CS
Citrate synthase, mitochondrial precursor (EC 2.3.3.1) (Citrate (Si)-synthase)
Publications[править]
- Strength Training (ST) reduces the cardiovascular risk of hypertensive elderly people; however, there is a need for efficient and low-cost ST programs that aim to reduce blood pressure (BP) in elderly people with adherence and affectivity in this population. : Evaluate the acute effect on BP and satisfaction with the practice of bodyweight-based strength training (BWST) in hypertensive older adults. : Participants performed a BWST session and a control session (CS). The BWST consisted of six exercises, with three sets of 30 seconds. In the CS, no activity was performed. BP was measured before and at 0, 10, 20, and 30 minutes post-session. Participants' satisfaction was assessed. : Eleven older adults (65.8 ± 4.6 years; 7 men) participated in the study. There was an increase ([i]p[/i] = .028) in systolic BP immediately after BWST, returning to baseline values in the intervals 10, 20, and 30 post-section. In the CS there was an increase ([i]p[/i] = .009) 30 minutes post-session compared to 20 minutes. Between sessions, a lower systolic BP was found in BWST (-6.54 ± 3.31; [i]p[/i] = .048) 30 minutes post-sessions. For satisfaction, 82% of participants were "totally satisfied" with BWST. : The SBP is lower 30 minutes after BWST session than control session, and BWST promoted a pleasant affective response in hypertensive older adults.
Keywords
- Exercise
- aging
- hypertension
- hypotension
- resistance training
Secondary aerosol formation in the aging process of primary emission is the main reason for haze pollution in eastern China. Pollution evolution with photochemical age was studied for the first time at a comprehensive field observation station during winter in Beijing. The photochemical age was used as an estimate of the timescale attributed to the aging process and was estimated from the ratio of toluene to benzene in this study. A low photochemical age indicates a fresh emission. The photochemical age of air masses during new particle formation (NPF) days was lower than that on haze days. In general, the strongest NPF events, along with a peak of the formation rate of 1.5 nm (J ) and 3 nm particles (J ), were observed when the photochemical age was between 12 and 24 h while rarely took place with photochemical ages less than 12 h. When photochemical age was larger than 48 h, haze occurred and NPF was suppressed. The sources and sinks of nanoparticles had distinct relation with the photochemical age. Our results show that the condensation sink (CS) showed a valley with photochemical ages ranging from 12 to 24 h, while H SO concentration showed no obvious trend with the photochemical age. The high concentrations of precursor vapours within an air mass lead to persistent nucleation with photochemical age ranging from 12 to 48 h in winter. Coincidently, the fast increase of PM mass was also observed during this range of photochemical age. Noteworthy, CS increased with the photochemical age on NPF days only, which is the likely reason for the observation that the PM mass increased faster with photochemical age on NPF days compared with other days. The evolution of particles with the photochemical age provides new insights into understanding how particles originating from NPF transform to haze pollution.
Keywords
- Condensation sink
- Haze
- New particle formation
- Photochemical aging
- Pollution evolution
Natural aging alters the surface physicochemical properties of biochars, which can affect the retention of heavy metals. This work investigated the effect of biochar aging on stabilization of heavy metals (Cd and Ni) and soil enzyme activities simulated with laboratory wet-dry (WD) and freeze-thaw (FT) cycling. A wheat straw (WS) biochar and a corn straw (CS) biochar were subjected to 30 WD or FT cycles, and Cd- and Ni-contaminated alkaline soils amended with the two fresh biochars (at 5% w/w) were subjected to 30-day constant moisture incubation and 30 WD or FT cycles. WD and FT aging caused slight reduction in the pH of the biochars, significant increases in their O contents and surface areas, and formation of new carbonate minerals. WS biochar was more effective than CS biochar at reducing the phytoavailable Cd in the soil, with reduction of 12.1%, 14.6%, and 12.9% under constant moisture incubation, WD aging, and FT aging, respectively. Reduction in phytoavailability of Ni by the addition of biochars was observed only under WD aging, by 17.0% and 18.5% in the presence of WS and CS biochars, respectively. Biochar amendment also reduced the distribution of Cd in the acid soluble and reducible fractions in all aging regimes. The addition of biochars decreased catalase activity in almost all aging regimes and invertase activity under FT aging, but increased urease activity under FT aging. Comparison of the enzyme activities in the soils amended with biochars under constant moisture and accelerated aging conditions indicates WD aging significantly decreased the activities of catalase, invertase, and urease in all treatments, while FT aging significantly increased urease activity in all treatments. These findings suggest that biochars can stabilize Cd in alkaline soils under changing environmental conditions, although the activities of some soil enzymes could be negatively impacted.
Keywords
- Accelerated aging
- Biochar
- Cadmium
- Enzyme activity
- Heavy metal stabilization
- Soil remediation
Cockayne syndrome (CS) is a rare premature aging disease, most commonly caused by mutations of the genes encoding the CSA or CSB proteins. CS patients display cachectic dwarfism and severe neurological manifestations and have an average life expectancy of 12 years. The CS proteins are involved in transcription and DNA repair, with the latter including transcription-coupled nucleotide excision repair (TC-NER). However, there is also evidence for mitochondrial dysfunction in CS, which likely contributes to the severe premature aging phenotype of this disease. While damaged mitochondria and impaired mitophagy were characterized in mice with CSB deficiency, such changes in the CS nematode model and CS patients are not fully known. Our cross-species transcriptomic analysis in CS postmortem brain tissue, CS mouse, and nematode models shows that mitochondrial dysfunction is indeed a common feature in CS. Restoration of mitochondrial dysfunction through NAD supplementation significantly improved lifespan and healthspan in the CS nematodes, highlighting mitochondrial dysfunction as a major driver of the aging features of CS. In cerebellar samples from CS patients, we found molecular signatures of dysfunctional mitochondrial dynamics and impaired mitophagy/autophagy. In primary cells depleted for CSA or CSB, this dysfunction can be corrected with supplementation of NAD precursors. Our study provides support for the interconnection between major causative aging theories, DNA damage accumulation, mitochondrial dysfunction, and compromised mitophagy/autophagy. Together, these three agents contribute to an accelerated aging program that can be averted by cellular NAD restoration.
Keywords
- AMPK
- Cockayne syndrome
- NAD
- accelerated ageing
- aging
- mitochondrial maintenance
- mitophagy
To characterize the optical and mechanical properties of a commercial and in-house translucent Y-TZP before and after aging in autoclave or hydrothermal reactor. In-house experimental discs were obtained through uniaxial and isostatic pressing a translucent Y-TZP powder and sintering at 1,550 °C/1 h. Commercial discs were milled from pre-sintered blocks fabricated with the same powder through uniaxial and isostatic pressing and sintering. Discs were allocated into three groups according to aging condition: immediate, aged via autoclave, or reactor (134 °C, 20 h, 2.2 bar). Crystalline content and microstructure were evaluated using X-ray diffraction (XRD) and scanning electron microscopy (SEM). Residual compressive stress (CS) was determined by Raman spectroscopy. Optical properties were determined by the contrast ratio (CR) and translucency parameter (TP) using reflectance data. Mechanical properties were assessed by Vickers hardness, fracture toughness and biaxial flexural strength tests. XRD and SEM revealed a typical Y-TZP crystalline content, chiefly tetragonal phase, and a dense crystalline matrix for both processing protocols. Reactor aging triggered a more pronounced t-m transformation relative to autoclave. In-house and commercial Y-TZPs demonstrated similar CR and TP, with reactor aging significantly increasing their translucency. Similarly, reactor aging influenced Vickers hardness and fracture toughness. In-house processed Y-TZP clearly demonstrated the presence of CS, whereas commercial Y-TZP showed no presence of CS. Non-aged in-house Y-TZP resulted in significantly lower characteristic strength relative to commercial Y-TZP. While aging protocols significantly increased the characteristic strength of in-house Y-TZP, reactor significantly decreased commercial Y-TZP characteristic strength. Both Y-TZP processing protocols demonstrated high reliability at high-stress missions, with no detrimental effect of aging. Laboratory aging methodology significantly influenced optical and mechanical properties of a commercial and in-house translucent Y-TZP.
