Cell Senescence as a Mediator of Age-Dependent Brain Inflammation

Abstract Cellular senescence and inflammation are interconnected causes and consequences of tissue aging. Here, we implemented orthogonal approaches to study their interaction in steady-state mature and aged mouse brain. Using single cell sequencing, we identified a putative senescent microglial population, which increased in abundance with age and was characterized by increased expression of p16 and chemotactic senescence associated secretory phenotype (SASP) factors. Using p16-INK-ATTAC transgenic mice to eliminate p16ink4a-positive senescent cells and mass cytometry, we show that p16ink4a-positive cell targeting reduced the abundance of activated inflammatory cells in the aged female brain. Age-dependent declines in executive cognitive function were improved following transgenic p16ink4a-positive cell targeting, and executive function robustly correlated with inflammatory brain cell composition in females. Collectively, our findings demonstrate fundamental differences in the age- and sex-dependent brain inflammatory landscape and implicate p16ink4a-positive senescent cell targeting as a therapeutic strategy to attenuate age-related inflammation and cognitive decline.

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The serotonin transporter gene and female personality variation in a free-living passerine

Scientific Reports ◽

10.1038/s41598-021-88225-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Bert Thys ◽

Andrea S. Grunst ◽

Nicky Staes ◽

Rianne Pinxten ◽

Marcel Eens ◽

...

Keyword(s):

Serotonin Transporter ◽

Strong Support ◽

Serotonin Transporter Gene ◽

Female Aggression ◽

Nucleotide Polymorphisms ◽

Transporter Gene ◽

Evolutionary Potential ◽

Free Living ◽

Age Related ◽

Age Dependent

AbstractQuantifying variation in behaviour-related genes provides insight into the evolutionary potential of repeatable among-individual variation in behaviour (i.e. personality). Yet, individuals typically also plastically adjust their behaviour in response to environmental conditions and/or age, thereby complicating the detection of genotype–phenotype associations. Here, using a population of free-living great tits (Parus major), we assessed the association between single nucleotide polymorphisms (SNPs) in the serotonin transporter gene (SERT) and two repeatable behavioural traits, i.e. female-female aggression and female hissing behaviour. For female-female aggression, a trait showing age-related plasticity, we found no evidence for associations with SERT SNPs, even when assessing potential age-dependent effects of SERT genotype on aggression. We also found no strong support for associations between SERT SNPs and hissing behaviour, yet we identified two synonymous polymorphisms (exon 13 SNP66 and exon 12 SNP144) of particular interest, each explaining about 1.3% of the total variation in hissing behaviour. Overall, our results contribute to the general understanding of the biological underpinning of complex behavioural traits and will facilitate further (meta-analytic) research on behaviour-related genes. Moreover, we emphasize that future molecular genetic studies should consider age-dependent genotype–phenotype associations for behavioural trait (co)variation, as this will vastly improve our understanding of the proximate causes and ultimate consequences of personality variation in natural populations.

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Random errors in protein synthesis activate an age-dependent program of muscle atrophy in mice

Communications Biology ◽

10.1038/s42003-021-02204-z ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

James Moore ◽

Rashid Akbergenov ◽

Martina Nigri ◽

Patricia Isnard-Petit ◽

Amandine Grimm ◽

...

Keyword(s):

Protein Synthesis ◽

Muscle Atrophy ◽

Strength Analysis ◽

Dependent Manner ◽

Random Errors ◽

Age Related ◽

Related Phenotype ◽

Age Dependent ◽

Translation Accuracy ◽

Transcriptomic Changes

AbstractRandom errors in protein synthesis are prevalent and ubiquitous, yet their effect on organismal health has remained enigmatic for over five decades. Here, we studied whether mice carrying the ribosomal ambiguity (ram) mutation Rps2-A226Y, recently shown to increase the inborn error rate of mammalian translation, if at all viable, present any specific, possibly aging-related, phenotype. We introduced Rps2-A226Y using a Cre/loxP strategy. Resulting transgenic mice were mosaic and showed a muscle-related phenotype with reduced grip strength. Analysis of gene expression in skeletal muscle using RNA-Seq revealed transcriptomic changes occurring in an age-dependent manner, involving an interplay of PGC1α, FOXO3, mTOR, and glucocorticoids as key signaling pathways, and finally resulting in activation of a muscle atrophy program. Our results highlight the relevance of translation accuracy, and show how disturbances thereof may contribute to age-related pathologies.

