Accelerated Cell Aging Research Articles

Experimental and Theoretical Analysis of Immersion Cooling of a Li-Ion Battery Module

Abstract Overheating of Li-ion cells and battery packs is an ongoing technological challenge for electrochemical energy conversion and storage, including in electric vehicles. Immersion cooling is a promising thermal management technique to address these challenges. This work presents experimental and theoretical analysis of the thermal and electrochemical impact of immersion cooling of a small module of Li-ion cells. Significant reduction in both surface and core temperature due to immersion cooling is observed, consistent with theoretical and simulation models developed here. However, immersion cooling is also found to result in a small but non-negligible increase in capacity fade of the cells. A number of hypotheses are formed and systematically tested through a comparison of experimental measurements with theoretical modeling and simulations. Electrochemical Impedance Spectroscopy measurements indicate that the accelerated cell aging due to immersion cooling is likely to be due to enhanced lithium plating. Therefore, careful consideration of the impact of immersion cooling on long-term performance may be necessary. The results presented in this work quantify both thermal and electrochemical impacts of a promising thermal management technique for Li-ion cells. These results may be of relevance for design and optimization of electrochemical energy conversion and storage systems.

A dynamic actin cytoskeleton is required to prevent constitutive VDAC-dependent MAPK signalling and aberrant lipid homeostasis

The dynamic nature of the actin cytoskeleton is required to coordinate many cellular processes, and a loss of its plasticity has been linked to accelerated cell aging and attenuation of adaptive response mechanisms. Cofilin is an actin-binding protein that controls actin dynamics and has been linked to mitochondrial signaling pathways that control drug resistance and cell death. Here we show that cofilin-driven chronic depolarization of the actin cytoskeleton activates cell wall integrity mitogen-activated protein kinase (MAPK) signalling and disrupts lipid homeostasis in a voltage-dependent anion channel (VDAC)-dependent manner. Expression of the cof1-5 mutation, which reduces the dynamic nature of actin, triggers loss of cell wall integrity, vacuole fragmentation, disruption of lipid homeostasis, lipid droplet (LD) accumulation, and the promotion of cell death. The integrity of the actin cytoskeleton is therefore essential to maintain the fidelity of MAPK signaling, lipid homeostasis, and cell health in S.cerevisiae.

Assessing the Impact of Polyethylene Nano/Microplastic Exposure on Human Vaginal Keratinocytes.

The global rise of single-use throw-away plastic products has elicited a massive increase in the nano/microplastics (N/MPLs) exposure burden in humans. Recently, it has been demonstrated that disposable period products may release N/MPLs with usage, which represents a potential threat to women's health which has not been scientifically addressed yet. By using polyethyl ene (PE) particles (200 nm to 9 μm), we showed that acute exposure to a high concentration of N/MPLs induced cell toxicity in vaginal keratinocytes after effective cellular uptake, as viability and apoptosis data suggest, along with transmission electron microscopy (TEM) observations. The internalised N/MPLs altered the expression of junctional and adherence proteins and the organisation of the actin cortex, influencing the level of genes involved in oxidative stress signalling pathways and that of miRNAs related to epithelial barrier function. When the exposure to PE N/MPLs was discontinued or became chronic, cells were able to recover from the negative effects on viability and differentiation/proliferation gene expression in a few days. However, in all cases, PE N/MPL exposure prompted a sustained alteration of DNA methyltransferase and DNA demethylase expression, which might impact epigenetic regulation processes, leading to accelerated cell ageing and inflammation, or the occurrence of malignant transformation.