Keywords
- Aging
- Ceramics
- Mechanical properties
- Optical properties
- Zirconia
Engagement in cognitively stimulating activities is associated with decreased rates of cognitive decline in older adults. However, most cognitively stimulating tasks require good vision, potentially affecting the ability of visually impaired adults to engage in these activities. We examined the relationship between vision and participation in cognitively stimulating activities. Data from the Health, Aging and Body Composition study (1999-2005) were analyzed. Associations between visual function (visual acuity (VA), contrast sensitivity (CS), and stereo acuity (SA) impairments) and annual rates of change in number of cognitively stimulating activities (by self-report) performed at least once a month, were examined. Analyses included 924 participants aged 75.2 ±2.8 years. At baseline, impaired CS (27%), and SA (29%) was associated with participation in fewer cognitive activities (β=-0.33, 95%CI=-0.63,-0.03; β=-0.32, 95%CI=-0.61,-0.03, respectively) while VA ( 8%) was not (β=-0.34, 95%CI=-0.81,0.13). In longitudinal models, groups with and without VA, CS, and SA impairments exhibited declines in monthly cognitive activities over time. Annual rates of decline were relatively higher in the VA (β=-0.16, 95%CI=-0.26,-0.05) and CS (β=-0.14, 95%CI=-0.19,-0.09) impaired groups than observed in the respective unimpaired groups (No VA: β=-0.12, 95%CI=-0.15,-0.10; No CS: β=-0.12, 95%CI=-0.15,-0.09), but did not achieve statistical significance. SA (β=-0.13, 95%CI=-0.17,-0.09) and no SA (β=-0.13, 95%CI=-0.16,-0.10) groups had similar rates of decline. Visually impaired older adults participate in fewer cognitive activities and although participation decline is similar to the non-impaired, lower overall participation indicates a need to identify cognitively stimulating activities accessible to visually impaired older adults.
Keywords
- Cognition
- Cognitive Aging
- Sensory
- Vision loss
We compared the effects of suspension training (ST) with traditional resistance training (TRT) on muscle mass, strength and functional performance in older adults. Forty-two untrained older adults were randomized in TRT, ST (both performed 3 sets of whole body exercises to muscle failure) or control group (CON). Muscle thickness (MT) of biceps brachii (MT ) and vastus lateralis (MT ), maximal dynamic strength test (1RM) for biceps curl (1RM ) and leg extension exercises (1RM ), and functional performance tests (chair stand [[[CS]]], timed up and go [TUG] and maximal gait speed [MGS]) were performed before and after 12 weeks of training. MT increased significantly and similarly for all training groups (TRT 23.35%; ST 21.56%). MT increased significantly and similarly for all training groups (TRT 13.03%; ST 14.07%). 1RM increased significantly and similarly for all training groups (TRT 16.06%; ST 14.33%). 1RM increased significantly and similarly for all training groups (TRT 14.89%; ST 18.06%). MGS increased significantly and similarly for all groups (TRT 6.26%; ST 5.99%; CON 2.87%). CS decreased significantly and similarly for all training groups (TRT - 20.80%; ST - 15.73%). TUG decreased significantly and similarly for all training groups (TRT - 8.66%; ST - 9.16%). Suspension training (ST) promotes similar muscle mass, strength and functional performance improvements compared to TRT in older adults.
Keywords
- Aging
- Functionality
- Instability resistance training
- Muscle hypertrophy
- TRX training
To determine if incidence of contrast sensitivity (CS) impairment differs by generation and identify factors to explain these differences. The Beaver Dam Eye Study (BDES) and Beaver Dam Offspring Study (BOSS) are cohort studies of aging adults in Beaver Dam, Wisconsin. Baseline examinations occurred from 1993 to 1995 (BDES) and 2005-2008 (BOSS). Follow-up examinations occurred in five-year intervals. CS testing was conducted with Pelli-Robson letter sensitivity charts; Incident impairment was a log CS score <1.55 in either eye at follow-up. Associations of incidence with generation were investigated using estimated hazard ratios (HR) with 95% confidence intervals (CI). Participants (N = 3185) had a mean age of 51.9 years at baseline (standard deviation = 9.9) and 51.9% were female. Ten-year cumulative incidence of CS impairment was 40.1%, was higher among women (41.7%) than men (38.8%), and increased by age group. The risk of incident CS impairment decreased by 39% per generation. In multivariable models, the Baby Boom Generation (HR = 0.42, 95%CI = 0.31, 0.58) and Generation X (HR = 0.56, 95%CI = 0.34, 0.91) had a significantly decreased risk of CS impairment compared to the Greatest Generation. Results were similar in sensitivity analyses excluding those with cataract, age-related macular degeneration, or visual acuity impairment. The risk of incident CS impairment decreased by birth cohort, with the greatest reduction in the Baby Boom Generation. The difference in risk suggests that there are unknown modifiable risk factors that may help to further explain the etiology of CS impairment and provide potential pathways for prevention in the future.
Keywords
- Aging
- Birth Cohort Effect
- Contrast Sensitivity
- Epidemiology
- Visual Function
Freshwater polyps of the genus Hydra do not age. However, temperature stress induces aging and a shift from reproduction by asexual budding to sexual gamete production in a cold-sensitive (CS) strain of H. oligactis. We sequenced the transcriptome of a male CS strain before and after this life history shift and compared changes in gene expression relative to those seen in a cold-resistant (CR) strain that does not undergo a life history shift in response to altered temperature. We found that the switch from non-aging asexual reproduction to aging and sexual reproduction involves upregulation of genes not only involved in gametogenesis but also genes involved in cellular senescence, apoptosis, and DNA repair accompanied by a downregulation of genes involved in stem cell maintenance. These results suggest that aging is a byproduct of sexual reproduction-associated cellular reprogramming and underscore the power of these H. oligactis strains to identify intrinsic mechanisms of aging.
