Identification of conserved transcriptome features between humans and Drosophila in the aging brain utilizing machine learning on combined data from the NIH Sequence Read Archive

Aging is universal, yet characterizing the molecular changes that occur in aging which lead to an increased risk for neurological disease remains a challenging problem. Aging affects the prefrontal cortex (PFC), which governs executive function, learning, and memory. Previous sequencing studies have demonstrated that aging alters gene expression in the PFC, however the extent to which these changes are conserved across species and are meaningful in neurodegeneration is unknown. Identifying conserved, age-related genetic and morphological changes in the brain allows application of the wealth of tools available to study underlying mechanisms in model organisms such as Drosophila melanogaster. RNA sequencing data from human PFC and fly heads were analyzed to determine conserved transcriptome signatures of age. Our analysis revealed that expression of 50 conserved genes can accurately determine age in Drosophila (R2 = 0.85) and humans (R2 = 0.46). These transcriptome signatures were also able to classify Drosophila into three age groups with a mean accuracy of 88% and classify human samples with a mean accuracy of 69%. Overall, this work identifies 50 highly conserved aging-associated genetic changes in the brain that can be further studied in model organisms and demonstrates a novel approach to uncovering genetic changes conserved across species from multi-study public databases.

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Molecular and phenotypic analysis of rodent models reveals conserved and species-specific modulators of human sarcopenia

Communications Biology ◽

10.1038/s42003-021-01723-z ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Anastasiya Börsch ◽

Daniel J. Ham ◽

Nitish Mittal ◽

Lionel A. Tintignac ◽

Eugenia Migliavacca ◽

...

Keyword(s):

Muscle Mass ◽

Inflammatory Responses ◽

Molecular Data ◽

Model Organisms ◽

Sequencing Data ◽

Phenotypic Analysis ◽

Age Related ◽

Analogous Data ◽

Species Specific ◽

And Function

AbstractSarcopenia, the age-related loss of skeletal muscle mass and function, affects 5–13% of individuals aged over 60 years. While rodents are widely-used model organisms, which aspects of sarcopenia are recapitulated in different animal models is unknown. Here we generated a time series of phenotypic measurements and RNA sequencing data in mouse gastrocnemius muscle and analyzed them alongside analogous data from rats and humans. We found that rodents recapitulate mitochondrial changes observed in human sarcopenia, while inflammatory responses are conserved at pathway but not gene level. Perturbations in the extracellular matrix are shared by rats, while mice recapitulate changes in RNA processing and autophagy. We inferred transcription regulators of early and late transcriptome changes, which could be targeted therapeutically. Our study demonstrates that phenotypic measurements, such as muscle mass, are better indicators of muscle health than chronological age and should be considered when analyzing aging-related molecular data.

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Senescent Accelerated Prone 8 (SAMP8) Mice as A Model of Age Dependent Neuroinflammation

10.21203/rs.3.rs-72160/v1 ◽

2020 ◽

Author(s):

Andrés Fernández ◽

Elena Quintana ◽

Patricia Velasco ◽

Belén de Andrés ◽

Maria Luisa Gaspar ◽

...

Keyword(s):

