Effect of NAMPT modulation in OIS-senescent IMR90 cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE336391 | GEO | 2026/09/23
REPOSITORIES: GEO
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Project description:Nicotinamide adenine dinucleotide (NAD+) metabolism becomes dysregulated with age and has emerged as a targetable feature of aging and age-related dysfunction, yet the cellular contexts in which altered NAD+ homeostasis creates therapeutic vulnerabilities remain incompletely defined. Here, we identify senescence as one such context. Senescent cells retained elevated levels of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAM salvage pathway yet exhibited a paradoxical reduction in NAD+ turnover, suggesting a disconnect between protein abundance and enzymatic output. In mice, SBI-0802162 reduced circulating nicotinamide (NAM), revealing a limitation of sustained NAM salvage pathway activation and prompting the development of a combination strategy with dietary NAM supplementation. Co-administration of SBI-0802162 and NAM robustly increased tissue NAD+, suppressed select age-associated inflammatory signatures in a tissue-specific manner and preserved physical performance of aged mice. These effects occurred alongside reductions in food intake and body weight, which were observed whether SBI-0802162 and NAM were administered voluntary in the diet or by oral gavage. Together, these findings identify elevated NAMPT coupled with reduced NAD+ turnover as a metabolic vulnerability in senescent cells and support combined NAMPT activation with dietary NAM as a novel strategy to restore NAD+ homeostasis and improve age-associated inflammation.
2026-09-23 | GSE336838 | GEO
Project description:Nicotinamide adenine dinucleotide (NAD+) metabolism becomes dysregulated with age and has emerged as a targetable feature of aging and age-related dysfunction, yet the cellular contexts in which altered NAD+ homeostasis creates therapeutic vulnerabilities remain incompletely defined. Here, we identify senescence as one such context. Senescent cells retained elevated levels of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAM salvage pathway yet exhibited a paradoxical reduction in NAD+ turnover, suggesting a disconnect between protein abundance and enzymatic output. Treatment with SBI-0802162 engaged the spare enzymatic capacity of NAMPT in senescent cells and produced a marked rise in intracellular NAD+ that, when sustained, reinforced their existing stress-associated transcriptional program and selectively reduced senescent cell viability while sparing proliferating cells. Together, these findings identify elevated NAMPT coupled with reduced NAD+ turnover as a metabolic vulnerability in senescent cells and support combined NAMPT activation with dietary NAM as a novel strategy to restore NAD+ homeostasis and improve age-associated inflammation.
2026-09-23 | GSE336534 | GEO
Project description:Type 2 diabetes (T2D) has become an epidemic in our modern lifestyle, likely due to calorie-rich diets overwhelming our adaptive metabolic pathways. One such pathway is mediated by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD+ biosynthesis, and the NAD+-dependent protein deacetylase SIRT1. Here we show that NAMPT-mediated NAD+ biosynthesis is severely compromised in metabolic organs by high-fat diet (HFD). Strikingly, nicotinamide mononucleotide (NMN), a product of the NAMPT reaction and a key NAD+ intermediate, ameliorates glucose intolerance by restoring NAD+ levels in HFD-induced T2D mice. NMN also enhances hepatic insulin sensitivity and restores gene expression related to oxidative stress, inflammatory response, and circadian rhythm, partly through SIRT1 activation. Furthermore, NAD+ and NAMPT levels show significant decreases in multiple organs during aging, and NMN improves glucose intolerance and lipid profiles in age-induced T2D mice. These findings provide critical insights into a novel intervention against diet- and age-induced T2D. 4 regular chow fed mice (RC1-4) vs 4 high-fat diet fed (HFD) (HFD1a-4a) mice were analyzed on one chip (Chip-A). 4 HFD mice (HFD1b-4b) vs 4 HFD-NMN treated mice (NMN1-4) were examined on the other chip (Chip-B).