Keywords
- Aging
- Cold-sensitive
- DNA repair
- Gametogenesis
- Hydra oligactis
- Transcriptome
Selectively attending to relevant information while blocking out distractors is crucial for goal-directed behavior, yet with advancing age, deficits emerge in attentional selectivity. Decrements in attention have been associated with altered noradrenergic activity in animals. However, research linking noradrenergic functioning to attention in aging humans is scarce, likely reflecting long-standing methodological challenges in noninvasive assessments. We studied whether age-related differences in the noradrenergic system predict differences in attention. We measured pupil dilation, a noninvasive marker of arousal-related norepinephrine (NE) release, while concurrently recording the EEG of male younger ([i]N[/i] = 39; 25.2 ± 3.2 years) and older adults ([i]N[/i] = 38; 70.6 ± 2.7 years). Arousal was modulated on a trial-by-trial basis using fear-conditioned (CS ) stimuli. During conditioning, pupil and EEG markers related to heightened arousal were identified. Afterward, in a dichotic listening task, participants were cued to direct attention to either the left or right ear while highly similar syllable pairs were presented simultaneously to both ears. During the dichotic listening task, presentation of fear-conditioned stimuli reinstated the acquired arousal response, as reflected in pupil and EEG α-β band responses. Critically, pupil dilation to CS was correlated with stronger EEG α-β desynchronization, suggesting a common dependence on NE release. On a behavioral level, stronger arousal reactions were associated with better attention. In particular, structural equation modeling revealed that the responsiveness of the NE system is associated with attention on a latent construct level, measured by several indicator tasks. Overall, our results suggest that the responsiveness of the NE system supports attention across the lifespan. In old age, the ability to selectively process relevant aspects of the environment fades. Animal research suggests that the neuromodulator norepinephrine helps to maintain selective attention. We tested younger and older adults across a variety of attention tasks. In addition, we used arousing stimuli to experimentally activate participants' noradrenergic system while recording pupillometry and EEG to infer its functional capacity. Older adults showed compromised attention and reduced noradrenergic responsiveness as indicated by interrelated pupil and EEG markers. Crucially, in both age groups, a more responsive noradrenergic system was strongly associated with attention. Our findings link animal and human studies on the neural underpinning of attention in aging and underscore the importance of the noradrenergic system in late-life cognition.
MeSH Terms
- Adult
- Aged
- Aging
- Attention
- Brain Waves
- Cortical Synchronization
- Humans
- Male
- Norepinephrine
- Reflex, Pupillary
Keywords
- cognitive aging
- locus coeruleus
- noradrenaline
- norepinephrine
- rhythmic neural activity
- selective attention
Conditioned pain modulation (CPM) is a laboratory test resulting in pain inhibition through activation of descending inhibitory mechanisms. Older adults consistently demonstrate reduced CPM compared with younger samples; however, studies of sex differences in younger cohorts have shown mixed results. This study tested for sex differences in CPM within samples of younger and older adults. Participants were 67 younger adults (mean age = 25.4 years) and 50 older adults (66.4 years). Study conditioning paradigms were the cold-pressor test and contact heat pain administered in separate sessions. Pressure pain threshold and ramping suprathreshold heat were the test stimuli across three time points after presentation of the conditioning stimuli (CS). Significant inhibition was observed during both testing sessions. The hypothesis for sex differences across both age cohorts was supported only for ∆PPTh. However, sex differences did not reach significance for either paradigm using ascending suprathreshold heat as the test stimuli. The overall trend was that younger males experienced the strongest CPM and older females the weakest. From a methodological perspective, duration differences were seen in CPM, with inhibition decaying more quickly for PPTh than for suprathreshold heat pain. Furthermore, there were no differences in inhibition induced by cold-pressor test and contact heat pain as CS. Sex differences were similar across both age cohorts with males experiencing greater inhibition than females. Cross-sectional associations were also demonstrated between CPM inhibition and measures of recent pain, further supporting CPM as an experimental model with clinical utility.
Keywords
- Aging
- CPM duration
- Conditioned pain modulation
- Conditioning stimulus
- Sex differences
- Test stimulus
Cellular senescence (CS) is a state of stable cell cycle arrest characterized by the production and secretion of inflammatory molecules. Early studies described oncogene-induced senescence (OIS) as a barrier to tumorigenesis, such that the therapeutic induction of CS might represent a rational anti-cancer strategy. Indeed, the validity of this approach has been borne out by the development and approval of the cyclin-dependent kinase (CDK) inhibitor palbociclib for the treatment of breast cancer. Apart from tumors, senescent cells have also been shown to accumulate during natural mammalian aging, where they produce detrimental effects on the physiology of surrounding tissues. Thus, pharmacological senescent cell depletion has been proposed as an approach to delay age-related functional decline; this has been formally demonstrated in animal models. In this review article, we describe the current mechanistic understanding of cellular senescence at the molecular level and how it informs the development of new therapeutic strategies to combat cancer and aging.
MeSH Terms
- Aging
- Animals
- Antineoplastic Agents
- Breast Neoplasms
- Cell Proliferation
- Cell Transformation, Neoplastic
- Cellular Senescence
- Cyclin-Dependent Kinases
- Drug Discovery
- Female
- Humans
- Piperazines
- Protein Kinase Inhibitors
- Pyridines
Keywords
- cancer
- cellular senescence
- healthy aging
- pro-senescence cancer therapy
- senolytic therapies
Men and women become infertile with age, but the mechanism of declining male fertility, more specifically, the decrease in in sperm quality, is not well known. Citrate synthase (CS) is a core enzyme of the mitochondrial tricarboxylic acid (TCA) cycle, which directly controls cellular function. Extra-mitochondrial CS (eCS) is produced and abundant in the sperm head; however, its role in male fertility is unknown. We investigated the role of eCS in male fertility by producing eCs-deficient (eCs-KO) mice. The initiation of the first spike of Ca oscillation was substantially delayed in egg fused with eCs-KO sperm, despite normal expression of sperm factor phospholipase C zeta 1. The eCs-KO male mice were initially fertile, but the fertility dropped with age. Metabolomic analysis of aged sperm revealed that the loss of eCS enhances TCA cycle in the mitochondria with age, presumably leading to depletion of extra-mitochondrial citrate. The data suggest that eCS suppresses age-dependent male infertility, providing insights into the decline of male fertility with age.
MeSH Terms
- Aging
- Animals
- Calcium Signaling
- Citrate (si)-Synthase
- Citric Acid Cycle
- Female
- Infertility, Male
- Male
- Metabolome
- Mice
- Ovum
- Spermatozoa
Chronic obstructive pulmonary disease (COPD) is a common respiratory disease that is characterized by functional and structural alterations primarily caused by long-term inhalation of harmful particles. Cigarette smoke (CS) induces airway inflammation in COPD, which is known to persist even after smoking cessation. This review discusses the basic pathogenesis of COPD, with particular focus on an endogenous protective mechanism against oxidative stress via Nrf2, altered immune response of the airway inflammatory cells, exaggerated cellular senescence of the lung structural cells, and cell death with expanded inflammation. Recently, CS-induced mitochondria autophagy is reported to initiate programmed necrosis (necroptosis). Necroptosis is a new concept of cell death which is driven by a defined molecular pathway along with exaggerated inflammation. This new cell death mechanism is of importance due to its ability to produce more inflammatory substances during the process of epithelial death, contributing to persistent airway inflammation that cannot be explained by apoptosis-derived cell death. Autophagy is an auto-cell component degradation system executed by lysosomes that controls protein and organelle degradation for successful homeostasis. As well as in the process of necroptosis, autophagy is also observed during cellular senescence. Aging of the lungs results in the acquisition of senescence-associated secretory phenotypes (SASP) that are known to secrete inflammatory cytokines, chemokines, growth factors, and matrix metalloproteinases resulting in chronic low-grade inflammation. In future research, we intend to highlight the genetic and epigenetic approaches that can facilitate the understanding of disease susceptibility. The goal of precision medicine is to establish more accurate diagnosis and treatment methods based on the patient-specific pathogenic characteristics. This review provides insights into CS-induced COPD pathogenesis, which contributes to a very complex disease. Investigating the mechanism of developing COPD, along with the availability of the particular inhibitors, will lead to new therapeutic approaches in COPD treatment.