Natural Melanogenesis Inhibitor, Antioxidant, and Collagen Biosynthesis Stimulator of Phytochemicals in Rice Bran and Husk Extracts from Purple Glutinous Rice (Oryza sativa L. cv. Pieisu 1 CMU) for Cosmetic Application

Oryza sativa L. cv. Pieisu 1 CMU (PES1CMU) has a high anthocyanin content in the colored bran and high phenolic content in the husk. Biologically active compounds in plants are available as dietary supplements and cosmetics. To expand the utilization of natural resources, PES1CMU will be a natural remedy for skin hyperpigmentation and aging. Cell-free tyrosinase inhibition and scavenging assays were used to screen all extracts, including PES1CMU-rice bran oil (RBO), PES1CMU-defatted rice bran (DFRB), and PES1CMU-husk (H). PES1CMU extracts were first examined in IBMX-stimulated B16 cells and H2O2-induced fibroblasts. The results exhibited that PES1CMU-DFRB was the most effective inhibitor of mushroom tyrosinase, intracellular melanin production (fold change of 1.11 ± 0.01), and tyrosinase activity (fold change of 1.22 ± 0.10) in IBMX-stimulated B16 cells. Particularly, PES1CMU-DFRB showed a comparable whitening effect to the standard arbutin with no significant difference (p > 0.05). Moreover, PES1CMU-DFRB and PES1CMU-H demonstrated strong scavenging activities. After accelerated cell aging caused by H2O2 exposure in fibroblasts, the levels of malondialdehyde production in all PES1CMU-treated fibroblasts were comparable with those of standard l-ascorbic acid (p > 0.05). Besides, PES1CMU-DFRB and PES1CMU-H treatment significantly inhibited collagen degradation against MMP-2 compared to l-ascorbic acid-treated cells (p > 0.05). PES1CMU rice-processing wastes (DFRB and H) could become potential natural sources for dermatocosmetic constituents in skin anti-aging and whitening products.

Artificially Sweetened Beverages Beyond the Metabolic Risks: A Systematic Review of the Literature.

We carried out a review of the available literature on the effects that artificially sweetened beverages (ASBs) such as diet soda (DS)have on health, particularly those not related to incident diabetes mellitus, obesity, and metabolic syndrome. A search of scientific articles was carried out using 11 different databases: PubMed, Cochrane, LILACS, MEDLINE Ovid, JAMA Network, IBECS, Cumed, Scopus, SciELO, MEDLINE-EBSCO, and Taylor & Francis Online. Articles published in the last 10 years were considered, considering cross-sectional studies, retrospective or prospective cohort studies, case-control studies, and randomized controlled clinical trials. Only articles in Spanish or English were considered using the MeSH (Medical Subject Heading) and DeCS (Descriptores en Ciencias de la Salud) terms, including "Diet soda," "Health," "Artificial sweetener," "Gaseosa sin azúcar," "Refresco sin azúcar," and "Salud." Additionally, Boolean operators "AND" and "Y" were used. A total of 1,323 articles were obtained in the initial search, of which 21 main ones were selected for review, which included the topic of DS consumptionand explored the health consequences that it poses on different organs. The question of whetherASBssuch as DSare a preferred substitute is becoming more and more important in terms of public policy due to mounting evidence of the potential negative health effects of their excessive consumption. This systematic review, the first of its kind to our knowledge, sheds light on how excessive DS consumption can affect multiple organ systems, and associations have been made to mental health burden, delays in child neurodevelopment, cardiac remodeling, worsening retinopathy in diabetics, incidental end-stage renal disease, non-Hodgkin's lymphoma and multiple myeloma in men, rheumatoid arthritis in women, hip fractures, dental erosion, increases in breath alcohol concentration when used in alcoholic beverages, and accelerated cell aging. Further studies should delve further to understand the pathophysiologic mechanisms of these associations.

Telomeres and oocyte maturation rate are not reduced by COVID-19 except in severe cases.

