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Biological properties, synthetic pathways and anti-aging mechanisms of

nicotinamide mononucleotide (NMN): Research progress and challenges

Article in Biogerontology · June 2025

DOI: 10.1007/s10522-025-10270-7

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Biogerontology (2025) 26:124
https://doi.org/10.1007/s10522-025-10270-7

REVIEW ARTICLE

Biological properties, synthetic pathways and anti‑aging

mechanisms of nicotinamide mononucleotide (NMN):
Research progress and challenges
Enhui Wang · Yuting Wang · Zhaofeng Zhang · Yanfei Jiang ·
Chunyue Zhao

Received: 14 April 2025 / Accepted: 3 June 2025

© The Author(s), under exclusive licence to Springer Nature B.V. 2025

Abstract The increasing global population aging targets and networks of NMN in core aging mecha-
has made the prevention and control of aging- nisms, such as DNA damage repair, mitochondrial
related diseases a major public health challenge in function regulation, inflammatory response balance,
the twenty-first century. Nicotinamide mononucleo- gut microbiota remodeling, and autophagy pathway
tide (NMN), as a precursor of nicotinamide adenine activation, are analyzed. The molecular mechanism
dinucleotide ­(NAD+), has garnered significant atten- of NMN in slowing down the aging process through
tion in recent years for its anti-aging potential. This multi-target synergistic effects is elucidated. How-
review comprehensively reviews the metabolic path- ever, critical issues such as age-stratified dosage mod-
ways and molecular mechanisms of NMN, compar- eling, long-term safety, and efficacy of NMN still
ing the technical characteristics and industrialization require in-depth research. This review provides a the-
prospects of chemical synthesis, microbial fermenta- oretical basis and research direction for translational
tion, and enzyme-catalyzed synthesis. The molecular research and precise anti-aging strategies of NMN.

E. Wang · Y. Wang · Y. Jiang (*) · C. Zhao (*)

Beijing Qingyan Boshi Health Management Co., Ltd,
Beijing, China
e-mail: [email protected]
C. Zhao
e-mail: [email protected]

E. Wang · Y. Wang · Z. Zhang · Y. Jiang · C. Zhao

Peking University Medical-Qingyan Boshi Joint
Laboratory for Skin Nutrition and Anti-Aging, Beijing,
China

Z. Zhang
Department of Nutrition and Food Hygiene, School
of Public Health, Peking University, Beijing, China

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Graphical abstract

Keywords Nicotinamide mononucleotide · process characterized by the progressive deteriora-

Nicotinamide adenine dinucleotide · Anti-aging · tion of interconnected molecular mechanisms, includ-
Chemical/biological synthesis · Gut microbiota · ing genomic instability, telomere attrition, epigenetic
Autophagy dysregulation, mitochondrial dysfunction, and loss
of proteostasis. This multidimensional decline ulti-
mately manifests as compromised cellular function
and increased vulnerability to age-associated pathol-
Introduction ogies (Guo et al. 2022). These pathophysiological
changes lead to a progressive decline in organismal
The global aging population is growing at an unprec- functionality and markedly elevate susceptibility to
edented rate, presenting a significant challenge for various chronic conditions, including chronic kidney
human society in the twenty-first century. In 2019, disease (Rattazzi et al. 2013), cardiovascular disor-
the global population aged 60 and above surpassed ders, neurodegenerative diseases (such as Alzheimer’s
1 billion, and it is projected to reach 2.1 billion by disease and Parkinson’s disease) (Chuang et al. 2016;
2050, constituting over 20% of the total population Zhu et al. 2020), and metabolic dysfunctions (nota-
(Song et al. 2023). This demographic shift not only bly type II diabetes mellitus and obesity). This dual
impacts socioeconomic development but also elevates burden severely compromises the quality of life in
aging-related health concerns to a core challenge in elderly populations and imposes substantial economic
global public health. Aging is a complex biological

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pressure on healthcare systems through increased pathway of its conversion to ­NAD+ in vivo, and its
demands for long-term care and disease management. regulatory mechanisms; (2) the synthesis pathways of
Nicotinamide mononucleotide (NMN), a criti- NMN, including the technological progress of chemi-
cal precursor of nicotinamide adenine dinucleotide cal synthesis, fermentation synthesis and enzymatic
­(NAD+), has garnered significant scientific interest synthesis; (3) the molecular mechanism of aging and
due to its therapeutic potential in combating age- the anti-aging effect of NMN. Through a systematic
related physiological decline. As an emerging candi- review of these topics, this review not only integrates
date in longevity research, the global NMN market existing research results, but also provides a theo-
was valued at USD 252.7 million in 2020, with pro- retical basis for the application of NMN in nutrition,
jections indicating expansion to USD 385.7 million medicine and healthy aging. At the same time, this
through 2027, reflecting a compound annual growth article summarizes the limitations of current research
rate of 6.2% driven by increasing geriatric popula- and explores possible future research directions, aim-
tions and anti-aging healthcare investments (Song ing to provide a reference for the further development
et al. 2023). Emerging evidence delineates NMN’s of this field.
pleiotropic biological functions through three princi-
pal mechanisms: (1) Attenuating degenerative pathol-
ogies via activation of N ­ AD+-dependent enzymes Pharmacokinetic profiles of NMN in ­NAD+
(SIRT1 and PARP1), demonstrating cardiorenal pro- biosynthesis
tection and facilitating tissue regeneration in acute
kidney injury and cerebral ischemia–reperfusion As a principal derivative of vitamin B3, NMN rep-
injury (Kiss et al. 2020); (2) Enhancing metabolic resents a bioactive nucleotide analogue with the
homeostasis by restoring pancreatic β-cell sensitivity molecular formula ­C11H15N2O8P (molecular weight:
and stimulating insulin secretion, thereby preventing 334.22 g/mol). Structurally, NMN comprises a nico-
type II diabetes mellitus and obesity through AMPK- tinamide (NAM) moiety linked to ribose-5-phosphate
mediated pathways (Liu et al. 2022); (3) Counter- via a β-1’-glycosidic bond, with exclusive biologi-
acting age-associated pathophysiological changes cal activity residing in the β-anomeric configuration
through ­NAD+ level restoration, effectively alleviat- (Fig. 1). NMN is found in fruits (0.26–1.60 mg/100 g)
ing oxidative stress and mitochondrial dysfunction and vegetables (0.25–1.88 mg/100 g), such as unripe
via FOXO3a/PGC-1α signaling cascades (Sverkeli pods, cabbage, cucumbers, broccoli, tomatoes, mush-
et al. 2021). Notably, experimental models confirm rooms and avocados. In animal foods, raw beef and
NMN’s neuroprotective capacity through dual mecha- raw shrimp also contain trace amounts of NMN
nisms: suppressing neuronal apoptosis via SIRT3- (0.06–0.42 mg/100 g) (Nadeeshani et al. 2022). In
dependent mitophagy and reducing reactive oxygen humans, NMN exhibits tissue-specific biodistribu-
species (ROS) generation through Nrf2 pathway acti- tion, with elevated concentrations observed in placen-
vation, consequently ameliorating cognitive impair- tal tissue compartments (3.2 ± 0.8 μM) compared to
ment in age-related neurodegeneration (Pencina et al. circulatory system biofluids (plasma: 0.05–0.3 μM;
2023). urine: < 0.02 μM). These findings collectively demon-
Although significant progress has been made in strate that dietary NMN intake contributes to main-
NMN research, several issues remain to be addressed. taining ­NAD+ homeostasis under physiological con-
Firstly, the biological characteristics of NMN in vivo ditions, though endogenous biosynthesis via NAM
and its regulatory mechanisms have not been fully phosphoribosyltransferase (NAMPT) remains the
clarified. Secondly, the synthesis pathways of NMN, dominant ­NAD+ production pathway in mammals.
especially the efficiency, economy and feasibility of From the perspective of metabolic pathways,
large-scale production of different synthesis methods, NMN is a crucial intermediate in the biosynthesis of
lack systematic comparative analysis. Most impor- ­NAD+. NMN must be initially transformed into nico-
tantly, an integrated theoretical framework for the tinamide riboside (NR) for transmembrane passage,
anti-aging effect of NMN has not been established. and subsequently reconverted to NMN intracellularly,
Based on this, this review focuses on the following ultimately resulting in the synthesis of ­NAD+ (Rata-
aspects: (1) the biological characteristics of NMN, the jczak et al. 2016). This transformation process is of

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Fig. 1  Natural sources, metabolic pathways and metabolic mechanisms of NMN

paramount significance for NMN to exert its biologi- a significant role in metabolic pathways demanding
­ AD+, as a core molecule in cellular
cal functions. N reducing power, such as antioxidant stress and fatty
metabolism, plays a pivotal role in multiple biological acid synthesis (Guo et al. 2023a, b). Beyond partici-
processes: Firstly, it acts as a significant coenzyme pating in energy metabolism, ­NAD+ also serves as a
in redox reactions, participating in energy metabolic cofactor or substrate for hundreds of enzymes, exten-
processes; Secondly, as a cofactor for non-redox- sively involved in the regulation of cellular processes
dependent enzymes, it regulates the activities of and functions. Recent studies have revealed that a
enzymes such as sirtuins and poly ADP-ribose poly- reduction in ­NAD+ levels is closely associated with
merases (PARPs). ­NAD+ serves as a hydride accep- various disease states, including metabolic and neu-
tor in dehydrogenase-mediated catalysis, generating rodegenerative diseases, and a decline in ­NAD+ lev-
NADH, a property that is crucial for the regulation els with aging has been observed in both rodents and
of dehydrogenase activities in catabolic pathways humans. Hence, restoring ­NAD+ levels through NMN
like glycolysis, glutaminolysis, and fatty acid oxida- supplementation has emerged as an important strat-
tion (Hopp et al. 2019). In eukaryotic cells, the elec- egy for treating age-related diseases (Lautrup et al.
trons generated by these reactions eventually enter the 2024).
electron transport chain, driving the synthesis of ATP. Regarding the metabolic mechanism of NMN
Additionally, ­NAD+ can be phosphorylated to form (Fig. 1), exogenous NMN administration signifi-
­NADP+, which is further reduced to NADPH, playing cantly elevates intracellular NAD⁺ levels. Following