Keywords
- Airway inflammation
- autophagy
- cellular senescence
- chronic obstructive pulmonary disease (COPD)
- necroptosis
- oxidative stress
Cigarette smoke (CS)-induced lung inflammation and Chronic Obstructive Pulmonary disease (COPD) involves mitochondrial dysfunction. Mesenchymal stem cells (MSC) and MSC-derived exosomes (EXO) are reported to show therapeutic effects in many animal models of inflammation and injury. In the present study, we determined the role of MSC and EXO intervention in CS-induced lung inflammation with a focus on mitochondrial dysfunction. EXO were characterized using Western blot for exosomal markers, tunable resistive pulse sensing by qNano and transmission electron microscopy (TEM). Mitochondrial reporter mice (mt-Keima and mito-QC) were exposed to air or CS for 10 days. mt-Keima mice were treated with intraperitoneal injections of MSC or EXO or MSC and EXO (MSC EXO) for 10 days. Total cell counts, differential cell counts were performed using automated cell counter and flow cytometry respectively. Further, the levels of pro-inflammatory mediators in bronchoalveolar lavage (BAL) fluid were measured using ELISA. Western blot analysis, quantitative PCR, confocal microscopy were used in the current study to determine the effects in the lungs of CS exposed mice. Seahorse flux analyzer was used to measure the oxidative-phosphorylation (OXPHOS) in the BEAS2B cells and BEAS2B - mMSC co-culture experiments. CS exposure increased the inflammatory cellular infiltrations in the lungs of the mt-Keima mice. MSC EXO treatment showed protection compared to individual treatments (MSC or EXO alone). There were no changes in the mitophagy proteins like PINK1 and Parkin, which was also found using the mito-QC mice. CS exposure led to significant increase in the mitochondrial fission protein DRP1 and other DAMPs pathway mediators like S100A4 and S100A8, HMGB1, RAGE and AGE. MSC EXO treatment increased the gene expression of (fusion genes) mfn1, mfn2 and opa1. Additionally, the rhot1 gene expression was increased in MSC EXO treatment group compared to Air- and CS exposed groups. BEAS2B-mMSC co-cultures showed protective response against the CSE-altered mitochondrial respiration parameters, confirming the beneficial effect of MSC towards human bronchial lung epithelial cells. CS affects some of early mitochondrial genes involved in the fission/fusion process, enhancing the damage response along with altered cytokine levels. MSC EXO combination treatment showed their protective effects. MSC EXO combination treatment may act against these early events caused by CS exposure owing to its anti-inflammatory and other mitochondrial transfer mechanisms.
MeSH Terms
- Alarmins
- Animals
- Cytokines
- Exosomes
- Lung
- Mesenchymal Stem Cells
- Mice
- Mitochondria
- Mitophagy
- Oxidative Phosphorylation
- Smoke
- Tobacco
Keywords
- COPD
- Cellular Senescence
- Exosomes
- Mesenchymal stem cells
- Mitochondria
Here, we describe the longevity and locomotor behavior of senescent Drosophila males with altered expression of Dgp-1 gene. In comparison with the wild-type Canton-S (CS) males, six characteristics of the phenotype of Dgp-1[843k] mutant were found: (1) low expression of isoform A; (2) augmented expression of isoform B; (3) reduction in the mean lifespan; (4) decrease in the running speed in 3-day-old flies; (5) maintenance of a high run frequency in senescent flies; and (6) resistance to heat stress manifested as maintenance of a high run frequency at 29 °C. After cessation of "cantonization" process, mean lifespan of the mutant males drifted from low to high values finally exceeding that for CS. In contrast, behavioral phenotype of the mutant was robust. Using the GAL4/UAS system, we showed that neurospecific overexpression of isoform B resulted in a slight decrease of longevity and a high level of run frequency in the senescent flies, similar to that in Dgp-1[843K] mutant. In addition, a decreased level of reactive oxygen species was found in Dgp-1[843K] mutant males maintained under stress conditions. The elevated resistance to oxidative stress probably explains the two distinctive features of the mutation: resistance to aging processes and thermal stress displayed at behavioral level.
MeSH Terms
- Aging
- Animals
- Drosophila Proteins
- Drosophila melanogaster
- Heat-Shock Response
- Locomotion
- Male
- Protein Isoforms
Keywords
- Drosophila Dgp-1 mutant
- Heat stress
- Locomotion
- Oxidative stress
- Senescence
Aging-related neurodegenerative disorders are frequently associated with the aggregation of multiple amyloidogenic proteins (APs), although the reason why such detrimental phenomena have emerged in the post-reproductive human brain across evolution is unclear. Speculatively, APs might provide physiological benefits for the human brain during developmental/reproductive stages. Of relevance, it is noteworthy that cross-seeding (CS) of APs has recently been characterized in cellular and animal models of neurodegenerative disease, and that normal physiological CS of multiple APs has also been observed in lower organisms, including yeast and bacteria. In this context, our main objective is to discuss a possible involvement of the CS of APs in promoting evolvability, a hypothetical view regarding the function of APs as an inheritance of acquired characteristics against human brain stressors, which are transgenerationally transmitted to offspring via germ cells. Mechanistically, the protofibrils formed by the CS of multiple APs might confer hormesis more potently than individual APs. By virtue of greater encoded stress information in parental brains being available, the brains of offspring can cope more efficiently with forth-coming stressors. On the other hand, subsequent neurodegeneration caused by APs in parental brain through the antagonistic pleiotropy mechanism in aging, may suggest that synergistically, multiple APs might be more detrimental compared to singular AP in neurodegeneration. Taken together, we suggest that the CS of multiple APs might be involved in both evolvability and neurodegenerative disease in human brain, which may be mechanistically and therapeutically important.
MeSH Terms
- Aging
- Amyloidogenic Proteins
- Animals
- Biological Evolution
- Brain
- Female
- Humans
- Inheritance Patterns
- Models, Neurological
- Neurodegenerative Diseases
- Pregnancy
- Stress, Physiological
Keywords
- Alzheimer’s disease
- Parkinson’s disease
- amyloid cascade hypothesis
- amyloidogenic proteins
- antimicrobial protection model
- cross-seeding
- evolvability hypothesis
Senescence is a mechanism associated with aging that alters tissue regeneration by depleting the stem cell pool. Chronic obstructive pulmonary disease (COPD) displays hallmarks of senescence, including a diminished stem cell population. DNA damage from cigarette smoke (CS) induces senescence via the p16 pathway. This study evaluated the contribution of p16 to CS-associated lung pathologies. p16 expression was prominent in human COPD lungs compared with normal subjects. CS induces impaired pulmonary function, emphysema, and increased alveolar epithelial cell (AECII) senescence in wild-type mice, whereas CS-exposed p16 mice exhibit normal pulmonary function, reduced emphysema, diminished AECII senescence, and increased pro-growth IGF1 signaling, suggesting that improved lung function in p16 mice was due to increased alveolar progenitor cell proliferation. In conclusion, our study suggests that targeting senescence may facilitate alveolar regeneration in COPD emphysema by promoting IGF1 proliferative signaling.
