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Ageing is an inherent and intricate biological process that takes place in living organisms as time progresses. It involves the decline of multiple physiological functions, leading to body structure and overall performance modifications. The ageing process differs among individuals and is influenced by various factors, including lifestyle, environment and genetic makeup. Metabolic changes and reduced locomotor activity are common hallmarks of ageing. Our study focuses on exploring these phenomena in prematurely ageing PolgA (D257A/D257A) mice (also known as PolgA) aged 41-42 weeks, as they closely mimic human ageing. We assess parameters such as oxygen consumption (VO 2 ), carbon dioxide production (VCO 2 ), respiratory exchange ratio (RER) and locomotor activity using a metabolic cage for 4 days and comparing them with age-matched wild-type littermates (WT). Our findings revealed that VO 2 , VCO 2 , RER, locomotor activities, water intake and feeding behaviour show a daily rhythm, aligning with roughly a 24-h cycle. We observed that the RER was significantly increased in PolgA mice compared to WT mice during the night-time of the light-dark cycle, suggesting a shift towards a higher reliance on carbohydrate metabolism due to more food intake during the active phase. Additionally, female PolgA mice displayed a distinct phenotype with reduced walking speed, walking distance, body weight and grip strength in comparison to male PolgA and WT mice, indicating an early sign of ageing. Taken together, our research highlights the impact of sex-specific patterns on ageing traits in PolgA mice aged 41-42 weeks, which may be attributable to human ageing phenotypes. The unique genetic composition and accelerated ageing characteristics of PolgA mice make them invaluable in ageing studies, facilitating the investigation of underlying biological mechanisms and the identification of potential therapeutic targets for age-related diseases., (© 2024 The Author(s). FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Type 2 diabetes (T2D) constitutes a major public health problem, and despite prevention efforts, this pandemic disease is one of the deadliest diseases in the world. In 2022, 6.7 million patients with T2D died prematurely from vascular complications. Indeed, diabetes increases the risk of myocardial infarction or stroke eightfold. The identification of the molecular factors involved in the occurrence of cardiovascular complications and their prevention are therefore major axes. Our hypothesis is that factors brought into play during physiological aging appear prematurely with diabetes progression. Our study focused on the aging of the extracellular matrix (ECM), a major element in the maintenance of vascular homeostasis. We characterized the morphological and functional aspects of aorta, with a focus on the collagen and elastic fibers of diabetic mice aged from 6 mo to nondiabetic mice aged 6 mo and 20 mo. The comparison with the two nondiabetic models (young and old) highlighted an exacerbated activity of proteases, which could explain a disturbance in the collagen accumulation and an excessive degradation of elastic fibers. Moreover, the generation of circulating elastin-derived peptides reflects premature aging of the ECM. These extracellular elements contribute to the appearance of vascular rigidity, often the origin of pathologies such as hypertension and atherosclerosis. In conclusion, we show that diabetic mice aged 6 mo present the same characteristics of ECM wear as those observed in mice aged 20 mo. This accelerated aortic wall remodeling could then explain the early onset of cardiovascular diseases and, therefore, the premature death of patients with T2D. NEW & NOTEWORTHY Aortic elastic fibers of young (6-mo old) individuals with diabetes degrade prematurely and exhibit an appearance like that found in aged (20-mo old) nondiabetic mice. Exacerbated elastolysis and elastin-derived peptide production are characteristic elements, contributing to early aortic wall rigidity and hypertension development. Therefore, limiting this early aging could be a judicious therapeutic approach to reduce cardiovascular complications and premature death in patients with diabetes.

Objectives: To assess the mitochondrial dysfunction, oxidative stress and premature aging in children with nutritional rickets., Methods: This cross-sectional study enrolled children aged 6 months - 5 years with nutritional rickets attending a tertiary care hospital between January 2021 and August 2022. Mitochondrial dysfunction, oxidative stress and premature aging were assessed by measuring the mitochondrial DNA (mtDNA) content, total antioxidant status (TAOS) and telomere length (TL) in 40 children with nutritional rickets and 40 age- and sex- matched healthy children without rickets (controls)., Results: The median (IQR) mtDNA content was significantly higher in children with rickets as compared to controls [152.27 (111.83, 218.66) vs 93.7 (72.5, 134.14); P < 0.001], implying mitochondrial dysfunction attributed to increased mitochondrial biogenesis in children with rickets. The median (IQR) TAOS ( mM Trolox equiv.) was significantly lower in children with rickets than controls [4.54 (3.93, 5.73) vs 7.86 (5.09, 9.58); P < 0.001)]. The median (IQR) TL in cases was significantly longer in children with rickets compared to controls [417.31 (111.83,218.66) vs 93.7 (72.5,134.14); P < 0.001] implying that children with rickets do not have premature aging., Conclusions: Children with rickets have high oxidative stress and mitochondrial dysfunction but no evidence of premature aging.

Bedrest as an experimental paradigm or as an in-patient stay for medical reasons has negative consequences for cardiovascular health. The effects of severe inactivity parallel many of the changes experienced with natural aging but over a much shorter duration. Cardiac function is reduced, arteries stiffen, neural reflex responses are impaired, and metabolic and oxidative stress responses impose burden on the heart and vascular systems. The effect of these changes is revealed in studies of integrative function. Aerobic fitness progressively deteriorates with bedrest and tolerance of upright posture is rapidly impaired. In this review we consider the similarities of aging and bedrest-induced cardiovascular deconditioning. We concur with many recent clinical recommendations that early and regular mobility with upright posture will reduce likelihood of hospital-associated disability related to bedrest., (Copyright © 2024 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

As the limits of fetal viability have increased over the past 30 years, there has been a growing body of evidence supporting the idea that chronic disease should be taken into greater consideration in addition to survival after preterm birth. Accumulating evidence also suggests there is early onset of biologic aging after preterm birth. Similarly, chronic kidney disease (CKD) is also associated with a phenotype of advanced biologic age which exceeds chronologic age. Yet, significant knowledge gaps remain regarding the link between premature biologic age after preterm birth and kidney disease. This review summarizes the four broad pillars of aging, the evidence of premature aging following preterm birth, and in the setting of CKD. The aim is to provide additional plausible biologic mechanisms to explore the link between preterm birth and CKD. There is a need for more research to further elucidate the biologic mechanisms of the premature aging paradigm and kidney disease after preterm birth. Given the emerging research on therapies for premature aging, this paradigm could create pathways for prevention of advanced CKD., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Premature brain aging is associated with poorer cognitive reserve and lower resilience to injury. When there are focal brain lesions, brain regions may age at different rates within the same individual. Therefore, we hypothesize that reduced gray matter volume within specific brain systems commonly associated with language recovery may be important for long-term aphasia severity. Here we show that individuals with stroke aphasia have a premature brain aging in intact regions of the lesioned hemisphere. In left domain-general regions, premature brain aging, gray matter volume, lesion volume and age were all significant predictors of aphasia severity. Increased brain age following a stroke is driven by the lesioned hemisphere. The relationship between brain age in left domain-general regions and aphasia severity suggests that degradation is possible to specific brain regions and isolated aging matters for behavior., (© 2024. The Author(s).)

This review presents data from the literature on the characteristics of the course of chronic kidney disease from the perspective of the geriatric patient. Chronic kidney disease and progression of renal failure is a prototype model of premature and accelerated aging. Many authors have stated that a better mechanistic understanding of the phenomenon of premature aging, early diagnosis of chronic kidney disease, and a geriatric approach to the patient can improve the effectiveness of management and prolongation of life in this category of patients. Comprehensive geriatric assessment is one of the most important tools used by geriatricians and their teams to globally assess elderly patients and plan effective interventions. It is concluded that the use of comprehensive geriatric assessment in patients with chronic kidney disease may improve the clinical status of patients and allow selection of patients who may benefit most from renal replacement therapy compared to a conservative approach. And even in the early stages of chronic kidney disease, a comprehensive geriatric assessment may be useful in formulating a complete intervention plan and optimizing quality of life, autonomy, and prognosis. However, despite recognition of the importance of comprehensive geriatric assessment, the means to implement this tool in nephrology departments have not been developed and require special training programs and appropriate skills. It is concluded that much more needs to be done to realize the continuity of nephrologists and geriatricians in the provision of meaningful skilled care to older patients with chronic kidney disease.

