Experimental gerontology最新文献

Senescent chondrocytes or signaling mechanisms leading to senescence are promising new therapeutic approaches for ameliorating cartilage degradation. Herein, we show that the transactive response DNA/RNA-binding protein (TDP-43) regulates chondrocyte senescence and ameliorates cartilage degradation. First, a significant decrease in TDP-43 was observed in 16-month-old mice compared with younger mice. Immunohistochemistry (IHC) analysis of mouse articular cartilage showed that p21, p16, p53, and matrix metalloprotein-13 (MMP13) were increased, but laminB1 and Collagen type II alpha1 1 chain (Col2a1) were decreased in 16-month-old mice. Furthermore, TDP-43 levels were decreased in vivo following D-galactose (D-gal) induction. Therefore, we investigated the role of TDP-43 in the senescent chondrocytes. ATDC5 cells were induced to overexpress TDP-43. Western blot analysis showed increased expression of laminB1, Ki67, and PCNA but decreased expression of p21, p16, p53, and MMP13. Senescence-associated-β-galactosidase (SA-β-Gal) assay, γH2AX staining, and EdU were performed to assess changes in chondrocytes, showing weaker SA-β-Gal and γH2AX staining but stronger EdU and Alican Blue staining. However, TDP-43 deficiency had opposing effects, and similar to D-gal stimulation results. Taken together, our data verified that TDP-43 negatively correlated with senescence markers, positively correlated with cell proliferation markers, and could alleviate cartilage degradation induced by D-gal. This may be an essential mechanism of cellular senescence and cartilage degradation.

Mountain cultivated ginseng (MCG) is planted in mountain forests to simulate traditional wild ginseng; therefore, it has a greater pharmacological effect than cultivated ginseng (CG) in the garden; however, insufficient evidence confirms this theory. In light of the health-promoting and life-extending properties of ginseng, we analyzed the efficacy of MCG and CG. Initial observations revealed that the phytosterols content of MCG was higher than that of CG, with a positive correlation to the duration of growth. The distinction between phytosterols in MCG and in CG is predominately determined by the stigmasterol content using High-Performance Liquid Chromatography (HPLC). The lifespan of Drosophila melanogaster (fruit flies) that aged naturally was prolonged by phytosterols in MCG and CG and stigmasterols. Further, they prolonged healthy ageing as measured by progeny numbers, length of sleep, climbing distance, and survival following oxidative damage. The findings of behavioral observations revealed that phytosterols in MCG were more efficacious than in CG in promoting health maintenance and life extension; moreover, stigmasterol indicated that these effects were dose-dependent. Stigmasterols, phytosterols in MCG and CG have restored age-associated decreases in steroid hormone levels. Notably, molecular docking was predicted to promote stigmasterol's binding to the steroid hormone receptor ECR due to its similarity to steroid hormones. In addition, stigmasterols triggered the steroid hormone signaling pathway by increasing the activity of key genes Eip75B and Br in 20E signaling and Jhamt, HmGR, Met, and Kr-h1 in JH signaling. Phytosterols, as a natural product, regulated health and longevity as a dietary supplement similar to that of steroids, which supported the social requirements of healthy ageing.

Background

Association of asthma with the risk of cardiovascular disease has not been fully elucidated. So, this study tried to explore the genetic effect of asthma on five cardiovascular diseases and 90 peripheral cardiovascular proteins to answer the above topic.

Methods

Instrumental variables predicting asthma was extracted from its genome-wide association study data. Two-sample and multivariate MR approaches were used to assess the genetic association of exposure factor (i.e., asthma) with outcome factors (i.e., hypertension, atrial fibrillation, angina pectoris, myocardial infarction, heart failure, and 90 peripheral cardiovascular proteins).

Results

First, asthma nominally increased the risk of hypertension and atrial fibrillation (OR = 1.009, 95%CI = 1.003–1.016, P = 0.004; OR = 1.074, 95%CI = 1.024–1.127, P = 0.003). Second, of the 90 cardiovascular proteins, asthma was associated with the increased levels of tumor necrosis factor ligand superfamily member 14 and CC motif chemokine 4 (β = 0.145, 95%CI = 0.077–0.212, P = 2.936e-05; β = 0.128, 95%CI = 0.063–0.193, P = 1.036e-04). Third, CC motif chemokine 4 increased the risk of hypertension (P = 0.043); and after adjusting for this protein, asthma still increased the risk of hypertension, but the strength of its P-value changed from 0.004 to 0.011.

