Age-related Pathologies Research Articles

Epigenetic Reader Bromodomain-Containing Protein 4 in Aging-Related Vascular Pathologies and Diseases: Molecular Basis, Functional Relevance, and Clinical Potential.

Aging is a key independent risk factor of various vascular diseases, for which the regulatory mechanisms remain largely unknown. Bromodomain-containing protein 4 (BRD4) is a member of the Bromodomain and Extra-Terminal domain (BET) family and is an epigenetic reader playing diverse roles in regulating transcriptional elongation, chromatin remodeling, DNA damage response, and alternative splicing in various cells and tissues. While BRD4 was initially recognized for its involvement in cancer progression, recent studies have revealed that the aberrant expression and impaired function of BRD4 were highly associated with aging-related vascular pathology, affecting multiple key biological processes in the vascular cells and tissues, providing new insights into the understanding of vascular pathophysiology and pathogenesis of vascular diseases. This review summarizes the recent advances in BRD4 biological function, and the progression of the studies related to BRD4 in aging-associated vascular pathologies and diseases, including atherosclerosis, aortic aneurism vascular neointima formation, pulmonary hypertension, and essential hypertension, providing updated information to advance our understanding of the epigenetic mechanisms in vascular diseases during aging and paving the way for future research and therapeutic approaches.

Molecular mechanism of caloric restriction mimetics-mediated neuroprotection of age-related neurodegenerative diseases: an emerging therapeutic approach.

Aging-induced neurodegenerative diseases (NDs) are significantly increasing health problem worldwide. It has been well documented that oxidative stress is one of the potential causes of aging and age-related NDs. There are no drugs for the treatment of NDs, therefore there is an immediate necessity for the development of strategies/treatments either to prevent or cure age-related NDs. Caloric restriction (CR) and intermittent fasting have been considered as effective strategies in increasing the healthspan and lifespan, but it is difficult to adhere to these routines strictly, which has led to the development of calorie restriction mimetics (CRMs). CRMs are natural compounds that provide similar molecular and biochemical effects of CR, and activate autophagy process. CRMs have been reported to regulate redox signaling by enhancing the antioxidant defense systems through activation of the Nrf2 pathway, and inhibiting ROS generation through attenuation of mitochondrial dysfunction. Moreover, CRMs also regulate redox-sensitive signaling pathways such as the PI3K/Akt and MAPK pathways to promote neuronal cell survival. Here, we discuss the neuroprotective effects of various CRMs at molecular and cellular levels during aging of the brain. The CRMs are envisaged to become a cornerstone of the pharmaceutical arsenal against aging and age-related pathologies.

Oxidative Stress and Antioxidants in Age-Related Macular Degeneration.

Oxidative stress plays a crucial role in aging-related eye diseases, including age-related macular degeneration (AMD), cataracts, and glaucoma. With age, antioxidant reparative capacity decreases, and excess levels of reactive oxygen species produce oxidative damage in many ocular cell types underling age-related pathologies. In AMD, loss of central vision in the elderly is caused primarily by retinal pigment epithelium (RPE) dysfunction and degeneration and/or choroidal neovascularization that trigger malfunction and loss of photo-sensing photoreceptor cells. Along with various genetic and environmental factors that contribute to AMD, aging and age-related oxidative damage have critical involvement in AMD pathogenesis. To this end, dietary intake of antioxidants is a proven way to scavenge free radicals and to prevent or slow AMD progression. This review focuses on AMD and highlights the pathogenic role of oxidative stress in AMD from both clinical and experimental studies. The beneficial roles of antioxidants and dietary micronutrients in AMD are also summarized.