Choroid Plexus ◽

Inflammatory Cytokines ◽

Hippocampal Formation ◽

Morphological Changes ◽

Interleukin 1 ◽

Brain Parenchyma ◽

Age Related ◽

Inflammatory Changes ◽

Samp8 Mice ◽

The Brain

Abstract Background: Aging and age related diseases are strong risk factors for the development of neurodegenerative diseases. Neuroinflammation (NIF), as the brain's immune response, plays an important role in aged associated degeneration of central nervous system (CNS). The need of animal models that will allow us to understand and modulate this process is required for the scientific community. Methods: We have analyzed aging-phenotypical and inflammatory changes of brain myeloid cells (bMyC) in a senescent accelerated prone aged (SAMP8) mouse model, and compared with their resistant to senescence control (SAMR1). We have performed morphometric methods to evaluate the architecture of cellular prolongations and analyzed Iba1+ clustered cells with aging. To analyse specific constant brain areas we have performed stereology measurements of Iba1+ cells in the hippocampal formation. We have isolated bMyC from brain parenchyma (BP) and choroid plexus and meningeal membranes (m/Ch), and analyzed their response to systemic LPS- driven inflammation.Results: Aged 10 month old SAMP8 mice presents many of the hallmarks of aging-dependent neuroinflammation when compared with their senescence resistant control (SAMR1); ie, increase of protein aggregates, presence of Iba1+ clusters, but not increase in the number of Iba1+ cells. We have further observed and increased of main inflammatory mediator IL-1β, and augment of border MHCII+Iba1+ cells. Isolated CD45+ bMyC from brain parenchyma (BP) and choroid plexus and meningeal membranes (m/Ch) have been analyzed showing that there is not significant increase of CD45+ from the periphery. Our data support that aged-driven pro-inflammatory cytokine interleukin 1 beta (IL1β) transcription is mainly enhanced in CD45+BP cells. Furthermore, we are showing that LPS-driven systemic inflammation produces inflammatory cytokines mainly in the border bMyC, sensed to a lesser extent by the BP bMyC, and is enhanced in aged SAMP8 compared to control SAMR1.Conclusion: Our data validate the SAMP8 model to study age-associated neuroinflammatory events, but careful controls for age and strain are required. These animals show morphological changes in their bMyC cell repertoires associated to age, corresponding to an increase in the production of main pro inflammatory cytokines such as IL-1β, which predispose the brain to an enhanced inflammatory response after LPS-systemic challenge.

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The aging mind: neuroplasticity in response to cognitive training

Dialogues in Clinical Neuroscience ◽

10.31887/dcns.2013.15.1/dpark ◽

2013 ◽

Vol 15 (1) ◽

pp. 109-119 ◽

Cited By ~ 48

Keyword(s):

Cognitive Function ◽

Cognitive Training ◽

Neural Plasticity ◽

Cognitive Effort ◽

Aging Brain ◽

Cognitive Domains ◽

Training Techniques ◽

Age Related ◽

Strategy Change ◽

The Brain

Is it possible to enhance neural and cognitive function with cognitive training techniques? Can we delay age-related decline in cognitive function with interventions and stave off Alzheimer's disease? Does an aged brain really have the capacity to change in response to stimulation? In the present paper, we consider the neuroplasticity of the aging brain, that is, the brain's ability to increase capacity in response to sustained experience. We argue that, although there is some neural deterioration that occurs with age, the brain has the capacity to increase neural activity and develop neural scaffolding to regulate cognitive function. We suggest that increase in neural volume in response to cognitive training or experience is a clear indicator of change, but that changes in activation in response to cognitive training may be evidence of strategy change rather than indicative of neural plasticity. We note that the effect of cognitive training is surprisingly durable over time, but that the evidence that training effects transfer to other cognitive domains is relatively limited. We review evidence which suggests that engagement in an environment that requires sustained cognitive effort may facilitate cognitive function.

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Age and outcome after aneurysmal subarachnoid hemorrhage: why do older patients fare worse?

Journal of Neurosurgery ◽

10.3171/jns.1996.85.3.0410 ◽

1996 ◽

Vol 85 (3) ◽

pp. 410-418 ◽

Cited By ~ 242

Author(s):

Giuseppe Lanzino ◽

Neal F. Kassell ◽

Teresa P. Germanson ◽

Gail L. Kongable ◽

Laura L. Truskowski ◽

...

Keyword(s):