MeSH Terms
- Alveolar Epithelial Cells
- Animals
- Cell Proliferation
- Cellular Senescence
- Cyclin-Dependent Kinase Inhibitor p16
- Cytokines
- Emphysema
- Insulin-Like Growth Factor I
- Lung
- Mice, Inbred C57BL
- Models, Biological
- Promoter Regions, Genetic
- Proto-Oncogene Proteins c-akt
- Pulmonary Disease, Chronic Obstructive
- RNA, Messenger
- Signal Transduction
- Smoking
Keywords
- Molecular biology
- Senescence
- Stem cells
Impaired theory of mind (ToM) is a neurobehavioral phenotype of epilepsy. Given that the age transitions affect cognitive development and decline, it is important to refine ToM across the lifespan. This study evaluated ToM in healthy subjects, taking into account education, gender, and other functions, aiming to clarify its specificity and relationships to major demographic and cognitive domains. A hundred and seventy subjects from ages 16 to 81 years (68 men) who received five to 17 years of schooling were evaluated using a Faux Pas Task (FPT) that is solved at the end of childhood and is highly sensitive to brain damage and tests for language, memory, praxis, visual perception, initiative, attention, shifting, and planning. Factor analysis, analysis of variance, and correlation and regression analyses were used to assess the data. The analysis yielded six factors: Beliefs, Delusions, and Facts, which express the understanding of mental states and contextual details; Matching-Learning, Executive, and Working Memory. On this basis, six composite scores (CSs) were computed. Age and schooling showed significant effects on the Matching-Learning, Executive, and Working Memory CSs. The FPT raw scores and CSs were unrelated to age or schooling, while females showed better performance than males. The Beliefs CS and FPT scores were predicted by the Executive, Working Memory, Delusions, and Facts CSs and gender. Theory of mind is a specific cognitive domain independent of age and formal education, but related to gender. Working memory, executive functions, and reality examination support some ToM processes. These findings may provide reference points against which impairment can be assessed. This article is part of the Special Issue "Epilepsy and social cognition across the lifespan".
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Cognition
- Executive Function
- Female
- Healthy Volunteers
- Humans
- Male
- Memory, Short-Term
- Middle Aged
- Neuropsychological Tests
- Theory of Mind
- Young Adult
Keywords
- Age
- Education
- Executive functions
- Gender
- Theory of mind
Chondrosarcoma (CS) is the second most common malignant bone sarcoma. Its treatment remains an issue, because this tumor is radio- and chemo-resistant. In the present study, we investigated the antitumoral potential of GSK-J4, a small molecule described as an inhibitor of histone demethylases UTX and JMJD3 (KDM6A and KDM6B), alone or in combination with cisplatin in CSs. Human CS-derived cell lines were treated with GSK-J4 in the presence or not of cisplatin. Survival curves were established and cell proliferation and cycle were evaluated by flow cytometry using dividing cell tracking technique utilizing carboxyfluorescein succinimidyl ester labeling, or DNA staining by propidium iodide. Apoptosis and senescence were also investigated. GSK-J4 decreased proliferation of CS cells. Additionally, it induced apoptosis in CH2879 and JJ012 cells, but not in SW1353 CSs. In addition, its association with cisplatin decreased cell proliferation more than drugs alone, whereas it did not increase apoptosis compared to cisplatin alone. Interestingly, GSK-J4 alone as well as in association with cisplatin did not affect chondrocyte survival or proliferation. In conclusion, this study suggests that demethylase inhibitors may be useful in improving therapy for CS in reducing its proliferation.
MeSH Terms
- Apoptosis
- Benzazepines
- Cell Cycle
- Cell Proliferation
- Cells, Cultured
- Chondrocytes
- Chondrosarcoma
- Histone Demethylases
- Humans
- Pyrimidines
Keywords
- apoptosis
- cell death
- chondrosarcoma
- histone demethylase
- senescence
The nucleolus organizes around the sites of transcription by RNA polymerase I (RNA Pol I). rDNA transcription by this enzyme is the key step of ribosome biogenesis and most of the assembly and maturation processes of the ribosome occur co-transcriptionally. Therefore, disturbances in rRNA transcription and processing translate to ribosomal malfunction. Nucleolar malfunction has recently been described in the classical progeria of childhood, Hutchinson-Gilford syndrome (HGPS), which is characterized by severe signs of premature aging, including atherosclerosis, alopecia, and osteoporosis. A deregulated ribosomal biogenesis with enlarged nucleoli is not only characteristic for HGPS patients, but it is also found in the fibroblasts of "normal" aging individuals. Cockayne syndrome (CS) is also characterized by signs of premature aging, including the loss of subcutaneous fat, alopecia, and cataracts. It has been shown that all genes in which a mutation causes CS, are involved in rDNA transcription by RNA Pol I. A disturbed ribosomal biogenesis affects mitochondria and translates into ribosomes with a reduced translational fidelity that causes endoplasmic reticulum (ER) stress and apoptosis. Therefore, it is speculated that disease-causing disturbances in the process of ribosomal biogenesis may be more common than hitherto anticipated.
MeSH Terms
- Aging, Premature
- Cell Nucleolus
- Child
- Cockayne Syndrome
- Endoplasmic Reticulum Stress
- Humans
- Mitochondria
- Progeria
- RNA Polymerase I
- Ribosomes
Keywords
- Cockayne syndrome
- Hutchinson–Gilford Progeria syndrome
- RNA polymerase I
- aging
- nucleolus
- ribosome
- translational fidelity
- trichothiodystrophy
The aim of the study was to evaluate the expression levels of proteins related to mitochondrial biogenesis regulation and bioenergetics in [i]vastus lateralis[/i] muscle biopsies from 16 elderly and 7 young people subjected to 14 days of bed-rest, causing atrophy, and subsequent 14 days of exercise training. Based on quantitative immunoblot analyses, in both groups a reduction of two key regulators of mitochondrial biogenesis/remodeling and activity, namely PGC-1α and Sirt3, was revealed during bed-rest, with a subsequent up-regulation after rehabilitation, indicating an involvement of PGC-1α-Sirt3 axis in response to the treatments. A difference was observed comparing the young and elderly subjects as, for both proteins, the abundance in the elderly was more affected by immobility and less responsive to exercise. The expression levels of TOM20 and Citrate Synthase, assayed as markers of outer mitochondrial membrane and mitochondrial mass, showed a noticeable sensitivity in the elderly group, where they were affected by bed-rest and rehabilitation recalling the pattern of PGC-1α. TOM20 and CS remained unchanged in young subjects. Single OXPHOS complexes showed peculiar patterns, which were in some cases dissimilar from PGC-1α, and suggest different influences on protein biogenesis and degradation. Overall, exercise was capable to counteract the effect of immobility, when present, except for complex V, which was markedly downregulated by bed-rest, but remained unaffected after rehabilitation, maybe as result of greater extent of degradation processes over biogenesis. Phosphorylation extent of AMPK, and its upstream activator LKB1, did not change after bed-rest and rehabilitation in either young or elderly subjects, suggesting that the activation of energy-sensing LKB1-AMPK signaling pathway was "missed" due to its transient nature, or was not triggered under our conditions. Our study demonstrates that, as far as the expression of various proteins related to mitochondrial biogenesis/remodeling, adaptations to bed-rest and rehabilitation in the two populations were different. The impact of bed-rest was greater in the elderly subjects, where the pattern (decrease after bed rest and recovery following rehabilitation) was accompanied by changes of mitochondrial mass. Modifications of protein abundance were matched with data obtained from gene expression analyses of four public human datasets focusing on related genes.
