NAD+ flux is maintained in aged mice

Abstract NAD+ is an essential coenzyme found in all living cells. NAD+ concentrations decline during aging, but whether this reflects impaired production or accelerated consumption remains unclear. Here we employed isotope tracing and mass spectrometry to probe NAD+ metabolism across tissues in aged mice. In 25-month-old mice, we observe modest tissue NAD+ depletion (median decrease ~ 30%) without significant changes in circulating NAD+ precursors. Isotope tracing showed unimpaired synthesis of circulating nicotinamide from tryptophan, and maintained flux of circulating nicotinamide into tissue NAD+ pools. Although absolute NAD+ biosynthetic flux was maintained in most tissues of aged mice, fractional tissue NAD+ labeling from infused labeled nicotinamide was modestly accelerated, consistent with increased activity of NAD+ consuming enzymes. Long-term calorie restriction partially mitigated age-associated NAD+ decline despite decreasing NAD+ synthesis, suggesting that calorie restriction reduces NAD+ consumption. Thus, age-related decline in NAD+ is relatively subtle and driven by increased NAD+ consumer activity rather than impaired production.

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Chondroitin 6-sulphate is required for neuroplasticity and memory in ageing

Molecular Psychiatry ◽

10.1038/s41380-021-01208-9 ◽

2021 ◽

Author(s):

Sujeong Yang ◽

Sylvain Gigout ◽

Angelo Molinaro ◽

Yuko Naito-Matsui ◽

Sam Hilton ◽

...

Keyword(s):

Chondroitin Sulphate ◽

Memory Loss ◽

Memory Deficits ◽

Long Term Potentiation ◽

Aged Mice ◽

Age Related ◽

Term Potentiation ◽

Early Memory

AbstractPerineuronal nets (PNNs) are chondroitin sulphate proteoglycan-containing structures on the neuronal surface that have been implicated in the control of neuroplasticity and memory. Age-related reduction of chondroitin 6-sulphates (C6S) leads to PNNs becoming more inhibitory. Here, we investigated whether manipulation of the chondroitin sulphate (CS) composition of the PNNs could restore neuroplasticity and alleviate memory deficits in aged mice. We first confirmed that aged mice (20-months) showed memory and plasticity deficits. They were able to retain or regain their cognitive ability when CSs were digested or PNNs were attenuated. We then explored the role of C6S in memory and neuroplasticity. Transgenic deletion of chondroitin 6-sulfotransferase (chst3) led to a reduction of permissive C6S, simulating aged brains. These animals showed very early memory loss at 11 weeks old. Importantly, restoring C6S levels in aged animals rescued the memory deficits and restored cortical long-term potentiation, suggesting a strategy to improve age-related memory impairment.

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Link between aging and atheroprotection in Mif-deficient atherosclerotic mice

10.1101/2021.12.14.471281 ◽

2021 ◽

Author(s):

Christine Maria Krammer ◽

Bishan Yang ◽

Sabrina Reichl ◽

Verena Bolini ◽

Corinna Schulte ◽

...

Keyword(s):

Atherogenic Diet ◽

Cell Recruitment ◽

Aged Mice ◽

Cell Responses ◽

Gene Deficiency ◽

Cytokines And Chemokines ◽

Age Related ◽

Chronic Inflammatory Condition ◽

Antibody Levels ◽

Old Mice

Atherosclerosis is a lipid-triggered chronic inflammatory condition of our arteries and the main underlying pathology of myocardial infarction and stroke. Pathogenesis is age-dependent, but the mechanistic links between disease progression, age, and atherogenic cytokines and chemokines are incompletely understood. Here, we studied the chemokine-like inflammatory cytokine macrophage migration inhibitory factor (MIF) in atherogenic Apoe-/- mice across different stages of aging and cholesterol-rich high-fat diet (HFD). MIF promotes atherosclerosis by mediating atherogenic monocyte and T-cell recruitment, amplifying lesional inflammation, and suppressing atheroprotective B-cell responses. However, age-related links between atherogenesis and MIF and its role in advanced atherosclerosis in aged mice have not been systematically explored. We compared effects of global Mif-gene deficiency in 30-, 42-, and 48-week-old Apoe-/- mice on HFD for 24, 36, or 42 weeks, respectively, and in 52-week-old mice on a 6-week HFD. While a regio-specific atheroprotective phenotype of Mif-deficiency was observed in the 30/24-week-old group, atheroprotection was not detected in the 48/42- and 52/6-week-old groups, suggesting that atheroprotection afforded by global Mif-gene deletion differs across aging stages and atherogenic diet duration. We identify a combination of mechanisms that could explain this phenotype: i) Mif-deficiency promotes lesional Trem2+ macrophage numbers in younger but not aged mice; ii) Mif-deficiency favors formation of lymphocyte-rich stage-I/II ATLOs in younger mice but ATLO numbers equalize with those in Apoe-/- controls in the older mice; and iii) plasma anti-oxLDL-IgM antibody levels are decreased in aged Mif-deficient mice. Of note, these three markers (Trem2+ macrophages, ATLOs, anti-oxLDL-IgM antibodies) have been previously linked to atheroprotection. Together, our study thus suggests that regio-specific atheroprotection due to global Mif-gene deficiency in atherogenic Apoe-/- mice is lost upon advanced aging and identifies mechanisms that could explain this phenotype shift. These observations may have implications for translational MIF-directed strategies.