Conclusion

Asthma was a risk factor for hypertension and atrial fibrillation at the genetic level, and CC motif chemokine 4 might play a mediating role in the mechanism by which asthma promoted hypertension. Thus, effective control of asthma may help reduce the risk of some cardiovascular diseases in older adults.

Background

The association between frailty and sex hormone-binding globulin (SHBG) or insulin-like growth factor-1(IGF-1) levels demonstrates sex differences with inconsistent conclusions. This study aims to explore the causal relationship between frailty and SHBG or IGF-1 levels through bidirectional Mendelian randomization (MR).

Methods

We conducted two-sample bidirectional sex-stratified MR analyses using summary-level data from genome-wide association studies (GWASs) to examine the causal relationship between frailty and IGF-1 or SHBG levels, as measured by frailty index (FI) and frailty phenotype (FP). We use the random-effects inverse-variance weighted (IVW), weighted median, MR-Egger, MR-Egger intercept, and leave-one-out approaches.

Result

The relationship between frailty and SHBG or IGF-1 levels is inversely related, with a significant decrease in SHBG levels in females. Specifically, SHBG levels significantly decrease with FI (β = −5.49; 95 % CI: −9.67 to −1.32; FDR = 0.02) and more pronounced with FP (β = −10.14; 95 % CI: −16.16 to −4.13; FDR = 0.01), as determined by the IVW approach. However, reverse analysis shows no significant effect of IGF-1 or SHBG levels on either FI or FP (p > 0.05).

Conclusion

Our study indicates a negative correlation between frailty and the levels of SHBG and IGF-1. It is suggested that further research is required to establish cut-off values for SHBG and IGF-1 levels in the frailty population. This is particularly important for females at higher risk, such as those undergoing menopause, to enable comprehensive assessment and early prevention efforts. While the findings imply that reduced IGF-1 and SHBG levels may not directly contribute to frailty, it is important not to overlook the underlying mechanisms through which they may indirectly influence frailty.

Aims

i) to compare 30-s sit-to-stand (STS) test repetitions and power between older adults with and without Parkinson's disease (PD) and ii) to evaluate the relationship of STS repetitions and power with functional measures in older people with PD.

Methods

STS repetitions and power (Alcazar's equation) during the 30-s STS test were assessed in forty-six age- and sex-matched older adults with and without PD. Functional measures included habitual (HGS) and maximum gait speed (MGS), timed-up-and-go (TUG) test and the Mini-Balance Evaluation System Test (Mini-BEST). PD-specific tests were as follows: the motor subscale of the Unified Parkinson's Disease Rating Scale (UPDRS-III), quality of life [Parkinson's Disease Questionnaire (PDQ-39)], perceived freezing of gait (FOG questionnaire), and fear of falling [Falls Efficacy Scale (FES)]. T scores, repeated measures ANOVA and linear regression analyses were used.

Results

T scores for older adults with PD were − 2.7 ± 4.5 for STS repetitions, −5.2 ± 4.2 for absolute STS power, and − 3.1 ± 4.6 for relative STS power compared to older adults without PD. T scores for absolute STS power were lower than T scores for STS repetitions (p < 0.001) and relative STS power (p < 0.001). Both absolute and relative STS power and STS repetitions showed similar correlations with functional measures (r = 0.44 to 0.59; both p < 0.05). Relative STS power (r = −0.55; p < 0.05) and STS repetitions (r = −0.47 to −0.55; p < 0.05) but not absolute STS power were correlated to PD-specific tests.

Conclusions

STS repetitions and power values estimated through the 30-s STS test were lower in older people with PD than without PD. Overall, STS power measures were similarly associated with functional performance as STS repetitions, indicating these power equations can be implemented when assessing lower extremity function in older people with PD.

