Nicotinamide phosphoribosyltransferase inhibitor ameliorates mouse aging-induced cognitive impairment

2021 ◽  
pp. 0271678X2110062
Author(s):  
Min Zeng ◽  
Tao-Feng Wei ◽  
Cong Chen ◽  
Chen Shen ◽  
Tong-Yao Gao ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mouse Brain ◽  
Serum Glucose ◽  
Aged Mouse ◽  
Neuroprotective Effects ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Nicotinamide Mononucleotide ◽  
Age Related ◽  
Anti Cancer ◽  
Key Enzyme

Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme for the synthesis of nicotinamide adenine dinucleotide (NAD) in the salvaging pathway. Though NAMPT inhibitors such as FK866 were originally developed as anti-cancer drugs, they also display neuroprotective effects. Here we show that the administration of FK866 at 0.5 mg/kg (ip, qod) for four weeks, i.e., ∼1% of the dose used for the treatment of cancer, significantly alleviates the aging-induced impairment of cognition and locomotor activity. Mechanistically, FK866 enhanced autophagy, reduced protein aggregation, and inhibited neuroinflammation indicated by decreasing TNFα, IL-6, GFAP, and Iba1 levels in the aged mouse brain. Though FK866 did not affect the total NAD and nicotinamide mononucleotide (NMN) levels in the mouse brain at the dose we used, FK866 increased nicotinamide (NAM) level in the young mouse brain and decreased NAM level in the aged mouse brain. On the other hand, FK866 did not affect the serum glucose, cholesterol, and triglyceride of young and aged mice and exhibited no effects on the various indices of young mice. Thus, the NAMPT inhibitor can be repurpose to counteract the cognitive impairment upon aging. We also envision that NAMPT inhibitor can be used for the treatment of age-related neurodegenerative diseases.

scholarly journals Nicotinamide Phosphoribosyltransferase as a Key Molecule of the Aging/Senescence Process

2021 ◽  
Vol 22 (7) ◽  
pp. 3709
Author(s):  
Fiqri D. Khaidizar ◽  
Yasumasa Bessho ◽  
Yasukazu Nakahata
Keyword(s):  
Nicotinamide Adenine Dinucleotide ◽  
The Elderly ◽  
Cellular Level ◽  
Salvage Pathway ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Nicotinamide Riboside ◽  
Nicotinamide Mononucleotide ◽  
Age Related ◽  
Rate Limiting ◽  
Over Time

Aging is a phenomenon underlined by complex molecular and biochemical changes that occur over time. One of the metabolites that is gaining strong research interest is nicotinamide adenine dinucleotide, NAD+, whose cellular level has been shown to decrease with age in various tissues of model animals and humans. Administration of NAD+ precursors, nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), to supplement NAD+ production through the NAD+ salvage pathway has been demonstrated to slow down aging processes in mice. Therefore, NAD+ is a critical metabolite now understood to mitigate age-related tissue function decline and prevent age-related diseases in aging animals. In human clinical trials, administration of NAD+ precursors to the elderly is being used to address systemic age-associated physiological decline. Among NAD+ biosynthesis pathways in mammals, the NAD+ salvage pathway is the dominant pathway in most of tissues, and NAMPT is the rate limiting enzyme of this pathway. However, only a few activators of NAMPT, which are supposed to increase NAD+, have been developed so far. In this review, we will focus on the importance of NAD+ and the possible application of an activator of NAMPT to promote successive aging.

Flavonoid Chrysin prevents age-related cognitive decline via attenuation of oxidative stress and modulation of BDNF levels in aged mouse brain

2015 ◽  
Vol 134 ◽  
pp. 22-30 ◽  
Author(s):  
Leandro Cattelan Souza ◽  
Michelle Silva Antunes ◽  
Carlos Borges Filho ◽  
Lucian Del Fabbro ◽  
Marcelo Gomes de Gomes ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cognitive Decline ◽  
Mouse Brain ◽  
Aged Mouse ◽  
Age Related ◽  
Age Related Cognitive Decline

scholarly journals Nicotinamide mononucleotide production by fructophilic lactic acid bacteria

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kazane Sugiyama ◽  
Kana Iijima ◽  
Miyako Yoshino ◽  
Hideo Dohra ◽  
Yuji Tokimoto ◽  
...  
Keyword(s):  
Lactic Acid ◽  
Lactic Acid Bacteria ◽  
Culture Media ◽  
Draft Genome ◽  
Acid Fermentation ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Nicotinamide Riboside ◽  
Nicotinamide Mononucleotide ◽  
Key Enzyme ◽  
Draft Genome Sequencing