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oral ingestion, NMN is rapidly absorbed via the gas- Among these methods, the acid/base hydroly-
trointestinal tract into systemic circulation, a process sis of AMP involves hydrolyzing AMP under acid
primarily regulated by the Slc12a8 gene. This gene, or base catalysis to generate ribose-5-phosphate,
highly expressed in the pancreas and small intestine, which then reacts with anhydrous ammonia in anhy-
encodes a cell membrane-specific transporter that drous ethylene glycol to form ribose-5-phosphate
directly mediates NMN transmembrane transport amide. This intermediate subsequently reacts with
through a sodium-dependent mechanism (Grozio 1-(2,4-dinitrophenyl)-3-carbamoylpyridinium chlo-
et al. 2019). This high-efficiency transport system ride to yield NMN (Walt et al. 1984). However, this
ensures rapid intestinal absorption of NMN, leading method not only requires strict anhydrous condi-
to a marked increase in plasma NMN concentration. tions but also results in a high proportion of inac-
Subsequently, NMN is distributed to peripheral tis- tive α-isomer in the product (α:β = 2:3) and relatively
sues via circulatory transport. At the tissue level, low purity. To address these limitations, researchers
extracellular NMN is initially hydrolyzed to NR by developed the bromoacetyl ribose method. Starting
the ectoenzyme CD73 (ecto-5’-nucleotidase), fol- with tetraacetyl ribose, this approach first bromi-
lowed by cellular uptake through equilibrative nucle- nates the material using hydrogen bromide (HBr),
oside transporters (ENTs) (Kropotov et al. 2021). followed by a condensation reaction with NAM to
Intracellularly, NMN is phosphorylated to NAD⁺ replace the bromine group, forming a nicotinamide
via the catalytic action of NMN adenylyltransferase triacetate intermediate. After deacetylation with
(NMNAT). Concurrently, NAD⁺ undergoes degrada- anhydrous ammonia, phosphorylation using ­POCl3/
tion to NAM through enzymatic hydrolysis by NAD⁺- trimethyl phosphate produces NMN, which is finally
consuming enzymes, including sirtuins, PARPs, and purified via resin chromatography. This method
ectoenzymes CD38/CD157. The resulting NAM is achieves a total yield of 57%, purity > 97%, and sig-
then recycled back to NMN through the rate-limiting nificantly reduces α-isomer content (α:β = 2:50)
enzyme NAMPT, forming a salvage pathway that is (Cheng et al. 2024). The TMSOTf-catalyzed conden-
critical for maintaining intracellular NAD⁺ homeosta- sation method further optimizes the synthesis. Using
sis (Okabe et al. 2019). tetraacetyl ribose and NAM as starting materials, the
reaction proceeds via TMSOTf-catalyzed condensa-
tion, followed by direct phosphorylation with P ­ OCl3
Synthesis of NMN to obtain NMN. Compared to traditional methods,
this approach avoids the use of HBr and S ­ O2, elimi-
Chemical synthesis nates the need for alkaline deacetylation, and enables
one-pot synthesis. Although trace α-isomer residues
In recent years, the advancement of multi-step chemi- remain (Tanimori et al. 2002), the method dramati-
cal synthesis methods has successfully enabled cally shortens reaction time, improves stereoselectiv-
large-scale industrial production of NMN. Currently, ity, simplifies solvent use and product isolation, and
the chemical synthesis of NMN primarily employs achieves high NMN yields.
tetraacetyl ribose, benzoyl-β-D-ribose, and NAM as In addition to the three primary synthesis meth-
starting materials, undergoing catalytic conversion ods mentioned above, researchers have recently
through key chemical reaction steps such as amidoly- developed a new pathway based on ketone-mediated
sis, phosphorylation, and glycosylation (Zheng et al. phosphorylation of NR (Cheng et al. 2024). Under
2024). Based on differences in starting materials and argon protection, this method first reacts NR with
reaction pathways, existing synthesis methods can be 2,2-dimethoxypropane to protect the 3,4-hydroxyl
categorized into the following three types (Fig. 2): groups, followed by phosphorylation of the pro-
tected NR using P ­OCl3. Finally, the protecting
(1) Acid/base hydrolysis of adenosine monophos- groups are removed with trifluoroacetic acid to
phate (AMP); yield highly active NMN (Fig. 2). This process is
(2) Bromoacetyl ribose method; characterized by simple steps and operational ease,
(3) Trimethylsilyl trifluoromethanesulfonate achieving a total yield of 69%. Overall, chemical
(TMSOTf)-catalyzed condensation method. catalytic synthesis methods demonstrate significant

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Fig. 2  Schematic diagram of different chemical synthesis pathways of NMN

advantages, including cost-effectiveness, read- of greener processes and improved selectivity to

ily available raw materials, and scalability. How- advance sustainable NMN production.
ever, challenges remain, such as harsh reaction
conditions, high organic solvent consumption, Fermentation synthesis
and limited stereoselectivity, which hinder fur-
ther technological advancement and application. Due to the challenges of complex processes and
Future research should prioritize the development high costs in chemical NMN synthesis, microbial

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fermentation has emerged as a green and sustainable findings highlight the importance of identifying and
alternative, attracting significant attention. Fermen- engineering more efficient NAMPTs to further boost
tation-based NMN synthesis leverages the metabolic NMN yields, while also confirming the superiority of
pathways of microorganisms (e.g., bacteria, yeast, or the NAM-based synthesis pathway.
fungi) to bioconvert specific substrates into NMN. However, excessive intracellular accumulation of
Compared to chemical methods, fermentation offers NMN may interfere with the normal physiological
simpler processes, higher yields, and superior con- processes of E. coli. Due to the lack of efficient trans-
version efficiency, making it more suitable for large- porters, NMN predominantly accumulates intracellu-
scale industrial production. A critical breakthrough in larly, limiting its biosynthesis efficiency. To address
NMN fermentation lies in the discovery and engineer- this, Shoji et al. (2021) introduced the NMN trans-
ing of key enzymes. Sorci et al. (2009) first identi- porter (BMpnuC), elevating extracellular NMN accu-
fied the NMN synthetase from Francisella tularensis mulation to 6.79 g/L—approximately 400-fold higher
(FtNadE), which catalyzes the amination of nicotinic than previously reported levels (Black et al. 2020a, b;
acid mononucleotide (NaMN) to NMN. Building on Marinescu et al. 2018). Huang et al. (2022a, b) fur-
this, Marinescu et al. (2018) boosted NMN produc- ther validated the critical role of transporters, achiev-
tion to 15.42 mg/L by supplementing Escherichia ing 124.1 mg/L NMN (60.4% of total accumulation)
coli (E. coli) with 10 g/L NAM and overexpressing in shake-flask cultures through pathway optimization,
HdNadV (from Haemophilus ducreyi). Black et al. suggesting the potential existence of native NMN
(2020a, b) further advanced the field by overexpress- transporters in E. coli. By integrating BMpnuC into
ing the FtNadE gene and knocking out the pncC engineered strains, NMN production reached 16.2 g/L
and nadR genes in E. coli, leading to a 1,000-fold in bioreactors with a 97.0% conversion rate within
increase in intracellular NMN accumulation, reaching 25 h, unequivocally demonstrating the transporter’s
501 mg/L. pivotal role in enhancing yields. Despite the remark-
Escherichia coli has become a critical industrial able improvements enabled by BMpnuC, its transport
microbial platform for synthesizing high-value prod- mechanism remains incompletely understood. Despite
ucts due to its short growth cycle, ease of genetic the fact that certain high-yielding Escherichia coli
manipulation, and low nutritional requirements. Cur- strains have attained notable NMN production lev-
rently, three main pathways exist for NMN synthesis els, as exemplified in the study by Kafle et al. (2023),
in E. coli, among which the NR-based pathway incurs where the maximum NMN concentration reached
significantly higher costs compared to those using 19.3 g/L within 28 h, with a NAM conversion rate of
NAM or nicotinic acid as substrates (Cheng et al. 98%—the highest reported yield and titer in fermen-
2024). Huang et al. (2022a, b) demonstrated that nic- tation approaches. Nevertheless, from the vantage
otinic acid has low solubility (< 20 g/L) and alters the point of large-scale industrial production, such yields
medium pH, necessitating additional alkaline addi- might not be sufficient to fully satiate the substantial
tives for pH adjustment, thereby increasing process market demand. Thus, there remains an imperative to
complexity. In contrast, NAM exhibits high solubil- further augment the production yield. Although fer-
ity (> 200 g/L) and pH-neutral compatibility, mak- mentation with high-yielding strains offers numer-
ing it more suitable for high-concentration feeding ous advantages, the impact of diverse fermentation
strategies. Notably, the key enzyme VpNadV shows conditions and genetic engineering manipulations on
optimal activity under neutral conditions (pH 6.8 or yield varies significantly. For example, different cul-
7.4), while its activity drastically declines in acidic ture medium compositions (e.g., the PYA8 medium
(pH 5.8) or alkaline (pH 8.9) environments. In the supplemented with 0.1% NAM and 1% lactose), fer-
NAM-to-NMN pathway, NAMPT serves as the rate- mentation durations (ranging from 12 to 25 h or 28 h;
limiting enzyme. Screening NAMPTs from diverse a longer fermentation time inevitably escalates pro-
sources can significantly enhance NMN production. duction costs, encompassing equipment occupation
For example, Liu et al. (2021a, b) achieved a 70.8% time and energy consumption), and other factors all
increase in NMN yield by screening exogenous exert an influence on the ultimate yield. This situation
NAMPTs. Shoji et al. (2021) improved NMN syn- exacerbates the complexity of process optimization
thesis by 2.4-fold through NAMPT screening. These and control in industrial production. Furthermore,

