The killifish visual system as an in vivo model to study brain aging and rejuvenation

AbstractWorldwide, people are getting older, and this prolonged lifespan unfortunately also results in an increased prevalence of age-related neurodegenerative diseases, contributing to a diminished life quality of elderly. Age-associated neuropathies typically include diseases leading to dementia (Alzheimer’s and Parkinson’s disease), as well as eye diseases such as glaucoma and age-related macular degeneration. Despite many research attempts aiming to unravel aging processes and their involvement in neurodegeneration and functional decline, achieving healthy brain aging remains a challenge. The African turquoise killifish (Nothobranchius furzeri) is the shortest-lived reported vertebrate that can be bred in captivity and displays many of the aging hallmarks that have been described for human aging, which makes it a very promising biogerontology model. As vision decline is an important hallmark of aging as well as a manifestation of many neurodegenerative diseases, we performed a comprehensive characterization of this fish’s aging visual system. Our work reveals several aging hallmarks in the killifish retina and brain that eventually result in a diminished visual performance. Moreover, we found evidence for the occurrence of neurodegenerative events in the old killifish retina. Altogether, we introduce the visual system of the fast-aging killifish as a valuable model to understand the cellular and molecular mechanisms underlying aging in the vertebrate central nervous system. These findings put forward the killifish for target validation as well as drug discovery for rejuvenating or neuroprotective therapies ensuring healthy aging.

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p16INK4a deficiency promotes IL-4–induced polarization and inhibits proinflammatory signaling in macrophages

Blood ◽

10.1182/blood-2010-10-313106 ◽

2011 ◽

Vol 118 (9) ◽

pp. 2556-2566 ◽

Cited By ~ 60

Author(s):

Céline Cudejko ◽

Kristiaan Wouters ◽

Lucía Fuentes ◽

Sarah Anissa Hannou ◽

Charlotte Paquet ◽

...

Keyword(s):

Molecular Mechanisms ◽

Inflammatory Diseases ◽

Macrophage Polarization ◽

Suppressor Gene ◽

In Vivo Model ◽

Macrophage Phenotype ◽

Age Related ◽

Increased Risk ◽

Increased Sensitivity

Abstract The CDKN2A locus, which contains the tumor suppressor gene p16INK4a, is associated with an increased risk of age-related inflammatory diseases, such as cardiovascular disease and type 2 diabetes, in which macrophages play a crucial role. Monocytes can polarize toward classically (CAMφ) or alternatively (AAMφ) activated macrophages. However, the molecular mechanisms underlying the acquisition of these phenotypes are not well defined. Here, we show that p16INK4a deficiency (p16−/−) modulates the macrophage phenotype. Transcriptome analysis revealed that p16−/− BM-derived macrophages (BMDMs) exhibit a phenotype resembling IL-4–induced macrophage polarization. In line with this observation, p16−/− BMDMs displayed a decreased response to classically polarizing IFNγ and LPS and an increased sensitivity to alternative polarization by IL-4. Furthermore, mice transplanted with p16−/− BM displayed higher hepatic AAMφ marker expression levels on Schistosoma mansoni infection, an in vivo model of AAMφ phenotype skewing. Surprisingly, p16−/− BMDMs did not display increased IL-4–induced STAT6 signaling, but decreased IFNγ-induced STAT1 and lipopolysaccharide (LPS)–induced IKKα,β phosphorylation. This decrease correlated with decreased JAK2 phosphorylation and with higher levels of inhibitory acetylation of STAT1 and IKKα,β. These findings identify p16INK4a as a modulator of macrophage activation and polarization via the JAK2-STAT1 pathway with possible roles in inflammatory diseases.