AbstractNicotinamide mononucleotide (NMN), an intermediate in nicotinamide adenine dinucleotide biosynthesis, is recently attracting much attention for its pharmacological and anti-aging efficacies. However, current commercial products containing NMN are very high-priced because efficient and facile methods for industrial NMN production are limited. In this study, aiming for its nutraceutical application, we attempted to screen lactic acid bacteria for intracellular and/or extracellular NMN production. Using a bioassay system with an auxotrophic yeast that requires nicotinamide riboside (NR; dephosphorylated NMN), three candidates were obtained from a library of 174 strains of facultative anaerobic lactic acid bacteria. All three candidates belonged to the genus Fructobacillus and produced NR in the culture media (0.8–1.5 mg/l). Lactic acid bacteria of the genus Fructobacillus are known to use d-fructose as an electron acceptor in anaerobic lactic acid fermentation; addition of d-fructose to the medium caused intracellular accumulation of NMN and NR, but no extracellular production of these compounds was observed. Draft genome sequencing for one of the candidates suggested that nicotinamide phosphoribosyltransferase, which exists commonly in mammals but is less reported in microorganisms, is a key enzyme for NMN and NR production in the fructophilic bacteria.

Activity Engagement in Cognitive Aging: A Review of the Evidence

2013 ◽  
Vol 23 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Yvonne Rogalski ◽  
Muriel Quintana
Keyword(s):  
Older Adults ◽  
Cognitive Decline ◽  
Cognitive Aging ◽  
Social Activity ◽  
Current Evidence ◽  
Omega 3 ◽  
Neuroprotective Effects ◽  
Activity Engagement ◽  
Age Related ◽  
Age Related Cognitive Decline

The population of older adults is rapidly increasing, as is the number and type of products and interventions proposed to prevent or reduce the risk of age-related cognitive decline. Advocacy and prevention are part of the American Speech-Language-Hearing Association’s (ASHA’s) scope of practice documents, and speech-language pathologists must have basic awareness of the evidence contributing to healthy cognitive aging. In this article, we provide a brief overview outlining the evidence on activity engagement and its effects on cognition in older adults. We explore the current evidence around the activities of eating and drinking with a discussion on the potential benefits of omega-3 fatty acids, polyphenols, alcohol, and coffee. We investigate the evidence on the hypothesized neuroprotective effects of social activity, the evidence on computerized cognitive training, and the emerging behavioral and neuroimaging evidence on physical activity. We conclude that actively aging using a combination of several strategies may be our best line of defense against cognitive decline.

Effect of alkaloid extracted from Huperzia phlegmaria on cognitive deficits scopolamine-induced in mice

2020 ◽  
Vol 16 ◽  
Author(s):  
Dang Kim Thu ◽  
Dao Thi Vui ◽  
Nguyen Thi Ngoc Huyen ◽  
Nguyen Thi Thanh Binh ◽  
Nguyen Thi Huyen ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mouse Brain ◽  
Cognitive Deficits ◽  
Inhibitory Activity ◽  
Water Maze ◽  
Ache Activity ◽  
Y Maze ◽  
Ache Inhibitory Activity ◽  
Kinetic Inhibition ◽  
Brain Tissues

Background: Huperzia phlegmaria has been used for the treatment of neurological disorder. Alkaloids are main bioactive compounds found in Huperzia phlegmaria. We aimed to investigate the acetylcholinesterase (AChE) inhibitory activity in vitro of Huperzia phlegmaria alkaloid extract (HpAE) and protective effects on mice which were induced cognitive deficits by scopolamine. Methods: AChE inhibitory activity and kinetic inhibition mechanism was investigated by Ellman's assay. Mice were administrated orally HpAE (30 mg/kg and 60 mg/kg) for fourteen days, and injected scopolamine at a dose of 1 mg/kg intraperitoneally for four days to induce cognitive impairment. The Y-maze and the Morris water maze were used for evaluating the memory behaviors. Acetylcholine (ACh) levels and AChE activity were measured in brain tissue. Glutathione peroxidase (GPx), superoxide dismutase (SOD) activities, and malondialdehyde (MDA) groups were also evaluated in the mouse brain tissues. Results: Our data showed that HpAE had the strong AChE inhibitory activity with an IC50 value of 5.12 ± 0.48 μg/mL in a concentration-dependent manner. Kinetic inhibition analysis demonstrated that HpPAE inhibited AChE followed the mixed inhibition type with Ki (representing the affinity of the enzyme and inhibitor) was 4.37 ± 0.35 µg/mL. Scopolamine induced the cognitive impairment in Morris Water Maze and Y-maze test along with reduced brain levels of ACh and antioxidant enzyme and increased AChE activity in mouse brain tissues. Treatment with HpAE at both dose (30 mg/kg and 60 mg/kg) decreased the SCP-induced cognitive impairment in both behavioral tests along with decreased acetylcholinesterase activity and MDA level, and increased ACh level and antioxidant enzyme in mouse brain tissues. Conclusion: Our results suggested that the HpAE at both dose (30 mg/kg and 60 mg/kg) may be used for prevent and treatment of Alzheimer’s disease.