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to enhance NMN production, a multitude of genetic systems. Although an ATP cycling system has been
engineering techniques have been employed, includ- established, further optimization of the reaction sys-
ing the overexpression of specific genes, the knock- tem is still essential. This includes refining culture
out of certain genes, and the introduction of trans- conditions, adjusting the concentration of biocata-
porters (Cheng et al. 2024). These measures not only lysts, and optimizing the concentrations of substrates
increase the intricacy of strain construction and pro- and co-substrates. These measures are crucial for val-
duction processes but also potentially introduce more idating the application potential and reliability of the
uncontrollable elements during production, thereby orthogonal cascade ATP synthesis system. Through
heightening the challenges and risks associated with enzyme molecular modification, the stability of NRK
industrial manufacturing. Consequently, this “high- has been enhanced, and its kinetic parameters have
yield-instability” paradox remains unaddressed. been optimized. Currently, its industrial applica-
These optimized laboratory conditions hold the tions remain limited. In the future, new high-activity
potential for industrial-scale production. Neverthe- wild-type NRKs can be screened via methods such
less, they are confronted with certain challenges and as genomic mining to expand the NRK gene library.
limitations. The biocatalytic synthesis of NMN offers Moreover, based on existing research, continuous
several advantages, including high stereoselectivity, protein engineering and immobilization modification
mild reaction conditions, and a minimal number of of NRK can be carried out to obtain NRKs that are
by-products. As a result, it has become the focus of more suitable for industrial production. Nonetheless,
research for major pharmaceutical companies. With the current research on NRK is relatively scarce, and
the depth exploration of the NMN metabolic pathway most recent research findings are mainly in the form
and the rapid advancement of metabolic engineering of patents. This situation restricts the production of
and enzyme engineering technologies, the biocata- NMN through one step enzymatic methods. Further-
lytic approach for synthesizing NMN from NR has more, the NRK synthesis pathway is plagued by prob-
emerged as the most promising and significant large- lems such as low catalytic efficiency, poor stability,
scale production strategy. Currently, the price per kil- and substrate degradation. Thus, the industrial sus-
ogram has decreased to the level of several thousand tainability of this pathway remains to be thoroughly
yuan, indicating a certain degree of progress in indus- investigated.
trial production. The ATP regeneration system based Future research should prioritize:
on polyphosphate kinase (PPK) can utilize stable,
cost-effective polyphosphate (polyP) as a phosphate (1) Elucidating the BMpnuC transport mechanism;
donor. This enables the efficient transfer of phosphate (2) Developing more efficient NMN transporters;
groups among AMP, ADP, ATP, and polyP, making (3) Optimizing synergy between transporters and
it the top choice for constructing ATP regeneration biosynthesis pathways.
systems (Cheng et al. 2024). Such a system is likely
to be more adaptable to industrial applications. By A series of genetic engineering strategies were
conducting research on the structure, properties, and implemented on Escherichia coli, including the
reaction mechanisms of PPKs from diverse sources, deletion of specific genes, the optimization of key
it is possible to obtain PPKs with desired enzymatic genes, and the introduction of transporters, aiming to
characteristics through protein engineering. The cou- enhance the production yield and secretion efficiency
pling of PPK and NRK reaction systems thus presents of NMN. These efforts will provide critical theoreti-
promising prospects. cal and technical foundations for building high-effi-
However, using ATP as a substrate in an equimo- ciency NMN biosynthesis systems, accelerating the
lar amount with other substrates significantly elevates industrialization of NMN fermentation.
production costs. This is the primary factor restricting
the application of ATP as a phosphate donor in indus- Enzymatic synthesis
trial biotechnology. Additionally, issues such as limi-
tations in enzyme kinetics and stability, along with In the biological synthesis methods of NMN, fer-
mass-transfer constraints associated with ATP, may mentation and enzymatic synthesis are two main
potentially obscure the potential of ATP regeneration technical routes. Among them, the fermentation

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method faces with significant challenges in indus- was 4.34 times higher than that of the wild type
trial production due to the presence of impurities (Peng et al. 2024). However, there is still a certain
such as yellow pigments in the fermentation broth, distance from large-scale production. It is worth
which makes the subsequent separation and purifi- noting that during the process of NAMPT catalyz-
cation process extremely complex. Additionally, the ing PRPP to NMN, the by-product pyrophosphate
diversity of microbial metabolic products during the (PPi) is produced. Studies have shown that adding
fermentation process also increases the difficulty of pyrophosphatase to degrade PPi can increase the
separating the target product, resulting in a relatively yield of NMN by about 50%, which may be due to
low overall production efficiency. In contrast, enzy- the elimination of by-products promoting the reaction
matic synthesis, as a more promising alternative, equilibrium to shift towards the product side (Bur-
has attracted much attention due to its advantages gos and Schramm 2008). In addition, in recent years,
of mild reaction conditions and high product purity. researchers have also been exploring the modification
More importantly, this method avoids the problem of of NAMPT through protein engineering to improve
separating and purifying the complex components of its catalytic efficiency and stability, thereby further
the culture medium in traditional fermentation, sig- optimizing this synthesis route. The second synthesis
nificantly simplifying the production process (Peng pathway utilizes the catalytic action of NRK, provid-
et al. 2024). Currently, there are mainly two techni- ing the energy required for the transfer of phosphate
cal routes for enzymatic synthesis of NMN: one is groups through the hydrolysis of ATP, converting NR
the synthesis pathway using NAMPT as a biocatalyst to NMN in one step. This method has the advantages
and NAM and 5′-phosphoribosyl-1′-pyrophosphate of fewer raw material types, simple process control,
(PRPP) as substrates (Gardell et al. 2019); the other high conversion efficiency, and high product purity.
is the pathway where NR is converted to NMN under Particularly noteworthy is that Qian et al. (2022) iso-
the action of NRK (Fletcher et al. 2017). Regarding lated and identified a novel NRK from Kluyveromy-
the first synthesis route, its advantage lies in the use ces marxianus (Klm-NRK), with a specific activity of
of a full enzyme system, and under the condition of 7.9 U/mg, which is the highest known NRK activity.
substrate concentration of 10–30 g/L, the theoreti- The researchers constructed an ATP recycling sys-
cal yield of NMN can exceed 70%. However, this tem by coupling Klm-NRK with acetate kinase, not
route has several limitations: first, the market supply only significantly reducing the consumption of ATP
of PRPP is limited and its cost is high; second, the and production costs, but also effectively avoiding the
catalytic activity of NAMPT is relatively low; third, inhibitory effect of by-product accumulation on the
this route involves a multi-enzyme cascade reaction, reaction. Under the condition of a substrate concen-
which not only makes the process complex but also tration of 100 g/L, Klm-NRK can achieve a conver-
easily leads to the generation of many by-products sion rate of 98.3% within 8 h, with a space–time yield
(Cheng et al. 2024; Hove-Jensen et al. 2017). PRPP, of 281 g/L/day (Yousefzadeh et al. 2021). However,
as a key intermediate in NMN synthesis, is too expen- it should be pointed out that the actual yield of the
sive and unstable to be directly used as an industrial NRK-based biocatalytic pathway under high concen-
substrate, and its supply has become a limiting factor tration NR substrate conditions is still not ideal, and
for increasing NMN production. Therefore, Hua et al. its industrial feasibility still needs further verification
(2023) constructed three pathways in Escherichia coli and optimization.
using glucose, xylose, and arabinose as substrates to From an industrial application perspective, enzy-
provide PRPP. By comparing the efficiency of NMN matic synthesis of NMN still faces several challenges.
synthesis through different pathways, they determined First, the cost and stability of enzymes remain critical
the optimal in vivo route for whole-cell catalysis and, barriers to large-scale implementation. While immo-
through optimizing cell culture and catalytic condi- bilized enzyme technology can improve enzyme reus-
tions, ultimately achieved an NMN titer of 1.8 mM. ability to some extent, further research is needed to
Researchers improved the efficiency of NMN synthe- enhance catalytic efficiency and operational stabil-
sis by designing phosphoribosyl pyrophosphate syn- ity. Second, the cost and availability of substrates
thetase (PRS) to control enzyme activity. The activ- significantly impact process economics. Developing
ity of the obtained mutant PRS-H150QNampt-Y15S low-cost, readily accessible alternative substrates or

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producing key substrates (e.g., PRPP) via biosyn- breaks (DSBs) represent one of the most severe types.
thetic pathways could be a promising future direction. Upon DSB occurrence, rapid phosphorylation of his-
Finally, product purification processes require optimi- tone ­H2AX at Ser139 (forming γH2AX foci) initiates
zation to increase overall yield and reduce production the DNA damage response (DDR) signaling cascade.
costs. This activates ATM/ATR kinases, triggering cell
cycle arrest to facilitate repair. However, persistently
activated DDR signaling drives cells toward apoptosis
Aging mechanisms and the anti‑aging effects or senescence, and this vicious cycle—where damage
of NMN accumulation outpaces repair capacity—is recognized
as a key pathological basis for tissue degeneration and
DNA damage repair age-related diseases (Soto-Palma et al. 2022).
Multiple studies have confirmed the DNA protec-
The accumulation of DNA damage has been widely tive effect of NMN through differentiated experi-
validated as one of the core molecular mechanisms mental models (Fig. 3). Jia et al. (2021) treated
driving cellular senescence (Yousefzadeh et al. 2021). human kidney cells (HK-2) with hydrogen perox-
During physiological aging, approximately 1­013 ide ­(H2O2) and low oxygen (1% ­O2) to induce DNA
human cells daily experience DNA damage caused damage and cellular senescence. In this study, after
by endogenous factors (e.g., reactive oxygen spe- 48 h of NMN treatment, the proportion of DNA-
cies) and exogenous stressors (e.g., radiation, chemi- damaged cells significantly decreased from 32.0
cal toxins). Among these lesions, DNA double-strand to 22.6%, and the proportion of SA-β-gal positive