Serum and follicular fluid levels of soluble receptor for advanced glycation end-products in women with and without polycystic ovary syndrome

BackgroundAdvanced glycation end products (AGEs) are known to associate with the pathogenesis of several chronic diseases via interaction with their corresponding receptor (RAGE). The soluble forms of RAGE (sRAGE) are considered as anti-inflammatory agents by inhibiting the consequent adverse effects of AGE. We aimed at comparing sRAGE levels in the follicular fluid (FF) and serum of women with or without Polycystic Ovary Syndrome (PCOS) who underwent controlled ovarian stimulation for in vitro fertilisation (IVF).MethodsA total of forty-five eligible women (26 non-PCOS (control) and 19 patients with PCOS (case)) were included the study. sRAGEs in FF and blood serum were measured using ELISA kit.ResultsNo statistically significant differences were found in FF and serum sRAGE between case and control groups. Correlation analysis showed a significant and positive relationship between serum levels of sRAGE and FF sRAGE in PCOS (r = 0.639; p = 0.004), in control participants (r = 0.481; p = 0.017), and in total participants (r = 0.552; p = 0.000). Data revealed a statistically significant difference in FF sRAGE concentration among all participants by body mass index (BMI) categories (p = 0.01) and in controls (p = 0.022). Significant differences were found for all the nutrients and AGEs consumption according to Food Frequency Questionnaire in both groups (p = 0.0001). A significant reverse relationship was found between FF levels of sRAGE and AGE in PCOS (r = -0.513; p = 0.025). The concentration of sRAGE in serum and FF is the same in PCOS and control.ConclusionThe present study revealed for the first time that there are no statistically significant differences between the concentration of serum sRAGE and FF sRAGE among Iranian women with and without PCOS. However, BMI and dietary intake of AGEs have more significant effects on sRAGE concentration in Iranian women. Future studies in developed and developing countries with larger sample sizes are required to determine the long-term consequences of chronic AGE over consumption and the optimal strategies for minimizing AGE-related pathology, specifically in low income and developing countries.

In major joint diseases the human synovium retains its potential to form repair cartilage

The inner surface layer of human joints, the synovium, is a source of stem cells for the repair of articular cartilage defects. We investigated the potential of the normal human synovium to form novel cartilage and compared its chondrogenic capacity with that of two patient groups suffering from major joint diseases: young adults with femoro-acetabular impingement syndromes of the hip (FAI), and elderly individuals with osteoarthritic degeneration of the knee (OA). Synovial membrane explants of these three patient groups were induced in vitro to undergo chondrogenesis by growth factors: bone morphogenetic protein-2 (BMP-2) alone, transforming growth factor-β1 (TGF-β1) alone, or a combination of these two. Quantitative evaluations of the newly formed cartilages were performed respecting their gene activities, as well as the histochemical, immunhistochemical, morphological and histomorphometrical characteristics. Formation of adult articular-like cartilage was induced by the BMP-2/TGF-β1 combination within all three groups, and was confirmed by adequate gene-expression levels of the anabolic chondrogenic markers; the levels of the catabolic markers remained low. Our data reveal that the chondrogenic potential of the normal human synovium remains uncompromised, both in FAI and OA. The potential of synovium-based clinical repair of joint cartilage may thus not be impaired by age-related joint pathologies.

Redox signaling in impaired cascades of wound healing: promising approach.

In the aging communities, wound healing management is a quite remarkable problem especially in elderly individuals. The optimal level of healing of wounds developed spontaneously or due to surgery is of critical importance in order to prevent the negative effects that may occur due to delayed healing (for example, organ or system damage caused by infections that may develop in the wound area). The deteriorated subcellular redox signaling is considered to be as the main factor in the chronicity of wounds. The pivotal role of mitochondria in redox regulation reveals the importance of modulation of redox signaling pathways in senescent cells. Secretory factors released upon the acquisition of senescence-associated secretory phenotype (SASP) function in a paracrine manner to disseminate impaired tissue redox status by affecting the redox metabolome of nearby cells, which could promote age-related pro-inflammatory pathologies. Evaluating the wound-site redox regulation in impaired redox signaling pathways may help prevent the formation of chronic wounds and the development of long-term complications of the wounds, especially in the elderly. Using the redox modulatory pharmacologically active substances targeting the senescent cells in chronic wound areas hopefully opens a new avenue in wound management. As the signaling mechanisms of wound healing and its relationship with advanced age become more clearly understood, many promising therapeutic approaches and redox modulator substances are coming into clinical view for the management of chronic wounds.