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Functionally Assessing the Age-Related Decline in the Detection Rate of Photons by Cone Photoreceptors

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.744444 ◽

2021 ◽

Vol 13 ◽

Author(s):

Asma Braham chaouche ◽

Maryam Rezaei ◽

Daphné Silvestre ◽

Angelo Arleo ◽

Rémy Allard

Keyword(s):

Visual System ◽

Detection Rate ◽

Healthy Aging ◽

Age Related Macular Degeneration ◽

Neural Signals ◽

Age Related ◽

Processing Step ◽

Neural Factors ◽

The Impact ◽

Retinal Pathologies

Age-related decline in visual perception is usually attributed to optical factors of the eye and neural factors. However, the detection of light by cones converting light into neural signals is a crucial intermediate processing step of vision. Interestingly, a novel functional approach can evaluate many aspects of the visual system including the detection of photons by cones. This approach was used to investigate the underlying cause of age-related visual decline and found that the detection rate of cones was considerably affected with healthy aging. This functional test enabling to evaluate the detection of photons by cones could be particularly useful to screen for retinal pathologies affecting cones such as age-related macular degeneration. However, the paradigm used to functionally measure the detection of photons was complex as it was evaluating many other properties of the visual system. The aim of the current mini review is to clarify the underlying rationale of functionally evaluating the detection of photons by cones, describe a simpler approach to evaluate it, and review the impact of aging on the detection rate of cones.

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Effects of High Dietary Carbohydrate and Lipid Intake on the Lifespan of C. elegans

Cells ◽

10.3390/cells10092359 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2359

Author(s):

Berenice Franco-Juárez ◽

Saúl Gómez-Manzo ◽

Beatriz Hernández-Ochoa ◽

Noemi Cárdenas-Rodríguez ◽

Roberto Arreguin-Espinosa ◽

...

Keyword(s):

High Glucose ◽

Molecular Mechanisms ◽

Critical Role ◽

In Vivo Model ◽

C Elegans ◽

Age Related ◽

Dietary Nutrients ◽

High Lipid ◽

Induced Changes

Health and lifespan are influenced by dietary nutrients, whose balance is dependent on the supply or demand of each organism. Many studies have shown that an increased carbohydrate–lipid intake plays a critical role in metabolic dysregulation, which impacts longevity. Caenorhabditis elegans has been successfully used as an in vivo model to study the effects of several factors, such as genetic, environmental, diet, and lifestyle factors, on the molecular mechanisms that have been linked to healthspan, lifespan, and the aging process. There is evidence showing the causative effects of high glucose on lifespan in different diabetic models; however, the precise biological mechanisms affected by dietary nutrients, specifically carbohydrates and lipids, as well as their links with lifespan and longevity, remain unknown. Here, we provide an overview of the deleterious effects caused by high-carbohydrate and high-lipid diets, as well as the molecular signals that affect the lifespan of C. elegans; thus, understanding the detailed molecular mechanisms of high-glucose- and lipid-induced changes in whole organisms would allow the targeting of key regulatory factors to ameliorate metabolic disorders and age-related diseases.

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Molecular Mechanisms of Complement System Proteins and Matrix Metalloproteinases in the Pathogenesis of Age-Related Macular Degeneration

Current Molecular Medicine ◽

10.2174/1566524019666190828150625 ◽

2019 ◽

Vol 19 (10) ◽

pp. 705-718 ◽

Cited By ~ 4

Author(s):

Naima Mansoor ◽

Fazli Wahid ◽

Maleeha Azam ◽

Khadim Shah ◽

Anneke I. den Hollander ◽

...

Keyword(s):