Fig. 3  NMN exerts anti-

aging effects by promoting
DNA damage repair, mito-
chondrial function regula-
tion, inflammatory response
homeostasis, gut microflora
remodeling, and autophagy
pathway activation

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cells also significantly decreased, indicating that (1) Enhancing PARP1-mediated DNA repair capac-
NMN not only slows down the progression of DNA ity;
damage but also inhibits the appearance of senes- (2) Activating deacetylases such as SIRT1 to main-
cent cell phenotypes. In in vivo experiments, inves- tain genomic stability.
tigators administered NMN to both aged and young
mice via intraperitoneal injection at a dosage of Despite existing studies supporting the DNA-pro-
500 mg/kg/d. The findings revealed that NMN ele- tective effects of NMN and NR, several limitations
vated the concentration of NAD⁺ within the livers require attention:
of the mice. Moreover, it augmented the activity of
PARP1 and facilitated the repair of damaged DNA (1) Most in vitro experiments use millimolar concen-
in the murine models (Wang et al. 2020). In in vitro trations (far exceeding physiological micromolar
studies, relatively high concentrations (ranging from levels in plasma), potentially overestimating their
100 μM to 1 mM) are generally requisite to elicit actual biological effects.
observable significant effects. This concentration (2) Cell-type variability in NMN and NR uptake
range may transcend the capacity to elevate N ­ AD+ efficiency may affect their tissue distribution and
to physiological levels in vivo. Upon oral ingestion efficacy.
in mice, NMN is absorbed through the intestinal (3) The impact of long-term supplementation on
tract and subsequently disseminated to diverse tis- NAD⁺ metabolic homeostasis remains unclear,
sues via the circulatory system. The entry of NMN particularly its potential interference with feed-
into cells is facilitated by specific transporters, such back regulation mechanisms in NAD⁺ biosynthe-
as Slc12a8. Once inside the cells, NMN is metabo- sis.
lized into ­ NAD+ (Grozio et al. 2019). However, (4) Differences in in vivo metabolic pathways: NMN
in vitro experiments lack the metabolic coordina- must be converted to NR before cellular entry,
tion among tissues (such as the liver’s conversion of whereas NR directly synthesizes NAD⁺ via the
NMN and the regulation of intestinal absorption), NAMPT pathway. These metabolic disparities
and they cannot simulate the systemic inflammation may influence their effects in different tissues.
or hormonal changes associated with aging. There-
fore, further experiments are needed to compare the
dynamic changes in ­NAD+ levels and aging markers Mitochondrial function regulation
in the same NMN dose between in vitro cells and
animal models. Mitochondria, as pivotal membrane-bound organelles
In addition to NMN, NR, as another NAD⁺ pre- in eukaryotic cells, serve not only as the ‘energy
cursor, has shown potential in protecting DNA from powerhouse’ but also as a central hub regulating
damage. Since NR and NMN are structurally simi- cellular metabolism, signal transduction, and pro-
lar, comparing their roles in DNA damage repair can grammed cell death. In most eukaryotic cells, mito-
provide deeper insights. Qiu et al. (2024) established chondria occupy approximately 20% of the total cel-
a DNA damage model by treating HeLa cells with lular volume, and their functional integrity is critical
10 μM cisplatin for 12 h, followed by treatment of the for maintaining cellular homeostasis. Recent studies
damaged cells with 10 mM NMN or NR, respectively. have demonstrated that mitochondrial dysfunction is
Evaluation via γH2AX immunofluorescence staining not only a hallmark of cellular aging but also a key
and alkaline comet assay revealed that both NMN and pathological basis for various age-related diseases,
NR alleviated cisplatin-induced DNA damage in a including neurodegenerative disorders and metabolic
dose-dependent manner, with comparable efficacy in syndromes (Hernandez-Segura et al. 2018). At the
elevating intracellular NAD⁺ levels. Notably, cisplatin molecular level, mitochondrial dysfunction and oxi-
treatment not only directly induces DNA damage but dative stress exhibit a complex bidirectional regula-
also significantly reduces intracellular NAD⁺ levels, tory relationship. With aging, declining efficiency
thereby exacerbating the cellular senescence process. of the mitochondrial electron transport chain (ETC)
By replenishing the NAD⁺ pool, NMN and NR likely leads to excessive production of ROS (Di Meo et al.
act on multiple fronts: 2016). ROS, as highly reactive molecules including

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superoxide anion (­O2⁻), ­H2O2, hydroxyl radical restoration of mitochondrial morphology. Sims et al.
(·OH), and singlet oxygen (1O₂), can cause oxidative (2018) in a decompensated hemorrhagic shock model
damage to biomolecules such as proteins, lipids, and further demonstrated that NMN treatment signifi-
DNA (Juan et al. 2021; Singh et al. 2022). Notably, cantly elevates hepatic and renal N ­ AD+ levels, pre-
mitochondria are both the primary source of cellular venting mitochondrial dysfunction. Particularly note-
ROS (~ 90% of total cellular ROS) and their primary worthy is that Klimova et al. (2019) revealed NMN’s
target, creating a self-reinforcing paradox that drives rapid-action mechanism: in 3-month-old male mice,
mitochondria into a vicious cycle of dysfunction. At a single intraperitoneal NMN injection (62.5 mg/kg)
the molecular level, the generation of mitochondrial increased hippocampal mitochondrial ­ NAD+ levels
reactive oxygen species (ROS) is mainly related to by 76.6% within 15 min and maintained this elevated
the “electron leakage” of the electron transport chain. state for 24 h. This ­NAD+ elevation is accompanied
Mechanistically, Complexes I and III mediate univa- by a significant increase in ATP content and SIRT3-
lent oxygen reduction via the ubiquinone cycle, while mediated deacetylation of mitochondrial proteins,
Complex II predominantly generates O₂⁻ (Giorgi et al. ultimately leading to reduced ROS levels and attenu-
2018). Excessive ROS attack mitochondrial DNA, ated mitochondrial fragmentation. These findings col-
inducing cumulative mutations while concurrently lectively demonstrate that NMN exerts mitochondrial
triggering oxidative modifications of mitochondrial protective effects through pleiotropic mechanisms:
proteins and lipid peroxidation. These damages will
further compromise the integrity of the mitochondrial (1) Direct NAD⁺ replenishment to potentiate mito-
membrane, lower the efficiency of ATP synthesis, chondrial bioenergetic metabolism;
and result in an elevated AMP/ATP ratio. Although (2) SIRT3 activation-driven deacetylation of mito-
the cellular energy sensor AMPK is capable of coun- chondrial proteins, enhancing antioxidant defense
tering energy crises by upregulating mitochondrial capacity;
biogenesis and facilitating quality control, persistent (3) Regulation of mitochondrial dynamics to main-
ATP deficiency will ultimately give rise to a decrease tain network homeostasis.
in mitochondrial biogenesis, an imbalance in quality
control, and functional impairments, forming the so- Notably, following the administration of NMN to
called “mitochondrial aging” phenotype (Guo et al. mice, while some studies have proposed that NMN
2023a, b). Among the numerous factors governing can mitigate age-associated weight gain, augment
mitochondrial function, the metabolic dysregulation energy metabolism, stimulate physical activity, and
of ­NAD+ is of particular significance. ­NAD+, serv- improve insulin sensitivity, no genetic evaluation has
ing as a coenzyme for over 400 enzymatic reactions, been carried out on the mediating factors underlying
undergoes a marked decline in its level with increas- these effects. Merely within the context of discus-
ing age. This decrease inhibits cellular respiration, sions has there been speculation that NMN might
leads to impairments in ATP generation, and poten- activate SIRT1, SIRT3, SIRT4, SIRT5, and SIRT6,
tially triggers cell death (Kristian et al. 2011). Recent yet there is a dearth of substantial evidence to sup-
studies have indicated that supplementing the N ­ AD+ port this postulation. Moreover, in the investigation of
precursor NMN can effectively sustain intracellular the impact of NR on murine metabolism, the research
­NAD+ levels and ameliorate mitochondrial dysfunc- team refrained from conducting a genetic inquiry
tion. This finding offers a novel perspective for anti- into the underlying mechanism. Instead, solely by
aging intervention. detecting the acetylation status of the nuclear tran-
Multiple animal studies have validated the mito- scription factor Foxo1 and mitochondrial superoxide
chondrial protective effects of NMN (Fig. 3). Long dismutase 2 (SOD2), they asserted that the beneficial
et al. (2015) found in an Alzheimer’s disease mouse effects of NR were mediated by SIRT1 and SIRT3.
model that subcutaneous injection of NMN (100 mg/ This study methodology may lack the requisite rigor.
kg, every other day for 28 days) could significantly Analogously, the research on NMN may also exhibit
improve brain mitochondrial function, as indicated comparable methodological shortcomings. There has
by the reversal of oxygen consumption defects, the been a lack of in-depth investigation into the factors
improvement of mitochondrial bioenergetics, and the that trigger the acetylation of these proteins, whether