COVID-19 does not affect the telomeres or fertility outcomes in mild cases. However, in women with severe symptoms, telomeres of granulosa cells are shorter, and the oocyte maturation rate is decreased. The coronavirus SARS-CoV-2 causes COVID-19 disease and affects primarily the lungs and also other organs, causing accelerated cell aging. One of the main pathways involved in aging is telomere attrition, which ultimately leads to defective tissue regeneration and organ dysfunction. Indeed, short telomeres in aged people aggravate the COVID-19 symptoms, and COVID-19 survivors showed shorter telomeres in blood cells. The SARS-CoV-2 has been detected in testis, but the ovaries, which express the viral entry factors, have not been fully explored. Our objective was to analyze telomeres and reproductive outcomes in women who had COVID-19 and controls. In this prospective cohort study, granulosa cells (GCs) and blood were collected from 65 women. Telomere length (TL) was measured by high-throughput in situ hybridization. Mean TL of GCs and peripheral blood mononuclear cells (PBMCs) was alike in control and mild cases. However, mean TL of GCs was lower in severe cases compared to controls (P = 0.017). Control and COVID groups had similar ovarian reserve and number of total oocytes after puncture. However, the oocyte maturation rate was lower in severe cases (P = 0.018). Interestingly, a positive correlation between the oocyte maturation rate and TL of GCs was found in the control group (P = 0.024). Our findings point to a potential impact of the coronavirus infection on telomeres and reproductive outcomes in severe cases. This might be considered upon possible new SARS-CoV threats, to favor treatments that enhance oocyte maturation in women severely affected by coronavirus undergoing ART.

Bisphenol A Induces Accelerated Cell Aging in Murine Endothelium.

Bisphenol A (BPA) is a widespread endocrine disruptor affecting many organs and systems. Previous work in our laboratory demonstrated that BPA could induce death due to necroptosis in murine aortic endothelial cells (MAECs). This work aims to evaluate the possible involvement of BPA-induced senescence mechanisms in endothelial cells. The β-Gal assays showed interesting differences in cell senescence at relatively low doses (100 nM and 5 µM). Western blots confirmed that proteins involved in senescence mechanisms, p16 and p21, were overexpressed in the presence of BPA. In addition, the UPR (unfolding protein response) system, which is part of the senescent phenotype, was also explored by Western blot and qPCR, confirming the involvement of the PERK-ATF4-CHOP pathway (related to pathological processes). The endothelium of mice treated with BPA showed an evident increase in the expression of the proteins p16, p21, and CHOP, confirming the results observed in cells. Our results demonstrate that oxidative stress induced by BPA leads to UPR activation and senescence since pretreatment with N-acetylcysteine (NAC) in BPA-treated cells reduced the percentage of senescent cells prevented the overexpression of proteins related to BPA-induced senescence and reduced the activation of the UPR system. The results suggest that BPA participates actively in accelerated cell aging mechanisms, affecting the vascular endothelium and promoting cardiovascular diseases.

Understanding the genetics of chronic obstructive pulmonary disease, α1-antitrypsin deficiency, and implications for clinical practice.

Cigarette smoking and poor air quality are the greatest risk factors for developing chronic obstructive pulmonary disease (COPD), but growing evidence indicates that genetic factors also affect predisposition to and clinical expression of disease. With the exception of α1-antitrypsin deficiency (AATD), a rare autosomal recessive disorder that is present in 1-3% of individuals with COPD, no single gene is associated with the development of obstructive lung disease. Instead, a complex interplay of genetic, epigenetic, and environmental factors is the basis for persistent inflammatory responses, accelerated cell aging, cell death, and fibrosis, leading to the clinical symptoms of COPD and different phenotypic presentations. In this brief review, we discuss current understanding of the genetics of COPD, pathogenetics of AATD, epigenetic influences on the development of obstructive lung disease, and how classifying COPD by phenotype can influence clinical treatment and patient outcomes.

Longitudinal Associations between Discrimination, Neighborhood Social Cohesion, and Telomere Length: The Multi-Ethnic Study of Atherosclerosis (MESA).