Keywords
- aging
- exercise
- immobility
- in silico gene expression data mining
- mitochondria-related proteins
- skeletal muscle
- western blot
To elucidate biochemical mechanisms leading to seed deterioration, we studied 23 wheat genotypes after exposure to seed bank storage for 6-16 years compared to controlled deterioration (CD) at 45 °C and 14 (CD14) and 18% (CD18) moisture content (MC) for up to 32 days. Under two seed bank storage conditions, seed viability was maintained in cold storage (CS) at 0 °C and 9% seed MC, but significantly decreased in ambient storage (AS) at 20 °C and 9% MC. Under AS and CS, organic free radicals, most likely semiquinones, accumulated, detected by electron paramagnetic resonance, while the antioxidant glutathione (GSH) was partly lost and partly converted to glutathione disulphide (GSSG), detected by HPLC. Under AS the glutathione half-cell reduction potential (E ) shifted towards more oxidising conditions, from -186 to -141 mV. In seeds exposed to CD14 or CD18, no accumulation of organic free radicals was observed, GSH and seed viability declined within 32 and 7 days, respectively, GSSG hardly changed (CD14) or decreased (CD18) and E shifted to -116 mV. The pH of extracts prepared from seeds subjected to CS, AS and CD14 decreased with viability, and remained high under CD18. Across all treatments, E correlated significantly with seed viability ([i]r[/i] = 0.8, [i]p[/i]<.001). Data are discussed with a view that the cytoplasm is in a glassy state in CS and AS, but during the CD treatments, underwent transition to a liquid state. We suggest that enzymes can be active during CD but not under the seed bank conditions tested. However, upon CD, enzyme-based repair processes were apparently outweighed by deteriorative reactions. We conclude that seed ageing by CD and under seed bank conditions are accompanied by different biochemical reactions.
MeSH Terms
- Antioxidants
- Disulfides
- Glutathione
- Hydrogen-Ion Concentration
- Oxidation-Reduction
- Seeds
- Sulfhydryl Compounds
- Time Factors
- Triticum
Keywords
- Antioxidants
- EPR
- ESR
- gene bank
- germination
- organic radicals
- seed longevity
Here, we reported for the first time an increased expression of c-Met protein in primary cultures of human dermal and pulmonary fibroblasts of late passages. This suggests that c-Met could serve as an early marker of cellular senescence (CS). The levels of c-Met-related signaling proteins phospho-Akt and Stat3 were also increased in (pre)senescent fibroblasts. Considering the anti-apoptotic activity of Akt and the involvement of Stat3 in mediating the effects of proinflammatory cytokines, the findings of this study indicate that c-Met could contribute through its downstream targets or partners to at least two major phenotypical features of CS - resistance to apoptosis and senescence-associated secretory phenotype.
MeSH Terms
- Biomarkers
- Cells, Cultured
- Cellular Senescence
- Fibroblasts
- Gene Expression Regulation
- Humans
- Proto-Oncogene Proteins c-akt
- Proto-Oncogene Proteins c-met
- STAT3 Transcription Factor
Keywords
- Akt
- Stat3
- c-Met
- cellular senescence
- human dermal and pulmonary fibroblasts
Biological control of spider mites in hot and dry weather is a serious technical issue. A high-temperature adapted strain (HTAS) of the predatory mite Neoseiulus barkeri Hughes was selected from its conventional strain (CS), via long-term heat acclimation and frequent heat hardenings in our previous studies. However, the environment of high temperature is usually associated with enhanced ultraviolet (UV) radiation. In the present study, the physiological effects of UV-B radiation on survival rate and egg damage of N. barkeri were investigated, as well as the activities and expression profiles of antioxidant enzymes to UV-B radiation stress. UV-B radiation had deleterious effects on egg hatchability and survival of N. barkeri. Adults of the HTAS strain were less UV-B resistant than those of the CS strain; they also had lower levels of enzymatic activity of superoxide dismutase (SOD) and catalase against oxidative damage and weaker upregulation of SOD genes. The mRNA expression of three SOD genes of CS adult females immediately increased whereas that of HTAS showed almost no difference under UV-B stress for 1 h. The results showed the HTAS of N. barkeri had lower fitness under UV-B stress compared with the CS of N. barkeri. These results suggested that long-term heat acclimation may exert a profound impact on the developmental physiology of N. barkeri.
MeSH Terms
- Adaptation, Biological
- Animals
- Antioxidants
- Arthropod Proteins
- Female
- Genetic Fitness
- Hot Temperature
- Longevity
- Mites
- Ovum
- Pest Control, Biological
- Predatory Behavior
- Transcription, Genetic
- Ultraviolet Rays
Keywords
- Antioxidant enzymes
- Cost of resistant
- Neoseiulus barkeri
- SOD genes
- UV-B radiation
It was found that the rate of change (kinetics) of the probability of death of representatives of living systems (LS) of different biological species - Drosophila, mice, rats, dogs, horses and people in the wild in their residence in different geographical areas, is described by a kinetic equation with similar values of the parameters. However, the kinetics of the probability of death of young people and rats, starting from birth, is more accurately described by the kinetic equation of a slightly different species, taking into account the prevailing process of development and adaptation of the organism to the environment. On the basis of a single kinetic approach to the description of the probability of death, an analytical model of the intensity of mortality in LS (approximation of the death rate - CS). It is shown that the approximation proposed by Gompertz to CS by an increasing exponent (law of Gompertz) is a special case of the unified mathematical model proposed in this paper.
MeSH Terms
- Aging
- Animals
- Ecosystem
- Humans
- Kinetics
- Models, Biological
- Mortality
- Probability
- Rats
Keywords
- Drosofila
- aging
- dogs
- extrapolation
- horses
- mathematical model
- mice
- population of the Russian Federation
- rats
- uniform kinetics
The Senior Fitness Test (SFT) is frequently used to assess physical fitness and functional independence in older people. To establish reference values for the SFT in Chilean physically active older women according to age ranges. Cross-sectional study that included 1048 Chilean women aged between 60 and 85 years. Chair stand (CS), arm curl (AC), two-min walk (2 min), chair sit-and-reach (CSr), back scratch (BS), and timed up-and-go test (TUG) were evaluated. The reference values are presented in percentiles (p5, p10, p25, p50, p75, p90 and p95) and are distributed age intervals (60-64, 65-69, 70-74, 75-79 and ≥ 80 years). There was a decrease in strength (CS and AC), aerobic resistance (2 min) and flexibility (CSr and BS) along with age, whereas the time required to perform the timed up and go increased along with age. Physically active older women show a deterioration in physical fitness along with age. These women have higher reference values in CS, AC, 2 min and CSr, and lower in BS and TUG, than those reported abroad for the SFT.
