Nicotinamide

Niacin (as Nicotinamide)

What is Niacin?

Niacin (vitamin B3) is a generic term for the water-soluble compounds nicotinic acid and nicotinamide (niacinamide), along with related derivatives that share vitamin B3 activity and serve as precursors for the essential redox cofactors NAD⁺ and NADP⁺ (Freese and Lysne, 2023). NAD⁺ (nicotinamide adenine dinucleotide) and NADP⁺ (nicotinamide adenine dinucleotide phosphate) are vitamin B3-derived coenzymes that act as electron carriers in cells, with NAD⁺ primarily participating in energy-producing metabolic reactions and NADP⁺ mainly supporting biosynthetic processes and antioxidant defences. Chemically, nicotinic acid is pyridine-3-carboxylic acid and nicotinamide is pyridine-3-carboxamide; these substituted pyridine rings are incorporated into the oxidized and reduced forms of NAD(H) and NADP(H). Through the de novo (i.e. from scratch, tryptophan–kynurenine), Preiss–Handler (nicotinic acid) and salvage (nicotinamide, nicotinamide riboside, NMN) pathways, they give rise to a broader “vitamin B3 metabolome” of NAD-related metabolites that support redox reactions and signalling (Makarov et al., 2019). The Preiss–Handler pathway refers to the nicotinamide adenine dinucleotide (NAD⁺) biosynthetic route in which dietary nicotinic acid is converted stepwise into NAD⁺ via nicotinic acid mononucleotide (NAMN) and nicotinic acid adenine dinucleotide (NAAD) by enzymes such as nicotinic acid phosphoribosyltransferase (NAPRT), nicotinamide mononucleotide adenylyltransferase (NMNAT) and NAD⁺ synthetase. In contrast, the salvage pathway describes the recycling route in which nicotinamide (NAM) and related precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are converted back into NAD⁺ primarily through the sequential actions of nicotinamide phosphoribosyltransferase (NAMPT), nicotinamide riboside kinase (NRK) and nicotinamide mononucleotide adenylyltransferase (NMNAT) (Makarov et al., 2019; Covarrubias et al., 2021) In humans, niacin is obtained both as pre-formed vitamin B3 (nicotinic acid, nicotinamide and coenzyme-bound NAD/NADP in foods) and indirectly from the indispensable amino acid tryptophan, with rich sources including meat, poultry, fish, offal, fortified cereals, nuts and legumes (Freese and Lysne, 2023). By sustaining cellular NAD⁺ pools, nicotinamide influences ageing through several interconnected factors: it supports mitochondrial energy metabolism and Adenosine Triphosphate (ATP) production, fuels DNA repair and genomic stability via NAD⁺-dependent Poly(adenosine diphosphate-ribose) polymerases (PARPs), regulates epigenetic and stress-response programmes through sirtuins, maintains redox balance via NADPH-dependent antioxidant systems and modulates cellular senescence, immune function and chronic low-grade inflammation that underlie many age-related diseases (Covarrubias et al., 2021; Iqbal and Nakagawa, 2024). In skin, where ageing changes are easily observed, nicotinamide supplementation replenishes NAD⁺/NADPH, enhances repair of UV-induced DNA damage, reduces oxidative stress and inflammatory cytokines, improves barrier lipids and extracellular matrix components and diminishes clinical signs of photoaging, providing a clear tissue-level example of how restoring vitamin B3-dependent NAD⁺ metabolism can counter multiple hallmarks of ageing (Camillo et al., 2025).

How Niacin Influences Aging:

Mitochondrial Energy Metabolism and ATP Production

Mitochondrial energy metabolism and ATP (adenosine triphosphate, the cell’s main energy currency) production are central to ageing because, as mitochondria (the cell’s “power plants”) become less efficient, tissues gradually lose strength, accumulate damage and become more vulnerable to age-related disease. Niacin, through vitamin B3 derivatives such as nicotinamide riboside and nicotinic acid, is converted into NAD⁺ (nicotinamide adenine dinucleotide), a coenzyme that fuels mitochondrial oxidative phosphorylation (the oxygen-using process in mitochondria that generates ATP), and several lines of work show that restoring NAD⁺ with these compounds can “rejuvenate” this energy system in aged cells and organisms. In aged mice, raising NAD⁺ with nicotinamide riboside improves mitochondrial respiratory function, enhances the ability of tissue stem cells to sustain regeneration and even extends lifespan, indicating that niacin-driven NAD⁺ repletion can preserve mitochondrial ATP production and delay functional decline at the whole-organism level (Zhang et al., 2016). In the ageing blood-forming system, nicotinamide riboside similarly restores a more youthful, low-stress mitochondrial state in haematopoietic stem cells by normalising their oxidative phosphorylation, reducing mitochondrial network size and stress signals, and improving their capacity to reconstitute the blood system, which ties niacin-dependent NAD⁺ restoration to better long-term tissue maintenance with age (Sun et al., 2021). Complementing these NAD⁺ precursor effects, nicotinamide mononucleotide boosts mitochondrial NAD⁺ in the brain, activates the deacetylase SIRT3 (sirtuin 3), improves mitochondrial dynamics and reduces mitochondria-derived reactive oxygen species (damaging oxygen by-products), showing that niacin-derived precursors can directly repair mitochondrial structure and function in ageing neural tissue (Klimova and Kristian, 2019). Furthermore, a trial in older inactive men shows that short-term nicotinic acid intake increases skeletal muscle mitochondrial respiration and boosts key components of the electron transport chain (the series of protein complexes that pass electrons to drive ATP synthesis), thereby increasing the capacity for ATP production in ageing human muscle (Deane et al., 2024). Taken together, these findings support a coherent picture in which niacin, by rebuilding NAD⁺ pools, recalibrates mitochondrial energy metabolism from a fatigued, inefficient and stress-prone state towards a more youthful, ATP-efficient state, and through this improvement in mitochondrial function contributes to an anti-ageing phenotype.

DNA Repair and Genomic Stability via PARP-Dependent NAD⁺ Signalling

DNA repair and genomic stability are central to ageing because every day cells accumulate DNA damage from sources like ultraviolet (UV) light and reactive oxygen species. If this damage is not properly repaired by enzymes such as PARPs (poly(ADP-ribose) polymerases), which use NAD⁺ as a fuel, mutations build up, chromosomes become unstable and cells drift towards cancer, dysfunction or senescence instead of healthy renewal. Niacin, mainly in the form of nicotinamide maintains cellular NAD⁺ pools and thus directly powers PARP-dependent DNA repair. When niacin is restricted in human skin cells, NAD⁺ levels fall, PARP activation after UV-like “photodamage” is blunted, background DNA damage increases and cells become more vulnerable to light-induced injury, whereas restoring niacin reverses these defects and normalises PARP signalling and repair capacity, showing that adequate niacin intake is required to keep the PARP–NAD⁺ DNA repair axis functioning under stress (Benavente et al., 2012). Mechanistic overviews emphasise that nicotinamide, by sustaining NAD⁺ as the sole PARP-1 substrate, supports rapid repair of DNA strand breaks, limits mutagenesis and helps maintain genomic stability, positioning vitamin B3 as a metabolic gatekeeper between efficient repair and carcinogenesis (Surjana et al., 2010; Fania et al., 2019). In human keratinocytes and ex vivo skin, pharmacological nicotinamide prevents UV-induced ATP depletion, enhances energy-dependent nucleotide excision and base excision repair pathways, and accelerates the removal of photolesions such as cyclobutane pyrimidine dimers and oxidised guanine bases, leading to fewer persistent DNA lesions after UV exposure (Surjana et al., 2013). Under more realistic environmental stress, combining UV with arsenic, nicotinamide again reduces both oxidative DNA damage and UV photoproducts in skin models, consistent with a broad enhancement of DNA repair capacity in at-risk epithelia (Thompson et al., 2015). Taken together, these findings support a coherent story in which niacin, by keeping NAD⁺ available for PARP-dependent DNA repair, preserves genomic stability in chronically exposed tissues like skin, reduces the accumulation of age-driving DNA damage and mutations, and thereby contributes to an anti-ageing, cancer-preventive phenotype at the tissue level.