Preclinical Characterization of the Tau PET Tracer [18F]SNFT-1: Comparison of Tau PET Tracers.

Tau PET tracers are expected to be sufficiently sensitive to track the progression of age-related tau pathology in the medial temporal cortex. The tau PET tracer N-(4-[18F]fluoro-5-methylpyridin-2-yl)-7-aminoimidazo[1,2-a]pyridine ([18F]SNFT-1) has been successfully developed by optimizing imidazo[1,2-a]pyridine derivatives. We characterized the binding properties of [18F]SNFT-1 using a head-to-head comparison with other reported 18F-labeled tau tracers. Methods: The binding affinity of SNFT-1 to tau, amyloid, and monoamine oxidase A and B was compared with that of the second-generation tau tracers MK-6240, PM-PBB3, PI-2620, RO6958948, JNJ-64326067, and flortaucipir. In vitro binding properties of 18F-labeled tau tracers were evaluated through the autoradiography of frozen human brain tissues from patients with diverse neurodegenerative disease spectra. Pharmacokinetics, metabolism, and radiation dosimetry were assessed in normal mice after intravenous administration of [18F]SNFT-1. Results: In vitro binding assays demonstrated that [18F]SNFT-1 possesses high selectivity and high affinity for tau aggregates in Alzheimer disease (AD) brains. Autoradiographic analysis of tau deposits in medial temporal brain sections from patients with AD showed a higher signal-to-background ratio for [18F]SNFT-1 than for the other tau PET tracers and no significant binding with non-AD tau, α-synuclein, transactiviation response DNA-binding protein-43, and transmembrane protein 106B aggregates in human brain sections. Furthermore, [18F]SNFT-1 did not bind significantly to various receptors, ion channels, or transporters. [18F]SNFT-1 showed a high initial brain uptake and rapid washout from the brains of normal mice without radiolabeled metabolites. Conclusion: These preclinical data suggest that [18F]SNFT-1 is a promising and selective tau radiotracer candidate that allows the quantitative monitoring of age-related accumulation of tau aggregates in the human brain.

Formerly bile-farmed bears as a model of accelerated ageing

Bear bile-farming is common in East and Southeast Asia and this farming practice often results in irreversible health outcomes for the animals. We studied long-term effects of chronic bacterial and sterile hepatobiliary inflammation in 42 Asiatic black bears (Ursus thibetanus) rescued from Vietnamese bile farms. The bears were examined under anesthesia at least twice as part of essential medical interventions. All bears were diagnosed with chronic low-grade sterile or bacterial hepatobiliary inflammation along with pathologies from other systems. Our main finding was that the chronic low-grade inflammatory environment associated with bile extraction in conjunction with the suboptimal living conditions on the farms promoted and accelerated the development of age-related pathologies such as chronic kidney disease, obese sarcopenia, cardiovascular remodeling, and degenerative joint disease. Through a biomimetic approach, we identified similarities with inflammation related to premature aging in humans and found significant deviations from the healthy ursid phenotype. The pathological parallels with inflammageing and immuno-senescence induced conditions in humans suggest that bile-farmed bears may serve as animal models to investigate pathophysiology and deleterious effects of lifestyle-related diseases.

Comparative analysis of calcified soft tissues revealed shared deregulated pathways.