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HEAT SHOCK PROTEIN 90 (90) IN AGE-DEPENDENT CHANGES IN THE NUMBER OF FIBROBLASTS IN HUMAN SKIN

Успехи геронтологии ◽

10.34922/ae.2020.33.1.004 ◽

2020 ◽

pp. 40-45

Author(s):

А. Г. Гунин ◽

Н. Н. Голубцова ◽

Н. К. Корнилова

Keyword(s):

Heat Shock ◽

Heat Shock Protein ◽

Heat Shock Protein 90 ◽

Nuclear Antigen ◽

Positive Staining ◽

Proliferating Cells ◽

Age Related ◽

Age Dependent ◽

Human Dermis ◽

Hsp 90

Целью работы стало исследование содержания белка теплового шока 90 ( HSP 90) в фибробластах дермы человека от эмбрионального развития и до глубокой старости (от 20 нед беременности до 85 лет), а также определение значения HSP 90 для возрастных изменений численности фибробластов в дерме человека. HSP 90, ядерный антиген пролиферирующих клеток ( PCNA ) выявляли в срезах кожи непрямым иммуногистохимическим методом. Результаты показали, что в коже человека от 20 нед беременности до 20 лет доля фибробластов дермы с положительной окраской на HSP 90 остается постоянной. С 21 года до 60 лет наблюдают планомерное уменьшение доли фибробластов дермы, имеющих положительную окраску на HSP 90. У людей 61-85 лет происходит резкое увеличение доли фибробластов дермы с положительной окраской на HSP 90. Возрастные изменения содержания HSP 90 положительных фибробластов в дерме статистически не связаны с возрастным уменьшением общего количества и доли PCNA -положительных фибробластов в дерме. The aim of this work was to examine the content of heat shock protein 90 ( HSP 90) in ﬁbroblasts of human dermis from the development until deep aging (from 20 weeks of pregnancy until 85 years old), and deﬁning of a role of HSP 90 in age-dependent changes in the number of ﬁbroblasts in the dermis. HSP 90, proliferating cells nuclear antigen ( PCNA ) were detected with indirect immunohistochemical technique. Results showed that a portion of ﬁbroblasts with positive staining for HSP 90 in the dermis is not changed from 20 weeks of development to 20 years old. Percent of HSP 90 positive ﬁbroblasts in dermis is decreased from 21 to 60 years old. From 61 year, the number of HSP 90 positive ﬁbroblasts in dermis is increased. Age-related changes in the number of HSP 90 positive ﬁbroblasts is not statistically associated with an age-related decrease in a total number and percent of PCNA positive ﬁbroblasts the dermis.

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Different ATP-catabolism in reperfused adult and newborn rat hearts

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1988.254.6.h1091 ◽

1988 ◽

Vol 254 (6) ◽

pp. H1091-H1098

Author(s):

P. W. Achterberg ◽

A. S. Nieukoop ◽

B. Schoutsen ◽

J. W. de Jong

Keyword(s):

Oxidase Activity ◽

Age Groups ◽

Similar Degree ◽

Ischemia And Reperfusion ◽

Xanthine Oxidoreductase ◽

Newborn Rat ◽

Age Related ◽

Rat Hearts ◽

Age Dependent ◽

Atp Breakdown

Age-dependent differences in the effects of ischemia and reperfusion on ATP breakdown were studied in perfused adult and newborn (10 days old) rat hearts. No-flow ischemia (15 min at 37, 30, or 23 degrees C) was applied and reperfusion (20 min at 37 degrees C) was studied after ischemia at 23 or 37 degrees C. Hypothermia during ischemia protected both age groups to a similar degree against ATP decline, which was linear with temperature. Reperfusion after normothermic ischemia resulted in higher ATP levels in newborn hearts with less release of ATP catabolites (purines). We found no age-related differences in lactate release but large differences in purine release. During normoxia, adult hearts released mainly urate (80% of total) and inosine (7%), but newborns released hypoxanthine (64%) and inosine (15%). Early during reperfusion adult hearts released inosine (58%) and adenosine (18%), but newborns released inosine (53%) and hypoxanthine (38%). These data suggested a lower activity of the potentially deleterious enzyme xanthine oxidoreductase in newborn hearts, which was confirmed by enzymatic assay. ATP-catabolite release during reperfusion was less in newborn than adult hearts, and this coincided with lower xanthine oxidase activity.