Elevated Inflammatory Markers and Arterial Stiffening Exacerbate Tau but Not Amyloid Pathology in Older Adults with Mild Cognitive Impairment

2021 ◽  
pp. 1-13
Author(s):  
Alexandra L. Clark ◽  
Alexandra J. Weigand ◽  
Kelsey R. Thomas ◽  
Seraphina K. Solders ◽  
Lisa Delano-Wood ◽  
...  
Keyword(s):  
Older Adults ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Inflammatory Markers ◽  
Memory Performance ◽  
Cognitive Testing ◽  
Interactive Effects ◽  
Protein Biomarkers ◽  
Age Related ◽  
T Tau

Background: Age-related cerebrovascular and neuroinflammatory processes have been independently identified as key mechanisms of Alzheimer’s disease (AD), although their interactive effects have yet to be fully examined. Objective: The current study examined 1) the influence of pulse pressure (PP) and inflammatory markers on AD protein levels and 2) links between protein biomarkers and cognitive function in older adults with and without mild cognitive impairment (MCI). Methods: This study included 218 ADNI (81 cognitively normal [CN], 137 MCI) participants who underwent lumbar punctures, apolipoprotein E (APOE) genotyping, and cognitive testing. Cerebrospinal (CSF) levels of eight pro-inflammatory markers were used to create an inflammation composite, and amyloid-beta 1–42 (Aβ 42), phosphorylated tau (p-tau), and total tau (t-tau) were quantified. Results: Multiple regression analyses controlling for age, education, and APOE ɛ4 genotype revealed significant PP x inflammation interactions for t-tau (B = 0.88, p = 0.01) and p-tau (B = 0.84, p = 0.02); higher inflammation was associated with higher levels of tau within the MCI group. However, within the CN group, analyses revealed a significant PP x inflammation interaction for Aβ 42 (B = –1.01, p = 0.02); greater inflammation was associated with higher levels of Aβ 42 (indicative of lower cerebral amyloid burden) in those with lower PP. Finally, higher levels of tau were associated with poorer memory performance within the MCI group only (p s <  0.05). Conclusion: PP and inflammation exert differential effects on AD CSF proteins and provide evidence that vascular risk is associated with greater AD pathology across our sample of CN and MCI older adults.

scholarly journals TAMI-08. A TALE OF TWO TELOMERE MAINTENANCE MECHANISMS: TERT EXPRESSION AND THE ALT PATHWAY INDUCE UNIQUE MRS-DETECTABLE METABOLIC REPROGRAMMING IN LOW-GRADE GLIOMAS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii214-ii214
Author(s):  
Pavithra Viswanath ◽  
Georgios Batsios ◽  
Anne Marie Gillespie ◽  
Hema Artee Luchman ◽  
Joseph Costello ◽  
...  
Keyword(s):  
Treatment Response ◽  
Metabolic Reprogramming ◽  
Telomere Maintenance ◽  
Imaging Biomarker ◽  
Low Grade ◽  
Tumor Proliferation ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Non Invasive ◽  
Key Enzyme ◽  
Tert Expression