Epigenetic and Stress-Response Regulation through Sirtuins

Epigenetic regulation and stress-response control are central to ageing because chemical marks on DNA and histone proteins (epigenetic modifications) and the way cells switch stress-response genes on and off gradually drift over time, so protective programs become less responsive while pro-ageing inflammatory and degenerative pathways become more active. Sirtuins are a family of NAD⁺ (nicotinamide adenine dinucleotide)-dependent deacetylases that “readjust” these epigenetic marks and transcriptional programs in response to metabolic and stress signals, and when NAD⁺ falls with age, sirtuin activity drops, contributing to this epigenetic drift. Niacin, via precursors such as nicotinamide mononucleotide (NMN) and nicotinamide riboside, rebuilds NAD⁺ pools and thereby restores sirtuin function. In aged brain blood vessels, NMN supplementation raises NAD⁺, reactivates sirtuin 1 (SIRT1) and reshapes gene expression towards a more youthful, stress-resilient pattern with better mitochondrial protection, less inflammation and less programmed cell death, consistent with a “rejuvenated” neurovascular epigenetic profile (Kiss et al., 2020). In old kidneys, the same precursor restores NAD⁺ and SIRT1, allowing stressed renal cells to activate protective stress-response pathways and resist injury that would otherwise be lethal in aged animals, an effect that disappears when SIRT1 is genetically reduced, directly tying niacin-derived NAD⁺ to sirtuin-dependent tissue resilience (Guan et al., 2017). In aged bone marrow, NMN-driven SIRT1 activation reprograms mesenchymal stromal cells so that epigenetic and transcriptional networks favour bone formation over fat accumulation, helping maintain skeletal integrity with age rather than drifting toward a frailer, fat-rich marrow state (Song et al., 2019). In systemic premature-ageing models, nicotinamide riboside raises NAD⁺, enhances sirtuin signalling, improves mitochondrial quality control and DNA repair and extends both lifespan and healthspan, illustrating how NAD⁺ precursors can globally reset sirtuin-governed stress responses in favour of longevity (Fang et al., 2016). Synthesising such work, broader reviews emphasise that vitamin B3–derived NAD⁺ boosters act as upstream regulators of the entire sirtuin family, stabilising epigenetic marks and stress-response circuits that normally deteriorate with age, which positions niacin-supported NAD⁺–sirtuin signalling as a key mechanism by which niacin can exert anti-ageing effects at the molecular, cellular and tissue levels (Bonkowski and Sinclair, 2016).

Redox Balance and NADPH-Dependent Antioxidant Defence

Redox balance and NADPH-dependent antioxidant defence play a key role in ageing, since cells constantly generate reactive oxygen species (ROS, chemically reactive oxygen by-products) that can damage lipids, proteins and DNA, and the ability to neutralise these ROS using antioxidant systems powered by NADPH (nicotinamide adenine dinucleotide phosphate, reduced form) gradually declines, leading to cumulative oxidative damage and tissue dysfunction. Niacin indirectly maintains NADPH generation and the activity of antioxidant pathways such as glutathione and thioredoxin, and NADPH is required for enzymes like glutathione reductase. Niacin intake has been shown to increase the activity of key antioxidant enzymes such as catalase, glutathione peroxidase and superoxide dismutase and to decrease lipid peroxidation, linking vitamin B3 status to stronger endogenous antioxidant protection and lower oxidative damage (Theodosis-Nobelos et al., 2024). Mechanistic reviews of niacinamide’s actions in skin highlight that raising NAD⁺/NADP⁺ enhances intracellular antioxidant capacity, lowers ROS, supports glutathione recycling and dampens oxidative-stress signalling, thereby reducing inflammation and pigmentary and structural changes associated with skin ageing (Marques et al., 2024; Camillo et al., 2025). In human primary keratinocytes exposed to ultraviolet B (UVB) and chemically induced oxidative stress, pretreatment with nicotinamide prevents the build-up of ROS, preserves energy metabolism and limits premature differentiation and senescence, effectively keeping a more “youthful” epidermal cell population under stress conditions (Tan et al., 2022). Under chronic environmental insult from airborne particulate matter (PM2.5), niacinamide similarly decreases ROS, protects lipids, proteins and DNA from oxidation and reduces apoptosis (programmed cell death), demonstrating that vitamin B3 can buffer real-world oxidative loads that drive both molecular and visible skin ageing (Zhen et al., 2019). Taken together, these findings support a coherent view in which niacin, by maintaining NAD⁺/NADP⁺ and thereby NADPH-dependent antioxidant defences, shifts cells from a ROS-overloaded, damage-accumulating state towards a better-protected redox environment, and through this mechanism contributes to an anti-ageing phenotype in oxidatively stressed tissues.