2011-12-05 | E-GEOD-31647 | biostudies-arrayexpress
Project description:Neural stem/progenitor cell (NSPC) proliferation and self-renewal, as well as insult-induced differentiation, decrease markedly with age, but the molecular mechanisms responsible for these declines remain unclear. Here we show that levels of NAD+ and nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in mammalian NAD+ biosynthesis, decrease with age in the hippocampus. Ablation of Nampt in adult NSPCs reduced their pool and proliferation in vivo. The decrease in the NSPC pool during aging can be rescued by enhancing hippocampal NAD+ levels. Nampt is the main source of NSPC NAD+ levels and required for G1/S progression of the NSPC cell cycle. Nampt is also critical for oligodendrocytic lineage fate decisions through a mechanism mediated redundantly by Sirt1 and Sirt2. Ablation of Nampt in the adult NSPCs in vivo reduced NSPC-mediated oligodendrogenesis upon injury. These phenotypes recapitulate defects in NSPCs during aging, implicating Nampt-mediated NAD+ biosynthesis as a mediator of these age-associated functional declines. Total RNA obtained from neurospheres derived from postnatal hippocampi subjected to 48 hours in vitro of incubation with Nampt-specific inhibitor FK866 (10 nM, 4 samples) or vehicle (DMSO, 1:1000, 4 samples).
2014-05-08 | E-GEOD-49784 | biostudies-arrayexpress
Project description:Type 2 diabetes (T2D) has become an epidemic in our modern lifestyle, likely due to calorie-rich diets overwhelming our adaptive metabolic pathways. One such pathway is mediated by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD+ biosynthesis, and the NAD+-dependent protein deacetylase SIRT1. Here we show that NAMPT-mediated NAD+ biosynthesis is severely compromised in metabolic organs by high-fat diet (HFD). Strikingly, nicotinamide mononucleotide (NMN), a product of the NAMPT reaction and a key NAD+ intermediate, ameliorates glucose intolerance by restoring NAD+ levels in HFD-induced T2D mice. NMN also enhances hepatic insulin sensitivity and restores gene expression related to oxidative stress, inflammatory response, and circadian rhythm, partly through SIRT1 activation. Furthermore, NAD+ and NAMPT levels show significant decreases in multiple organs during aging, and NMN improves glucose intolerance and lipid profiles in age-induced T2D mice. These findings provide critical insights into a novel intervention against diet- and age-induced T2D.
2011-12-05 | GSE31647 | GEO
Project description:Neural stem/progenitor cell (NSPC) proliferation and self-renewal, as well as insult-induced differentiation, decrease markedly with age, but the molecular mechanisms responsible for these declines remain unclear. Here we show that levels of NAD+ and nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in mammalian NAD+ biosynthesis, decrease with age in the hippocampus. Ablation of Nampt in adult NSPCs reduced their pool and proliferation in vivo. The decrease in the NSPC pool during aging can be rescued by enhancing hippocampal NAD+ levels. Nampt is the main source of NSPC NAD+ levels and required for G1/S progression of the NSPC cell cycle. Nampt is also critical for oligodendrocytic lineage fate decisions through a mechanism mediated redundantly by Sirt1 and Sirt2. Ablation of Nampt in the adult NSPCs in vivo reduced NSPC-mediated oligodendrogenesis upon injury. These phenotypes recapitulate defects in NSPCs during aging, implicating Nampt-mediated NAD+ biosynthesis as a mediator of these age-associated functional declines.
2014-05-08 | GSE49784 | GEO
Project description:NAD is an obligate co-factor for the catabolism of metabolic fuels in all cell types. However, the availability of NAD in several tissues can become limited during genotoxic stress and the course of natural aging. The point at which NAD restriction imposes functional limitations on tissue physiology remains unknown. We examined this question in murine skeletal muscle by specifically depleting Nampt, an essential enzyme in the NAD salvage pathway. Knockout mice exhibited a dramatic 85% decline in intramuscular NAD content, accompanied by fiber degeneration and progressive loss of both muscle strength and treadmill endurance. Administration of the NAD precursor nicotinamide riboside rapidly ameliorated functional deficits and restored muscle mass, despite having only a modest effect on the intramuscular NAD pool. Additionally, lifelong overexpression of Nampt preserved muscle NAD levels and exercise capacity in aged mice, supporting a critical role for tissue-autonomous NAD homeostasis in maintaining muscle mass and function. Messenger RNA was isolated from quadriceps muscle of mice from three different age groups and three different genotypes. Wildtype mice were aged 4, 7, and 24 months. Mice deficient for Nampt in skeletal muscle (mNKO) were aged 7 months. Mice overexpressing Nampt in skeletal muscle were aged 4 and 24 months.