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Age-dependent Increases in Adrenal Cytochrome b5 and Serum 5-Androstenediol-3-sulfate

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2016-2864 ◽

2016 ◽

Vol 101 (12) ◽

pp. 4585-4593 ◽

Cited By ~ 17

Author(s):

Juilee Rege ◽

Shigehiro Karashima ◽

Antonio M. Lerario ◽

Joshua M. Smith ◽

Richard J. Auchus ◽

...

Keyword(s):

Cytochrome B5 ◽

Serum Levels ◽

Dehydroepiandrosterone Sulfate ◽

Zona Fasciculata ◽

Adrenocortical Cells ◽

Normal Children ◽

Age Related ◽

Age Dependent ◽

Lyase Activity ◽

Liquid Chromatography Tandem Mass

Context: Adrenal production of dehydroepiandrosterone sulfate (DHEA-S) increases throughout childhood owing to expansion of the zona reticularis (ZR). ZR features cells with a steroidogenic phenotype distinct from that of the adjacent zona fasciculata, with higher expression of cytochrome b5 type A (CYB5A) and steroid sulfotransferase type 2A1 but decreased 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2). In addition to DHEA-S, three adrenal Δ5-steroid sulfates could provide additional tools to define adrenal maturation. Objective: This study sought to simultaneously measure serum levels of four adrenal Δ5-steroid sulfates, pregnenolone sulfate (Preg-S), 17α-hydroxypregnenolone sulfate (17OHPreg-S), DHEA-S, and 5-androstenediol-3-sulfate (Adiol-S) as a function of age and relate their production to the age-dependent adrenal localization of CYB5A. Participants and Methods: Δ5-steroid sulfates were quantified by liquid chromatography–tandem mass spectrometry in sera from 247 normal children (129 males,118 females) age 1.5–18 y and 42 adults (20 males, 22 females). Immunofluorescence localized HSD3B2 and CYB5A in normal adrenal glands from subjects age 2–35 y. Finally, HAC15 adrenocortical cells were transduced with lentiviral short hairpin RNA to suppress CYB5A expression. Results: Of the Δ5-steroid sulfates quantified, DHEA-S was most abundant. Adiol-S increased in parallel with DHEA-S. Steroid ratios (17OHPreg-S/DHEA-S) suggested increases in 17,20-lyase activity during childhood. Immunofluorescence analysis showed age-related increases in ZR CYB5A immunoreactivity. Furthermore, silencing CYB5A in HAC15 adrenocortical cells significantly reduced DHEA-S and Adiol-S production. Conclusion: Adiol-S shows a similar age-related increase to that of DHEA-S. This likely results from the childhood expansion of CYB5A-expressing ZR, which enhances 17,20-lyase activity and the production of DHEA-S and Adiol-S.

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A Multivariate Assessment of Age-Related Cognitive Impairment in Octodon degus

Frontiers in Integrative Neuroscience ◽

10.3389/fnint.2021.719076 ◽

2021 ◽

Vol 15 ◽

Author(s):

Daniela S. Rivera ◽

Carolina B. Lindsay ◽

Carolina A. Oliva ◽

Francisco Bozinovic ◽

Nibaldo C. Inestrosa

Keyword(s):