MeSH Terms
- Age Factors
- Aged
- Aged, 80 and over
- Aging
- Chile
- Cross-Sectional Studies
- Exercise
- Exercise Test
- Female
- Geriatric Assessment
- Humans
- Middle Aged
- Muscle Strength
- Physical Fitness
- Range of Motion, Articular
- Reference Values
- Time Factors
It's widely acknowledged that, as a neurodegenerative aging disease representing an intermediate stage between cognitive intactness and Alzheimer's disease (AD), Mild cognitive impairment (MCI) poses an excessive burden on patients' well-being, family members, health-care providers as well as the whole society. This study focuses on three cognitive interventions proposed by Clare and Woods, which are, Cognitive stimulation (CS), Cognitive training (CT) and Cognitive rehabilitation (CR). Our Network meta-analysis (NMA) aims to compar them with one another to determine the optimal cognitive intervention for elderly adults with MCI in improving their cognitive function. We applied extensive strategies to preliminary literature retrieval to identify relevant randomized controlled trials (RCTs) which scrupulously compared any two of the three cognitive interventions with one another or any one of the three with a control group as the placebo or non-active group in treating elder patients with MCI in accordance with Petersen's criteria. Our NMA of cognitive interventions for patients diagnosed with MCI appraised the relative effectiveness of cognitive interventions across trials simultaneously. Our study attempts to summarize available data to suggest that CS (Mean difference [MD] = 0.95, 95% confidence interval [CI]:0.27, 1.70) and CT (MD = 0.70, [CI]:0.11,1.30) were significantly beneficial to MCI patients for improving their cognition status while CR (MD = 0.59, [CI]:-0.30,1.50) scored lowest. Our study suggested CS was most likely to be the best intervention for improving the cognitive function of MCI patients.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Bayes Theorem
- Cognition
- Cognitive Behavioral Therapy
- Cognitive Dysfunction
- Humans
- Network Meta-Analysis
- Randomized Controlled Trials as Topic
- Treatment Outcome
Keywords
- Bayesian network meta-analysis
- Cognitive intervention
- Mild cognitive impairment
- Systematic review
Caesarean section (CS) rates are increasing in many parts of the world, recently reaching about 20% worldwide. The postmodern lifestyle characteristics, obesity and delayed childbirth, have been put forward as the main reasons for high CS rates. The present study tests the association patterns between lifestyle parameters and delivery mode on a data set of 3786 births in Vienna between 2005 and 2013. The focus is exclusively on singleton term births. As well as maternal age, prepregnancy weight status, maternal body height and gestational weight gain, newborn size (birth weight, birth length, and head circumference), Apgar scores and child presentation were recorded. Planned as well as emergency CS rates increased significantly ([i]p[/i] < 0.0001) with increasing maternal age and decreasing maternal body height. Emergency CS rates, however, increased significantly with increasing maternal prepregnancy weight status and gestational weight gain. An especially high risk of emergency CS occurred among four groups of mothers: those older than 40 years (OR = 2.68; 95% CI 1.87⁻3.86), those who were obese (OR = 1.44; 95% 1.15⁻1.81), those experiencing a gestational weight gain above 15 kg (OR = 1.32; 95% CI 1.13⁻1.54), and those shorter than 160 cm (OR = 1.216; 95% CI 1.02⁻1.45). Emergency CS rates were significantly higher among low-weight newborns (<2500 g) and macrosome newborns (>4000 g) than among normal-weight newborns. Furthermore, breech presentation was associated with an increased risk of caesarean delivery (OR 6.97; 95% CI 6.09⁻7.96). Logistic regression analyses reveal that maternal age, maternal body height, prepregnancy weight status, gestational weight gain, birth weight, newborn head circumference and child presentation show an independent, highly significant association with caesarean delivery. We conclude that maternal and newborn characteristics typical of recent lifestyle patterns, such as advanced maternal age, obesity, increased gestational weight gain and increased newborn size, are highly significantly associated with increased emergency CS rates. Moreover, maternal shortness and breech presentation are risk factors for emergency CS.
MeSH Terms
- Adult
- Aging
- Apgar Score
- Austria
- Breech Presentation
- Cesarean Section
- Female
- Humans
- Life Style
- Maternal Age
- Obesity
- Odds Ratio
- Pregnancy
- Risk Factors
- Term Birth
- Thinness
Keywords
- caesarean section rates
- child presentation
- delivery mode
- macrosomia
- maternal age
- maternal height
- newborn size
- obesity
- recent environment
Cerebral stiffness (CS) reflects the biophysical environment in which neurons grow and function. While long-term CS changes can occur in the course of chronic neurological disorders and aging, little is known about acute variations of CS induced by intracranial pressure variations. Current gold standard methods for CS and intracranial pressure such as magnetic resonance elastography and direct pressure recordings are either expensive and slow or invasive. The study objective was to develop a real-time method for in vivo CS measurement and to demonstrate its sensitivity to physiological aging and intracranial pressure variations induced by the Valsalva maneuver in healthy volunteers. We used trans-temporal ultrasound time-harmonic elastography (THE) with external shear-wave stimulation by continuous and superimposed vibrations in the frequency range from 27 to 56 Hz. Multifrequency wave inversion generated maps of shear wave speed (SWS) as a surrogate maker of CS. On average, cerebral SWS was 1.56 ± 0.08 m/s with a tendency to reduce with age (R = -0.76, p < 0.0001) while Valsalva maneuver induced an immediate stiffening of the brain as reflected by a 10.8 ± 2.5% increase (p < 0.0001) in SWS. Our results suggest that CS is tightly linked to intracranial pressure and might be used in the future as non-invasive surrogate marker for intracranial pressure, which otherwise requires invasive measurements.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Brain
- Elasticity Imaging Techniques
- Female
- Healthy Volunteers
- Humans
- Intracranial Pressure
- Male
- Middle Aged
- Valsalva Maneuver
- Young Adult
To examine relationships between the thicknesses of ganglion cell (GC)-related macular layers and central photopic or mesopic contrast sensitivity (CS) in healthy eyes. Measurements were made in 38 young and 38 older healthy individuals. Total, inner, and outer retinal layer (IRL) thicknesses were measured in the macula region through spectral-domain optical coherence tomography (SD-OCT) across three subfields, or rings, centered at the fovea: central foveal, pericentral, and peripheral. Ganglion cell complex and circumpapillary retinal nerve fiber layer thicknesses were also measured. Low-spatial-frequency CS for gratings presented at the central 10° visual field were measured through computerized psychophysical tests under photopic and mesopic conditions. Relationships were examined by uni- and multivariate regression analysis. Peripheral IRL thickness emerged as the only independent predictor of photopic CS (P = 0.001) in the young group and of photopic (P = 0.026) and mesopic CS (P = 0.001) in the older group. The slopes of regression lines used to predict CS from peripheral IRL thickness were significantly different for pair-wise comparisons of both photopic CS and age group (P = 0.0001) and mesopic CS (P = 0.0001) and age group. These models explained 37% of the variability in photopic CS and 36% of the variability in mesopic CS. Macular IRL thinning likely due to GC loss was related to reduced photopic and mesopic CS in older healthy eyes. In contrast, in the young eyes, a thicker macular IRL, possibly indicating transient gliosis, was associated with reduced CS.