Prognostic Factors ◽

Subarachnoid Hemorrhage ◽

Age Groups ◽

Age Group ◽

Content Type ◽

Poor Outcome ◽

Symptomatic Vasospasm ◽

Age Related ◽

Increased Risk ◽

Fine Print

✓ Advanced age is a recognized prognostic indicator of poor outcome after subarachnoid hemorrhage (SAH). The relationship of age to other prognostic factors and outcome was evaluated using data from the multicenter randomized trial of nicardipine in SAH conducted in 21 neurosurgical centers in North America. Among the 906 patients who were studied, five different age groups were considered: 40 years or less, 41 to 50, 51 to 60, 61 to 70, and more than 71 years. Twenty-three percent of the individuals enrolled were older than 60 years of age. Women outnumbered men in all age groups. Level of consciousness (p = 0.0002) and World Federation of Neurological Surgeons grade (p = 0.0001) at admission worsened with advancing age. Age was also related to the presence of a thick subarachnoid clot (p = 0.0001), intraventricular hemorrhage (p = 0.0003), and hydrocephalus (p = 0.0001) on an admission computerized tomography scan. The rebleeding rate increased from 4.5% in the youngest age group to 16.4% in patients more than 70 years of age (p = 0.002). As expected, preexisting medical conditions, such as diabetes (p = 0.028), hypertension (p = 0.0001), and pulmonary (p = 0.0084), myocardial (p = 0.0001), and cerebrovascular diseases (p = 0.0001), were positively associated with age. There were no age-related differences in the day of admission following SAH, timing of the surgery and/or location, and size (small vs. large) of the ruptured aneurysm. During the treatment period, the incidence of severe complications (that is, those complications considered life threatening by the reporting investigator) increased with advancing age, occurring in 28%, 33%, 36%, 40%, and 46% of the patients in each advancing age group, respectively (p = 0.0002). No differences were observed in the reported frequency of surgical complications. No age-related differences were found in the overall incidence of angiographic vasospasm; however, symptomatic vasospasm was more frequently reported in the older age groups (p = 0.01). Overall outcome, assessed using the Glasgow Outcome Scale at 3 months post-SAH, was poorer with advancing age (p < 0.001). Multivariate analysis of overall outcome, adjusting for the different prognostic factors, did not remove the age effect, which suggests that the aging brain has a less optimal response to the initial bleeding. Age as a risk factor is a continuum; however, there seems to be a significant increased risk of poor outcome after the age of 60 years.

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Marked Increase in Incident Gynecomastia: A 20-Year National Registry Study, 1998 to 2017

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa440 ◽

2020 ◽

Vol 105 (10) ◽

pp. 3134-3140 ◽

Cited By ~ 1

Author(s):

Trine Koch ◽

Elvira V Bräuner ◽

Alexander S Busch ◽

Martha Hickey ◽

Anders Juul

Keyword(s):

Age Groups ◽

Population Based ◽

Incidence Rates ◽

National Registry ◽

Registry Study ◽

Age Related ◽

Danish Health ◽

Increased Risk ◽

National Patient ◽

First Time

Abstract Context Gynecomastia, the proliferation of mammary glandular tissue in the male, is a frequent but little-studied condition. Available prevalence data are based on selected patient populations or autopsy cases with their inherent bias. Objective The objective of this work is to evaluate the age-related incidence and secular trends in gynecomastia in the general population. Design An observational, 20-year national registry study was conducted. Setting This population-based study used nationwide registry data. Participants Participants included all Danish males (age 0-80 years) with a first-time diagnosis of gynecomastia. Main Outcome Measures All Danish males (age 0-80 years) were followed up for incident diagnosis of gynecomastia in the Danish National Patient Registry from 1998 to 2017 using the International Codes of Diseases, 10th revision, and the Danish Health Care Classification System. Age-specific incidence rates were estimated. The hypothesis tested in this study was formulated prior to data collection. Results Overall, a total 17 601 males (age 0-80 years) were registered with an incident diagnosis of gynecomastia within the 20-year study period, corresponding to 880 new cases per year and an average 20-year incidence of 3.4 per 10 000 men (age 0-80 years). The average annual incidence was 6.5/10 000 in postpubertal males age 16 to 20 years and 4.6/10 000 in males age 61 to 80 years, with a respective 5- and 11-fold overall increase in these 2 age groups over the 20-year period. Conclusions The incidence of gynecomastia has dramatically increased over the last 20 years, implying that the endogenous or exogenous sex-steroid environment has changed, which is associated with other adverse health consequences in men such as an increased risk of prostate cancer, metabolic syndrome, type 2 diabetes, or cardiovascular disorders.

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Changes in the Dynamic Stability of Walking in Active Healthy Older Adults Independent of Changes in Walking Speed

Volume 2: Biomedical and Biotechnology Engineering ◽

10.1115/imece2008-67807 ◽

2008 ◽

Author(s):

Hyun Gu Kang ◽

Jonathan B. Dingwell

Keyword(s):