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A Long-Term Enriched Environment Ameliorates the Accelerated Age-Related Memory Impairment Induced by Gestational Administration of Lipopolysaccharide: Role of Plastic Mitochondrial Quality Control

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2020.559182 ◽

2021 ◽

Vol 14 ◽

Author(s):

Zhan-Qiang Zhuang ◽

Zhe-Zhe Zhang ◽

Yue-Ming Zhang ◽

He-Hua Ge ◽

Shi-Yu Sun ◽

...

Keyword(s):

Learning And Memory ◽

Spatial Learning ◽

Memory Impairment ◽

Spatial Learning And Memory ◽

Mitochondrial Quality Control ◽

Protein Levels ◽

Age Related ◽

Old Mice ◽

Lps Treatment

Studies have shown that gestational inflammation accelerates age-related memory impairment in mother mice. An enriched environment (EE) can improve age-related memory impairment, whereas mitochondrial dysfunction has been implicated in the pathogenesis of brain aging. However, it is unclear whether an EE can counteract the accelerated age-related memory impairment induced by gestational inflammation and whether this process is associated with the disruption of mitochondrial quality control (MQC) processes. In this study, CD-1 mice received daily intraperitoneal injections of lipopolysaccharide (LPS, 50 μg/kg) or normal saline (CON group) during gestational days 15–17 and were separated from their offspring at the end of normal lactation. The mothers that received LPS were divided into LPS group and LPS plus EE (LPS-E) treatment groups based on whether the mice were exposed to an EE until the end of the experiment. At 6 and 18 months of age, the Morris water maze test was used to evaluate spatial learning and memory abilities. Quantitative reverse transcription polymerase chain reaction and Western blot were used to measure the messenber RNA (mRNA) and protein levels of MQC-related genes in the hippocampus, respectively. The results showed that all the aged (18 months old) mice underwent a striking decline in spatial learning and memory performances and decreased mRNA/protein levels related to mitochondrial dynamics (Mfn1/Mfn2, OPA1, and Drp1), biogenesis (PGC-1α), and mitophagy (PINK1/parkin) in the hippocampi compared with the young (6 months old) mice. LPS treatment exacerbated the decline in age-related spatial learning and memory and enhanced the reduction in the mRNA and protein levels of MQC-related genes but increased the levels of PGC-1α in young mice. Exposure to an EE could alleviate the accelerated decline in age-related spatial learning and memory abilities and the accelerated changes in MQC-related mRNA or protein levels resulting from LPS treatment, especially in aged mice. In conclusion, long-term exposure to an EE can counteract the accelerated age-related spatial cognition impairment modulated by MQC in CD-1 mother mice that experience inflammation during pregnancy.

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Neuroinflammation in Aged Brain: Impact of the Oral Administration of Ellagic Acid Microdispersion

International Journal of Molecular Sciences ◽

10.3390/ijms21103631 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3631 ◽

Cited By ~ 2

Author(s):

Raffaella Boggia ◽

Federica Turrini ◽

Alessandra Roggeri ◽

Guendalina Olivero ◽

Francesca Cisani ◽

...

Keyword(s):

Oral Administration ◽

Ellagic Acid ◽

Ex Vivo ◽

Behavioral Skills ◽

Aged Mice ◽

Age Related ◽

The Central Nervous System ◽

The Impact ◽

Old Mice

The immune system and the central nervous system message each other to preserving central homeostasis. Both systems undergo changes during aging that determine central age-related defects. Ellagic acid (EA) is a natural product which is beneficial in both peripheral and central diseases, including aging. We analyzed the impact of the oral administration of a new oral ellagic acid micro-dispersion (EAm), that largely increased the EA solubility, in young and old mice. Oral EAm did not modify animal weight and behavioral skills in young and old mice, but significantly recovered changes in “ex-vivo, in vitro” parameters in old animals. Cortical noradrenaline exocytosis decreased in aged mice. EAm administration did not modify noradrenaline overflow in young animals, but recovered it in old mice. Furthermore, GFAP staining was increased in the cortex of aged mice, while IBA-1 and CD45 immunopositivities were unchanged when compared to young ones. EAm treatment significantly reduced CD45 signal in both young and old cortical lysates; it diminished GFAP immunopositivity in young mice, but failed to affect IBA-1 expression in both young and old animals. Finally, EAm treatment significantly reduced IL1beta expression in old mice. These results suggest that EAm is beneficial to aging and represents a nutraceutical ingredient for elders.

