signals related to blood pressure and arterial stiffness that the authors recommended be investigated in larger studies.
A 2021 randomized controlled trial of NMN supplementation in postmenopausal women with prediabetes who were overweight or obese found that NMN was associated with improvements in skeletal muscle insulin sensitivity compared to placebo. This is a population directly relevant to the metabolic changes some women experience in midlife.
A separate 2022 clinical trial of NMN in healthy older men reported increased blood NAD+ levels and small improvements in some measures of muscle function. The authors noted that the muscle findings were nominally significant and should be validated in larger studies.
It is important to be precise about the limits of current evidence. Most human clinical trials of NAD+ precursors have been relatively short, typically 8 to 16 weeks, and have focused on biomarker changes and specific functional outcomes rather than long-term health outcomes.
The translation from biomarker changes to long-term outcomes such as reduced disease incidence or extended health span has not been established in humans. Animal studies are encouraging, but animal-to-human translation in aging research has a mixed track record.
What can be said based on current published trials is that NAD+ precursor supplementation can raise NAD+ levels in human blood, and that some functional effects have been observed in specific populations. The research is genuine and growing, while still maturing.
Intravenous NAD+ is offered at some longevity-focused practices and delivers NAD+ directly into the circulation rather than relying on oral conversion. The subjective effects reported by people who receive IV NAD+, including changes in energy and mental clarity, are sometimes described as more pronounced than with oral supplementation, although individual responses vary.
The trade-off is practical. IV administration requires clinical oversight, takes longer, and is generally more expensive than oral options. The published research base for IV NAD+ in healthy aging is smaller than for oral precursors, in part because larger randomized trials of IV interventions are more difficult to run.
If you are weighing IV NAD+, this is a conversation to have with a clinician familiar with your full health picture.
NAD+ precursors have been studied in clinical trials at doses commonly ranging from around 250 mg to 1,000 mg per day without significant adverse effects in healthy adults.
The mild side effects reported in some trials at higher doses include nausea, flushing, and gastrointestinal discomfort. These tend to be dose-dependent and resolve with dose reduction.
A note of caution: NAD+ supports cellular processes broadly, and some researchers have advised caution in people with a history of certain cancers pending more data. This is a conversation to have with your oncologist or primary clinician if it applies to you.
The overlap between age-related changes in NAD+ and the hormonal changes of perimenopause and menopause is part of why this topic is relevant for women aged 40+.
The fatigue that does not resolve with sleep, the reduced exercise tolerance, the slower recovery, the cognitive heaviness... many women experience these in midlife. They are consistent with multiple underlying factors, including sleep disruption, hormonal changes, iron deficiency, thyroid dysfunction, and cellular energy changes.
NAD+ support is not a replacement for hormonal care, sleep, or nutrition. It is most appropriately considered as one part of a broader cellular health strategy, in conversation with a clinician who knows your full picture.
The science of NAD+ has moved from theoretical interest to active clinical research faster than most areas of aging biology. The current evidence is meaningful and still developing. Understanding it gives midlife women a fuller picture of the tools being studied to support healthy aging during one of the most biologically significant transitions of their lives.
Sources
Verdin E. NAD+ in aging, metabolism, and neurodegeneration. Science. 2015.
Haigis MC, Guarente LP. Mammalian sirtuins: emerging roles in physiology, aging, and calorie restriction. Genes Dev. 2006.
Bai P, Cantó C, Oudart H, et al. PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab. 2011.
Zhu XH, Lu M, Lee BY, Ugurbil K, Chen W. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. Proc Natl Acad Sci USA. 2015.
Chini CCS, Zeidler JD, Kashyap S, Warner G, Chini EN. Evolving concepts in NAD+ metabolism. Cell Metab. 2021.
Martens CR, Denman BA, Mazzo MR, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun. 2018.
Yoshino M, Yoshino J, Kayser BD, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. 2021.
Igarashi M, Nakagawa-Nagahama Y, Miura M, et al. Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men. NPJ Aging. 2022.
Nacarelli T, Lau L, Fukumoto T, et al. NAD+ metabolism governs the proinflammatory senescence-associated secretome. Nat Cell Biol. 2019.
This article is for informational purposes only and is not medical advice. Always consult a qualified clinician to discuss your health and treatment options.
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These statements have not been evaluated by the Food and Drug Administration. Compounded medications have not been evaluated or approved by the FDA for safety, efficacy, or quality. This content is intended for informational purposes only and does not constitute medical advice.
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