Older Adults ◽

Young Adults ◽

Dynamic Stability ◽

Walking Speed ◽

Age Groups ◽

Leg Strength ◽

Age Related ◽

Increased Risk ◽

Risk Of Falls ◽

Walking Speeds

Older adults commonly walk slower, which many believe helps improve their walking stability. However, they remain at increased risk of falls. We investigated how differences in age and walking speed independently affect dynamic stability during walking, and how age-related changes in leg strength and ROM affected this relationship. Eighteen active healthy older and 17 younger adults walked on a treadmill for 5 minutes each at each of 5 speeds (80–120% of preferred). Local divergence exponents and maximum Floquet multipliers (FM) were calculated to quantify each subject’s responses to small inherent perturbations during walking. These older adults exhibited the same preferred walking speeds as the younger subjects (p = 0.860). However, these older adults still exhibited greater local divergence exponents (p<0.0001) and higher maximum FM (p<0.007) than young adults at all walking speeds. These older adults remained more unstable (p<0.04) even after adjusting for declines in both strength and ROM. In both age groups, local divergence exponents decreased at slower speeds and increased at faster speeds (p<0.0001). Maximum FM showed similar changes with speed (p<0.02). The older adults in this study were healthy enough to walk at normal speeds. However, these adults were still more unstable than the young adults, independent of walking speed. This greater instability was not explained by loss of leg strength and ROM. Slower speeds led to decreased instability in both groups.

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Impaired Mitophagy in Neurons and Glial Cells during Aging and Age-Related Disorders

International Journal of Molecular Sciences ◽

10.3390/ijms221910251 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10251

Author(s):

Vladimir Sukhorukov ◽

Dmitry Voronkov ◽

Tatiana Baranich ◽

Natalia Mudzhiri ◽

Alina Magnaeva ◽

...

Keyword(s):

Glial Cells ◽

Brain Aging ◽

Cellular Level ◽

Aging Brain ◽

The Past ◽

Age Related ◽

Accumulation Of Damage ◽

Quantity Control ◽

The Brain

Aging is associated with a decline in cognitive function, which can partly be explained by the accumulation of damage to the brain cells over time. Neurons and glia undergo morphological and ultrastructure changes during aging. Over the past several years, it has become evident that at the cellular level, various hallmarks of an aging brain are closely related to mitophagy. The importance of mitochondria quality and quantity control through mitophagy is highlighted by the contribution that defects in mitochondria–autophagy crosstalk make to aging and age-related diseases. In this review, we analyze some of the more recent findings regarding the study of brain aging and neurodegeneration in the context of mitophagy. We discuss the data on the dynamics of selective autophagy in neurons and glial cells during aging and in the course of neurodegeneration, focusing on three mechanisms of mitophagy: non-receptor-mediated mitophagy, receptor-mediated mitophagy, and transcellular mitophagy. We review the role of mitophagy in neuronal/glial homeostasis and in the molecular pathogenesis of neurodegenerative disorders, such as Parkinson’s disease, Alzheimer’s disease, and other disorders. Common mechanisms of aging and neurodegeneration that are related to different mitophagy pathways provide a number of promising targets for potential therapeutic agents.

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Chronic administration of a positive allosteric modulator at the α5-GABAA receptor reverses age-related dendritic shrinkage

10.1101/2020.02.28.964742 ◽

2020 ◽

Author(s):

Thomas D. Prevot ◽

Akiko Sumitomo ◽

Toshifumi Tomoda ◽

Daniel E. Knutson ◽

Guanguan Li ◽

...

Keyword(s):

Life Expectancy ◽

Cognitive Decline ◽

Neuronal Morphology ◽

Aging Brain ◽

Primary Neuronal Culture ◽

Efficient Treatment ◽

Gaba A ◽

Age Related ◽

Β Amyloid ◽

The Brain

ABSTRACTOver the last 15 years, worldwide life expectancy increased by 5 years jumping from 66 years to 71 years. With progress in science, medicine, and care we tend to live longer. Such extended life expectancy is still associated with age-related changes, including in the brain. The aging brain goes through various changes that can be called morphomolecular senescence. Overall, the brain volume changes, neuronal activity is modified and plasticity of the cells diminishes, sometimes leading to neuronal atrophy and death. Altogether, these changes contribute to the emergence of cognitive decline that still does not have an efficient treatment available. Many studies in the context of cognitive decline focused on pathological aging, targeting β-amyloid in Alzheimer’s disease, for example. However, β-amyloid plaques are also present in healthy adults and treatments targeting plaques have failed to improve cognitive functions. In order to improve the quality of life of aging population, it is crucial to focus on the development of novel therapies targeting different systems altered during aging, such as the GABAergic system. In previous studies, it has been shown that positive allosteric modulators (PAM) acting at the α5-containing GABA-A receptors improve cognitive performances, and that these α5-GABA-A receptors are implicated in dendritic growth of pyramidal neurons. Here, we hypothesized that targeting the α5-GABA-A receptors could contribute to the reduction of cognitive decline, directly through activity of the receptors, and indirectly by increasing neuronal morphology. Using primary neuronal culture and chronic treatment in mice, we demonstrated that an α5-PAM increased dendritic length, spine count and spine density in brain regions involved in cognitive processes (prefrontal cortex and hippocampus). We also confirmed the procognitive efficacy of the α5-PAM and showed that the washout period diminishes the precognitive effects without altering the effect on neuronal morphology. Future studies will be needed to investigate what downstream mechanisms responsible for the neurotrophic effect of the α5-PAM.