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Stroke Induces a BDNF-Dependent Improvement in Cognitive Flexibility in Aged Mice

Neural Plasticity ◽

10.1155/2019/1460890 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 5

Author(s):

Josh Houlton ◽

Lisa Y. Y. Zhou ◽

Deanna Barwick ◽

Emma K. Gowing ◽

Andrew N. Clarkson

Keyword(s):

Animal Model ◽

Cognitive Flexibility ◽

Cognitive Deficits ◽

Cox Regression ◽

Reversal Task ◽

Critical Window ◽

Aged Mice ◽

Sham Surgery ◽

Age Related ◽

Old Mice

Stroke remains a leading cause of disability worldwide. Recently, we have established an animal model of stroke that results in delayed impairment in spatial memory, allowing us to better investigate cognitive deficits. Young and aged brains show different recovery profiles after stroke; therefore, we assessed aged-related differences in poststroke cognition. As neurotrophic support diminishes with age, we also investigated the involvement of brain-derived neurotrophic factor (BDNF) in these differences. Young (3-6 months old) and aged (16-21 months old) mice were trained in operant touchscreen chambers to complete a visual pairwise discrimination (VD) task. Stroke or sham surgery was induced using the photothrombotic model to induce a bilateral prefrontal cortex stroke. Five days poststroke, an additional cohort of aged stroke animals were treated with intracerebral hydrogels loaded with the BDNF decoy, TrkB-Fc. Following treatment, animals underwent the reversal and rereversal task to identify stroke-induced cognitive deficits at days 17 and 37 poststroke, respectively. Assessment of sham animals using Cox regression and log-rank analyses showed aged mice exhibit an increased impairment on VD reversal and rereversal learning compared to young controls. Stroke to young mice revealed no impairment on either task. In contrast, stroke to aged mice facilitated a significant improvement in reversal learning, which was dampened in the presence of the BDNF decoy, TrkB-Fc. In addition, aged stroke control animals required significantly less consecutive days and correction trials to master the reversal task, relative to aged shams, an effect dampened by TrkB-Fc. Our findings support age-related differences in recovery of cognitive function after stroke. Interestingly, aged stroke animals outperformed their sham counterparts, suggesting reopening of a critical window for recovery that is being mediated by BDNF.

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Macrophage LC3-associated phagocytosis is an immune defense against Streptococcus pneumoniae that diminishes with host aging

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2015368117 ◽

2020 ◽

Vol 117 (52) ◽

pp. 33561-33569

Author(s):

Megumi Inomata ◽

Shuying Xu ◽

Pallavi Chandra ◽

Simin N. Meydani ◽

Genzou Takemura ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Inflammatory Responses ◽

The Elderly ◽

Invasive Disease ◽

Immune Defense ◽

Bacterial Killing ◽

Murine Bone Marrow ◽

Aged Mice ◽

Age Related ◽

Old Mice

Streptococcus pneumoniae is a leading cause of pneumonia and invasive disease, particularly, in the elderly. S. pneumoniae lung infection of aged mice is associated with high bacterial burdens and detrimental inflammatory responses. Macrophages can clear microorganisms and modulate inflammation through two distinct lysosomal trafficking pathways that involve 1A/1B-light chain 3 (LC3)-marked organelles, canonical autophagy, and LC3-associated phagocytosis (LAP). The S. pneumoniae pore-forming toxin pneumolysin (PLY) triggers an autophagic response in nonphagocytic cells, but the role of LAP in macrophage defense against S. pneumoniae or in age-related susceptibility to infection is unexplored. We found that infection of murine bone-marrow-derived macrophages (BMDMs) by PLY-producing S. pneumoniae triggered Atg5- and Atg7-dependent recruitment of LC3 to S. pneumoniae-containing vesicles. The association of LC3 with S. pneumoniae-containing phagosomes required components specific for LAP, such as Rubicon and the NADPH oxidase, but not factors, such as Ulk1, FIP200, or Atg14, required specifically for canonical autophagy. In addition, S. pneumoniae was sequestered within single-membrane compartments indicative of LAP. Importantly, compared to BMDMs from young (2-mo-old) mice, BMDMs from aged (20- to 22-mo-old) mice infected with S. pneumoniae were not only deficient in LAP and bacterial killing, but also produced higher levels of proinflammatory cytokines. Inhibition of LAP enhanced S. pneumoniae survival and cytokine responses in BMDMs from young but not aged mice. Thus, LAP is an important innate immune defense employed by BMDMs to control S. pneumoniae infection and concomitant inflammation, one that diminishes with age and may contribute to age-related susceptibility to this important pathogen.