The structure and integrity of the ageing brain is interchangeably linked to physical health, and cardiometabolic risk factors (CMRs) are associated with dementia and other brain disorders. In this mixed cross-sectional and longitudinal study (interval mean = 19.7 months), including 790 healthy individuals (mean age = 46.7 years, 53% women), we investigated CMRs and health indicators including anthropometric measures, lifestyle factors, and blood biomarkers in relation to brain structure using MRI-based morphometry and diffusion tensor imaging (DTI). We performed tissue specific brain age prediction using machine learning and performed Bayesian multilevel modeling to assess changes in each CMR over time, their respective association with brain age gap (BAG), and their interaction effects with time and age on the tissue-specific BAGs. The results showed credible associations between DTI-based BAG and blood levels of phosphate and mean cell volume (MCV), and between T1-based BAG and systolic blood pressure, smoking, pulse, and C-reactive protein (CRP), indicating older-appearing brains in people with higher cardiometabolic risk (smoking, higher blood pressure and pulse, low-grade inflammation). Longitudinal evidence supported interactions between both BAGs and waist-to-hip ratio (WHR), and between DTI-based BAG and systolic blood pressure and smoking, indicating accelerated ageing in people with higher cardiometabolic risk (smoking, higher blood pressure, and WHR). The results demonstrate that cardiometabolic risk factors are associated with brain ageing. While randomized controlled trials are needed to establish causality, our results indicate that public health initiatives and treatment strategies targeting modifiable cardiometabolic risk factors may also improve risk trajectories and delay brain ageing., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Obesity is highly prevalent in schizophrenia, with implications for psychiatric prognosis, possibly through links between obesity and brain structure. In this longitudinal study in first episode of psychosis (FEP), we used machine learning and structural magnetic resonance imaging (MRI) to study the impact of psychotic illness and obesity on brain ageing/neuroprogression shortly after illness onset., Methods: We acquired 2 prospective MRI scans on average 1.61 years apart in 183 FEP and 155 control individuals. We used a machine learning model trained on an independent sample of 504 controls to estimate the individual brain ages of study participants and calculated BrainAGE by subtracting chronological from the estimated brain age., Results: Individuals with FEP had a higher initial BrainAGE than controls (3.39 ± 6.36 vs 1.72 ± 5.56 years; β = 1.68, t(336) = 2.59, P = .01), but similar annual rates of brain ageing over time (1.28 ± 2.40 vs 1.07±1.74 estimated years/actual year; t(333) = 0.93, P = .18). Across both cohorts, greater baseline body mass index (BMI) predicted faster brain ageing (β = 0.08, t(333) = 2.59, P = .01). For each additional BMI point, the brain aged by an additional month per year. Worsening of functioning over time (Global Assessment of Functioning; β = -0.04, t(164) = -2.48, P = .01) and increases especially in negative symptoms on the Positive and Negative Syndrome Scale (β = 0.11, t(175) = 3.11, P = .002) were associated with faster brain ageing in FEP., Conclusions: Brain alterations in psychosis are manifest already during the first episode and over time get worse in those with worsening clinical outcomes or higher baseline BMI. As baseline BMI predicted faster brain ageing, obesity may represent a modifiable risk factor in FEP that is linked with psychiatric outcomes via effects on brain structure., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Xeroderma pigmentosum (XP) is an autosomal recessive disease with defective DNA repair, a markedly increased risk of skin cancer, and premature aging. Reports from North Africa have described thyroid nodules in XP patients, but thyroid nodule prevalence has never been determined in XP patients enrolled in our natural history study at the National Institutes of Health (NIH)., Methods: We performed thyroid ultrasound examinations on all 29 XP patients examined from 2011 to 2019 and assessed nodule malignancy using the Thyroid Imaging Reporting and Data System. Thyroid nodule prevalence was also obtained from comparison cohorts. DNA sequencing was performed on thyroid tissue from XP patients who had surgery for thyroid cancer., Results: Thyroid nodules were identified in 18/29 XP patients (62%). The median age of patients with thyroid nodules in our XP cohort (20 years) was younger than that of three comparison groups: 36 years (California study-208 subjects), 48 years (Korean study-24,757 subjects), and 52 years (NIH-682 research subjects). Multiple (2-4) thyroid nodules were found in 12/18 (67%) of the patients with nodules. Autopsy examination revealed follicular adenomas in 4/8 (50%) additional XP patients. DNA sequencing revealed rare mutations in two other XP patients with papillary thyroid cancer., Conclusions: XP patients have an increased incidence of thyroid nodules at an early age in comparison to the general population. These finding confirm another premature aging feature of XP.

Importance: Individuals with mental disorders are at an elevated risk of developing chronic age-related physical diseases. However, it is not clear whether psychopathology is also associated with processes of accelerated aging that precede the onset of age-related disease., Objective: To test the hypothesis that a history of psychopathology is associated with indicators of accelerated aging at midlife., Design, Setting, and Participants: This prospective cohort study was based on the Dunedin Multidisciplinary Health and Development Study, a population-representative birth cohort of 1037 individuals born between April 1, 1972, and March 31, 1973, in Dunedin, New Zealand. Members were followed up to age 45 years (until April 2019). Data were analyzed from January 6 to December 7, 2020., Exposures: Mental disorders were assessed in 6 diagnostic assessments from ages 18 to 45 years and transformed through confirmatory factor analysis into continuous measures of general psychopathology (p-factor) and dimensions of internalizing, externalizing, and thought disorders (all standardized to a mean [SD] of 100 [15])., Main Outcomes and Measures: Signs of aging (biological pace of aging; declines in sensory, motor, and cognitive functioning; and facial age) were assessed up to age 45 years using previously validated measures including biomarkers, clinical tests, and self-reports., Results: Of the original 1037 cohort participants, 997 were still alive at age 45 years, of whom 938 (94%) were assessed (474 men [50.5%]). Participants who had experienced more psychopathology exhibited a faster pace of biological aging (β, 0.27; 95% CI, 0.21-0.33; P < .01); experienced more difficulties with hearing (β, 0.18; 95% CI, 0.12-0.24; P < .01), vision (β, 0.08; 95% CI, 0.01-0.14; P < .05), balance (β, 0.20; 95% CI, 0.14-0.26; P < .01), and motor functioning (β, 0.19; 95% CI, 0.12-0.25; P < .01); experienced more cognitive difficulties (β, 0.24; 95% CI, 0.18-0.31; P < .01); and were rated as looking older (β, 0.20; 95% CI, 0.14-0.26; P < .01). Associations persisted after controlling for sex, childhood health indicators, maltreatment, and socioeconomic status and after taking into account being overweight, smoking, use of antipsychotic medication, and the presence of physical disease. Tests of diagnostic specificity revealed that associations were generalizable across externalizing, internalizing, and thought disorders., Conclusions and Relevance: In this cohort study, a history of psychopathology was associated with accelerated aging at midlife, years before the typical onset of age-related diseases. This link is not specific to any particular disorder family but generalizes across disorders. Prevention of psychopathology and monitoring of individuals with mental disorders for signs of accelerated aging may have the potential to reduce health inequalities and extend healthy lives.