Calcification of soft tissues is a common age-related pathology that primarily occurs within vascular tissue. The mechanisms underlying pathological calcification in humans and tissue specificity of the process is still poorly understood. Previous studies examined calcified tissues on one to one basis, thus preventing comparison of deregulated pathways across tissues. This study aimed to establish common and tissue-specific changes associated with calcification in aorta, artery tibial, coronary artery and pituitary gland in subjects from the Genotype-Tissue Expression (GTEx) dataset using its RNA sequencing and histological data. We used publicly available data from the GTEx database https://gtexportal.org/home/aboutGTEx. All GTEx tissue samples were derived by the GTEx consorcium from deceased donors, with age from 20 to 79, both men and women. GTEx study authorization was obtained via next-of-kin consent for the collection and banking of de-identified tissue samples for scientific research. Hematoxylin and eosin (H&E) staining of arteries were manually graded based on the presence of calcification on a scale from zero to four, where zero designates absence of calcification and four designates severe calcification. Samples with fat contamination and mislabeled tissues were excluded, which left 430 aorta, 595 artery tibial, 124 coronary artery, and 283 pituitary samples for downstream gene expression analysis. Transcript levels of protein-coding genes were associated with calcification grade using sex, age bracket and cause of death as covariates, and tested for pathway enrichment using gene set enrichment analysis. We identified calcification deposits in 28 (6.5%) aortas, 121 (20%), artery tibials, 54 (43%), coronary arteries, and 24 (8%) pituitary glands of GTEx subjects. We observed an age-dependent increase in incidence of calcification in all vascular tissues, but not in pituitary. Subjects with calcification in the artery tibial were significantly more likely to have calcification in the coronary artery (OR = 2.56, p = 6.3e-07). Markers of calcification previously established in preclinical and in vitro studies, e.g., BMP2 and RUNX2, were deregulated in the calcified tibial and coronary arteries, confirming the relevance of these genes to human pathology. Differentially expressed genes associated with calcification poorly overlapped across tissues suggesting tissue-specific nuances in mechanisms of calcification. Nevertheless, calcified arteries unanimously down-regulated pathways of intracellular transport and up-regulated inflammatory pathways suggesting these as universal targets for pathological calcification. In particular, PD-1 and PD-L1 genes were up-regulated in calcified tissues but not in the blood of the same subjects, suggesting that localized inflammation contributes to pathological calcification. Pathological calcification is a prevalent disease of aging that shares little changes in expression in individual genes across tissues. However, our analysis suggests that it potentially can be targeted by alleviating local inflammation of soft tissues.

Central and Peripheral Inflammation: A Common Factor Causing Addictive and Neurological Disorders and Aging-Related Pathologies.

Many diseases and degenerative processes affecting the nervous system and peripheral organs trigger the activation of inflammatory cascades. Inflammation can be triggered by different environmental conditions or risk factors, including drug and food addiction, stress, and aging, among others. Several pieces of evidence show that the modern lifestyle and, more recently, the confinement associated with the COVID-19 pandemic have contributed to increasing the incidence of addictive and neuropsychiatric disorders, plus cardiometabolic diseases. Here, we gather evidence on how some of these risk factors are implicated in activating central and peripheral inflammation contributing to some neuropathologies and behaviors associated with poor health. We discuss the current understanding of the cellular and molecular mechanisms involved in the generation of inflammation and how these processes occur in different cells and tissues to promote ill health and diseases. Concomitantly, we discuss how some pathology-associated and addictive behaviors contribute to worsening these inflammation mechanisms, leading to a vicious cycle that promotes disease progression. Finally, we list some drugs targeting inflammation-related pathways that may have beneficial effects on the pathological processes associated with addictive, mental, and cardiometabolic illnesses.

A rationally designed fluorescence probe achieves highly specific and long-term detection of senescence in vitro and in vivo.

Senescent cells (SnCs) are implicated in aging and various age-related pathologies. Targeting SnCs can treat age-related diseases and extend health span. However, precisely tracking and visualizing of SnCs is still challenging, especially in in vivo environments. Here, we developed a near-infrared (NIR) fluorescent probe (XZ1208) that targets β-galactosidase (β-Gal), a well-accepted biomarker for cellular senescence. XZ1208 can be cleaved rapidly by β-Gal and produces a strong fluorescence signal in SnCs. We demonstrated the high specificity and sensitivity of XZ1208 in labeling SnCs in naturally aged, total body irradiated (TBI), and progeroid mouse models. XZ1208 achieved a long-term duration of over 6 days in labeling senescence without causing significant toxicities and accurately detected the senolytic effects of ABT263 on eliminating SnCs. Furthermore, XZ1208 was applied to monitor SnCs accumulated in fibrotic diseases and skin wound healing models. Overall, we developed a tissue-infiltrating NIR probe and demonstrated its excellent performance in labeling SnCs in aging and senescence-associated disease models, indicating great potential for application in aging studies and diagnosis of senescence-associated diseases.