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Sirt isoenzymes are indeed accountable for their dea- would enhance the pro-inflammatory SASP in senes-
cetylation, and the significance of these modifications cent cells induced by oncogenes and promote the pro-
to the mechanism of action of NMN. In addition, gression of pancreatic cancer in mouse models. Other
while sirtuins are capable of catalyzing intriguing studies have shown that the cell-permeable analog of
biochemical reactions and performing crucial func- NMN would activate SARM1 to produce cyclic ADP-
tions within organisms, their regulatory capacity is ribose and induce non-apoptotic cell death (Zhao
relatively limited when juxtaposed with most other et al. 2019). Moreover, excessive doses of NMN may
enzymes in the N ­ AD+ system (Brenner 2022). Conse- have an impact on fertility. Although the number of
quently, it is overly simplistic to postulate that NMN existing human clinical trials is limited, the results
exerts a substantial ameliorative effect on SIRT. An show that NMN has the potential to be an anti-aging
objective assessment of sirtuin function, particularly agent. Some clinical trials have evaluated the safety
in establishing them as longevity enzymes or the pri- of oral NMN, its potential anti-aging effects, and
mary mediators of the effects of N ­ AD+ supplementa- the changes in NAD⁺ or its metabolite concentra-
tion, necessitates further validation. tions in blood, PBMCs, plasma, skeletal muscle or
The contradictory research on the role of NMN in urine. However, it is still unclear whether the ben-
human trials mainly lies in its impact on NAD⁺ con- eficial effects of NMN are limited to specific groups
centration, safety and efficacy: Some studies have or applicable to all populations. The administration
shown that oral NMN can significantly increase the method and dosage of NMN still need more research
NAD⁺ concentration in whole blood. For instance, to determine in the future.
taking 250 mg/days NMN for 10 weeks can increase These mechanistic insights position NMN sup-
the NAD⁺ concentration in whole blood by 2.57 plementation as a promising therapeutic strategy for
times, and the concentration of NAD⁺ metabolites preventing and treating age-related pathologies. How-
in the whole blood of healthy participants also sig- ever, its long-term safety profile and clinical efficacy
nificantly improves. Taking 250 mg/days NMN for require rigorous validation through phase III rand-
10 weeks can significantly increase the baseline omized controlled trials.
NAD⁺ concentration in peripheral blood mononuclear
cells (PBMCs) of pre-diabetic women and improve Inflammatory response balance
muscle insulin sensitivity, but it cannot increase
the NAD⁺ concentration in skeletal muscle. Simi- Aging constitutes a complex biological process char-
larly, in human clinical trials of NR, the NAD⁺ con- acterized by a systemic chronic inflammatory state,
centration in skeletal muscle did not increase either concurrent with cellular senescence, immunose-
(Song et al. 2023). Most human clinical trials have nescence, organ dysfunction, and the development
shown that oral NMN is safe and well tolerated. For of multiple age-related pathologies. This chronic
instance, a short-term study conducted by Keio Uni- inflammatory phenomenon, termed “inflammag-
versity School of Medicine in 2016 on 10 healthy ing”, represents a pivotal conceptual framework in
men showed that a single oral dose of up to 500 mg aging research (Xia et al. 2016). Under physiologi-
of NMN was safe, and the participants tolerated it cal conditions, the inflammatory response serves as
well (Irie et al. 2020). Other multiple studies with dif- a critical defense mechanism against tissue injury
ferent doses and durations have also reached similar or pathogenic invasion. Upon tissue damage, local-
conclusions, including a recent investigation of 31 ized cellular-level inflammation is immediately initi-
healthy individuals aged 20–65, which demonstrated ated, activating immune cells such as macrophages
that NMN is non-mutagenic, safe and well-tolerated and monocytes to secrete cytokines including tumor
(Fukamizu et al. 2022; Okabe et al. 2022). However, necrosis factor-α (TNF-α) and interleukin-6 (IL-6).
there are also some studies reporting potential toxic These molecular mediators amplify through signal-
effects of NMN. For instance, Di Stefano et al. (2017) ing cascades, propagating the inflammatory response
reported that NMN supplementation had a neuro- to systemic levels. The acute phase exhibits cardinal
degenerative effect on axons in a mouse model of clinical manifestations—fever, edema, erythema,
chemotherapy-induced peripheral neuropathy. Nac- and pain—with its primary functions encompassing
arelli et al. (2019) found that NMN supplementation pathogen clearance, initiation of tissue repair, and

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restoration of homeostatic equilibrium (Parisien et al. mechanisms of NMN are intrinsically linked to its
2022). However, the inflammatory response during role in NAD⁺ biosynthesis. NAMPT, serving as the
aging exhibits distinct pathophysiological character- rate-limiting enzyme, catalyzes the conversion of
istics: a chronic, low-grade, subclinical inflamma- NAM and PRPP to NMN, which is subsequently
tory state. While sharing molecular mechanisms with adenylated to NAD⁺ by NMN adenylyltransferases
acute inflammation, this state differs fundamentally (Imai 2009). NAMPT exists in two distinct isoforms:
in intensity and temporal persistence (Jenny 2012). intracellular (iNAMPT) and extracellular (eNAMPT).
Senescent cells secrete senescence-associated secre- Crucially, eNAMPT is predominantly secreted by
tory phenotype (SASP) factors, which not only facili- adipose tissue and facilitates plasma NMN synthe-
tate the progression of chronic inflammation but also sis (Revollo et al. 2007). This compartmentaliza-
induce senescence in normal cells. The SASP fac- tion explains pancreatic islets’ functional reliance
tors encompass diverse pro-inflammatory cytokines, on circulatory eNAMPT for NAD⁺ replenishment,
chemokines, growth factors, and proteases, which given their inherently low iNAMPT expression lev-
exert paracrine effects on the surrounding tissue els. Caton et al. (2011) demonstrated that chronic
microenvironment (Li et al. 2023). Simultaneously, high-fructose feeding induces a triad of pathologi-
chronic inflammation expedites the senescence of cal alterations in mice: reduced eNAMPT secretion,
immune cells, resulting in immune dysfunction and exacerbated islet inflammation, and β-cell dysfunc-
establishing a mutually reinforcing vicious cycle tion—all of which were ameliorated by NMN sup-
between inflammation and senescence. This sustained plementation. Further mechanistic insights emerged
inflammatory state leads to damage in multiple organs from macrophage inflammation models. Liu et al.
such as the bone marrow, liver, and lungs, ultimately (2021a, b) revealed that lipopolysaccharide (LPS)
giving rise to age-related diseases. Hence, inflam- challenge triggers NAD⁺ depletion in bone marrow-
mation is considered a crucial endogenous factor of derived macrophages (BMDMs), compromising
aging, and modulating inflammation might emerge as SIRT1/SIRT3-mediated deacetylase activity critical
a potential strategy for anti-aging. for NF-κB pathway suppression. Sirtuins, a class of
Recent studies have elucidated the anti-inflam- NAD⁺-dependent histone deacetylases, play a crucial
matory properties of NMN, with emerging evi- role in modulating inflammatory responses. NMN
dence highlighting its therapeutic potential (Fig. 3). supplementation not only restores NAD⁺ levels but
Mechanistic investigations reveal NMN’s capacity also significantly suppresses the expression of IL-6
to ameliorate inflammatory conditions through mul- and IL-1β. Proteomic analyses reveal that NMN can
tiple pathways. In type II diabetes research, β-cell downregulate the expression of LPS-induced inflam-
exhaustion constitutes a central pathological event matory response proteins, particularly markedly
driving insulin resistance progression, where proin- reducing the expression level of cyclooxygenase-2
flammatory cytokines play a pivotal regulatory role. (COX-2). Concurrently, the reduced level of prosta-
Caton et al. (2011) demonstrated that inflammatory glandin E2 (PGE2) indicates that NMN may inhibit
cytokines Interleukin-1β (IL-1β) and TNF-α pro- macrophage activation via the COX-2-PGE2 pathway.
foundly suppress glucose- and leucine-stimulated Furthermore, the anti-inflammatory effects of NMN
insulin secretion (GSIS/LSIS) in pancreatic islet are also manifested in studies of the reproductive
cells. Intriguingly, NMN co-incubation rescued this system. Ahmed et al. (2024) discovered that in the
suppression, suggesting β-cell protective potential LPS-induced inflammatory model of follicular gran-
through cytokine signaling modulation. Subsequent ulosa cells (GCs), NMN supplementation was capa-
investigations revealed NMN’s capacity to suppress ble of restoring NAD⁺ levels and the NAD⁺/NADH
IL-1β/TNF-α-mediated transcriptional upregulation ratio, and significantly lowering the expression of
of IL-1β and subsequent protein-level IL-1β eleva- pro-inflammatory factors such as IL-1β, IL-6, COX-
tion. These mechanistic insights were corroborated 2, and TNF-α. Concurrently, NMN reduced apoptosis
through in vivo validation: NMN supplementation by modulating apoptosis-related proteins (down-reg-
rescued inflammation-associated islet dysfunction ulating Caspase-3, Caspase-9, and Bax, and up-reg-
in a high-fructose diet-induced β-cell impairment ulating Bcl-2), and exerted anti-inflammatory effects
model (Caton et al. 2011). The anti-inflammatory by inhibiting the TLR4/NF-κB/MAPK signaling