Cells respond to stress by activating a variety of defense signaling pathways, including cell survival and cell death pathways. Although cell survival signaling helps the cell to recover from acute insults, cell death or senescence pathways induced by chronic insults can lead to unresolved pathologies. Arterial hypertension results from chronic physiological maladaptation against various stressors represented by abnormal circulating or local neurohormonal factors, mechanical stress, intracellular accumulation of toxic molecules, and dysfunctional organelles. Hypertension and aging share common mechanisms that mediate or prolong chronic cell stress, such as endoplasmic reticulum stress and accumulation of protein aggregates, oxidative stress, metabolic mitochondrial stress, DNA damage, stress-induced senescence, and proinflammatory processes. This review discusses common adaptive signaling mechanisms against these stresses including unfolded protein responses, antioxidant response element signaling, autophagy, mitophagy, and mitochondrial fission/fusion, STING (signaling effector stimulator of interferon genes)-mediated responses, and activation of pattern recognition receptors. The main molecular mechanisms by which the vasculature copes with hypertensive and aging stressors are presented and recent advancements in stress-adaptive signaling mechanisms as well as potential therapeutic targets are discussed.

Arterial stiffening and cardiac dysfunction are hallmarks of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), but the molecular regulators remain unknown. Here, we show that the LaminA G609G mouse model of HGPS recapitulates the premature arterial stiffening and early diastolic dysfunction seen in human HGPS. Lysyl oxidase (LOX) is up-regulated in the arteries of these mice, and treatment with the LOX inhibitor, β-aminopropionitrile, improves arterial mechanics and cardiac function. Genome-wide and mechanistic analysis revealed reduced expression of the LOX-regulator, miR-145, in HGPS arteries, and forced expression of miR-145 restores normal LOX gene expression in HGPS smooth muscle cells. LOX abundance is also increased in the carotid arteries of aged wild-type mice, but its spatial expression differs from HGPS and its up-regulation is independent of changes in miR-145 abundance. Our results show that miR-145 is selectively misregulated in HGPS and that the consequent up-regulation of LOX is causal for premature arterial stiffening and cardiac dysfunction., (© 2021 von Kleeck et al.)

Prenatal hypoxia is among leading causes of progressive brain pathologies in postnatal life. This study aimed to analyze the characteristics of the hippocampal glutamatergic system and behavior of rats in early (2 weeks), adult (3 months) and advanced (18 months) postnatal ontogenesis after exposure to prenatal severe hypoxia (PSH, 180 Torr, 5% O2, 3 h) during the critical period in the formation of the hippocampus (days 14-16 of gestation). We have shown an age-dependent progressive decrease in the hippocampal glutamate levels, a decrease of the neuronal cell number in the CA1 hippocampal region, as well as impairment of spatial long-term memory in the Morris water navigation task. The gradual decrease of glutamate was accompanied by decreased expression of the genes that mediate glutamate metabolism and recycling in the hippocampus. That deficiency apparently correlated with an increase of the metabotropic glutamate receptor type 1 (mGluR1) and synaptophysin expression. Generation of the lipid peroxidation products in the hippocampus of adult rats subjected to prenatal severe hypoxia (PSH rats) was not increased compared to the control animals when tested in a model of glutamate excitotoxicity induced by severe hypoxia. This demonstrates that excessive glutamate sensitivity in PSH rats does not compensate for glutamate deficiency. Our results show a significant contribution of the glutamate system dysfunction to age-associated decrease of this mediator, cognitive decline, and early neuronal loss in PSH rats.

Progeroid disorders make up a heterogeneous group of very rare hereditary diseases characterized by clinical signs that often mimic physiological aging in a premature manner. Apart from Hutchinson-Gilford progeria syndrome, one of the best-investigated progeroid disorders, a wide spectrum of other premature aging phenotypes exist, which differ significantly in their clinical presentation and molecular pathogenesis. Next-generation sequencing (NGS)-based approaches have made it feasible to determine the molecular diagnosis in the early stages of a disease. Nevertheless, a broad clinical knowledge on these disorders and their associated symptoms is still fundamental for a comprehensive patient management and for the interpretation of variants of unknown significance from NGS data sets. This review provides a detailed overview on characteristic clinical features and underlying molecular genetics of well-known as well as only recently identified premature aging disorders and also highlights novel findings towards future therapeutic options., (© 2020 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Hutchinson-Gilford progeria syndrome (HGPS) is among the most devastating of the laminopathies, rare genetic diseases caused by mutations in genes encoding nuclear lamina proteins. HGPS patients age prematurely and die in adolescence, typically of atherosclerosis-associated complications. The mechanisms of HGPS-related atherosclerosis are not fully understood due to the scarcity of patient-derived samples and the availability of only one atheroprone mouse model of the disease. Here, we generated a new atherosusceptible model of HGPS by crossing progeroid Lmna G609G/G609G mice, which carry a disease-causing mutation in the Lmna gene, with Ldlr -/- mice, a commonly used preclinical atherosclerosis model. Ldlr -/- Lmna G609G/G609G mice aged prematurely and had reduced body weight and survival. Compared with control mice, Ldlr -/- Lmna G609G/G609G mouse aortas showed a higher atherosclerosis burden and structural abnormalities typical of HGPS patients, including vascular smooth muscle cell depletion in the media, adventitial thickening, and elastin structure alterations. Atheromas of Ldlr -/- Lmna G609G/G609G mice had features of unstable plaques, including the presence of erythrocytes and iron deposits and reduced smooth muscle cell and collagen content. Ldlr -/- Lmna G609G/G609G mice faithfully recapitulate vascular features found in patients and thus provide a new tool for studying the mechanisms of HGPS-related atherosclerosis and for testing therapies.

Hypertension has been described as a condition of premature vascular aging, relative to actual chronological age. In fact, many factors that contribute to the deterioration of vascular function as we age are accelerated and exacerbated in hypertension. Nonetheless, the precise mechanisms that underlie the aged phenotype of arteries from hypertensive patients and animals remain elusive. Classically, the aged phenotype is the buildup of cellular debris and dysfunctional organelles. One means by which this can occur is insufficient degradation and cellular recycling. Mitophagy is the selective catabolism of damaged mitochondria. Mitochondria are organelles that contribute importantly to the determination of cellular age via their production of reactive oxygen species (ROS; Harman's free radical theory of aging). Therefore, the accumulation of dysfunctional and ROS-producing mitochondria could contribute to the acceleration of vascular age in hypertension. This review will address and critically evaluate the current literature on mitophagy in vascular physiology and hypertension., (© American Journal of Hypertension, Ltd 2020. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Life history theory argues that exposure to early life adversity (ELA) accelerates development, although existing evidence for this varies. We present a meta-analysis and systematic review testing the hypothesis that ELA involving threat (e.g., violence exposure) will be associated with accelerated biological aging across multiple metrics, whereas exposure to deprivation (e.g., neglect, institutional rearing) and low-socioeconomic status (SES) will not. We meta-analyze 54 studies ( n = 116,010) examining associations of ELA with pubertal timing and cellular aging (telomere length and DNA methylation age), systematically review 25 studies ( n = 3,253) examining ELA and neural markers of accelerated development (cortical thickness and amygdala-prefrontal cortex functional connectivity) and evaluate whether associations of ELA with biological aging vary according to the nature of adversity experienced. ELA overall was associated with accelerated pubertal timing ( d = -0.10) and cellular aging ( d = -0.21), but these associations varied by adversity type. Moderator analysis revealed that ELA characterized by threat was associated with accelerated pubertal development ( d = -0.26) and accelerated cellular aging ( d = -0.43), but deprivation and SES were unrelated to accelerated development. Systematic review revealed associations between ELA and accelerated cortical thinning, with threat-related ELA consistently associated with thinning in ventromedial prefrontal cortex, and deprivation and SES associated with thinning in frontoparietal, default, and visual networks. There was no consistent association of ELA with amygdala-PFC connectivity. These findings suggest specificity in the types of early environmental experiences associated with accelerated biological aging and highlight the importance of evaluating how accelerated aging contributes to health disparities and whether this process can be mitigated through early intervention. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Non-focal prospective memory (PM) is sensitive to age-related decline; an additional impairment in focal PM is characteristic of mild stage Alzheimer's disease. This research explored whether, by mid-adulthood, the distinct demands of focal and non-focal PM expose differences in carriers of an APOE ε4 allele, a genetic risk factor for Alzheimer's disease. Thirty-three young and 55 mid-age adults, differentiated by APOE genotype, completed a category-decision task with a concurrent focal or non-focal PM demand. Only mid-age ε4 carriers showed a cost of carrying a focal PM intention. In addition, mid-age ε4 carriers showed a significantly greater cost of carrying a non-focal PM intention than young ε4 carriers, supporting a profile of accelerated aging. Consistency in the profile of cost differences observed in mid-age ε4 carriers and pathological aging may indicate premature vulnerability. Future research correlating a shift in PM performance with early genotype differences in brain-based markers of decline is important.

