NMN reverses D-galactose-induced neurodegeneration and enhances the intestinal barrier of mice by activating the Sirt1 pathway
BackgroundAge-related decline in nicotinamide adenine dinucleotide (NAD+)—a central regulator of cellular metabolism, DNA repair, and immune homeostasis—is strongly associated with physiological dysfunction. Nicotinamide mononucleotide (NMN), a potent NAD+ precursor, shows promise in counteracting a...
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Frontiers Media S.A.
2025-04-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1545585/full |
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| author | Yuxian Lin Yuxian Lin Yajing Wang Xinxin Yang Ziwei Ding Mingye Hu Xianfeng Huang Qichun Zhang Yingcong Yu |
| author_facet | Yuxian Lin Yuxian Lin Yajing Wang Xinxin Yang Ziwei Ding Mingye Hu Xianfeng Huang Qichun Zhang Yingcong Yu |
| author_sort | Yuxian Lin |
| collection | DOAJ |
| description | BackgroundAge-related decline in nicotinamide adenine dinucleotide (NAD+)—a central regulator of cellular metabolism, DNA repair, and immune homeostasis—is strongly associated with physiological dysfunction. Nicotinamide mononucleotide (NMN), a potent NAD+ precursor, shows promise in counteracting aging-related pathologies, particularly neurodegenerative decline.MethodsAn aging model was established in mice through 8-week D-galactose (D-gal) exposure, followed by NMN oral supplementation. Behavioral outcomes (open field test, Morris water maze) were analyzed alongside oxidative stress markers (SOD, CAT, AGEs), inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-10), and neurotransmitters (LC-MS/MS). Apoptotic activity (TUNEL, p16/p21), mitochondrial regulators (Sirt1, p-AMPK, PGC-1α), and intestinal barrier integrity (HE/AB-PAS staining) were evaluated. Sirt1 dependency was confirmed using inhibitor Ex527.ResultsNMN restored locomotor activity and spatial memory in D-gal mice without altering body weight. Mechanistically, NMN synergistically attenuated oxidative stress and systemic inflammation, elevating antioxidant enzymes (SOD, CAT) and IL-10 while suppressing pro-inflammatory cytokines (TNF-α, IL-6) and AGEs. Cortical/hippocampal analyses revealed reduced apoptosis (TUNEL+ cells) and senescence markers (p16, p21), with enhanced mitochondrial function via Sirt1/AMPK/PGC-1α activation (Sirt1, p-AMPK). NMN concurrently preserved intestinal mucosal architecture, mitigating D-gal-induced barrier disruption. Crucially, all benefits were abolished by Sirt1 inhibition, confirming pathway specificity.ConclusionOur findings establish NMN as a multifaceted therapeutic agent that preserves neurocognitive function and intestinal homeostasis in aging models by orchestrating antioxidative, anti-inflammatory, and antiapoptotic responses through Sirt1/AMPK/PGC-1α activation. This work provides translational insights into NAD+-boosting strategies for age-related disorders. |
| format | Article |
| id | doaj-art-4ba2aa8cf48a4452a7815f8c1ecfd72d |
| institution | DOAJ |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-4ba2aa8cf48a4452a7815f8c1ecfd72d2025-08-20T03:08:35ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-04-011610.3389/fphar.2025.15455851545585NMN reverses D-galactose-induced neurodegeneration and enhances the intestinal barrier of mice by activating the Sirt1 pathwayYuxian Lin0Yuxian Lin1Yajing Wang2Xinxin Yang3Ziwei Ding4Mingye Hu5Xianfeng Huang6Qichun Zhang7Yingcong Yu8The Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou, Zhejiang, ChinaSchool of Pharmacy, Yantai University, Yantai, Shandong, ChinaSchool of Pharmacy, Changzhou University, Changzhou, Jiangsu, ChinaDepartment of Infectious Diseases, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University, The Third Affiliated Hospital of Shanghai University, Wenzhou People’s Hospital, Wenzhou, ChinaSchool of Pharmacy, Changzhou