We aimed to examine if neighborhood social cohesion moderated longitudinal associations between baseline reports of discrimination and 10-year changes in Leukocyte Telomere Length (LTL). Data are from the Multi-Ethnic Study of Atherosclerosis (MESA; N=1,064; age range 45-84 years). Baseline discrimination was measured using the Major Experiences of Discrimination Scale (MDS; none, 1 domain, ≥2 domains) and the Experiences of Discrimination Scale (EDS; none, moderate, high). Neighborhood social cohesion at baseline was assessed via a community survey within census tract defined neighborhoods. 10-year change in LTL was defined as Regression to the Mean corrected 10-year difference in the ratio of telomeric DNA to a single copy gene (T/S). In linear mixed effects models, we found that neighborhood social cohesion modified the effect of baseline reports of MDS on 10-year changes in LTL, independent of sociodemographic characteristics, health behaviors, and health conditions (p(χ 2)=0.01). Among those residing in neighborhoods with low social cohesion, experiencing major discrimination in ≥2 domains was associated with faster LTL attrition over 10-years, compared to reporting no discrimination (β=-0.03; 95% CI: -0.06, -0.003). We found no main associations for either discrimination measure and no interaction between EDS and neighborhood social cohesion. Results indicate that neighborhood social cohesion is an important dimension of the neighborhood context that may moderate the impact of major experiences of discrimination on telomere length attrition. These findings help advance our understanding of the integral role that neighborhood environments play in attenuating the effect of discrimination on accelerated cell aging.

LncRNAs activate longevity regulation pathway due to aging of Leydig cells caused by DEHP exposure: A transcriptome-based study

Di-(2-ethylhexyl) phthalate (DEHP), one of the most commonly used endocrine-disrupting chemicals, has been shown to cause reproductive dysfunction in humans and animal models. However, very few studies have investigated the impact of DEHP at the post-transcriptional level in mouse testes, and the underlying mechanisms remain unclear. In the present research, TM3 Leydig cells were treated with 200 µM phthalic acid mono-2-ethylhexyl ester (MEHP, bio-metabolite of DEHP), and then the mRNA and lncRNA sequencing of TM3 Leydig cells was performed. Mice were exposed prepubertally to 0 or 500 mg DEHP/kg/day. RNA sequencing of mouse testes was performed to verify the RNA-seq results in vitro. The expression patterns of relevant genes and proteins were verified using real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting. DEHP and MEHP exposure led to testicular damage and accelerated cell aging via ROS accumulation. RNA sequencing analyses indicated that FOXO signaling and longevity regulation pathways were activated in resistance to ROS accumulation. FOXO signaling and longevity regulation pathway-related genes and proteins were also activated. By constructing a competing endogenous RNA (ceRNA) network, we observed that the ceRNA network might play a role in regulating FOXO signaling and longevity regulation pathways in response to excessive ROS accumulation and cell aging. In summary, our data here suggests that the ceRNA network may play a role in regulating FOXO signaling and longevity pathways in response to DEHP exposure in mouse testes.

Comparing lithium-ion battery architecture performances with Colored Petri Net

Conventionally, the basic cells constituting the multicellular energy storage systems are modeled by electrical schemes based on Thevenin’s model. Other, more complex models incorporate the aging phenomena, resulting in a decrease in the State of Health of each cell. All these models remain analytical models and not discrete event systems. In this article, a discrete model is proposed, by detailing how each physical parameter is modeled. It is based on a no-timed Colored High-Level Petri Net. An example of a battery is simulated to validate this theoretical model. Its structure (number of cells) is declined under different architectures (connections between the cells) and is subjected to different resource dynamic allocation strategies. This Petri Net (PN) model makes easy, by adding a sub-network, to simulate different control laws and different resource management algorithms, whether or not allow commutations by forbiding all configurations that do not meet the specification or that will lead to accelerated cell aging. PN is used as a tool for comparing hardware architectures and cell control logic for a battery. Various conventional and innovative architecture are simulate. Different control laws can be compared in terms of performance, as lifespan and use of resources.

Submandibular gland-specific inflammaging-induced hyposalivation in the male senescence-accelerated mouse prone -1line (SAM-P1).