Autophagy is a membrane traffic system that provides sustainable degradation of cellular components for homeostasis, and is thus considered to promote health and longevity, though its activity declines with aging. The present findings show deterioration of autophagy in association with premature skin aging. Autophagy flux was successfully determined in skin tissues, which demonstrated significantly decreased autophagy in hyperpigmented skin such as that seen in senile lentigo. Furthermore, an exacerbated decline in autophagy was confirmed in xerotic hyperpigmentation areas, accompanied by severe dehydration and a barrier defect, which showed correlations with skin physiological conditions. The enhancement of autophagy in skin ex vivo ameliorated skin integrity, including pigmentation and epidermal differentiation. The present results indicate that the restoration of autophagy can contribute to improving premature skin aging by various intrinsic and extrinsic factors via the normalization of protein homeostasis.

The present study aimed to explore the relationship between electrocardiographic (ECG) and pulse wave analysis variables in patients with hypertension (HT) and high normal blood pressure (HNBP). A total of 56 consecutive, middle-aged hypertensive and HNBP patients underwent pulse wave analysis and standard 12-lead ECG. Pulse wave velocity (PWV), heart rate, intrinsic heart rate (IHR), P wave and QT interval durations were as follows: 7.26 ± 0.69 m/s, 69 ± 11 beats/minute, 91 ± 3 beats/minute, 105 ± 22 mm and 409 ± 64 mm, respectively. Significant correlations were obtained between PWV and IHR and P wave duration, respectively, between early vascular aging (EVA) and P wave and QT interval durations, respectively. Linear regression analysis revealed significant associations between ECG and pulse wave analysis variables but multiple regression analysis revealed only IHR as an independent predictor of PWV, even after adjusting for blood pressure variables and therapy. Receiver-operating characteristic (ROC) curve analysis revealed P wave duration (area under curve (AUC) = 0.731; 95% CI: 0.569-0.893) as a predictor of pathological PWV, and P wave and QT interval durations were found as sensitive and specific predictors of EVA. ECG provides information about PWV and EVA in patients with HT and HNBP. IHR and P wave durations are independent predictors of PWV, and P wave and QT interval may predict EVA.

Objective: Patients with systemic lupus erythematosus (SLE) often have atherosclerotic complications at a young age but normal low-density lipoprotein (LDL) levels. This study was undertaken to investigate the role of LDL composition in promoting early vascular aging in SLE patients., Methods: Plasma LDL from 45 SLE patients (SLE-LDL) and from 37 normal healthy controls (N-LDL) was chromatographically divided into 5 subfractions (L1-L5), and the subfraction composition was analyzed. Correlations between subfraction levels and signs of early vascular aging were assessed. Mechanisms of lipid-mediated endothelial dysfunction were explored using in vitro assays and experiments in apoE -/- mice., Results: The L5 percentage was increased 3.4 times in the plasma of SLE patients compared with normal controls. This increased percentage of SLE-L5 was positively correlated with the mean blood pressure (r = 0.27, P = 0.04), carotid intima-media thickness (IMT) (right carotid IMT, r = 0.4, P = 0.004; left carotid IMT, r = 0.36, P = 0.01), pulse wave velocity (r = 0.29, P = 0.04), and blood levels of CD16+ monocytes (r = 0.35, P = 0.004) and CX3CL1 cytokines (r = 0.43, P < 0.001) in SLE patients. Matrix-assisted laser desorption ionization-time-of-flight mass spectrometry analysis revealed that plasma levels of lysophosphatidylcholine (LPC) and platelet-activating factor (PAF) were increased in SLE-LDL and in the SLE-L5 plasma subfraction. Injecting SLE-LDL, SLE-L5, or LPC into young, male apoE -/- mice caused increases in plasma CX3CL1 levels, aortic fatty-streak areas, aortic vascular aging, and macrophage infiltration into the aortic wall, whereas injection of N-LDL or SLE-L1 had negligible effects (n = 3-8 mice per group). In vitro, SLE-L5 lipid extracts induced increases in CX3CR1 and CD16 expression in human monocytes; synthetic PAF and LPC had similar effects. Furthermore, lipid extracts of SLE-LDL and SLE-L5 induced the expression of CX3CL1 and enhanced monocyte-endothelial cell adhesion in assays with bovine aortic endothelial cells., Conclusion: An increase in plasma L5 levels, not total LDL concentration, may promote early vascular aging in SLE patients, leading to premature atherosclerosis., (© 2020, American College of Rheumatology.)

We investigated the transcriptomic landscape of the murine myocardium along the course of natural aging and in three distinct mouse models of premature aging with established aging-related cardiac dysfunction. Genome-wide total RNA-seq was performed and the expression patterns of protein-coding genes and non-coding RNAs were compared between hearts from naturally aging mice, mice with cardiac-specific deficiency of a component of the DNA repair machinery, mice with reduced mitochondrial antioxidant capacity and mice with reduced telomere length. Our results demonstrate that no dramatic changes are evident in the transcriptomes of naturally senescent murine hearts until two years of age, in contrast to the transcriptome of accelerated aged mice. Additionally, these mice displayed model-specific alterations of the expression levels of protein-coding and non-coding genes with hardly any overlap with age-related signatures. Our data demonstrate very limited similarities between the transcriptomes of all our murine aging models and question their reliability to study human cardiovascular senescence.

The World Health Organization estimates a 12-month prevalence rate of 8+% for an alcohol use disorder (AUD) diagnosis in people age 15 years and older in the United States and Europe, presenting significant health risks that have the potential of accelerating age-related functional decline. According to neuropathological studies, white matter systems of the cerebellum are vulnerable to chronic alcohol dependence. To pursue the effect of AUD on white matter structure and functions in vivo, this study used T1-weighted, magnetic resonance imaging (MRI) to quantify the total corpus medullare of the cerebellum and a finely grained analysis of its surface in 135 men and women with AUD (mean duration of abstinence, 248 d) and 128 age- and sex-matched control participants; subsets of these participants completed motor testing. We identified an AUD-related volume deficit and accelerated aging in the total corpus medullare. Novel deformation-based surface morphometry revealed regional shrinkage of surfaces adjacent to lobules I-V, lobule IX, and vermian lobule X. In addition, accelerated aging was detected in the regional surface areas adjacent to lobules I-V, lobule VI, lobule VIIB, and lobules VIII, IX, and X. Sex differences were not identified for any measure. For both volume-based and surface-based analyses, poorer performance in gait and balance, manual dexterity, and grip strength were linked to greater regional white matter structural deficits. Our results suggest that local deformation of the corpus medullare has the potential of identifying structurally and functionally segregated networks affected in AUD., (© 2019 Society for the Study of Addiction.)