Recognition Memory ◽

Cognitive Performance ◽

Natural Aging ◽

Long Term Memory ◽

Barnes Maze ◽

Short Term ◽

Term Memory ◽

Age Related ◽

Age Dependent

Aging is a progressive functional decline characterized by a gradual deterioration in physiological function and behavior. The most important age-related change in cognitive function is decline in cognitive performance (i.e., the processing or transformation of information to make decisions that includes speed of processing, working memory, and learning). The purpose of this study is to outline the changes in age-related cognitive performance (i.e., short-term recognition memory and long-term learning and memory) in long-lived Octodon degus. The strong similarity between degus and humans in social, metabolic, biochemical, and cognitive aspects makes it a unique animal model for exploring the mechanisms underlying the behavioral and cognitive deficits related to natural aging. In this study, we examined young adult female degus (12- and 24-months-old) and aged female degus (38-, 56-, and 75-months-old) that were exposed to a battery of cognitive-behavioral tests. Multivariate analyses of data from the Social Interaction test or Novel Object/Local Recognition (to measure short-term recognition memory), and the Barnes maze test (to measure long-term learning and memory) revealed a consistent pattern. Young animals formed a separate group of aged degus for both short- and long-term memories. The association between the first component of the principal component analysis (PCA) from short-term memory with the first component of the PCA from long-term memory showed a significant negative correlation. This suggests age-dependent differences in both memories, with the aged degus having higher values of long-term memory ability but poor short-term recognition memory, whereas in the young degus an opposite pattern was found. Approximately 5% of the young and 80% of the aged degus showed an impaired short-term recognition memory; whereas for long-term memory about 32% of the young degus and 57% of the aged degus showed decreased performance on the Barnes maze test. Throughout this study, we outlined age-dependent cognitive performance decline during natural aging in degus. Moreover, we also demonstrated that the use of a multivariate approach let us explore and visualize complex behavioral variables, and identified specific behavioral patterns that allowed us to make powerful conclusions that will facilitate further the study on the biology of aging. In addition, this study could help predict the onset of the aging process based on behavioral performance.

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Metformin protects lens epithelial cells against senescence in a naturally aged mouse model

Cell Death Discovery ◽

10.1038/s41420-021-00800-w ◽

2022 ◽

Vol 8 (1) ◽

Author(s):

Mengmeng Chen ◽

Yushan Fu ◽

Xu Wang ◽

Ruitong Wu ◽

Dongmei Su ◽

...

Keyword(s):

Epithelial Cells ◽

Vision Loss ◽

Adenosine Monophosphate ◽

Underlying Mechanism ◽

Ageing Process ◽

Lens Epithelial Cells ◽

Control Group ◽

Aged Mouse ◽

Ampk Pathway ◽

Age Related

AbstractThe senescence of lens epithelial cells (LECs) is a major factor leading to age-related cataract (ARC). ARC results in visual impairment and severe vision loss in elderly patients. However, the specific mechanism of ARC remains unclear, and there are no effective therapeutic agents to halt the formation of ARC. This study aimed to assess the underlying mechanism of the formation of ARC and investigate the potential anti-ageing effect of metformin (MET) on ARC. Male C57BL/6 mice were divided into three groups: the control group having young mice (3 months old, n = 40), the naturally aged group (aged 20 months, n = 60) and the MET group (MET, 20 months, n = 60). Mice in the control and the naturally aged groups were fed a standard purified mouse diet ad libitum and water, whereas those in the MET group were fed chows supplemented with 0.1% MET for 10 months. The transparency of the lens and age-associated proteins p21 and p53 were analysed in the LECs of these three groups. Furthermore, we determined the expressions of the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway and the effect of MET on this pathway in LECs during the ageing process of ARC. In addition, the relationship between autophagy and the senescence of LECs and the role of MET in the autophagy of LECs during the ageing process of ARC were examined. Our results indicated that age-related inactivation of the AMPK pathway and impairment of autophagy might contribute to the senescence of LECs and the occurrence of ARC. More importantly, these results demonstrated that MET effectively alleviated the senescence of LECs and the formation of ARC probably via inactivation of the AMPK pathway and augmentation of autophagy. These findings revealed that MET can be exploited as a potentially useful drug for ARC prevention. Our study will help in enlightening the development of innovative strategies for the clinical treatment of ARC.

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The Age-Dependent Decline in Neuron Growth Potential in the CNS is Associated with an Age-Related Dysfunction of Neuronal Mitochondria

10.1101/2021.05.14.444223 ◽

2021 ◽

Author(s):

Theresa C. Sutherland ◽

Arthur Sefiani ◽

Darijana Horvat ◽

Taylor E. Huntington ◽

Yuanjiu Lei ◽

...

Keyword(s):

Cortical Neurons ◽

Traumatic Injury ◽

Axon Growth ◽

Neurite Growth ◽

Growth Potential ◽

Age Related ◽

Mitochondrial Functions ◽

Cord Injury ◽

Age Dependent ◽

Neuron Growth

The age of incidence of Spinal Cord Injury (SCI) and the average age of people living with SCI is continuously increasing. In contrast, SCI is extensively modelled in young adult animals, hampering translation of research to clinical application. While there has been significant progress in manipulating axon growth after injury, how it is impacted by aging impacts this is still unknown. Aging is associated with a decline in mitochondrial functions, whereas mitochondria are essential to successful neurite and axon growth. Using isolation and culture of adult cortical neurons, we have analyzed mitochondrial changes in 2-, 6-, 12- and 18-month mice. We observed reduced neurite growth in older neurons. Older neurons also showed dysfunctional respiration, reduced membrane potential, and altered mitochondrial membrane transport proteins; however mitochondrial DNA (mtDNA) abundance and cellular ATP were increased. Taken together, these data suggest dysfunctional mitochondria in older neurons are involved in the age-dependent reduction in neuron growth. Both normal aging and traumatic injury are associated with mitochondrial dysfunction, posing a challenge for an aging SCI population as the two elements can compound one another to worsen injury outcomes. The results of this study highlight this as an area of great interest in CNS trauma.