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pathway (Ahmed et al. 2024). These research findings Studies have shown that the gut microbiota charac-
suggest that NMN exerts its anti-inflammatory effects teristics of healthy elderly individuals are manifested
through multiple targets and pathways, providing a by a decrease in the core microbiome (especially
crucial theoretical foundation for the development of Bacteroides) and an increase in beneficial bacterial
NMN-based anti-aging strategies. Nevertheless, the metabolites. This distinct microbiota signature may
long-term safety and efficacy of NMN in the human potentially serve as a biomarker for healthy aging
body still require further in-depth investigations to (Wilmanski et al. 2022). Bacterial-derived metabo-
furnish more sufficient evidence for the development lites not only affect the intestinal aging process but
of safe and effective anti-aging intervention strategies. also are involved in the development of multiple age-
related diseases. These metabolites may become sig-
Remodeling of the gut microbiota nificant biological mediators and therapeutic targets
for promoting healthy aging (Wang et al. 2021). In
The gut microbiota has been increasingly recognized recent years, remarkable progress has been achieved
as a pivotal modulator in aging and age-associated in enhancing lifespan (Bárcena et al. 2019), retarding
pathologies. The human gastrointestinal tract harbors immune senescence (Conway and Duggal 2021), alle-
a complex microbial ecosystem comprising approxi- viating age-related cognitive decline (Rei et al. 2022),
mately 100 trillion microorganisms representing over and improving metabolic syndrome and intestinal
2,000 distinct bacterial species (Ghosh et al. 2022). aging manifestations through microbial intervention
This commensal consortium engages in multifaceted approaches such as fecal microbiota transplantation
symbiotic interactions with the host, executing three and single-strain intervention (Qi et al. 2023). These
cardinal physiological roles: discoveries indicate that age-related gut microbiota
dysbiosis plays a crucial role in the aging process,
(1) Colonization resistance: Provides pathogen pro- and modulating the gut microbiota may become an
tection through nutrient competition and antimi- important strategy for anti-aging (Fig. 3).
crobial compound production; In the domain of neurodegenerative disease
(2) Immune homeostasis: Enhances intestinal bar- research, Zhao et al. (2023) made the pioneering
rier integrity via tight junction protein induction, report on the mechanism through which NMN ame-
stimulates secretory IgA production, and orches- liorates AD by modulating the gut microbiota. The
trates immune system maturation; study employed AD model mice and administered
(3) Metabolic regulation: Facilitates biosynthesis of 300 mg/kg of NMN intragastrically every day starting
essential micronutrients (e.g., biotin and folate) from 6 months of age for a duration of 16 weeks. The
and energy harvesting through fermentation of outcomes revealed that the NMN intervention signifi-
indigestible substrates. cantly transformed the composition of the gut micro-
biota in AD mice, particularly augmenting the abun-
Notably, both environmental stressors (includ- dance of Lactobacillus and Bacteroides that generate
ing infections, inflammatory states, dietary patterns, short-chain fatty acids (SCFAs). Among them, Lacto-
and pharmacological interventions) and host genetic bacillus not only produces lactic acid but also gener-
determinants dynamically shape microbial com- ates SCFAs such as acetic acid and butyric acid,
munity architecture. Disruption of this equilibrium which possess neuroprotective functions. The
termed dysbiosis has been mechanistically linked to research discovered that butyric acid levels were posi-
diverse disease states spanning metabolic disorders tively correlated with clinical cognitive function indi-
(obesity, diabetes), autoimmune conditions, neuro- cators [Mini-Mental State Examination (MMSE),
degenerative diseases, and malignancies (Levy et al. Wechsler Adult Intelligence Scale (WAIS)] and the
2017; Yoshimoto et al. 2013). Furthermore, longi- anti-inflammatory cytokine interferon-γ (IFN-γ),
tudinal studies reveal progressive age-dependent while negatively correlated with pro-inflammatory
alterations in microbial diversity and functional gene cytokines TNF-α and IL-6, and could inhibit the acti-
repertoires, with this gerontological dysbiosis being vation of the intestinal NF-κB signaling pathway
intricately linked to inflammaging and the pathogen- (Zhao et al. 2023). Bacteroides, as a major constituent
esis of age-related multimorbidity (Fu et al. 2023). of the gut microbiota, its polysaccharide utilization

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loci (PULs) not only influence butyric acid produc- Furthermore, NMN has demonstrated remarkable
tion but also exert anti-inflammatory, antioxidant, and ameliorative effects on intestinal microbiota dysbiosis
neuroprotective effects by regulating the metabolism induced by sleep deprivation (SD). Fang et al. (2023)
of flavonoids, thereby mitigating AD-related cogni- established an SD mouse model through continuous
tive impairments (Zhao et al. 2017). SCFAs are a set rotational disturbance for three days and discovered
of metabolites generated by gastrointestinal bacteria that NMN supplementation could significantly
via the fermentation of dietary fiber, and they assume enhance the α-diversity of the intestinal microbiota
a crucial role in host-microbiota interactions. SCFAs (with increased Chao 1 and Simpson indices). Princi-
are capable of modulating the functions of multiple pal component analysis (PCA) indicated that NMN
systems, encompassing the intestinal, nervous, endo- intervention largely reversed the alterations in fecal
crine, and hematopoietic systems. Specifically, they microbiota structure caused by SD. Histopathological
can potentially mediate the treatment of AD by miti- analyses further substantiated that NMN was capable
gating microglia-mediated neuroinflammation of alleviating pathological changes resulting from
through the regulation of the gut–brain axis (GBA) SD, such as colonic atrophy, mucosal congestion, and
(Boets et al. 2017; Nagpal et al. 2018). In the context excessive lymphocyte infiltration. The supplementa-
of AD, the brain exhibits hypometabolism, which tion of NMN exerts an impact on the abundance of
gives rise to neuronal dysfunction. SCFAs can act as intestinal microbiota species. With the increase in
substrates for energy metabolism, offering alternative NMN concentration, the overall diversity of the intes-
energy sources to counterbalance the hypometabo- tinal microbiota gradually diminishes. By analyzing
lism in the brain that leads to neuronal dysfunction, several indices of α-diversity, it was revealed that fol-
thus attenuating neuroinflammation. Among SCFAs, lowing the administration of NMN, the Chao1 index
acetate and propionate are potent anti-inflammatory and other indices of observed species decreased, and
mediators. They have the ability to suppress the these changes exhibited a negative correlation with
release of pro-inflammatory cytokines by neutrophils the NMN concentration. Principal coordinate analysis
and macrophages. Butyric acid inhibit histone deacet- (PCoA) indicated that NMN at a concentration of
ylases through epigenetic mechanisms, normalizing 0.6 mg/mL had a notable effect on the microbial com-
abnormal histone acetylation, which is beneficial for position of mouse feces (Huang et al. 2021). NMN
the treatment of AD and alleviating neuroinflamma- has the potential to enhance the abundance of
tion (Zhao et al. 2023). Therefore, there is a certain butyrate-producing bacteria, including Ruminococ-
causal relationship in this change, that is, NMN caceae_UCG-014 and Prevotellaceae_NK3B31.
reduces neuroinflammation by increasing SCFAs and Ruminococcaceae, as beneficial microorganisms, col-
other products and regulating GBA. Meanwhile, onize the cecum and colon. These bacteria possess
NAD⁺, as an important coenzyme in cellular energy the ability to degrade polysaccharides and fibers,
metabolism, is also involved in the catabolism and thereby generating SCFAs. SCFAs serve as the pri-
synthesis of SCFAs. During the metabolic process of mary energy source for colonocytes. The absence or
SCFAs produced by intestinal microorganisms, NAD⁺ deficiency of Ruminococcaceae can result in the
acts as a coenzyme in the re-dehydrogenation step of impairment of intestinal barrier function (Hamer
β-oxidation. Moreover, NAD⁺ can be phosphorylated et al. 2012). Therefore, NMN contributes to the main-
to form NADP⁺, which participates in the synthesis of tenance of intestinal barrier function by augmenting
SCFAs (Covarrubias et al. 2021; Dalile et al. 2019). the abundance of these bacteria. Akkermansia also
Therefore, microorganisms are indirectly associated showed an increase in the NMN treated group. Akker-
with NMN production through influencing the metab- mansia, a gut symbiotic bacterium that colonizes the
olism of SCFAs. Overall, NMN and microorganisms mucus layer, is regarded as a promising candidate for
may interact through influencing the composition of probiotics (Berry et al. 2013). This bacterium is capa-
the intestinal microbiota, the production of SCFAs, ble of degrading mucin and promoting its synthesis,
and participating in NAD⁺-related metabolism, etc. thereby facilitating mucin turnover. When it enhances
These interactions may be related to the development the number of intestinal goblet cells and the thickness
and treatment of AD, but the specific interaction of the mucus layer, it can prevent external bacteria
mechanisms still need further research to be clarified. from making direct contact with the epithelial layer