MeSH Terms
- Adult
- Aged
- Aging
- Color Vision
- Contrast Sensitivity
- Cross-Sectional Studies
- Female
- Healthy Volunteers
- Humans
- Macula Lutea
- Male
- Mesopic Vision
- Middle Aged
- Nerve Fibers
- Retinal Ganglion Cells
- Tomography, Optical Coherence
- Visual Fields
- Young Adult
Mitochondrial diseases are complex disorders that exhibit their primary effects in energetically active tissues. Damage generated by mitochondria is also thought to be a key component of aging and age-related disease. An important model for mitochondrial dysfunction is the bang sensitive (bs) mutants in [i]Drosophila melanogaster[/i] Although these mutants all show a striking seizure phenotype, several bs mutants have gene products that are involved with mitochondrial function, while others affect excitability another way. All of the bs mutants ([i]para [/i] , [i]eas[/i], [i]jus[/i], [i]ses B[/i], [i]tko[/i] are examined here[i])[/i] paralyze and seize upon challenge with a sensory stimulus, most notably mechanical stimulation. These and other excitability mutants have been linked to neurodegeneration with age. In addition to these phenotypes, we have found age-related defects for several of the bs strains. The mutants [i]eas[/i], [i]ses B[/i], and [i]tko[/i] display shortened lifespan, an increased mean recovery time from seizure with age, and decreased climbing ability over lifespan as compared to isogenic CS or [i]w [/i] lines. Other mutants show a subset of these defects. The age-related phenotypes can be rescued by feeding melatonin, an antioxidant, in all the mutants except [i]ses B[/i] The age-related defects do not appear to be correlated with the seizure phenotype. Inducing seizures on a daily basis did not exacerbate the phenotypes and treatment with antiepileptic drugs did not increase lifespan. The results suggest that the excitability phenotypes and the age-related phenotypes may be somewhat independent and that these phenotypes mutants may arise from impacts on different pathways.
MeSH Terms
- Animals
- Drosophila Proteins
- Drosophila melanogaster
- Longevity
- Mutation
Keywords
- Drosophila
- aging
- bang sensitive
- mitochondria
Cigarette smoke (CS)-induced accumulation of mitochondrial damage has been widely implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. Mitophagy plays a crucial role in eliminating damaged mitochondria, and is governed by the PINK1 (PTEN induced putative protein kinase 1)-PRKN (parkin RBR E3 ubiquitin protein ligase) pathway. Although both increased PINK1 and reduced PRKN have been implicated in COPD pathogenesis in association with mitophagy, there are conflicting reports for the role of mitophagy in COPD progression. To clarify the involvement of PRKN-regulated mitophagy in COPD pathogenesis, prkn knockout (KO) mouse models were used. To illuminate how PINK1 and PRKN regulate mitophagy in relation to CS-induced mitochondrial damage and cellular senescence, overexpression and knockdown experiments were performed in airway epithelial cells (AEC). In comparison to wild-type mice, prkn KO mice demonstrated enhanced airway wall thickening with emphysematous changes following CS exposure. AEC in CS-exposed prkn KO mice showed accumulation of damaged mitochondria and increased oxidative modifications accompanied by accelerated cellular senescence. In vitro experiments showed PRKN overexpression was sufficient to induce mitophagy during CSE exposure even in the setting of reduced PINK1 protein levels, resulting in attenuation of mitochondrial ROS production and cellular senescence. Conversely PINK1 overexpression failed to recover impaired mitophagy caused by PRKN knockdown, indicating that PRKN protein levels can be the rate-limiting factor in PINK1-PRKN-mediated mitophagy during CSE exposure. These results suggest that PRKN levels may play a pivotal role in COPD pathogenesis by regulating mitophagy, suggesting that PRKN induction could mitigate the progression of COPD. Abbreviations: AD: Alzheimer disease; AEC: airway epithelial cells; BALF: bronchoalveolar lavage fluid; AKT: AKT serine/threonine kinase; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; COPD: chronic obstructive pulmonary disease; CS: cigarette smoke; CSE: CS extract; CXCL1: C-X-C motif chemokine ligand 1; CXCL8: C-X-C motif chemokine ligand 8; HBEC: human bronchial epithelial cells; 4-HNE: 4-hydroxynonenal; IL: interleukin; KO: knockout; LF: lung fibroblasts; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; 8-OHdG: 8-hydroxy-2'-deoxyguanosine; OPTN: optineurin; PRKN: parkin RBR E3 ubiquitin protein ligase; PCD: programmed cell death; PFD: pirfenidone; PIK3C: phosphatidylinositol-4:5-bisphosphate 3-kinase catalytic subunit; PINK1: PTEN induced putative kinase 1; PTEN: phosphatase and tensin homolog; RA: rheumatoid arthritis; ROS: reactive oxygen species; SA-GLB1/β-Gal: senescence-associated-galactosidase, beta 1; SASP: senescence-associated secretory phenotype; SNP: single nucleotide polymorphism; TNF: tumor necrosis factor.
MeSH Terms
- Animals
- Cell Cycle Proteins
- Cell Line
- Cellular Senescence
- Cigarette Smoking
- Disease Models, Animal
- Epithelial Cells
- Humans
- Lung
- Membrane Transport Proteins
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Microscopy, Electron
- Mitochondria
- Mitophagy
- Nuclear Proteins
- PTEN Phosphohydrolase
- Protein Kinases
- Pulmonary Disease, Chronic Obstructive
- Pyridones
- Reactive Oxygen Species
- Ubiquitin-Protein Ligases
Keywords
- COPD
- Cellular senescence
- PINK1
- PRKN
- mitophagy
{{medline-entry |title=Vascular mitochondrial respiratory function: the impact of advancing age. |pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30192630 |abstract=Little is known about vascular mitochondrial respiratory function and the impact of age. Therefore, skeletal muscle feed arteries were harvested from young (33 ± 7 yr, n = 10), middle-aged (54 ± 5 yr, n = 10), and old (70 ± 7 yr, n = 10) subjects, and mitochondrial respiration as well as citrate synthase (CS) activity were assessed. Complex I (CI) and complex I II (CI II) state 3 respiration were greater in young (CI: 10.4 ± 0.8 pmol·s ·mg and CI II: 12.4 ± 0.8 pmol·s ·mg , P < 0.05) than middle-aged (CI: 7 ± 0.6 pmol·s ·mg and CI II: 8.3 ± 0.5 pmol·s ·mg ) and old (CI: 7.2 ± 0.4 pmol·s ·mg and CI II: 7.6 ± 0.5 pmol·s ·mg ) subjects and, as in the case of complex II (CII) state 3 respiration, were inversely correlated with age [ r = -0.56 (CI), r = -0.7 (CI II), and r = 0.4 (CII), P < 0.05]. In contrast, state 4 respiration and mitochondria-specific superoxide levels were not different across groups. The respiratory control ratio was greater in young (2.2 ± 0.2, P < 0.05) than middle-aged and old (1.4 ± 0.1 and 1.1 ± 0.1, respectively) subjects and inversely correlated with age ( r = -0.71, P < 0.05). As CS activity was inversely correlated with age ( r = -0.54, P < 0.05), when normalized for mitochondrial content, the age-related differences and relationships with state 3 respiration were ablated. In contrast, mitochondrion-specific state 4 respiration was now lower in young (15 ± 1.4 pmol·s ·mg ·U CS , P < 0.05) than middle-aged and old (23.4 ± 3.6 and 27.9 ± 3.4 pmol·s ·mg ·U CS , respectively) subjects and correlated with age ( r = 0.46, P < 0.05). Similarly, superoxide/CS levels were lower in young (0.07 ± 0.01) than old (0.19 ± 0.41) subjects and correlated with age ( r = 0.44, P < 0.05). Therefore, with aging, vascular mitochondrial respiratory function declines, predominantly as a consequence of falling mitochondrial content. However, per mitochondrion, aging likely results in greater mitochondrion-derived oxidative stress, which may contribute to age-related vascular dysfunction. NEW