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Update on the NAS-NRC Twin Registry

Twin Research and Human Genetics ◽

10.1375/twin.9.6.985 ◽

2006 ◽

Vol 9 (6) ◽

pp. 985-987 ◽

Cited By ~ 7

Author(s):

William F. Page

Keyword(s):

Risk Factor ◽

Healthy Aging ◽

Morphological Changes ◽

White Male ◽

National Research Council ◽

The United States ◽

Age Related Macular Degeneration ◽

Aging Brain ◽

Twin Registry ◽

Age Related

AbstractThe National Academy of Sciences-National Research Council (NAS-NRC) Twin Registry is one of the oldest, national population-based twin registries in the United States. It consists of 15,924 white male twin pairs born in the years 1917 to 1927 (inclusive), both of whom served in the armed forces, mostly during World War II. This article updates activity in this registry since the earlier 2002 article in Twin Research. The results of clinically based studies on dementia, Parkinson's disease, age-related macular degeneration, and primary osteoarthritis were published, as well as articles based on previously collected questionnaire data on chronic fatigue syndrome, functional limitations, and healthy aging. In addition, risk factor studies are being planned to merge clinical data with earlier collected risk factor data from questionnaires. Examination data from the subset of National Heart, Lung, and Blood Institute (NHLBI) twins resulted in a number of articles, including the relationship of endogenous sex hormones to coronary heart disease and morphological changes in aging brain structures. The NEO Five-Factor Personality Inventory (a paper-and-pencil self-administered questionnaire) has been fielded for the first time. A push to consolidate the various data holdings of the registry is being made.

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N-acetyl-l-cysteine attenuates oxidative damage and neurodegeneration in rat brain during aging

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2018-0209 ◽

2018 ◽

Vol 96 (12) ◽

pp. 1189-1196 ◽

Cited By ~ 2

Author(s):

Geetika Garg ◽

Sandeep Singh ◽

Abhishek Kumar Singh ◽

Syed Ibrahim Rizvi

Keyword(s):

Rat Brain ◽

Neuroprotective Effect ◽

Neuron Specific Enolase ◽

Sirtuin 1 ◽

Marker Genes ◽

Aging Brain ◽

Age Related ◽

Nonenzymatic Antioxidants ◽

Old Rats ◽

The Brain

N-acetyl-l-cysteine (NAC) is a precursor of cysteine, which is known to increase the level of glutathione (GSH) in the brain. Several neurodegenerative changes linked to oxidative stress take place in the aging brain. This study aimed to assess the neuroprotective effect of NAC supplementation on age-dependent neurodegeneration in the rat brain. Young (4 months) and old (24 months) Wistar rats (n = 6 rats/group) were supplemented with NAC (100 mg/kg b.w. orally) for 14 days. Enzymatic and nonenzymatic antioxidants such as superoxide dismutase and catalase, and GSH and total thiol respectively, prooxidants such as protein carbonyl, advanced oxidation protein products, reactive oxygen species, and malondialdehyde were assessed in the brain homogenates. Furthermore, nitric oxide level, acetylcholinesterase activity, and Na+/K+–ATPase activity were measured and gene expression studies were also performed. The results indicated that NAC augmented the level of enzymatic and nonenzymatic antioxidants with a significant reduction in prooxidant levels in old rats. NAC supplementation also downregulated the expression of inflammatory markers (TNF-α, IL-1β, IL-6) and upregulated the expression of marker genes associated with aging (sirtuin-1) and neurodegeneration (neuron-specific enolase, neuroglobin, synapsin-I, myelin basic protein 2) in old rats. The present findings support a neuroprotective role of NAC which has therapeutic implication in controlling age-related neurological disorders.

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