Persistent low-grade inflammation and premature ageing are hallmarks of the uremic phenotype and contribute to impaired health status, reduced quality of life, and premature mortality in chronic kidney disease (CKD). Because there is a huge global burden of disease due to CKD, treatment strategies targeting inflammation and premature ageing in CKD are of particular interest. Several distinct features of the uremic phenotype may represent potential treatment options to attenuate the risk of progression and poor outcome in CKD. The nuclear factor erythroid 2-related factor 2 (NRF2)-kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1 (KEAP1) signaling pathway, the endocrine phosphate-fibroblast growth factor-23-klotho axis, increased cellular senescence, and impaired mitochondrial biogenesis are currently the most promising candidates, and different pharmaceutical compounds are already under evaluation. If studies in humans show beneficial effects, carefully phenotyped patients with CKD can benefit from them.

The mitochondrial theory of aging attributes much of the aging process to mitochondrial DNA damage. The polymerase gamma (PolG) mutant mouse was designed to evaluate this theory and thus carries a mutated proofreading region of polymerase gamma (D257A) that exclusively transcribes the mitochondrial genome. As a result, PolGD257A mice accumulate mitochondrial DNA (mtDNA) mutations that lead to premature aging, as evidenced by hair loss, weight loss, kyphosis, increased rates of apoptosis, organ damage, and an early death, occurring around 12 months of age. Research has shown that exercise decreases skeletal muscle mtDNA mutations and normalizes protein levels in PolG mice. However, brain mtDNA changes with exercise in PolG mice have not been studied. We found no effects of exercise on mtDNA mutations or copy number in either the brain or liver of PolG mice, despite changes to body mass. Our results suggest that mitochondrial mutations play little role in exercise-brain interactions in the PolG model of accelerated aging. In addition to evaluating the effect of exercise on mtDNA outcomes, we also implemented novel methods for both extracting mtDNA and measuring mtDNA mutations, with aims for improving the efficiency and accuracy of these methods., Competing Interests: The authors have declared that no competing interests exist.

The study of behavioral and psychological symptoms of dementia (BPSD) has been largely neglected in most experimental research on Alzheimer's disease (AD) classically focused on cognitive symptoms. The aquatic environment of the Morris water maze (MWM) implies a stressful condition for mice leading to cognitive performances with presence of other behaviors related to emotionality. This can be critical in models such as the 3xTg-AD mice that exhibit a noticeable BPSD-like profile. The present work is aimed to provide a quantitative (number of episodes and duration) and qualitative (prevalence) analysis of flotation and circling, the most common 'non-searching behaviors' elicited in the MWM. We studied the expression of these behaviors in 6-month-old gold-standard wildtype C57BL/6 mice (genetic background) and 3xTg-AD mice (onset of disease) and when both genotypes were submitted to chronic d-galactose induced accelerated aging. Elicitation of floating and circling was recorded during three standard MWM paradigms: visual perceptual learning, place task for spatial reference memory and a final probe trial for short-term memory. In view of the results, we demonstrate that the index of 'flotation', characteristic of non-transgenic performance, is sensitive (reduction) to accelerated aging and AD. Conversely, circling behavior, characteristic of 3xTg-AD mice, can be an additional tool for evaluating BPSD-like symptoms in AD-models while its index unveils bizarre behavior induced by d-galactose induced aging. These results can be useful in relation to preventive and/or therapeutical interventions targeting AD but they may also be suitable in the evaluation of the potential risk factors in animals with normal aging., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The presence of an extra copy of human chromosome 21 (Hsa21) leads to a constellation of phenotypic manifestations in Down syndrome (DS), including prominent effects on the brain and immune system. Intensive efforts to unravel the molecular mechanisms underlying these phenotypes may help developing effective therapies, both in DS and in the general population. Here we review recent progress in genetic and epigenetic analysis of trisomy 21 (Ts21). New mouse models of DS based on syntenic conservation of segments of the mouse and human chromosomes are starting to clarify the contributions of chromosomal subregions and orthologous genes to specific phenotypes in DS. The expression of genes on Hsa21 is regulated by epigenetic mechanisms, and with recent findings of highly recurrent gene-specific changes in DNA methylation patterns in brain and immune system cells with Ts21, the epigenomics of DS has become an active research area. Here we highlight the value of combining human studies with mouse models for defining DS critical genes and understanding the trans-acting effects of a simple chromosomal aneuploidy on genome-wide epigenetic patterning. These genetic and epigenetic studies are starting to uncover fundamental biological mechanisms, leading to insights that may soon become therapeutically relevant., (© 2020 Elsevier B.V. All rights reserved.)

The association of epilepsy with structural brain changes and cognitive abnormalities in midlife has raised concern regarding the possibility of future accelerated brain and cognitive aging and increased risk of later life neurocognitive disorders. To address this issue we examined age-related processes in both structural and functional neuroimaging among individuals with temporal lobe epilepsy (TLE, N = 104) who were participants in the Epilepsy Connectome Project (ECP). Support vector regression (SVR) models were trained from 151 healthy controls and used to predict TLE patients' brain ages. It was found that TLE patients on average have both older structural (+6.6 years) and functional (+8.3 years) brain ages compared to healthy controls. Accelerated functional brain age (functional - chronological age) was mildly correlated (corrected P = 0.07) with complex partial seizure frequency and the number of anti-epileptic drug intake. Functional brain age was a significant correlate of declining cognition (fluid abilities) and partially mediated chronological age-fluid cognition relationships. Chronological age was the only positive predictor of crystallized cognition. Accelerated aging is evident not only in the structural brains of patients with TLE, but also in their functional brains. Understanding the causes of accelerated brain aging in TLE will be clinically important in order to potentially prevent or mitigate their cognitive deficits., Competing Interests: Declaration of Competing Interest None of the authors have any conflict of interest to disclose., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

In the era of combined antiretroviral therapy (cART), HIV-1 infection has transformed from adeath sentenceto a manageable, chronic disease. Although the lifeexpectancy of HIV+ individuals is comparable to that of the uninfectedsubjects paradoxically, there is increased prevalence ofage-associatedcomorbidities such asatherosclerosis, diabetes, osteoporosis & neurological deficits in the context of HIV infection. Drug abuse is a commoncomorbidityofHIV infection andis often associated withincreased neurological complications. Chronic neuroinflammation (abnormal microglial and astrocyte activation) and neuronal synaptodendritic injury are the features of CNS pathology observed inHIV (+) individualsthat are takingcART & that abuse drugs. Neuroinflammation is thedrivingforceunderlying prematureaging associated with HIV (+) infection, cART and drugs of abuse. Autophagy is a highly conserved process critical for maintaining cellular homeostasis. Dysregulated autophagyhas been shown to be linked with abnormal immune responses & aging. Recent emerging evidence implicatesthe role ofHIV/HIV proteins, cART, & abused drugsin disrupting theautophagy process in brain cells such as microglia, astrocytes, and neurons. It can thus be envisioned that co-exposure of CNS cells to HIV proteins, cART and/or abused drugs couldhavesynergistic effects on theautophagy process, thereby leading to exaggerated microglial/astrocyte activation, ultimately, promotingthe aging process. Restoration of autophagic functioncould thusprovide an alternative therapeuticstrategy formitigating neuroinflammation & ameliorating the premature aging process. The current review aims to unravel the role of dysregulated autophagy in the context of single or co-exposure of microglia, astrocytes, and neurons to HIV/HIV proteins, drugs of abuse &/or cART and will also discuss the pathways involved in dysregulated autophagy-mediated neuroinflammation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Improved methods are needed to detect and quantify age-related muscle change. In this study we assessed the electrical properties of muscle impacted by acquired mitochondrial DNA mutations via the PolG mouse, which exhibits typical age-associated features, and the impact of a potential therapy, nicotinamide mononucleotide (NMN)., Methods: The gastrocnemii of 24 PolG and 30 wild-type (WT) mice (8 PolG and 17 WT treated with NMN) were studied in an electrical impedance-measuring cell. Conductivity and relative permittivity were determined from the impedance data. Myofiber cross-sectional area (CSA) was quantified histologically., Results: Untreated PolG mice demonstrated alterations in several impedance features, including 50-kHz relative permittivity and center frequency. A potential effect of NMN was also observed in these parameters in PolG but not WT animals. Impedance values correlated with myofiber CSA., Discussion: Electrical impedance is sensitive to myofiber features considered characteristic of aging and to the impact of a potential therapy., (© 2019 Wiley Periodicals, Inc.)