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Long-term intake of Lactobacillus paracasei KW3110 prevents age-related chronic inflammation and retinal cell loss in physiologically aged mice

Aging ◽

10.18632/aging.101583 ◽

2018 ◽

Vol 10 (10) ◽

pp. 2723-2740 ◽

Cited By ~ 6

Author(s):

Yuji Morita ◽

Kenta Jounai ◽

Akihiko Sakamoto ◽

Yasuyuki Tomita ◽

Yoshihiko Sugihara ◽

...

Keyword(s):

Chronic Inflammation ◽

Cell Loss ◽

Lactobacillus Paracasei ◽

Retinal Cell ◽

Aged Mice ◽

Age Related

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Comparative Analysis of Age-Related Changes in Lacrimal Glands and Meibomian Glands of a C57BL/6 Male Mouse Model

International Journal of Molecular Sciences ◽

10.3390/ijms21114169 ◽

2020 ◽

Vol 21 (11) ◽

pp. 4169 ◽

Cited By ~ 3

Author(s):

Chang Ho Yoon ◽

Jin Suk Ryu ◽

Ho Sik Hwang ◽

Mee Kum Kim

Keyword(s):

Oxidative Stress ◽

Mouse Model ◽

Dependent Manner ◽

Ki 67 ◽

Aged Mice ◽

Age Related ◽

Ifn Γ ◽

One Year ◽

Corneal Staining ◽

Old Mice

It is not known how biological changes in the lacrimal (LGs) and meibomian (MGs) glands contribute to dry eye disease (DED) in a time-dependent manner. In this study, we investigated time-sequenced changes in the inflammation, oxidative stress, and senescence of stem cells in both glands of an aging-related DED mouse model. Eight-week (8W)-, one-year (1Y)-, and two-year (2Y)-old C57BL/6 male mice were used. MG areas of the upper and lower eyelids were analyzed by transillumination meibography imaging. The number of CD45+, 8-OHdG+, Ki-67+, and BrdU+ cells was compared in both glands. Increased corneal staining and decreased tear secretion were observed in aged mice. The MG dropout area increased with aging, and the age-adjusted MG area in lower lids was negatively correlated with the National Eye Institute (NEI) score. Increased CD4+ interferon (IFN)-γ+ cells in LGs were found in both aged mice. An increase in 8-OHdG+ cells in both glands was evident in 2Y-old mice. Reduced Ki-67+ cells, but no change in CD45+ cells, was observed in the MGs of 1Y-old mice. Increased BrdU+ cells were observed in the LGs of aged mice. This suggests that age-dependent DED in C57BL/6 mice is related to inflammation of the LGs, the development of MG atrophy, and oxidative stress in both glands.

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Nrf2/ARE Activators Improve Memory in Aged Mice via Maintaining of Mitochondrial Quality Control of Brain and the Modulation of Gut Microbiome

Pharmaceuticals ◽

10.3390/ph14070607 ◽

2021 ◽

Vol 14 (7) ◽

pp. 607

Author(s):

Irina S. Sadovnikova ◽

Artem P. Gureev ◽

Daria A. Ignatyeva ◽

Maria V. Gryaznova ◽

Ekaterina V. Chernyshova ◽

...

Keyword(s):

Quality Control ◽

Gut Microbiome ◽

Dimethyl Fumarate ◽

Term Treatment ◽

Long Term Memory ◽

Mitochondrial Quality Control ◽

Aged Mice ◽

Long Term Treatment ◽

Old Mice

Aging is one of the most serious factors for central nervous dysfunctions, which lead to cognitive impairment. New highly effective drugs are required to slow the development of cognitive dysfunction. This research studied the effect of dimethyl fumarate (DMF), methylene blue (MB), and resveratrol (RSV) on the cognitive functions of 15-month-old mice and their relationship to the maintenance of mitochondrial quality control in the brain and the bacterial composition of the gut microbiome. We have shown that studied compounds enhance mitochondrial biogenesis, mitophagy, and antioxidant defense in the hippocampus of 15-month-old mice via Nrf2/ARE pathway activation, which reduces the degree of oxidative damage to mtDNA. It is manifested in the improvement of short-term and long-term memory. We have also shown that memory improvement correlates with levels of Roseburia, Oscillibacter, Christensenellaceae R-7, Negativibacillus, and Faecalibaculum genera of bacteria. At the same time, long-term treatment by MB induced a decrease in gut microbiome diversity, but the other markers of dysbiosis were not observed. Thus, Nrf2/ARE activators have an impact on mitochondrial quality control and are associated with a positive change in the composition of the gut microbiome, which together lead to an improvement in memory in aged mice.

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