Oxidative Stress-Induced Cellular Senescence: Is Labile Iron the Connecting Link?

Cellular senescence, a cell state characterized by a generally irreversible cell cycle arrest, is implicated in various physiological processes and a wide range of age-related pathologies. Oxidative stress, a condition caused by an imbalance between the production and the elimination of reactive oxygen species (ROS) in cells and tissues, is a common driver of cellular senescence. ROS encompass free radicals and other molecules formed as byproducts of oxygen metabolism, which exhibit varying chemical reactivity. A prerequisite for the generation of strong oxidizing ROS that can damage macromolecules and impair cellular function is the availability of labile (redox-active) iron, which catalyzes the formation of highly reactive free radicals. Targeting labile iron has been proven an effective strategy to counteract the adverse effects of ROS, but evidence concerning cellular senescence is sparse. In the present review article, we discuss aspects of oxidative stress-induced cellular senescence, with special attention to the potential implication of labile iron.

DYRK1B inhibition exerts senolytic effects on endothelial cells and rescues endothelial dysfunctions

Aging is the major risk factor for chronic disease development. Cellular senescence is a key mechanism that triggers or contributes to age-related phenotypes and pathologies. The endothelium, a single layer of cells lining the inner surface of a blood vessel, is a critical interface between blood and all tissues. Many studies report a link between endothelial cell senescence, inflammation, and diabetic vascular diseases. Here we identify, using combined advanced AI and machine learning, the Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1B (DYRK1B) protein as a possible senolytic target for senescent endothelial cells. We demonstrate that upon induction of senescence in vitro DYRK1B expression is increased in endothelial cells and localized at adherens junctions where it impairs their proper organization and functions. DYRK1B knock-down or inhibition restores endothelial barrier properties and collective behavior. DYRK1B is therefore a possible target to counteract diabetes-associated vascular diseases linked to endothelial cell senescence.

The Stria Vascularis in Mice and Humans Is an Early Site of Age-Related Cochlear Degeneration, Macrophage Dysfunction, and Inflammation.

Age-related hearing loss, or presbyacusis, is a common degenerative disorder affecting communication and quality of life for millions of older adults. Multiple pathophysiologic manifestations, along with many cellular and molecular alterations, have been linked to presbyacusis; however, the initial events and causal factors have not been clearly established. Comparisons of the transcriptome in the lateral wall (LW) with other cochlear regions in a mouse model (of both sexes) of "normal" age-related hearing loss revealed that early pathophysiological alterations in the stria vascularis (SV) are associated with increased macrophage activation and a molecular signature indicative of inflammaging, a common form of immune dysfunction. Structure-function correlation analyses in mice across the lifespan showed that the age-dependent increase in macrophage activation in the stria vascularis is associated with a decline in auditory sensitivity. High-resolution imaging analysis of macrophage activation in middle-aged and aged mouse and human cochleas, along with transcriptomic analysis of age-dependent changes in mouse cochlear macrophage gene expression, support the hypothesis that aberrant macrophage activity is an important contributor to age-dependent strial dysfunction, cochlear pathology, and hearing loss. Thus, this study highlights the SV as a primary site of age-related cochlear degeneration and aberrant macrophage activity and dysregulation of the immune system as early indicators of age-related cochlear pathology and hearing loss. Importantly, novel new imaging methods described here now provide a means to analyze human temporal bones in a way that had not previously been feasible and thereby represent a significant new tool for otopathological evaluation.SIGNIFICANCE STATEMENT Age-related hearing loss is a common neurodegenerative disorder affecting communication and quality of life. Current interventions (primarily hearing aids and cochlear implants) offer imperfect and often unsuccessful therapeutic outcomes. Identification of early pathology and causal factors is crucial for the development of new treatments and early diagnostic tests. Here, we find that the SV, a nonsensory component of the cochlea, is an early site of structural and functional pathology in mice and humans that is characterized by aberrant immune cell activity. We also establish a new technique for evaluating cochleas from human temporal bones, an important but understudied area of research because of a lack of well-preserved human specimens and difficult tissue preparation and processing approaches.