Aging has pronounced effects on mammalian tissues and cells, but the impacts of aging on salivary gland function are relatively unknown. This study aims to evaluate the effects of aging on submandibular gland (SMG) and parotid gland (PG) functions in the male senescence-accelerated mouse. In vivo analysis at the systemic level revealed that salivary secretion induced by pilocarpine, a muscarinic agonist, from the SMG was significantly decreased in aged mice, whereas salivary secretion from the PG was not affected. To evaluate organ-level function, the SMG was perfused with the muscarinic agonists carbachol and calcium ionophore A23187 ex vivo to induce salivary secretion, and decreased saliva production was also observed in the aged SMG. Histological analysis revealed the presence of CD4-positive lymphocytes infiltrating the aged SMG. Furthermore, real-time PCR revealed that the aged SMG exhibited accelerated cell aging, increased levels of the inflammatory cytokine interleukin-6, and decreased mRNA levels of the water channel protein aquaporin-5 (AQP5). In summary, these results demonstrate that SMG function in aged mice was diminished, and that cell senescence, chronic inflammation, and the decreased gene expression of AQP5 are the likely causes of hyposalivation in the SMG of aged mice.

S13. Can Psychological Treatment Slow Down Cellular Aging in Social Anxiety Disorder? An Intervention Study Evaluating Changes in Telomere Length and Telomerase Activity

Background: Mental illness, including anxiety disorders, is linked to accelerated cell aging. This is evidenced by shorter leukocyte telomere length. Cells with critically short telomeres may under ...

The Association Between Psychiatric Disorders and Telomere Length: A Meta-Analysis Involving 14,827 Persons.

This study examined the relationship between leukocyte telomere length (LTL), a marker of cell aging, and psychiatric disorders in adults compared with controls using meta-analytic methods. Data were abstracted from studies examining the relationship between LTL and adult psychiatric disorders. In addition to an overall estimate of effect size, subgroup analyses and meta-regression were performed to examine whether covariates (including psychiatric diagnoses) moderated the estimate. A significant overall effect size showing LTL shortening was found across all psychiatric disorders (Hedge g = -0.50, p < .001). Subgroup analyses did not demonstrate significant differences in effect size based on individual covariates (psychiatric disorder, sex, age, or assay method). The meta-regression indicated that although type of disorder and, likely, age moderate the overall effect size, the heterogeneity between studies could not be explained by a model that included these variables as well as sex and assay method. Although not significantly different, posttraumatic stress disorder, anxiety disorders, and depressive disorders had comparatively larger effect sizes (-1.27, -0.53, and -0.55), and psychotic and bipolar disorders had comparatively smaller ones (-0.23 and -0.26). We observed a robust effect size of LTL shortening for psychiatric disorders as a whole compared with controls. The results were less straightforward regarding relative differences in the strength of this association by specific disorder. Future studies should focus on mechanisms explaining accelerated cell aging with psychiatric illness, defining directions (if any) of causality and elucidating possible differences in this association between disorders.

Influence of aqueous electrolyte concentration on parasitic reactions in high-voltage electrochemical capacitors

Increasing operating voltage is a straightforward approach to increase the specific energy of aqueous electrolyte based electrical double-layer capacitors (EDLCs). A broader operating voltage window, however, comes at the expense of accelerated cell ageing processes. Two complementary in situ gas analysis techniques, i.e., internal cell pressure measurement and Online Electrochemical Mass Spectrometry (OEMS), were applied to study the influence of electrolyte salt concentration on the electrochemical degradation of the electrode and decomposition of electrolyte during cycling of symmetrical carbon based EDLCs. Higher concentrations of Li2SO4 aqueous electrolyte salt increase the coulombic efficiency of the cell and reduce the amount of volatile side reaction products (e.g., CO, CO2, and H2) arising from carbon corrosion and water electrolysis. The lower amount of degradation products when increasing the salt to solvent ratio is believed to result from a favorable stabilization of the increasingly coordinated electrolyte solvent-salt bonds, which in turn increases the energy barrier for H2O decomposition. Higher salt concentrations not only increase the electrochemical reversibility at high cell voltages but also increase cell charging capacities as a result of increased electrolyte conductivity, which all-in-all facilitates implementation of future high energy aqueous EDLCs.