Matrix Metalloproteinases ◽

Macular Degeneration ◽

Complement System ◽

Molecular Mechanisms ◽

Critical Role ◽

Age Related Macular Degeneration ◽

Genetic Changes ◽

Complement System Proteins ◽

Age Related ◽

Common Genetic Variants

: Age-related macular degeneration (AMD) is an eye disorder affecting predominantly the older people above the age of 50 years in which the macular region of the retina deteriorates, resulting in the loss of central vision. The key factors associated with the pathogenesis of AMD are age, smoking, dietary, and genetic risk factors. There are few associated and plausible genes involved in AMD pathogenesis. Common genetic variants (with a minor allele frequency of >5% in the population) near the complement genes explain 40–60% of the heritability of AMD. The complement system is a group of proteins that work together to destroy foreign invaders, trigger inflammation, and remove debris from cells and tissues. Genetic changes in and around several complement system genes, including the CFH, contribute to the formation of drusen and progression of AMD. Similarly, Matrix metalloproteinases (MMPs) that are normally involved in tissue remodeling also play a critical role in the pathogenesis of AMD. MMPs are involved in the degradation of cell debris and lipid deposits beneath retina but with age their functions get affected and result in the drusen formation, succeeding to macular degeneration. In this review, AMD pathology, existing knowledge about the normal and pathological role of complement system proteins and MMPs in the eye is reviewed. The scattered data of complement system proteins, MMPs, drusenogenesis, and lipofusogenesis have been gathered and discussed in detail. This might add new dimensions to the understanding of molecular mechanisms of AMD pathophysiology and might help in finding new therapeutic options for AMD.

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Crosstalk between Long-Term Sublethal Oxidative Stress and Detrimental Inflammation as Potential Drivers for Age-Related Retinal Degeneration

Antioxidants ◽

10.3390/antiox10010025 ◽

2020 ◽

Vol 10 (1) ◽

pp. 25

Author(s):

Lara Macchioni ◽

Davide Chiasserini ◽

Letizia Mezzasoma ◽

Magdalena Davidescu ◽

Pier Luigi Orvietani ◽

...

Keyword(s):

Oxidative Stress ◽

Molecular Mechanisms ◽

Age Related Macular Degeneration ◽

Inflammasome Activation ◽

Related Factor ◽

Nuclear Factor ◽

Rpe Cells ◽

Age Related ◽

Oxidative Insult

Age-related retinal degenerations, including age-related macular degeneration (AMD), are caused by the loss of retinal pigmented epithelial (RPE) cells and photoreceptors. The pathogenesis of AMD, deeply linked to the aging process, also involves oxidative stress and inflammatory responses. However, the molecular mechanisms contributing to the shift from healthy aging to AMD are still poorly understood. Since RPE cells in the retina are chronically exposed to a pro-oxidant microenvironment throughout life, we simulated in vivo conditions by growing ARPE-19 cells in the presence of 10 μM H2O2 for several passages. This long-term oxidative insult induced senescence in ARPE-19 cells without affecting cell proliferation. Global proteomic analysis revealed a dysregulated expression in proteins involved in antioxidant response, mitochondrial homeostasis, and extracellular matrix organization. The analyses of mitochondrial functionality showed increased mitochondrial biogenesis and ATP generation and improved response to oxidative stress. The latter, however, was linked to nuclear factor-κB (NF-κB) rather than nuclear factor erythroid 2–related factor 2 (Nrf2) activation. NF-κB hyperactivation also resulted in increased pro-inflammatory cytokines expression and inflammasome activation. Moreover, in response to additional pro-inflammatory insults, senescent ARPE-19 cells underwent an exaggerated inflammatory reaction. Our results indicate senescence as an important link between chronic oxidative insult and detrimental chronic inflammation, with possible future repercussions for therapeutic interventions.

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Complement C5 is not critical for the formation of sub-RPE deposits in Efemp1 mutant mice

Scientific Reports ◽

10.1038/s41598-021-89978-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Donita L. Garland ◽

Eric A. Pierce ◽

Rosario Fernandez-Godino

Keyword(s):

Macular Degeneration ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Deposit Formation ◽

Genetic Ablation ◽

Age Related ◽

Complement Dysregulation

AbstractThe complement system plays a role in the formation of sub-retinal pigment epithelial (RPE) deposits in early stages of age-related macular degeneration (AMD). But the specific mechanisms that connect complement activation and deposit formation in AMD patients are unknown, which limits the development of efficient therapies to reduce or stop disease progression. We have previously demonstrated that C3 blockage prevents the formation of sub-RPE deposits in a mouse model of EFEMP1-associated macular degeneration. In this study, we have used double mutant Efemp1R345W/R345W:C5-/- mice to investigate the role of C5 in the formation of sub-RPE deposits in vivo and in vitro. The data revealed that the genetic ablation of C5 does not eliminate the formation of sub-RPE deposits. Contrarily, the absence of C5 in RPE cultures promotes complement dysregulation that results in increased activation of C3, which likely contributes to deposit formation even in the absence of EFEMP1-R345W mutant protein. The results also suggest that genetic ablation of C5 alters the extracellular matrix turnover through an effect on matrix metalloproteinases in RPE cell cultures. These results confirm that C3 rather than C5 could be an effective therapeutic target to treat early AMD.