Werner syndrome (WS) is an autosomal recessive progeroid disease characterized by patients' early onset of aging, increased risk of cancer and other age-related pathologies. WS is caused by mutations in WRN, a RecQ helicase that has essential roles responding to DNA damage and preventing genomic instability. While human WRN has both an exonuclease and helicase domain, Drosophila WRNexo has high genetic and functional homology to only the exonuclease domain of WRN. Like WRN-deficient human cells, Drosophila WRNexo null mutants (WRNexo Δ ) are sensitive to replication stress, demonstrating mechanistic similarities between these two models. Compared to age-matched wild-type controls, WRNexo Δ flies exhibit increased physiological signs of aging, such as shorter lifespans, higher tumor incidence, muscle degeneration, reduced climbing ability, altered behavior, and reduced locomotor activity. Interestingly, these effects are more pronounced in females suggesting sex-specific differences in the role of WRNexo in aging. This and future mechanistic studies will contribute to our knowledge in linking faulty DNA repair mechanisms with the process of aging., (Copyright © 2019 Elsevier Inc. All rights reserved.)

CDGSH iron-sulfur domain-containing protein 2 (Cisd2) is pivotal to mitochondrial integrity and intracellular Ca2+ homeostasis. In the heart of Cisd2 knockout mice, Cisd2 deficiency causes intercalated disc defects and leads to degeneration of the mitochondria and sarcomeres, thereby impairing its electromechanical functioning. Furthermore, Cisd2 deficiency disrupts Ca2+ homeostasis via dysregulation of sarco/endoplasmic reticulum Ca2+-ATPase (Serca2a) activity, resulting in an increased level of basal cytosolic Ca2+ and mitochondrial Ca2+ overload in cardiomyocytes. Most strikingly, in Cisd2 transgenic mice, a persistently high level of Cisd2 is sufficient to delay cardiac aging and attenuate age-related structural defects and functional decline. In addition, it results in a younger cardiac transcriptome pattern during old age. Our findings indicate that Cisd2 plays an essential role in cardiac aging and in the heart's electromechanical functioning. They highlight Cisd2 as a novel drug target when developing therapies to delay cardiac aging and ameliorate age-related cardiac dysfunction., Competing Interests: The authors have declared that no competing interests exist.

Objective: To assess the age at menarche and menopause of women with xeroderma pigmentosum, a DNA repair disease with premature aging, in a longitudinal natural history study., Methods: We conducted a natural history study that reviewed medical records for gynecologic and reproductive health of all female patients with xeroderma pigmentosum aged older than 9 years examined at the National Institutes of Health (NIH). We performed gynecologic and laboratory examinations on a subset of the patients. Women in a second subset, who could not be examined, were interviewed using a questionnaire. Women who were deceased or lost to follow-up formed a third subset., Results: Sixty females with xeroderma pigmentosum aged older than 9 years (median 29 years, range 10-61 years) were evaluated at the NIH from 1971 to 2018. Of these 60, 31 had history, questionnaire, record review, and gynecologic evaluation; 14 had record review and questionnaire interview by telephone; and 15 had only NIH record review. Menarche in females with xeroderma pigmentosum occurred at a median age of 12.0 years (range 9-17 years), which was comparable with the U.S. general population. Among the 18 patients with menopause, the median age at menopause of 29.5 years (range 18-49.5 years) was more than 20 years younger than in the U.S. general population (52.9 years). Premature menopause (before age 40 years) occurred in 14 of the 45 (31%) women aged 18 years or older, and primary ovarian insufficiency was documented in nine of them. There were 32 live births among 21 of the women, five of whom subsequently developed premature menopause., Conclusion: Females with xeroderma pigmentosum in our study had a normal age at menarche and were fertile but had increased incidence of premature menopause. Premature menopause, a symptom of premature aging, should be considered for gynecologic and reproductive health as well as implicating DNA repair in maintaining normal ovarian function., Clinical Trial Registration: ClinicalTrials.gov, NCT00001813.

Within a couple, partners influence each other's mental and physical health. This review focuses on how couples' relationships, the partners' individual and joint vulnerabilities, and their health behaviors influence health through changes in the gut microbiota, metabolism, and immune function. Couples' shared stressors and emotions and their intertwined lifestyles and routines serve to promote common disease risks in part through parallel changes in their gut microbiotas. Marital discord, stress, and depression have strong bidirectional links, fueling one another. Chronic marital stress and depression can elevate the risk for obesity, metabolic syndrome, and cardiovascular disease by altering resting energy expenditure, insulin production, and triglyceride responses after unhealthy meals. During stressful times, health behaviors typically suffer-and sleep disturbances, poor diets, and sedentary behavior all influence these metabolic pathways while also promoting gut dysbiosis. Dysbiosis increases intestinal permeability (gut leakiness), providing a mechanistic pathway from marital distress and depression to heightened inflammation and accelerated aging. Age-related changes in the gut microbiota's composition and gut leakiness foster immunosenescence, as well as the progression of inflamm-aging; these age-related risks may be altered by stress and depression, diet, sleep, exercise habits, and developmental shifts in emotion regulation strategies. Consideration of the strong mutual influences that partners have on each other's mood and health behaviors, as well as the biological pathways that underlie these influences, provides a new way to view marriage's health implications.