Shortened telomere length in patients with depression: A meta-analytic study

BackgroundAccelerated telomere shortening is associated with stress-related cell damage and aging. Patients with depression have been shown to have shortened life expectancy and to be associated with multiple age-related systemic diseases. Previous studies have examined leukocyte telomere length (LTL) in patients with depression, but have shown inconsistent results. MethodsWe conducted meta-analyses by pooling relevant results strictly from all eligible case–control studies for cross-sectional comparison of LTL between depressive patients and control subjects (16 studies involving 7207 subjects). The effect sizes (shown as Hedges' g) of each individual study were synthesized by using a random effects model. ResultsOur analysis revealed telomere length is significantly shorter in subjects with depression in comparison to healthy controls (Hedges' g = −0.42, p = 1 × 10−5, corresponding to r = −0.21). Significant heterogeneity among studies examining LTL in subjects with depression was found (Q = 116.07, df = 16, I2 = 86.21%, p < 1 × 10−8), which can possibly be explained by methods used in measuring telomere length (Q = 18.42, df = 2, p = 1 × 10−4). There was no significant publication bias, nor moderating effect of age, female percentage, or illness duration of depression on synthesized results. ConclusionsOur results support the hypothesis that depression is associated with accelerated cell aging. Future studies are required to clarify whether the association is mediated through environmental stress, and whether effective treatment can halt cell aging.

Complexation and molecular modeling studies of europium(III)–gallic acid–amino acid complexes

With many metal-based drugs extensively used today in the treatment of cancer, attention has focused on the development of new coordination compounds with antitumor activity with europium(III) complexes recently introduced as novel anticancer drugs. The aim of this work is to design new Eu(III) complexes with gallic acid, an antioxida'nt phenolic compound. Gallic acid was chosen because it shows anticancer activity without harming health cells. As antioxidant, it helps to protect human cells against oxidative damage that implicated in DNA damage, cancer, and accelerated cell aging. In this work, the formation of binary and ternary complexes of Eu(III) with gallic acid, primary ligand, and amino acids alanine, leucine, isoleucine, and tryptophan was studied by glass electrode potentiometry in aqueous solution containing 0.1M NaNO3 at (298.2±0.1) K. Their overall stability constants were evaluated and the concentration distributions of the complex species in solution were calculated. The protonation constants of gallic acid and amino acids were also determined at our experimental conditions and compared with those predicted by using conductor-like screening model for realistic solvation (COSMO-RS) model. The geometries of Eu(III)–gallic acid complexes were characterized by the density functional theory (DFT). The spectroscopic UV–visible and photoluminescence measurements are carried out to confirm the formation of Eu(III)–gallic acid complexes in aqueous solutions.

MULTIDIMENSIONAL ANEURYSMAL GROWTH - A NOVEL TECHNIQUE DERIVED FROM BIOMEDICAL ENGINEERING PRINCIPLES TO HELP REFINE ASSESSMENT OF AORTIC GROWTH

rare medial cell senescence that was 4.2-fold more prevalent in dilated aortas (0.83 0.10%) than in non-dilated aortas (0.20 0.10%, p1⁄40.048). Expression of p16 was abundantly detected in medial SMCs within dilated aortas (24.0 1.5%) and 3-fold more abundant than in non-dilated aortas (8.2 1.5%, p<0.0001). Interestingly, medial p16 expression did not correlate with telomere length of medial cells, as determined by quantitative and standardized PCR (p1⁄40.35). Immunostaining for gH2A.X (phosphorylated Ser139) interestingly revealed discrete nuclear DNA double-strand breakage signals in 25.7 3.8% of medial cells in dilated aortas from patients with BAV, which was 2.3-fold higher than that found in non-dilated aortas (11.0 4.9, p1⁄40.03). Medial cell outgrowths from BAV patients showed increased senescenceassociated s-galactosidase activity compared to control patient SMC outgrowths (38.9 2.9 vs. 19.5 1.9, p1⁄40.0005). Furthermore, incubation of early passage SMCs with 50nM of angiotensin II for 3 days caused a 1.4-fold increase in senescence-associated s-galactosidase expressing SMCs from BAV patients (p1⁄40.0006), but elicited no change in senescence-associated s-galactosidase expression in SMCs from control patients (p1⁄40.83). CONCLUSION: These findings identify a previously unrecognized phenomenon of accelerated SMC aging in the aortas of patients with BAV, with cellular senescence and unresolved DNA breaks. Accelerated cell aging could thus be a driver of aortic wall degeneration in these patients and a potential therapeutic target.