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Caenorhabditis elegans as an in vivo Model to Assess Amphetamine Tolerance

Brain Behavior and Evolution ◽

10.1159/000514858 ◽

2021 ◽

pp. 1-9

Author(s):

Dayana Torres Valladares ◽

Sirisha Kudumala ◽

Murad Hossain ◽

Lucia Carvelli

Keyword(s):

Caenorhabditis Elegans ◽

Molecular Mechanisms ◽

Drugs Of Abuse ◽

Genetic Model ◽

In Vivo Model ◽

C Elegans ◽

Hyperactivity Disorder ◽

In Vitro Data

Amphetamine is a potent psychostimulant also used to treat attention deficit/hyperactivity disorder and narcolepsy. In vivo and in vitro data have demonstrated that amphetamine increases the amount of extra synaptic dopamine by both inhibiting reuptake and promoting efflux of dopamine through the dopamine transporter. Previous studies have shown that chronic use of amphetamine causes tolerance to the drug. Thus, since the molecular mechanisms underlying tolerance to amphetamine are still unknown, an animal model to identify the neurochemical mechanisms associated with drug tolerance is greatly needed. Here we took advantage of a unique behavior caused by amphetamine in <i>Caenorhabditis elegans</i> to investigate whether this simple, but powerful, genetic model develops tolerance following repeated exposure to amphetamine. We found that at least 3 treatments with 0.5 mM amphetamine were necessary to see a reduction in the amphetamine-induced behavior and, thus, to promote tolerance. Moreover, we found that, after intervals of 60/90 minutes between treatments, animals were more likely to exhibit tolerance than animals that underwent 10-minute intervals between treatments. Taken together, our results show that <i>C. elegans</i> is a suitable system to study tolerance to drugs of abuse such as amphetamines.

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Scotopic thresholds on dark-adapted chromatic perimetry in healthy aging and age-related macular degeneration

Scientific Reports ◽

10.1038/s41598-021-89677-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Manjot Kaur Grewal ◽

Shruti Chandra ◽

Alan Bird ◽

Glen Jeffery ◽

Sobha Sivaprasad

Keyword(s):

Macular Degeneration ◽

Healthy Aging ◽

Intraclass Correlation ◽

Age Related Macular Degeneration ◽

Healthy Individuals ◽

Age Related ◽

Rod Function ◽

The Mean ◽

Highly Correlated ◽

Effect Of Age

AbstractTo evaluate the effect of aging, intra- and intersession repeatability and regional scotopic sensitivities in healthy and age-related macular degeneration (AMD) eyes. Intra- and intersession agreement and effect of age was measured in healthy individuals. The mean sensitivity (MS) and pointwise retinal sensitivities (PWS) within the central 24° with 505 nm (cyan) and 625 nm (red) stimuli were evaluated in 50 individuals (11 healthy and 39 AMD eyes). The overall intra- and intersession had excellent reliability (intraclass correlation coefficient, ICC > 0.90) and tests were highly correlated (Spearman rs = 0.75–0.86). Eyes with subretinal drusenoid deposit (SDD) had reduced PWS centrally, particularly at inferior and nasal retinal locations compared with controls and intermediate AMD (iAMD) without SDD. There was no difference in MS or PWS at any retinal location between iAMD without SDD and healthy individuals nor between iAMD with SDD and non-foveal atrophic AMD groups. Eyes with SDD have reduced rod function compared to iAMD without SDD and healthy eyes, but similar to eyes with non-foveal atrophy. Our results highlight rod dysfunction is not directly correlated with drusen load and SDD location.