2016-07-22 | E-GEOD-74570 | biostudies-arrayexpress
Project description:Age-related microvascular dysfunction disrupts nutrient homeostasis and waste clearance, leading to organ failure. However, a critical gap remains in our understanding of the specific molecular drivers of vascular deterioration and how they orchestrate organism-wide aging. Here, we identify progressive activation of the CCAAT/enhancer-binding protein β (C/EBPβ)/asparagine endopeptidase (AEP) pathway in aging vascular endothelial cells contributes to vascular degeneration and lifespan reduction. Endothelial-specific C/EBPβ or AEP overexpression accelerated vascular aging and shortened lifespan in mice. Mechanistically, AEP mediates proteolytic cleavage of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in nicotinamide adenine dinucleotide (oxidised form, NAD+) biosynthesis, resulting in systemic NAD⁺ depletion and senescence that elicits both central and peripheral vascular dysfunction and ultimately systemic aging. Genetic ablation of AEP or expression of AEP-resistant NAMPT N136A mutant significantly ameliorated vascular aging and extended lifespan in endothelial-specific Tie 2-C/EBPβ transgenic mice. Pharmacologically, AEP inhibitor CP#11A or nicotinamide mononucleotide (NMN) supplementation alleviated age-related vascular decline, with CP#11A showing superior efficacy. These findings support a model in which endothelial senescence contributes to vascular dysfunction and systemic aging mediated by C/EBPβ/AEP signaling, and establish C/EBPβ/AEP as a therapeutic target to preserve vascular integrity and mitigate systemic frailty in aging populations.
2026-05-30 | E-MTAB-17006 | biostudies-arrayexpress
Project description:Cellular senescence is a stable cell growth arrest that is implicated in tissue aging and cancer. Senescent cells are characterized by an upregulation of proinflammatory and immunosuppressive cytokines and chemokines, which is termed as senescence-associated secretory phenotype (SASP). NAD+ metabolism plays a critical role in both tissue aging and cancer. However, the role of NAD+ metabolism in regulating the SASP is not well understood. Here we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, governs the strengths of proinflammatory SASP during senescence. In contrast to downregulation of NAMPT during replicative senescence, NAMPT is upregulated during oncogene-induced senescence. NAMPT selectively regulates proinflammatory, but not immunosuppressive, SASP. NAMPT is regulated by HMGA1 through a distal enhancer element during senescence. HMGA1/NAMPT/NAD+ signaling axis promotes proinflammatory SASP through enhancing glycolysis and mitochondria respiration. Mechanistically, HMGA1/NAMPT promotes proinflammatory SASP through NAD+-mediated suppression of AMPK kinase, which suppresses p53-mediated inhibition of p38MAPK to enhance NFb activity. SASP regulation by NAD+ metabolism is independent of senescence-associated cell growth arrest. An increase in NAD+ levels is sufficient to convert SASP from low to high levels during replicative senescence. Together, we conclude that NAD+ metabolism governs the strengths of proinflammatory SASP. Given the tumor promoting effects of proinflammatory SASP, our results suggest that anti-ageing dietary NAD+ augmentation should be administered with precision.
2019-03-14 | GSE111841 | GEO
Project description:Nicotinamide adenine dinucleotide (NAD+) is a universal coenzyme regulating cellular energy metabolism in many cell types. Recent studies have demonstrated the close relationships between defective NAD+ metabolism and aging and age-associated metabolic diseases. The major purpose of the present study was to test the hypothesis that NAD+ biosynthesis, mediated by a rate-limiting NAD+ biosynthetic enzyme, nicotinamide phosphoribosyltransferase (NAMPT), is essential for maintaining normal adipose tissue function and whole-body metabolic health during the aging process. To this end, we provided in-depth and comprehensive metabolic assessments for female adipocyte-specific Nampt knockout (ANKO) mice during aging. We first evaluated body fat mass in young (≤ 4-month-old), middle aged (10 to 14-month-old), and old (≥ 18-month-old) mice. Intriguingly, adipocyte-specific Nampt deletion protected against age-induced obesity without changing energy balance. However, data obtained from the hyperinsulinemic euglycemic clamp procedure demonstrated that, despite the lean phenotype, old ANKO mice had severe insulin resistance in skeletal muscle, heart, and white adipose tissue (WAT). Old ANKO mice also exhibited hyperinsulinemia and hypoadiponectinemia. Mechanistically, loss of Nampt caused marked decreases in WAT gene expression of lipogenic targets of peroxisome proliferator-activated receptor gamma (PPARγ) in an age-dependent manner. In addition, administration of a PPARγ agonist rosiglitazone restored fat mass and improved metabolic abnormalities in old ANKO mice. In conclusion, these findings highlight the importance of the NAMPT-NAD+-PPARγ axis in maintaining functional integrity and quantity of adipose tissue, and whole-body metabolic function in female mice during aging.
2024-05-31 | GSE152067 | GEO