THORACIC AORTIC DILATIONS IN PATIENTS WITH BICUSPID AORTIC VALVE DISEASE IS MARKED BY ACCELERATED SMOOTH MUSCLE CELL AGING

Individuals with a bicuspid aortic valve (BAV) are at increased risk for ascending aortic dilation and dissection. Loss of aortic medial smooth muscle cells (SMCs) and disruption of the extracellular matrix are well-recognized pathologies, but the underlying cellular mechanisms remain elusive. We tested the hypothesis that the dilated aorta in patients with BAV was marked by accelerated cellular aging. Samples of human ascending aorta were obtained from individuals with BAV undergoing thoracic aorta replacement (n=37, age 54.7±2.2, aortic diameter 4.8±0.9 cm) or patients with a tricuspid aortic valve and non-dilated aorta undergoing heart transplantation or coronary bypass procedures (n=8, age 55.3±8.1, aortic diameter 3.1±0.3 cm). Assessment of fresh aortic samples for senescence-associated β-galactosidase revealed evidence for rare medial cell senescence that was 4.2-fold more prevalent in dilated aortas (0.83±0.10%) than in non-dilated aortas (0.20±0.10%, p=0.048). Expression of p16 was abundantly detected in medial SMCs within dilated aortas (24.0±1.5%) and 3-fold more abundant than in non-dilated aortas (8.2±1.5%, p<0.0001). Interestingly, medial p16 expression did not correlate with telomere length of medial cells, as determined by quantitative and standardized PCR (p=0.35). Immunostaining for γH2A.X (phosphorylated Ser139) interestingly revealed discrete nuclear DNA double-strand breakage signals in 25.7±3.8% of medial cells in dilated aortas from patients with BAV, which was 2.3-fold higher than that found in non-dilated aortas (11.0±4.9, p=0.03). Medial cell outgrowths from BAV patients showed increased senescence-associated ß-galactosidase activity compared to control patient SMC outgrowths (38.9±2.9 vs. 19.5±1.9, p=0.0005). Furthermore, incubation of early passage SMCs with 50nM of angiotensin II for 3 days caused a 1.4-fold increase in senescence-associated ß-galactosidase expressing SMCs from BAV patients (p=0.0006), but elicited no change in senescence-associated ß-galactosidase expression in SMCs from control patients (p=0.83). These findings identify a previously unrecognized phenomenon of accelerated SMC aging in the aortas of patients with BAV, with cellular senescence and unresolved DNA breaks. Accelerated cell aging could thus be a driver of aortic wall degeneration in these patients and a potential therapeutic target.

Circadian desynchronization triggers premature cellular aging in a diurnal rodent.

Chronic jet lag or shift work is deleterious to human metabolic health, in that such circadian desynchronization is associated with being overweight and the prevalence of altered glucose metabolism. Similar metabolic changes are observed with age, suggesting that chronic jet lag and accelerated cell aging are intimately related, but the association remains to be determined. We addressed whether jet lag induces metabolic and cell aging impairments in young grass rats (2-3 mo old), using control old grass rats (12-18 mo old) as an aging reference. Desynchronized young and control old subjects had impaired glucose tolerance (+60 and +280%) when compared with control young animals. Despite no significant variation in liver DNA damage, shorter telomeres were characterized, not only in old animal liver cells (-18%), but also at an intermediate level in desynchronized young rats (-9%). The same pattern was found for deacetylase sirtuin (SIRT)-1 (-57 and -29%), confirming that jet-lagged young rats have an intermediate aging profile. Our data indicate that an experimental circadian desynchronization in young animals is associated with a precocious aging profile based on 3 well-known markers, as well as a prediabetic phenotype. Such chronic jet lag-induced alterations observed in a diurnal species constitute proof of principle of the need to develop preventive treatments in jet-lagged persons and shift workers.