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The anti-angiogenic isoforms of VEGF in health and disease

Biochemical Society Transactions ◽

10.1042/bst0371207 ◽

2009 ◽

Vol 37 (6) ◽

pp. 1207-1213 ◽

Cited By ~ 76

Author(s):

Yan Qiu ◽

Coralie Hoareau-Aveilla ◽

Sebastian Oltean ◽

Steven J. Harper ◽

David O. Bates

Keyword(s):

Splice Site ◽

Site Selection ◽

Age Related Macular Degeneration ◽

Splicing Factor ◽

Splice Site Selection ◽

Age Related ◽

Normal Human ◽

Radical Revision

Anti-angiogenic VEGF (vascular endothelial growth factor) isoforms, generated from differential splicing of exon 8, are widely expressed in normal human tissues but down-regulated in cancers and other pathologies associated with abnormal angiogenesis (cancer, diabetic retinopathy, retinal vein occlusion, the Denys–Drash syndrome and pre-eclampsia). Administration of recombinant VEGF165b inhibits ocular angiogenesis in mouse models of retinopathy and age-related macular degeneration, and colorectal carcinoma and metastatic melanoma. Splicing factors and their regulatory molecules alter splice site selection, such that cells can switch from the anti-angiogenic VEGFxxxb isoforms to the pro-angiogenic VEGFxxx isoforms, including SRp55 (serine/arginine protein 55), ASF/SF2 (alternative splicing factor/splicing factor 2) and SRPK (serine arginine domain protein kinase), and inhibitors of these molecules can inhibit angiogenesis in the eye, and splice site selection in cancer cells, opening up the possibility of using splicing factor inhibitors as novel anti-angiogenic therapeutics. Endogenous anti-angiogenic VEGFxxxb isoforms are cytoprotective for endothelial, epithelial and neuronal cells in vitro and in vivo, suggesting both an improved safety profile and an explanation for unpredicted anti-VEGF side effects. In summary, C-terminal distal splicing is a key component of VEGF biology, overlooked by the vast majority of publications in the field, and these findings require a radical revision of our understanding of VEGF biology in normal human physiology.

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CIB2 regulates mTORC1 signaling and is essential for autophagy and visual function

Nature Communications ◽

10.1038/s41467-021-24056-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Saumil Sethna ◽

Patrick A. Scott ◽

Arnaud P. J. Giese ◽

Todd Duncan ◽

Xiaoying Jian ◽

...

Keyword(s):

Visual Function ◽

Molecular Mechanisms ◽

Neurodegenerative Disorder ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Negative Regulator ◽

Age Related Macular Degeneration ◽

Age Related ◽

Mtorc1 Signaling ◽

Marked Accumulation

AbstractAge-related macular degeneration (AMD) is a multifactorial neurodegenerative disorder. Although molecular mechanisms remain elusive, deficits in autophagy have been associated with AMD. Here we show that deficiency of calcium and integrin binding protein 2 (CIB2) in mice, leads to age-related pathologies, including sub-retinal pigment epithelium (RPE) deposits, marked accumulation of drusen markers APOE, C3, Aβ, and esterified cholesterol, and impaired visual function, which can be rescued using exogenous retinoids. Cib2 mutant mice exhibit reduced lysosomal capacity and autophagic clearance, and increased mTORC1 signaling—a negative regulator of autophagy. We observe concordant molecular deficits in dry-AMD RPE/choroid post-mortem human tissues. Mechanistically, CIB2 negatively regulates mTORC1 by preferentially binding to ‘nucleotide empty’ or inactive GDP-loaded Rheb. Upregulated mTORC1 signaling has been implicated in lymphangioleiomyomatosis (LAM) cancer. Over-expressing CIB2 in LAM patient-derived fibroblasts downregulates hyperactive mTORC1 signaling. Thus, our findings have significant implications for treatment of AMD and other mTORC1 hyperactivity-associated disorders.

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