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(Ijssennagger et al. 2015; Shin et al. 2014). In addi- Specifically, the contents of primary bile acids and
tion, in a variety of diseases, including inflammatory secondary bile acids increased markedly. Addition-
bowel disease (IBD), the abundance of Akkermansia ally, there were differences in the levels of several
muciniphila decreases (Everard et al. 2013). The ele- other metabolites, including taurine, betaine, phenol,
vation of its abundance by NMN may contribute to and 5-hydroxyindoleacetic acid (Huang et al. 2021).
the prevention of related diseases. NMN significantly Among these, TDCA can preserve the integrity of
reduces the abundance of Bilophila. Bilophila was the intestinal mucosa by diminishing cell apoptosis,
initially isolated from the appendiceal tissues of stimulating cell proliferation, and augmenting the
patients with gangrenous and perforated appendicitis. villus length. Additionally, it can facilitate intestinal
Subsequently, it has also been isolated from clinical mucosal renewal by mediating the farnesoid X recep-
infection specimens such as those of sepsis and chol- tor (FXR) to upregulate the expression of c-Myc. It is
ecystitis. Study has indicated that it may be associated postulated that the increase in fecal bile acid concen-
with the onset and progression of diseases. The tration induced by NMN is attributable to a decrease
reduction of its abundance by NMN is conducive to in ileal reabsorption. This exemplifies the specific
the improvement of enteritis (Baron et al. 1989, 1992; influence of long-term NMN treatment on the con-
Devkota et al. 2012). The abundance of Oscillibacter centrations of common metabolites in feces.
also exhibited a decreasing trend. It is associated with Furthermore, NMN ingestion can also promote
trimethylamine N-oxide, a risk factor for cardiovascu- intestinal autophagy and elevate the expression of
lar and cerebrovascular diseases. This serves as com- LC3. Meanwhile, recent research has demonstrated
pelling evidence that NMN can mitigate cardiovascu- that the integrity of the intestinal epithelial barrier
lar diseases (Yin et al. 2015). The endotoxins is regulated by autophagy (Feng et al. 2018). By
(primarily LPS) produced by Desulfovibrionaceae establishing a starvation model, it was revealed that
have a high likelihood of inducing inflammation autophagy can induce the strengthening of tight junc-
(Xiao et al. 2014). NMN can suppress the growth of tions, reducing the paracellular flux of small mol-
Desulfovibrionaceae, thereby exerting an anti-inflam- ecules without affecting the trans-epithelial flux of
matory effect. On one hand, NMN inhibits the inflam- large-molecule paracellular probes. Moreover, in this
matory microenvironment, creating conditions that experiment, it was observed that the protein level of
are inhospitable for the survival of Desulfovibrion- Claudin-2 was significantly downregulated, and its
aceae. On the other hand, NMN significantly elevates localization shifted from the membrane to the lys-
the concentrations of bile acid-related metabolites, osomes within the cytoplasm. This suggests that
such as cholic acid (CA) and taurodeoxycholic acid under starvation conditions, autophagy enhances tight
(TDCA). Bile acids and their metabolites (e.g., deox- junctions by inducing the degradation of Claudin-2
ycholic acid, DCA) possess potent inhibitory effects (Nighot et al. 2015). This also implies that NMN
on bacterial growth. As an integral component of the maintains the integrity of the mucosal barrier to a
intestinal microbiota, Desulfovibrionaceae encoun- certain extent by promoting autophagy. On the other
ters survival-selection pressures imposed by bile hand, intestinal microbiota can also regulate NAD⁺
acids. Consequently, its growth is inhibited, which in metabolism through a large number of primary and
turn helps maintain the normal intestinal secondary metabolites they produce. These metabo-
environment. lites act as local and global signaling molecules,
NMN also exerted an impact on the concentrations driving host stress responses and tissue maintenance
of common metabolites in feces. After observing the (Salekeen et al. 2021).
influence of NMN on the intestinal microbiota, the Evidence indicates that certain microbial charac-
researchers carried out a non-targeted metabolomics teristics are associated with NAD⁺ synthesis, the acti-
analysis to investigate how long-term NMN treatment vation of SIRTs, and the reduction of oxidative stress.
affects the concentrations of common metabolites Nevertheless, the underlying molecular interactions
in feces. The findings indicated that, in comparison remain largely obscure and inadequately explored.
with the control group, the contents of bile acid- Current research on anti-aging therapies endeavors
related metabolites in the group supplemented with to harness this metabolic network by mimicking vari-
0.6 mg/mL NMN underwent significant alterations. ous epigenetic stressors, including different caloric

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restriction regimens, exercise, and intermittent stress homeostasis and promoting cell differentiation, devel-
exposures. Certain small molecules in the diet, such as opment, and survival (Aman et al. 2021; Levine and
resveratrol, quercetin, fisetin, curcumin, epigallocate- Klionsky 2017). This process involves the formation
chin gallate (EGCG), metformin, and synthetic deriv- of double-membrane autophagosomes that encap-
atives such as SRT1720, can directly or indirectly sulate the substances to be degraded and transport
modulate NAD⁺ metabolism, conferring benefits to them to lysosomes for degradation, thereby enabling
physiological homeostasis and longevity. However, the recycling of cellular components. Nevertheless,
these molecules are plagued by issues such as low as age progresses, autophagy functionality gradu-
bioavailability, inconsistent performance in experi- ally becomes dysregulated, influencing multiple cel-
ments, and potential in vivo toxicity (Salekeen et al. lular and molecular processes related to aging (i.e.,
2021). In recent years, studies have revealed that the the hallmarks of aging), such as imbalance in protein
patterns of gut microbiota are associated with lifes- homeostasis, reduced capacity for stress response,
pan and health. Certain beneficial bacterial taxa (such disordered cellular energy metabolism, persistent
as the ratio of Firmicutes to Bacteroidetes) can serve cellular senescence, exhaustion of stem cells, epige-
as indirect biomarkers or hallmarks of healthy aging netic alterations, defective intercellular communica-
(Biagi et al. 2016). Meanwhile, there is a connec- tion, accumulation of macromolecular damage, and
tion between gut microbiota and NAD⁺ metabolism. telomere attrition (Kaushik et al. 2021). The diverse
SIRTs (particularly SIRT1) and NAD⁺ metabolism functions of autophagy and its complex interactions
are related to intestinal inflammation and dysbiosis, with other aging determinants render it one of the
which can result in alterations in the composition of core mechanisms in regulating the aging process.
the gut microbiota community (Wellman et al. 2017). Hence, the development of intervention strategies
The metabolites produced by gut microbiota may capable of directly modulating autophagy function
play a role in the impact of NAD⁺ on longevity. How- has emerged as a significant research direction for
ever, the underlying molecular interactions in this delaying aging and extending healthy lifespan.
area still await further research for supplementation. In recent years, the role of NMN in regulating
In conclusion, NMN regulates the intestinal micro- autophagy has garnered widespread attention (Fig. 3).
biota through multiple targets, including increasing In the domain of neurodegenerative disease research,
the abundance of beneficial bacteria, promoting the Ma et al. (2024) conducted a systematic study on
generation of SCFAs, improving intestinal barrier the ameliorative effect of NMN (400 mg/kg bw) on
function, and modulating immune responses, thereby mouse models of AD. The research findings indicated
demonstrating substantial potential in improving neu- that NMN supplementation significantly improved
rodegenerative diseases and anti-aging. These discov- spatial working memory and cognitive dysfunction
eries provide significant theoretical underpinnings for in AD mice. Mechanistic investigations revealed
the development of NMN-based intestinal microbiota that NMN facilitated the clearance of phosphoryl-
regulation strategies and have opened new avenues ated tau protein (p-tau) by enhancing autophagic
for anti-aging research. Nevertheless, issues such as activity. This discovery was further validated in vitro
the optimal dosage of NMN at different age stages, experiments: in the Aβ-induced PC12 cell model,
the safety of long-term usage, and the synergistic autophagy inhibitors chloroquine (CQ) or bafilomy-
effects with other anti-aging intervention measures cin A1 (BafA1) could markedly inhibit the clearance
still require further in-depth investigations. of p-tau by NMN. Furthermore, NMN was capable
of activating the Nrf2/Keap1/NQO1 signaling path-
Positive modulation of the autophagy pathway way, reducing oxidative stress levels and thereby
alleviating neuronal damage in AD mice. These
Autophagy is a highly conserved cellular process findings suggest that NMN exerts neuroprotective
that selectively removes damaged or dysfunctional effects and ultimately ameliorates cognitive dysfunc-
molecules and subcellular components, includ- tion by inducing reciprocal regulation between anti-
ing nucleic acids, proteins, lipids, and organelles, oxidative stress and autophagy, effectively reducing
via a lysosome-mediated degradation mechanism, p-tau levels. Ovarian aging, a natural physiological
and plays a critical role in maintaining intracellular phenomenon, is characterized by a decline in the

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quantity and quality of follicles, accompanied by effect of NMN on autophagy has proven to be benefi-
ovarian atrophy, diminished secretory function, and cial. The autophagic process serves to remove dam-
the depletion of non-growing follicles in the ovar- aged organelles and misfolded proteins within cells,
ian reserve (Cuomo and Ambrosino 2019). The hor- thereby maintaining the stability of the intracellular
monal changes induced by ovarian aging can trigger environment. NMN can elevate the intracellular level
various health complications, including vasomotor of NAD⁺, activating autophagy-associated signal-
symptoms, cardiovascular diseases, osteoporosis, ing pathways, such as those involving SIRT1. The
cognitive impairment, and depression (Stevenson activation of SIRT1 can stimulate the expression of
2011). Huang et al. (2022a, b) investigated the role autophagy-related genes, enhancing autophagic activ-
of NMN in improving age-related decline in ovarian ity. This, in turn, enables cells to more effectively
reserve function through mitophagy promotion. The clear waste and damaged components, thus preserv-
study employed 40-week-old female mice subjected ing cellular health (Kiss et al. 2020). With advancing
to 0.5 mg/mL NMN intervention for 20 consecutive age, the autophagic function of cells gradually dete-
weeks. Results demonstrated that NMN supplementa- riorates, resulting in the accumulation of intracellular
tion significantly increased the numbers of primordial waste and functional decline. NMN aids in delaying
follicles (385 vs. 43), primary follicles (569.67 vs. the cellular aging process by enhancing autophagy. In
148.0), secondary follicles (97.00 vs. 13.67), antral several animal experiments, it has been demonstrated
follicles (19.67 vs. 0), and corpora lutea (13.67 vs. 0). that NMN supplementation can elevate the autophagy
The marked increase in primordial and primary fol- level in cells of aged animals, improve the function-
licle counts indicates that NMN effectively enhances ality of tissues and organs, and extend the healthy
ovarian reserve capacity. Mechanistic studies revealed lifespan of animals (Rubinsztein et al. 2011). When
that NMN upregulates the expression of autophagy- cells are confronted with stressors such as oxida-
related biomarkers, including microtubule-associated tive stress and nutrient deprivation, autophagy acts
protein 1 light chain 3 beta (LC3B) and lysosome- as an adaptive response, supplying essential nutri-
associated membrane protein 1 (LAMP-1), suggest- ents and energy to the cells. NMN can potentiate the
ing that NMN ameliorates ovarian aging by activat- autophagic response of cells under stress conditions,
ing the autophagy-lysosome pathway. Notably, NMN enhance their stress tolerance, and safeguard cells
also demonstrates potential antitumor effects through from damage. It is noteworthy that in the context of
autophagy modulation in oncology research. Sun the ovaries, studies have shown that NMN may sal-
et al. (2024) reported that treatment of hepatocellu- vage the ovarian reserve in middle-aged mice by
lar carcinoma cells (HepG2 and Huh-7) with 500 μM reducing autophagy. This indicates that in ovarian tis-
NMN for 48 h significantly elevated intracellular sue, the effect of NMN on autophagy does not uni-
­NAD+ levels and the N ­ AD+/NADH ratio. Concur- formly promote autophagy to confer universal ben-
rently, NMN treatment markedly increased the LC3B efits (Huang et al. 2022a, b). Simultaneously, research
II/LC3B I ratio, upregulated autophagy-related pro- by Tamura et al. has indicated that melatonin can
teins Beclin 1 and ATG5, and downregulated p62 delay ovarian aging by upregulating the expression
levels. The conversion of LC3B I to LC3B II, a hall- of LC3 mRNA in mice (Tamura et al. 2017). This
mark of autophagic activation, indicated that NMN finding is inconsistent with the research conducted
effectively induces autophagy. In vivo experiments by Huang et al. The impact of NMN on autophagy
further confirmed that NMN administration (800 mg/ in the ovaries does not follow a uniformly beneficial
kg bw) suppressed tumor growth in nude mice by singular pattern. This further implies that the ques-
activating the autophagy/ferroptosis pathway, pro- tion of whether autophagic activity plays a pivotal
moting apoptosis and necrosis in tumor tissues (Sun role in ovarian aging necessitates further investiga-
et al. 2024). Current studies suggest that the effect of tion. While moderate autophagy confers benefits to
NMN on autophagy is generally beneficial in most cells, excessive autophagy can potentially result in
instances. However, it is overly simplistic to con- cell damage or even cell death. In certain scenarios,
sider its impact uniformly advantageous, as its action it remains an open question whether NMN might over
exhibits a certain degree of complexity and tissue activate the autophagy signaling pathway, thereby
specificity. In research related to AD, the promoting rendering the autophagy process uncontrollable,