Abstract Telomeres are nucleoprotein structures at chromosomal ends that shorten with cell division and constitute a natural barrier to proliferation. In order to proliferate indefinitely, all tumors require a telomere maintenance mechanism (TMM). Telomerase reverse transcriptase (TERT) expression is the TMM in most tumors, including low-grade oligodendrogliomas (LGOGs). In contrast, low-grade astrocytomas (LGAs) use the alternative lengthening of telomeres (ALT) pathway as their TMM. As molecular hallmarks of tumor proliferation, TMMs are attractive tumor biomarkers and therapeutic targets. Non-invasive imaging of TMM status will, therefore, allow assessment of tumor proliferation and treatment response. However, translational methods of imaging TMM status are lacking. Here, we show that TERT expression and the ALT pathway are associated with unique magnetic resonance spectroscopy (MRS)-detectable metabolic reprogramming in LGOGs and LGAs respectively. In genetically-engineered and patient-derived LGOG models, TERT expression is linked to elevated 1H-MRS-detectable NAD(P)/H, glutathione, aspartate and AXP. In contrast, the ALT pathway in LGAs is associated with higher α-ketoglutarate, glutamate, alanine and AXP. Importantly, elevated flux of hyperpolarized [1-13C]-alanine to pyruvate, which depends on α-ketoglutarate, is a non-invasive in vivo imaging biomarker of the ALT pathway in LGAs while elevated flux of hyperpolarized [1-13C]-alanine to lactate, which depends on NADH, is an imaging biomarker of TERT expression in LGOGs. Mechanistically, the ALT pathway in LGAs is linked to higher glutaminase (GLS), a key enzyme for α-ketoglutarate biosynthesis while TERT expression in LGOGs is associated with elevated nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme for NADH biosynthesis. Notably, TERT expression and the ALT pathway are linked to MRS-detectable metabolic reprogramming in LGOG and LGA patient biopsies, emphasizing the clinical validity of our observations. Collectively, we have identified unique metabolic signatures of TMM status that integrate critical oncogenic information with noninvasive imaging modalities that can improve diagnosis and treatment response monitoring for LGOG and LGA patients.

scholarly journals A Preliminary Analysis of Hearing Loss and Its Association With Mild Cognitive Impairment

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 451-452
Author(s):  
Mary Caroline Yuk ◽  
Rebecca Allen ◽  
Marcia Hay-McCutcheon ◽  
Dana Carroll ◽  
Anne Halli-Tierney
Keyword(s):  
Hearing Loss ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Emotional Health ◽  
Medical Center ◽  
Pearson Correlation ◽  
Well Being ◽  
Hearing Screening ◽  
Community Dwelling ◽  
Age Related

Abstract Age related hearing loss, or presbycusis, is a global condition that is increasing in its prevalence. Despite being one of the most common chronic conditions among the older population, there is much more to understand about its association with other aspects of physical and emotional health and well-being. Current research is suggesting that hearing loss is more prevalent in those with cognitive impairment compared to those without cognitive impairment. This study analyzed the incidence of hearing loss and its linkage to mild cognitive impairment in a community-dwelling geriatric population. With the increasing prevalence of this condition in both rural and urban communities of Alabama, it becomes a more pressing matter to understand comorbidities and risk factors for future decline in functioning. This study was conducted in an interdisciplinary geriatrics primary care outpatient clinic in a Family, Internal, and Rural Medicine department affiliated with a university medical center in the Deep South. Ninety-one participants completed the Montreal Cognitive Assessment (MoCA) and a hearing screening. Hearing screenings were conducted in quiet rooms in the medical center using Phonak hearing screening cards. Detection of 500, 1000, 2000, and 4000 Hz tones was assessed. Pearson correlation analyses demonstrated an association between hearing loss mild cognitive impairment. Poorer hearing was significantly associated with lower scores on the MoCA. Conducting behavioral health screenings like this in other primary geriatrics clinics and community settings could improve care and identification of patient needs by integrating important data regarding comorbidities and independent living.

scholarly journals Formaldehyde and De/Methylation in Age-Related Cognitive Impairment

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 913
Author(s):  
Ting Li ◽  
Yan Wei ◽  
Meihua Qu ◽  
Lixian Mou ◽  
Junye Miao ◽  
...  
Keyword(s):  
Amino Acids ◽  
Cell Proliferation ◽  
Cognitive Impairment ◽  
Metabolic Pathways ◽  
Memory Formation ◽  
Epigenetic Alterations ◽  
Diagnostic Biomarker ◽  
Reactive Substance ◽  
Age Related ◽  
Novel Therapeutic

Formaldehyde (FA) is a highly reactive substance that is ubiquitous in the environment and is usually considered as a pollutant. In the human body, FA is a product of various metabolic pathways and participates in one-carbon cycle, which provides carbon for the synthesis and modification of bio-compounds, such as DNA, RNA, and amino acids. Endogenous FA plays a role in epigenetic regulation, especially in the methylation and demethylation of DNA, histones, and RNA. Recently, epigenetic alterations associated with FA dysmetabolism have been considered as one of the important features in age-related cognitive impairment (ARCI), suggesting the potential of using FA as a diagnostic biomarker of ARCI. Notably, FA plays multifaceted roles, and, at certain concentrations, it promotes cell proliferation, enhances memory formation, and elongates life span, effects that could also be involved in the aetiology of ARCI. Further investigation of and the regulation of the epigenetics landscape may provide new insights about the aetiology of ARCI and provide novel therapeutic targets.

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