Cellular Senescence, Immune Modulation and Chronic Inflammation in Ageing:

Cellular senescence, immune dysregulation and chronic low-grade inflammation (“inflammaging”) are major drivers of ageing because senescent cells stop dividing but remain metabolically active, secreting a senescence-associated secretory phenotype (SASP) rich in inflammatory cytokines, while ageing immune cells become less effective at defence and more prone to fuelling persistent tissue inflammation, together promoting tissue damage, cancer risk and functional decline. Niacin, mainly via nicotinamide (niacinamide) and nicotinamide riboside, replenishes NAD⁺ (nicotinamide adenine dinucleotide) and in doing so dampens these pro-ageing processes. In a human progeroid disorder (Cockayne syndrome), nicotinamide supplementation shifts patient cells away from a highly inflamed, stress-induced state by normalising expression of inflammatory and autophagy-related genes and restoring antioxidant defences, which limits accelerated ageing phenotypes at the cellular level (Chikhaoui et al., 2024). In skin, where senescent cells and chronic inflammation accumulate with photoageing, nicotinamide lowers reactive oxygen species, suppresses nuclear factor kappa B (NF-κB, a key pro-inflammatory transcription factor), reduces SASP-like cytokine release and diminishes senescence markers, while improving barrier function and DNA repair, indicating that vitamin B3 can simultaneously blunt senescence and inflammaging in a chronically exposed tissue (Camillo et al., 2025). In older adults, oral nicotinamide riboside increases muscle NAD⁺ and induces an anti-inflammatory gene expression signature in skeletal muscle, accompanied by reductions in circulating inflammatory cytokines, showing that an NAD⁺ precursor can remodel systemic immune signalling in humans towards a less inflammatory profile (Elhassan et al., 2019). In aged and DNA repair–deficient mice, the same precursor improves the lymphoid output of haematopoietic stem cells, counteracting aspects of immunosenescence and helping maintain a healthier balance of immune cell types with age (Zong et al., 2021). Complementing these effects, oral nicotinamide in healthy volunteers significantly reduces ultraviolet (UV)-induced immunosuppression in skin without overactivating the immune system at baseline, demonstrating that niacin can protect immune competence against environmental stress that would otherwise promote cancer and degenerative change (Yiasemides et al., 2009). Taken together, these findings support a coherent view in which niacin, by maintaining NAD⁺-dependent stress and immune signalling, reduces cellular senescence burden, rebalances immune responses and mitigates chronic inflammation, thereby contributing to a more youthful, less disease-prone ageing trajectory.

Overall, niacin (particularly as nicotinamide) emerges as a central nutritional regulator of ageing because it sustains cellular NAD⁺ and NADP⁺ pools that feed into multiple, intersecting longevity pathways. By maintaining NAD⁺ availability, niacin helps preserve mitochondrial oxidative phosphorylation and ATP production, supports PARP-dependent DNA repair and genomic stability, stabilises epigenetic and stress-response programmes via sirtuins, and underpins NADPH-driven antioxidant defences that limit chronic oxidative damage. At the tissue level, these upstream effects translate into reduced cellular senescence burden, dampened immune-mediated inflammaging, and improved resilience of highly exposed compartments such as skin, muscle, brain, kidney and the haematopoietic system. Taken together, current preclinical and early clinical data support a coherent view in which adequate niacin intake and, in some contexts, niacin-derived NAD⁺ precursors can shift cells and tissues from energy-depleted, damage-accumulating, pro-inflammatory states toward more youthful, stress-resilient phenotypes, positioning niacin not as a stand-alone “anti-ageing drug” but as a key metabolic enabler of healthy ageing.