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disrupting the normal intracellular structure and func- diseases. However, there is a paucity of concrete
tion, and exerting a negative influence on cells. Con- evidence from human clinical trials regarding the
versely, another aspect to be considered is whether anti-aging effects of NMN. In most human clini-
the autophagy-promoting effect of NMN facilitates cal trials, the number of participants is limited, and
tumor survival under conditions of nutrient scar- the majority of these trials are at the Phase I clinical
city. At present, however, research on NMN-induced trial stage. Only the trial conducted by the University
excessive autophagy is relatively limited. Given the of Tsukuba in Japan has scarcely reached the Phase
inter-individual variability in cellular physiological II clinical trial level. The limitations in sample size
states, genetic backgrounds, and metabolic levels, the and research design have precluded a comprehensive
impact of NMN on autophagy can vary significantly evaluation of the effects of NMN. For instance, the
among individuals. Some individuals may not show a decline in NAD+ levels is more pronounced in the
significant response to NMN, or due to their own spe- elderly. When the trial subjects are healthy adults,
cial physiological conditions, the effect of NMN on the resulting effects may not be discernible. Moreo-
autophagy is not universally beneficial. Its role in dif- ver, questions remain regarding the appropriateness
ferent tissues and systems still requires more research of trial endpoint indicators. Specifically, whether
to clarify. Future research should center on elucidat- suitable biomarkers have been selected to assess the
ing the molecular mechanisms through which NMN anti-aging effects, rather than relying solely on the
regulates autophagy and exploring its synergistic variation in NAD+ levels. Secondly, there might be
effects with other anti-aging intervention measures, fundamental disparities in NAD⁺ metabolism between
thereby providing more comprehensive theoretical mice and humans. For example, the NAD⁺ synthesis
support for the development of NMN-based anti- pathways, tissue distribution patterns, or consump-
aging therapeutic regimens. tion routes in mice could diverge significantly from
those in humans. This divergence can result in vary-
ing outcomes when the same supplementation strat-
Discussion and conclusion egies are employed. Moreover, humans may possess
more intricate compensatory mechanisms or addi-
NMN, a key molecule with remarkable anti-aging tional metabolic pathways dedicated to maintaining
potential, demonstrates extensive biological effects NAD⁺ levels. This, in turn, could potentially attenu-
through the multi-target and multi-pathway syner- ate the effects of NMN. As a macromolecule, NMN
gistic regulation of core aging mechanisms, such may encounter challenges such as low oral absorption
as DNA damage repair, mitochondrial functional efficiency, intestinal degradation, or significant first-
homeostasis, inflammatory response equilibrium, pass metabolism. In animal experiments, the desired
gut microbiota remodeling, and autophagy pathway effects are frequently achieved through intraperitoneal
activation. It is notable that NMN must be converted injection or the administration of high dosages. How-
into ­NAD+ within the body to exert its biological ever, in human trials, it is arduous to replicate these
activity. The content of NMN in natural food sources dosing methods due to strict safety constraints. There
(like vegetables, fruits, raw beef, and raw shrimp) is may exist species specific differences in the compo-
limited, rendering artificial synthesis as the primary sition of gut microbiota and the expression levels of
source. Among these, the biosynthesis approaches NAD⁺ synthesis enzymes (e.g., NAMPT) between
(fermentation synthesis, enzymatic synthesis) have humans and mice. These differences can potentially
gradually supplanted the traditional chemical syn- influence the efficiency of NMN conversion to NAD⁺.
thesis method to become the mainstream, owing to Relying solely on surrogate markers such as blood
their advantages like mild reaction conditions, high NAD⁺ concentration might not accurately mirror
product purity, and environmental friendliness. Cur- tissue-specific alterations (e.g., in muscles and the
rent research evidence suggests that NMN regulates brain). Moreover, whether an elevation in NAD⁺ lev-
the aging process through a multi-target network and els directly correlates with functional enhancement
exhibits significant therapeutic potential in ameliorat- remains a matter of debate. The NAD⁺ turnover rate
ing age-related diseases, such as neurodegenerative in mice is notably faster than that in humans, ren-
disorders, metabolic syndrome, and cardiovascular dering mice potentially more sensitive to precursor

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supplementation. In contrast, the regulatory network Bárcena C, Valdés-Mas R, Mayoral P, Garabaya C, Durand
of NAD⁺ homeostasis in humans may possess more S, Rodríguez F, Fernández-García MT, Salazar N,
Nogacka AM, Garatachea N, Bossut N, Aprahamian F,
robust compensatory mechanisms (e.g., inhibiting Lucia A, Kroemer G, Freije JMP, Quirós PM, López-
the endogenous synthesis pathway). In animal mod- Otín C (2019) Healthspan and lifespan extension by
els, synergistic effects of NMN in combination with fecal microbiota transplantation into progeroid mice.
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supplementing NMN under a sedentary lifestyle may and sp. nov., a unique gram-negative anaerobic rod
be restricted. In the future, more accurate popula- recovered from appendicitis specimens and human fae-
tion stratification (e.g., based on NAD⁺ baseline lev- ces. J Gen Microbiol 135(12):3405–3411
Baron EJ, Curren M, Henderson G, Jousimies-Somer H,
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multi-omics biomarker analysis will be essential for lates from clinical specimens. J Clin Microbiol
a more effective assessment of the potential effects of 30(7):1882–1884
Berry D, Stecher B, Schintlmeister A, Reichert J, Brugir-
NMN. At the current stage, extreme caution must be oux S, Wild B, Wanek W, Richter A, Rauch I, Decker
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stable isotope probing. Proc Natl Acad Sci USA
Acknowledgements We thank Dr Yuchen Wang and Hua- 110(12):4720–4725
qing Cui for discussions of the work. Biagi E, Franceschi C, Rampelli S, Severgnini M, Ostan R,
Turroni S, Consolandi C, Quercia S, Scurti M, Monti D,
Author contributions Conceptualization: Chunyue Zhao Capri M, Brigidi P, Candela M (2016) Gut microbiota
and Yanfei Jiang; Funding acquisition: Yanfei Jiang; Investiga- and extreme longevity. Curr Biol 26(11):1480–1485
tion: Enhui Wang; Supervision: Yanfei Jiang; writing-original Black WB, Aspacio D, Bever D, King E, Zhang L, Li H
draft: Enhui Wang, Yuting Wang and Chunyue Zhao; Writ- (2020a) Metabolic engineering of Escherichia coli for
ing—review & editing: Enhui Wang, Zhaofeng Zhang, Yanfei optimized biosynthesis of nicotinamide mononucleo-
Jiang and Chunyue Zhao. All authors reviewed the manuscript. tide, a noncanonical redox cofactor. Microb Cell Fact
19(1):150
Black WB, Zhang L, Mak WS, Maxel S, Cui Y, King E, Fong
Funding This work receives no external fundings.
B, Sanchez Martinez A, Siegel JB, Li H (2020b) Engi-
neering a nicotinamide mononucleotide redox cofactor
Data availability No datasets were generated or analysed
system for biocatalysis. Nat Chem Biol 16(1):87–94
during the current study.
Boets E, Gomand SV, Deroover L, Preston T, Vermeulen K, De
Preter V, Hamer HM, Van den Mooter G, De Vuyst L,
Declarations
Courtin CM, Annaert P, Delcour JA, Verbeke KA (2017)
Systemic availability and metabolism of colonic-derived
Conflict of interest The authors have no conflicts of interest
short-chain fatty acids in healthy subjects: a stable iso-
to declare.
tope study. J Physiol 595(2):541–555
Brenner C (2022) Sirtuins are not conserved longevity genes.
Ethical approval It is not applicable because this study is
Life Metab 1(2):122–133
based exclusively on published literature.
Burgos ES, Schramm VL (2008) Weak coupling of ATP
hydrolysis to the chemical equilibrium of human nico-
tinamide phosphoribosyltransferase. Biochemistry
47(42):11086–11096
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