There is an unmet need to develop and validate therapies that can treat or at least prevent premature therapy-induced frailty, multi-morbidity and mortality in long-term tumour survivors. In an approach to develop a first mouse model for therapy-induced long-term frailty, we irradiated male C57Bl/6 mice at 5-6 months of age sub-lethally with 3 × 3 Gy (whole body) and assessed subsequent frailty for up to 6 months using a Rockwood-type frailty index (FI). Frailty scorers were trained to obtain excellent inter- and intra-observer reproducibility. Irradiated mice developed progressive frailty approximately twice as fast as controls. This was premature frailty; it was phenotypically identical to that in non-irradiated mice at higher age. As expected, frailty was associated with decreased cognition and predicted mortality. In irradiated mice, frailty and neuromuscular performance, measured by Rotarod and Hanging Wire tests, were not associated with each other, probably because of long-term decreased body weights after irradiation. We conclude that progressive frailty following sub-lethal irradiation comprises a sensitive and easy to use test bed for interventions to stop premature ageing in long-term tumour survivors., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Lonely people's heightened risks for chronic health conditions and early mortality may emerge in part through cellular aging. Lonelier people have more severe sympathetic responses to acute stress, increasing their risk for herpesvirus reactivation, a possible path to shorter telomeres. Parasympathetic function may modulate this risk., Purpose: The current study aimed to examine the associations among loneliness, herpesvirus reactivation, and telomere length, with parasympathetic activity as a moderator, in healthy middle-aged and older adults., Methods: A sample of 113 healthy men and women of ages 40-85 provided blood samples that were assayed for telomere length, as well as the latent herpesviruses cytomegalovirus (CMV) and Epstein-Barr virus (EBV). They also provided heart rate variability (HRV), a measure of parasympathetic activity, and reported on their feelings of loneliness., Results: Lonelier people with lower HRV (i.e., lower parasympathetic activity) had greater CMV reactivation and shorter telomeres compared with their less lonely counterparts, above and beyond demographics, health behaviors, resting heart rate, and social network size. However, loneliness was not associated with viral reactivation or telomere length among those with higher HRV. In turn, greater CMV and EBV reactivation was associated with shorter telomeres., Conclusions: Taken together, these data implicate parasympathetic function in novel links between loneliness and accelerated cellular aging., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society of Behavioral Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: People with Down syndrome (DS) experience premature aging. Whether this accelerated aging also involves early declines in muscle mass, strength and physical performance is presently unclear. The present study investigated the prevalence of sarcopenia parameters in adults with DS. In addition, the relationship between well-established muscle mass indexes and a set of body composition, functional, biological, and clinical parameters was explored., Methods: One hundred-five adults with DS participated in the study. Demographic, clinical, anthropometric, and functional parameters were assessed. Lean body mass (LBM) was estimated using bioelectrical impedance analysis. Bone mineral density (BMD) of the hip and the spine was measured through dual X-ray absorptiometry. For the analysis, participants were categorized into two subgroups (i.e., low and high) for each LBM-related measurement (i.e., crude LBM, LBM to body mass index ratio, and skeletal muscle index) according to their median values., Results: The mean age of participants was 38.4 ± 12.1 years, with 43 men (41%). Muscle mass, handgrip strength, and gait speed were lower than established cutoffs for sarcopenia. All muscle mass indexes were negatively correlated with age. However, only crude LBM and the skeletal muscle index were correlated with a set of anthropometric parameters and BMD., Conclusion: Findings from this exploratory study indicate that adults with DS show muscle mass indexes and physical performance levels similar to or lower than older adults with sarcopenia. The assessment of muscle mass and functional status should therefore be included in the routine evaluation of this population starting at young age., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To perform a comprehensive assessment of the placental aging process in small term fetuses classified as being small-for-gestational age (SGA) or having fetal growth restriction (FGR) through analysis of senescence and apoptosis markers., Methods: This was a prospective nested case-control study of singleton pregnancies delivered at term, including 21 control pregnancies with normally grown fetuses and 36 with a small fetus classified as SGA (birth weight between the 3 rd and 9 th percentiles and normal fetoplacental Doppler; n = 18) or FGR (birth weight < 3 rd percentile and/or abnormal cerebroplacental ratio and/or uterine artery Doppler; n = 18). Telomerase activity, telomere length (quantified by comparing the amount of amplification product for the telomere sequence (T) to that of a single copy of the gene 36B4 (S)) and RNA expression of senescence (Sirtuins 1, 3 and 6) and apoptosis (p53, p21, BAX and Caspases 3 and 9) markers (analyzed using the 2 -ΔΔCt method) were determined in placental samples collected at birth and compared between the three groups., Results: Compared to pregnancies with a normally grown fetus, both SGA and FGR pregnancies presented signs of accelerated placental aging, including lower telomerase activity (mean ± SD, 12.8 ± 6.6% in controls vs 7.98 ± 4.2% in SGA vs 7.79 ± 4.6% in FGR; P = 0.008), shorter telomeres (mean ± SD T/S ratio, 1.20 ± 0.6 in controls vs 1.08 ± 0.9 in SGA vs 0.66 ± 0.5 in FGR; P = 0.047) and reduced Sirtuin-1 RNA expression (mean ± SD 2 -ΔΔCt , 1.55 ± 0.8 in controls vs 0.91 ± 0.8 in SGA vs 0.63 ± 0.5 in FGR; P = 0.001) together with increased p53 RNA expression (median (interquartile range) 2 -ΔΔCt , 1.07 (0.3-3.3) in controls vs 5.39 (0.6-15) in SGA vs 3.75 (0.9-7.8) in FGR; P = 0.040). FGR cases presented signs of apoptosis, with increased Caspase-3 RNA levels (median (interquartile range) 2 -ΔΔCt , 0.94 (0.7-1.7) in controls vs 3.98 (0.9-31) in FGR; P = 0.031) and Caspase-9 RNA levels (median (interquartile range) 2 -ΔΔCt , 1.21 (0.6-4.0) in controls vs 3.87 (1.5-9.0) in FGR; P = 0.037) compared with controls. In addition, Sirtuin-1 RNA expression, telomerase activity, telomere length and Caspase-3 activity showed significant linear trends across groups as severity of the condition increased., Conclusions: Accelerated placental aging was observed in both clinical forms of late-onset fetal smallness (SGA and FGR), supporting a common pathophysiology and challenging the concept of SGA fetuses being constitutionally small. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.)

(1) Background: Chronic obstructive pulmonary disease (COPD) is defined as an inflammatory disorder that presents an increasingly prevalent health problem. Accelerated aging has been examined as a pathologic mechanism of many chronic diseases like COPD. We examined whether COPD is combined with accelerated aging, studying two hormones, dehydroepiandrosterone (DHEA) and growth hormone (GH), known to be characteristic biological markers of aging. (2) Methods: Data were collected from 119 participants, 70 (58.8%) COPD patients and 49 (41.2%) from a health control group over the period of 2014⁻2016 in a spirometry program. Information about their medical history, tobacco use, and blood tests was obtained. (3) Results: The average age of the health control patients was 73.5 years (SD = 5.5), and that of the COPD patients was 75.4 years (SD = 6.9). Both groups were similar in age and sex. A greater proportion of smokers were found in the COPD group (87.1%) versus the control group (36.7%). The majority of COPD patients were classified as STAGE II (51.4%) and STAGE III (37.1%) according to GOLD (Global Initiative for Chronic Obstructive Pulmonary Disease). Levels of DHEA (SD = 17.1) and GH (SD = 0.37) were significantly lower in the COPD group ( p < 0.001) compared to those in the controls (SD = 26.3, SD = 0.79). DHEA and GH were more significant and negatively correlated with age. The regression equation of DHEA with age produced a coefficient equal to 1.26. In this study, the difference in DHEA between COPD patients and controls was, on average, 30.2 μg/dL, indicating that the biological age of a COPD patient is on average about 24 years older than that of a control subject of the same age. Similarly, the difference in GH between COPD patients and controls was, on average, 0.42 ng/mL, indicating that the biological age of a COPD patient is on average about 13.1 years older than that of a control subject of the same age. (4) Conclusions: The findings of our study strongly suggest the presence of premature biological aging in COPD patients. Their biological age could actually vary from 13 to 23 years older than non-COPD controls according to DHEA and GH variation.

Depression has been associated with circadian disruption and premature aging. Nevertheless, mechanisms underlying the link between long-term stress with premature aging and possible associations with circadian rhythms remain elusive. Here, mice were exposed to chronic mild stress for 16 weeks to induce depression-like symptoms, which were confirmed with the open field test, tail suspension test, and sucrose preference test. Then, the circadian rhythms of age-related indexes were compared between control and stressed mice. Long-term stress resulted in decreased body weight gain and locomotor activities, accompanied by losses of subcutaneous backside fat, decreased amounts of thigh muscle fibers, and shortened telomere length in hepatocytes. Stressed mice showed increased oxidative damage, causing impaired mitochondrial function and inflammatory responses, which may be mediated by the sirtuin 3 (SIRT3)-superoxide dismutase 2 (SOD2) signaling pathway. These changes may be associated with partial disruption of circadian rhythms or shifting phase values of some age-related indicators induced by long-term stress. These findings suggest that long-term exposure to stress may increase the risk of depression and regulate age-related phenotypes through associations with circadian rhythms., (Copyright © 2018. Published by Elsevier Inc.)

Physiological and premature aging are frequently associated with an accumulation of prelamin A, a precursor of lamin A, in the nuclear envelope of various cell types. Here, we aimed to underpin the hitherto unknown mechanisms by which prelamin A alters myonuclear organization and muscle fiber function. By experimentally studying membrane-permeabilized myofibers from various transgenic mouse lines, our results indicate that, in the presence of prelamin A, the abundance of nuclei and myosin content is markedly reduced within muscle fibers. This leads to a concept by which the remaining myonuclei are very distant from each other and are pushed to function beyond their maximum cytoplasmic capacity, ultimately inducing muscle fiber weakness.

