Age-related susceptibility to insulin resistance is due to a combination of CPT1B decline and lipid overload

AbstractBACKGROUNDAdvanced age increases the susceptibility to diet-induced insulin resistance (IR). A key driver of this phenomenon is lipid accumulation in the skeletal muscle. It is debated, however, whether this is due to dietary lipid overload or decline of mitochondrial function. To address the interplay of diet and age in the flexibility of muscle lipid and glucose handling, we put young and aged mice on a low- or high-fat diet (HFD).RESULTSAs expected, aged mice were more susceptible to IR when given a HFD than young mice. The HFD induced intramuscular lipid accumulation specifically in aged mice, including C18:0-containing ceramides and diacylglycerols. This was reflected by the mitochondrial β-oxidation capacity, which was upregulated by the HFD in young, but not in old mice. Conspicuously, most β-oxidation proteins were upregulated by the HFD in both groups, but carnitine palmitoyltransferase 1B (CPT1B) declined in aged animals. Computational modelling traced the flux control mostly to CPT1B, suggesting a CPT1B-driven loss of flexibility to the HFD with age. Finally, in old animals glycolytic protein levels were reduced and less flexible to the diet.CONCLUSIONWe conclude that intramuscular lipid accumulation and decreased insulin sensitivity are not due to age-related mitochondrial dysfunction or nutritional overload alone, but rather to their interaction. Moreover, we identify CPT1B as a potential target to counteract age-dependent intramuscular lipid accumulation and thereby IR.

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Age-related susceptibility to insulin resistance arises from a combination of CPT1B decline and lipid overload

BMC Biology ◽

10.1186/s12915-021-01082-5 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Marcel A. Vieira-Lara ◽

Marleen B. Dommerholt ◽

Wenxuan Zhang ◽

Maaike Blankestijn ◽

Justina C. Wolters ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Mitochondrial Function ◽

Lipid Accumulation ◽

High Fat Diet ◽

Computational Modelling ◽

High Fat ◽

Aged Mice ◽

Age Related ◽

Intramuscular Lipid

Abstract Background The skeletal muscle plays a central role in glucose homeostasis through the uptake of glucose from the extracellular medium in response to insulin. A number of factors are known to disrupt the normal response to insulin leading to the emergence of insulin resistance (IR). Advanced age and a high-fat diet are factors that increase the susceptibility to IR, with lipid accumulation in the skeletal muscle being a key driver of this phenomenon. It is debated, however, whether lipid accumulation arises due to dietary lipid overload or from a decline of mitochondrial function. To gain insights into the interplay of diet and age in the flexibility of muscle lipid and glucose handling, we combined lipidomics, proteomics, mitochondrial function analysis and computational modelling to investigate young and aged mice on a low- or high-fat diet (HFD). Results As expected, aged mice were more susceptible to IR when given a HFD than young mice. The HFD induced intramuscular lipid accumulation specifically in aged mice, including C18:0-containing ceramides and diacylglycerols. This was reflected by the mitochondrial β-oxidation capacity, which was upregulated by the HFD in young, but not in old mice. Conspicuously, most β-oxidation proteins were upregulated by the HFD in both groups, but carnitine palmitoyltransferase 1B (CPT1B) declined in aged animals. Computational modelling traced the flux control mostly to CPT1B, suggesting a CPT1B-driven loss of flexibility to the HFD with age. Finally, in old animals, glycolytic protein levels were reduced and less flexible to the diet. Conclusion We conclude that intramuscular lipid accumulation and decreased insulin sensitivity are not due to age-related mitochondrial dysfunction or nutritional overload alone, but rather to their combined effects. Moreover, we identify CPT1B as a potential target to counteract age-dependent intramuscular lipid accumulation and thereby IR.

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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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Aging Influences the Metabolic and Inflammatory Phenotype in an Experimental Mouse Model of Acute Lung Injury

The Journals of Gerontology Series A ◽

10.1093/gerona/glaa248 ◽

2020 ◽

Author(s):

Kevin W Gibbs ◽

Chia-Chi Chuang Key ◽

Lanazha Belfield ◽

Jennifer Krall ◽

Lina Purcell ◽

...

Keyword(s):

Acute Lung Injury ◽

Fatty Acid ◽

Lung Injury ◽

Whole Body ◽

Acid Oxidation ◽

Aged Mice ◽

Protein Levels ◽

Adult Mice ◽

Age Related ◽

Before And After

Abstract Increased age is a risk factor for poor outcomes from respiratory failure and acute respiratory distress syndrome (ARDS). In this study, we sought to define age-related differences in lung inflammation, muscle injury, and metabolism after intratracheal lipopolysaccharide (IT-LPS) acute lung injury (ALI) in adult (6 months) and aged (18–20 months) male C57BL/6 mice. We also investigated age-related changes in muscle fatty acid oxidation (FAO) and the consequences of systemic FAO inhibition with the drug etomoxir. Aged mice had a distinct lung injury course characterized by prolonged alveolar neutrophilia and lack of response to therapeutic exercise. To assess the metabolic consequences of ALI, aged and adult mice underwent whole body metabolic phenotyping before and after IT-LPS. Aged mice had prolonged anorexia and decreased respiratory exchange ratio, indicating increased reliance on FAO. Etomoxir increased mortality in aged but not adult ALI mice, confirming the importance of FAO on survival from acute severe stress and suggesting that adult mice have increased resilience to FAO inhibition. Skeletal muscles from aged ALI mice had increased transcription of key fatty acid metabolizing enzymes, CPT-1b, LCAD, MCAD, FATP1 and UCP3. Additionally, aged mice had increased protein levels of CPT-1b at baseline and after lung injury. Surprisingly, CPT-1b in isolated skeletal muscle mitochondria had decreased activity in aged mice compared to adults. The distinct phenotype of aged ALI mice has similar characteristics to the adverse age-related outcomes of ARDS. This model may be useful to examine and augment immunologic and metabolic abnormalities unique to the critically ill aged population.

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CrossTalk proposal: Intramuscular lipid accumulation causes insulin resistance

The Journal of Physiology ◽

10.1113/jp278219 ◽

2020 ◽

Vol 598 (18) ◽

pp. 3803-3806 ◽

Cited By ~ 1

Author(s):

Bret H. Goodpaster

Keyword(s):

Insulin Resistance ◽

Lipid Accumulation ◽

Intramuscular Lipid

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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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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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