University, Changzhou, Jiangsu, ChinaThe Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou, Zhejiang, ChinaSchool of Pharmacy, Changzhou University, Changzhou, Jiangsu, ChinaSchool of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, ChinaThe Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou, Zhejiang, ChinaBackgroundAge-related decline in nicotinamide adenine dinucleotide (NAD+)—a central regulator of cellular metabolism, DNA repair, and immune homeostasis—is strongly associated with physiological dysfunction. Nicotinamide mononucleotide (NMN), a potent NAD+ precursor, shows promise in counteracting aging-related pathologies, particularly neurodegenerative decline.MethodsAn aging model was established in mice through 8-week D-galactose (D-gal) exposure, followed by NMN oral supplementation. Behavioral outcomes (open field test, Morris water maze) were analyzed alongside oxidative stress markers (SOD, CAT, AGEs), inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-10), and neurotransmitters (LC-MS/MS). Apoptotic activity (TUNEL, p16/p21), mitochondrial regulators (Sirt1, p-AMPK, PGC-1α), and intestinal barrier integrity (HE/AB-PAS staining) were evaluated. Sirt1 dependency was confirmed using inhibitor Ex527.ResultsNMN restored locomotor activity and spatial memory in D-gal mice without altering body weight. Mechanistically, NMN synergistically attenuated oxidative stress and systemic inflammation, elevating antioxidant enzymes (SOD, CAT) and IL-10 while suppressing pro-inflammatory cytokines (TNF-α, IL-6) and AGEs. Cortical/hippocampal analyses revealed reduced apoptosis (TUNEL+ cells) and senescence markers (p16, p21), with enhanced mitochondrial function via Sirt1/AMPK/PGC-1α activation (Sirt1, p-AMPK). NMN concurrently preserved intestinal mucosal architecture, mitigating D-gal-induced barrier disruption. Crucially, all benefits were abolished by Sirt1 inhibition, confirming pathway specificity.ConclusionOur findings establish NMN as a multifaceted therapeutic agent that preserves neurocognitive function and intestinal homeostasis in aging models by orchestrating antioxidative, anti-inflammatory, and antiapoptotic responses through Sirt1/AMPK/PGC-1α activation. This work provides translational insights into NAD+-boosting strategies for age-related disorders.https://www.frontiersin.org/articles/10.3389/fphar.2025.1545585/fullagingNMNoxidative stressneuroinflammationintestinal barrierSIRT1 |
| spellingShingle | Yuxian Lin Yuxian Lin Yajing Wang Xinxin Yang Ziwei Ding Mingye Hu Xianfeng Huang Qichun Zhang Yingcong Yu NMN reverses D-galactose-induced neurodegeneration and enhances the intestinal barrier of mice by activating the Sirt1 pathway Frontiers in Pharmacology aging NMN oxidative stress neuroinflammation intestinal barrier SIRT1 |
| title | NMN reverses D-galactose-induced neurodegeneration and enhances the intestinal barrier of mice by activating the Sirt1 pathway |
| title_full | NMN reverses D-galactose-induced neurodegeneration and enhances the intestinal barrier of mice by activating the Sirt1 pathway |
| title_fullStr | NMN reverses D-galactose-induced neurodegeneration and enhances the intestinal barrier of mice by activating the Sirt1 pathway |
| title_full_unstemmed | NMN reverses D-galactose-induced neurodegeneration and enhances the intestinal barrier of mice by activating the Sirt1 pathway |
| title_short | NMN reverses D-galactose-induced neurodegeneration and enhances the intestinal barrier of mice by activating the Sirt1 pathway |
| title_sort | nmn reverses d galactose induced neurodegeneration and enhances the intestinal barrier of mice by activating the sirt1 pathway |
| topic | aging NMN oxidative stress neuroinflammation intestinal barrier SIRT1 |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1545585/full |
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