The Assessment of Acute Chorioretinal Changes Due to Intensive Physical Exercise in Senior Elite Athletes.

Regular physical exercise is known to lower the incidence of age-related eye diseases. We aimed to assess the acute chorioretinal alterations in older adults following intense physical strain. Seventeen senior elite athletes were recruited who underwent an aerobic exercise on a cycle ergometer and macular scanning by optical coherence tomography. A significant thinning of the entire retina was observed 1min after exercise, followed by a thickening at 5min, after which the thickness returned to baseline. This trend was similar in almost every single retinal layer, although a significant change was observed only in the inner retina. Choroidal thickness changes were neither significant nor did they correlate with the thickness changes of intraretinal layers. The mechanism of how these immediate retinal changes chronically impact age-related sight-threatening pathologies that, in turn, result in a substantially reduced quality of life warrants further investigation on nontrained older adults as well.

Cellular senescence and premature aging in Down Syndrome

Down syndrome (DS) is a genetic disorder caused by an extra copy of chromosome 21, resulting in cognitive impairment, physical abnormalities, and an increased risk of age-related co-morbidities. Individuals with DS exhibit accelerated aging, which has been attributed to several cellular mechanisms, including cellular senescence, a state of irreversible cell cycle arrest that is associated with aging and age-related diseases. Emerging evidence suggests that cellular senescence may play a key role in the pathogenesis of DS and the development of age-related disorders in this population. Importantly, cellular senescence may be a potential therapeutic target in alleviating age-related DS pathology. Here, we discuss the importance of focusing on cellular senescence to understand accelerated aging in DS. We review the current state of knowledge regarding cellular senescence and other hallmarks of aging in DS, including its putative contribution to cognitive impairment, multi-organ dysfunction, and premature aging phenotypes.

Association of DNA methylation signatures with premature ageing and cardiovascular death in patients with end-stage kidney disease: a pilot epigenome-wide association study

ABSTRACT Patients with end-stage kidney disease (ESKD) display features of premature aging. There is strong evidence that changes in DNA methylation (DNAm) contribute to age-related pathologies; however, little is known about their association with premature aging and cardiovascular mortality in patients with ESKD. We assayed genome-wide DNAm in a pilot case-control study of 60 hemodialysis patients with (n=30, cases) and without (n=30, controls) a fatal cardiovascular event. DNAm was profiled on the Illumina EPIC BeadChip. Four established DNAm clocks (i.e., Horvath-, Hannum-, Pheno-, and GrimAge) were used to estimate epigenetic age (DNAmAge). Epigenetic age acceleration (EAA) was derived as the residuals of regressing DNAmAge on chronological age (chroAge), and its association with cardiovascular death was examined using multivariable conditional logistic regression. An epigenome-wide association study (EWAS) was performed to identify differentially methylated CpGs associated with cardiovascular death. All clocks performed well at predicting chroAge (correlation between DNAmAges and chroAge of r=0.76-0.89), with GrimAge showing the largest deviation from chroAge (a mean of +21.3 years). There was no significant association of EAAs with cardiovascular death. In the EWAS, a CpG (cg22305782) in the FBXL19 gene had the strongest association with cardiovascular death with significantly lower DNAm in cases vs. controls (P FDR=2.0x10−6). FBXL19 is involved in cell apoptosis, inflammation, and adipogenesis. Overall, we observed more accelerated aging in patients with ESKD, although there was no significant association of EAAs with cardiovascular death. EWAS suggests a potential novel DNAm biomarker for premature cardiovascular mortality in ESKD.

GPR19 Coordinates Multiple Molecular Aspects of Stress Responses Associated with the Aging Process.