The development of frailty scores suitable for mice and which resemble those used in the clinical scenario is of great importance to understand human frailty. The aim of the study was to determine an individual frailty score for each mouse at different ages and analyze the association between the frailty score and its lifespan. For this purpose, the "Valencia Score" for frailty was used. Thus, a longitudinal study in mice was performed analyzing weight loss, running time and speed, grip strength and motor coordination at the late-adult, mature and old ages (40, 56 and 80 weeks old, respectively). These parameters are equivalent to unintentional weight loss, poor endurance, slowness, weakness, and low activity level, respectively, in humans. A cut-off point was used to identify frail mice for each criterion. All the measurements were also performed on chronologically adult prematurely aging mice. The results show that by using the "Valencia Score" for frailty a prematurely aged phenotype can be identified even during the adulthood of animals. This opens up the possibility of carrying out preventive long-term interventions. Moreover, the individual frailty score of a given mouse at the late-adult, mature and old ages is shown to be a relevant predictor of its lifespan.

A 51-year-old Caucasian male was referred for evaluation of variceal bleeding. Laboratory tests were remarkable for mild thrombocytopenia and moderate alkaline phosphatase elevation. Synthetic liver function was well preserved. Abdominal computed tomography scan revealed moderate splenomegaly, gastric varices, and normal hepatic contour. A transjugular liver biopsy was performed revealing findings of nodular regenerative hyperplasia with no significant fibrosis or necroinflammatory activity. Hepatic venous pressure gradient was elevated at 31 mmHg, consistent with clinically significant portal hypertension. The clinical course was complicated by refractory gastric variceal bleeding requiring a surgical portosystemic shunt. Approximately seven years after the initial presentation, the patient developed progressive dyspnoea and a diagnosis of idiopathic pulmonary fibrosis was made. Contrast-enhanced echocardiogram was not suggestive of hepatopulmonary syndrome or portopulmonary hypertension. Given this new diagnosis a telomere biology disorder was suspected. A flow-fluorescence in situ hybridisation analysis for telomere length assessment revealed telomere lengths below the first percentile in both lymphocytes and granulocytes. Next generation sequencing analysis identified a heterozygous mutation involving the hTERT gene (Histidine983Threonine). The lung disease unfortunately progressed in the subsequent two years, leading to the patient's death nine years after his initial presentation with portal hypertension. During those nine years two brothers also developed idiopathic pulmonary fibrosis. The questions that arise from this case include., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

The improvement in survival of childhood cancer observed across the past 50 years has resulted in a growing acknowledgment that simply extending the lifespan of survivors is not enough. It is incumbent on both the cancer research and the clinical care communities to also improve the health span of survivors. It is well established that aging adult survivors of childhood cancer are at increased risk of chronic health conditions, relative to the general population. However, as the first generation of survivors age into their 50s and 60s, it has become increasingly evident that this population is also at risk of early onset of physiologic aging. Geriatric measures have uncovered evidence of reduced strength and speed and increased fatigue, all components of frailty, among survivors with a median age of 33 years, which is similar to adults older than 65 years of age in the general population. Furthermore, frailty in survivors independently increased the risk of morbidity and mortality. Although there has been a paucity of research investigating the underlying biologic mechanisms for advanced physiologic age in survivors, results from geriatric populations suggest five biologically plausible mechanisms that may be potentiated by exposure to cancer therapies: increased cellular senescence, reduced telomere length, epigenetic modifications, somatic mutations, and mitochondrial DNA infidelity. There is now a critical need for research to elucidate the biologic mechanisms of premature aging in survivors of childhood cancer. This research could pave the way for new frontiers in the prevention of these life-changing outcomes.

Background: Klotho is a well-known anti-aging hormone, which serves as a suppressor of aging through a variety of mechanisms. Aging of skeletal muscle is concomitant with a decrease in muscle stem cell function resulting in impaired regeneration., Methods: Here we investigate the functional role of the anti-aging hormone Klotho for muscle stem cell function after cardiotoxin-induced injury of skeletal muscle using a klotho hypomorphic mouse line, which is characterized by a premature aging phenotype. Furthermore, we perform floating single myofiber cultures with their adjacent muscle stem cells to investigate the interplay between canonical Wnt signaling and Klotho function., Results: We demonstrate that muscle stem cell numbers are significantly decreased in klotho hypomorphic mice. Furthermore, we show that muscle stem cell function is also severely impaired upon loss of klotho expression, in culture and during regeneration in vivo. Moreover, we demonstrate that addition of recombinant Klotho protein inhibits aberrant excessive Wnt signaling in aged muscle stem cells thereby restoring their functionality., Conclusions: The anti-aging hormone Klotho counteracts aberrant canonical Wnt signaling in muscle stem cells and might be one of the naturally occurring inhibitors of canonical Wnt signaling in skeletal muscle.

Progeria is sporadic, very rare, autosomal dominant, deadly childhood disorder. It is one of the progeroid syndromes also known as Hutchinson-Gilford progeria syndrome (HGPS). Aging is a developmental process that begins with fertilization and ends up with death involving a lot of environmental and genetic factors. The disease firstly involves premature aging and then death from complications of atherosclerosis such as myocardial infarction, stroke, atherosclerosis, or heart failure. The lifespan of the patient is normally up to teen age or early twenties. It is usually not inherited because a patient normally dies before the age of reproduction. The most important genetic linkage between progeria and aging is shortening of telomere ends with each replication cycle. The patients are normally observed to have extremely short telomeres. Currently, 90% of the patients are said to have de novo point mutations in the LMNA gene that substitute cytosine with thymine and have been found in individuals with HGPS. Lmna encodes lamins A and C, and the A-type lamins have important structural function in the nuclear envelope. The most common type of HGPS mutation is located at codon 608 (G608G). It could not be diagnosed at birth, but after the age of 2 years, visible, prominent symptoms can be observed. Still, lot of research is needed to solve this mystery; hopefully, future research on HGPS would provide important clues for progeria and other fatal age-related disorders.

A-lamins, encoded by the LMNA gene, are major structural components of the nuclear lamina coordinating essential cellular processes. Mutations in the LMNA gene and/or alterations in its expression levels have been linked to a distinct subset of human disorders, collectively known as laminopathies, and to cancer. Mechanisms regulating A-lamins are mostly obscure. Here, we identified E3 ubiquitin ligase Smurf2 as a physiological regulator of lamin A and its disease-associated mutant form progerin (LAΔ50), whose expression underlies the development of Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging syndrome. We show that Smurf2 directly binds, ubiquitinates, and negatively regulates the expression of lamin A and progerin in Smurf2 dose- and E3 ligase-dependent manners. Overexpression of catalytically active Smurf2 promotes the autophagic-lysosomal breakdown of lamin A and progerin, whereas Smurf2 depletion increases lamin A levels. Remarkably, acute overexpression of Smurf2 in progeria fibroblasts was able to significantly reduce the nuclear deformability. Furthermore, we demonstrate that the reciprocal relationship between Smurf2 and A-lamins is preserved in different types of mouse and human normal and cancer tissues. These findings establish Smurf2 as an essential regulator of lamin A and progerin and lay a foundation for evaluating the efficiency of progerin clearance by Smurf2 in HGPS, and targeting of the Smurf2-lamin A axis in age-related diseases such as cancer., (© 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

A crisis looms as research and clinical programs have not kept pace with dramatic increases in the number of older adults with schizophrenia. This article provides an overview of the advances in the conceptualization and study of schizophrenia in later life. Theoretic and clinical models in psychiatry and gerontology are integrated. Specifically, recovery is examined in the context of aging, how clinical dimensionality affects diagnoses in older adults, how various features of schizophrenia are implicated in models of accelerated and paradoxic aging, and how outcome in later life is a more dynamic and heterogeneous than assumed previously., (Copyright © 2017 Elsevier Inc. All rights reserved.)