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A unique adipocyte progenitor population promotes age-related adiposity

10.21203/rs.3.rs-888694/v1 ◽

2021 ◽

Author(s):

Qiong Wang ◽

Guan Wang ◽

Gaoyan Li ◽

Anying Song ◽

Wenting Dai ◽

...

Keyword(s):

Adult Stem Cells ◽

Metabolic Disorders ◽

Visceral Obesity ◽

Lineage Tracing ◽

Fat Cell ◽

A Cells ◽

Age Related ◽

Tissue Aging

Abstract The average fat mass in adults increases dramatically with age, and older people often suffer from visceral obesity and related adverse metabolic disorders. Unfortunately, how aging leads to fat accumulation is poorly understood. It is known that fat cell (adipocyte) turnover is very low in young mice, similar to that in young humans. Here, we find that mice mimic age-related fat expansion in humans. In vivo lineage tracing shows that massive adipogenesis (the generation of new adipocytes), especially in the visceral fat, is triggered during aging. Thus, in contrast to most types of adult stem cells that exhibit a reduced ability to proliferate and differentiate, the adipogenic potential of adipocyte progenitor cells (APCs) is unlocked by aging. In vivo transplantation and 3D imaging of transplants show that APCs in aged mice cell-autonomously gain high adipogenic capacity. Single-cell RNA sequencing analyses reveal that aging globally remodels APCs. Herein, we identify a novel committed preadipocyte population that is age-specific (CP-A), existing both in mice and humans, with a global activation of proliferation and adipogenesis pathways. CP-A cells display high proliferation and adipogenesis activity, both in vivo and in vitro. Macrophages may regulate the remodeling of APCs and the generation of CP-A cells during aging. Together, these findings define a new fundamental mechanism involved in fat tissue aging and offer prospects for preventing and treating age-related metabolic disorders.

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Age and genetic background modify hybrid male sterility in house mice

10.1101/2020.06.26.173047 ◽

2020 ◽

Author(s):

Samuel J. Widmayer ◽

Mary Ann Handel ◽

David L. Aylor

Keyword(s):

Male Sterility ◽

House Mouse ◽

Genetic Background ◽

Genetic Architecture ◽

Hybrid Male ◽

Hybrid Male Sterility ◽

X Chromosomes ◽

Age Related ◽

Age Dependent ◽

In The Wild

AbstractHybrid male sterility (HMS) contributes to reproductive isolation commonly observed among house mouse (Mus musculus) subspecies, both in the wild and in laboratory crosses. Incompatibilities involving specific Prdm9 alleles and certain Chromosome (Chr) X genotypes are known determinants of fertility and HMS, and previous work in the field has demonstrated that genetic background modifies these two major loci. We constructed hybrids that have identical genotypes at Prdm9 and identical X chromosomes, but differ widely across the rest of the genome. In each case, we crossed female PWK/PhJ mice representative of the M. m. musculus subspecies to males from a classical inbred strain representative of M. m. domesticus: 129S1/SvImJ, A/J, C57BL/6J, or DBA/2J. We detected three distinct trajectories of fertility among the hybrids using breeding experiments. The PWK129S1 males were always infertile. PWKDBA2 males were fertile, despite their genotypes at the major HMS loci. We also observed age-dependent changes in fertility parameters across multiple genetic backgrounds. The PWKB6 and PWKAJ males were always infertile before 15 weeks and after 35 weeks, yet some PWKB6 and PWKAJ males were fertile between fifteen and 35 weeks. This observation could resolve previous contradictory reports about the fertility of PWKB6. Taken together, these results point to multiple segregating HMS modifier alleles, some of which have age-related modes of action. The ultimate identification of these alleles and their age-related mechanisms will advance understanding both of the genetic architecture of HMS and of how reproductive barriers are maintained between house mouse subspecies.

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