G protein-coupled receptors (GPCRs) play a significant role in controlling biological paradigms such as aging and aging-related disease. We have previously identified receptor signaling systems that are specifically associated with controlling molecular pathologies associated with the aging process. Here, we have identified a pseudo-orphan GPCR, G protein-coupled receptor 19 (GPR19), that is sensitive to many molecular aspects of the aging process. Through an in-depth molecular investigation process that involved proteomic, molecular biological, and advanced informatic experimentation, this study found that the functionality of GPR19 is specifically linked to sensory, protective, and remedial signaling systems associated with aging-related pathology. This study suggests that the activity of this receptor may play a role in mitigating the effects of aging-related pathology by promoting protective and remedial signaling systems. GPR19 expression variation demonstrates variability in the molecular activity in this larger process. At low expression levels in HEK293 cells, GPR19 expression regulates signaling paradigms linked with stress responses and metabolic responses to these. At higher expression levels, GPR19 expression co-regulates systems involved in sensing and repairing DNA damage, while at the highest levels of GPR19 expression, a functional link to processes of cellular senescence is seen. In this manner, GPR19 may function as a coordinator of aging-associated metabolic dysfunction, stress response, DNA integrity management, and eventual senescence.

Serum C-reactive Protein and Protein Electrophoretic Pattern Correlated With Age in Horses

Inflammaging or chronic, low-grade inflammation is a phenomenon characterizing age-related pathologies and natural processes in aging tissues. This study aimed to investigate the effect of age on the serum levels of C-reactive protein and protein electrophoretic pattern in horses. Thirty Italian Saddle horses from the same horse training center, were enrolled and divided in three equal groups according to their age: Group A (2-4 years), Group B (7-10 years), Group C (15-20 years). Blood samples were collected from each horse to evaluate hematological parameters and the serum concentration of C-reactive protein (CRP), total proteins, albumin, α1-, α-2, β1-, β2- and γ-globulins. One-way analysis of variance showed an age-related difference in the concentration of CRP, α1- and α2-globulins (P < 0.001) which increased with aging. Albumin and albumin:globulin ratio showed lower values in Groups B and C than Group A (P < 0.001). Age of horses showed a negative correlation with the values of albumin, and a positive correlation with CRP, α1- and α2-globulins concentration. The results of the current study suggest an increased acute phase response in adult and old horses compared to young ones. As α-globulin fractions include many other acute phase proteins (APPs) in addition to CRP, further studies to assess what other APPs could be involved in chronic inflammation or “inflammaging” are recommended in horse in order to improve knowledge on the key inflammatory biomarkers during aging in this species.

The heterogeneity of late-life depression and its pathobiology: a brain network dysfunction disorder.

Depression is frequent in older individuals and is often associated with cognitive impairment and increasing risk of subsequent dementia. Late-life depression (LLD) has a negative impact on quality of life, yet the underlying pathobiology is still poorly understood. It is characterized by considerable heterogeneity in clinical manifestation, genetics, brain morphology, and function. Although its diagnosis is based on standard criteria, due to overlap with other age-related pathologies, the relationship between depression and dementia and the relevant structural and functional cerebral lesions are still controversial. LLD has been related to a variety of pathogenic mechanisms associated with the underlying age-related neurodegenerative and cerebrovascular processes. In addition to biochemical abnormalities, involving serotonergic and GABAergic systems, widespread disturbances of cortico-limbic, cortico-subcortical, and other essential brain networks, with disruption in the topological organization of mood- and cognition-related or other global connections are involved. Most recent lesion mapping has identified an altered network architecture with "depressive circuits" and "resilience tracts", thus confirming that depression is a brain network dysfunction disorder. Further pathogenic mechanisms including neuroinflammation, neuroimmune dysregulation, oxidative stress, neurotrophic and other pathogenic factors, such as β-amyloid (and tau) deposition are in discussion. Antidepressant therapies induce various changes in brain structure and function. Better insights into the complex pathobiology of LLD and new biomarkers will allow earlier and better diagnosis of this frequent and disabling psychopathological disorder, and further elucidation of its complex pathobiological basis is warranted in order to provide better prevention and treatment of depression in older individuals.