Background

The role of main work during the life course in predicting frailty, a typical geriatric syndrome, is still largely unknown. Therefore, with this research, we aimed to investigate the potential association between the main work done during the life with frailty and pre-frailty among participants 60 years and older of the UK Biobank study.

Methods

Frailty and pre-frailty presence were ascertained using a model including 5 indicators (weakness, slowness, weight loss, low physical activity, and exhaustion); the main employment status was ascertained using self-reported information. The association between frailty and main work was explored using an ordinal logistic regression model and reported as odds ratios (ORs) with their 95 % confidence intervals (CIs).

Results

The final sample comprised a total of 50,447 individuals (mean age: 64.2 years, females: 50.2 %). Individuals with higher qualifications had a reduced risk of frailty (OR = 0.881, 95%CI = 0.83–0.95, p-value<0.001 for pre-frail and OR = 0.681, 95%CI = 0.63–0.73, p-value<0.001 for frail) compared to those with lower qualifications. Moreover, active participation in the workforce, compared to being inactive, emerged as a protective factor from frailty (OR = 0.753, 95%CI = 0.70–0.81, p-value<0.001). The categories of Associate Professional and Technical Occupations exhibited protective effects against both pre-frailty and frailty. Similarly, occupations categorized as Professional and Management demonstrated protective effects against pre-frailty and frailty when compared to Elementary Occupations. Additionally, engagement in Trades and Services occupations, as opposed to Elementary Occupations, appeared to be protective against frailty.

Conclusions

In this large cross-sectional investigation based on the data of the UK Biobank we found that work during lifetime could be an important factor in determining frailty later in life.

Glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) are putative non-amyloid biomarkers indicative of ongoing inflammatory and neurodegenerative disease processes. Hence, this study aimed to demonstrate the relationship between plasma biomarkers (GFAP and NfL) and ¹⁸F-AV-1451 tau PET images, and to explore their effects on cognitive function. Ninety-one participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database and 20 participants from the Shanghai Action of Prevention Dementia for the Elderly (SHAPE) cohort underwent plasma biomarker testing, ¹⁸F-AV-1451 tau PET scans and cognitive function assessments. Within the ADNI, there were 42 cognitively normal (CN) individuals and 49 with mild cognitive impairment (MCI). Similarly, in the SHAPE, we had 10 CN and 10 MCI participants. We calculated the standardized uptake value ratios (SUVRs) for the regions of interest (ROIs) in the ¹⁸F-AV-1451 PET scans. Using plasma biomarkers and regional SUVRs, we trained machine learning models to differentiate between MCI and CN subjects with ADNI database and validated in SHAPE.

Results showed that eight selected variables (including left amygdala SUVR, right amygdala SUVR, left entorhinal cortex SUVR, age, education, plasma NfL, plasma GFAP, plasma GFAP/ NfL) identified by LASSO could differentiate between the MCI and CN individuals, with AUC ranging from 0.783 to 0.926. Additionally, cognitive function was negatively associated with the plasma biomarkers and tau deposition in amygdala and left entorhinal cortex. Increased tau deposition in amygdala and left entorhinal cortex were related to increased plasma biomarkers. Moreover, tau pathology mediated the effect of plasma biomarkers level on the cognitive decline. The present study provides valuable insights into the association among plasma markers (GFAP and NfL), regional tau deposition and cognitive function. This study reports the mediation effect of brain regions tau deposition on the plasma biomarkers level and cognitive function, indicating the significance of tau pathology in the MCI patients.

Background

Facet joint osteoarthritis (FJOA) is a prevalent condition contributing to low back pain, particularly in the elderly population. This study aimed to investigate the potential role of Cytokine Receptor-like Factor 1 (CRLF1) in FJOA pathogenesis and its therapeutic implications.

Methods

Bioinformatics analysis was utilized to identify CRLF1 as the target gene, followed by quantification of CRLF1 expression levels and joint degeneration degree using immunohistochemistry (IHC). In primary chondrocytes, the inhibition of CRLF1 expression by siRNA was performed, and Western blot analysis was conducted to evaluate the involvement of the extracellular matrix and MAPK/ERK signaling pathway. Flow cytometry was employed to assess the apoptosis rate of chondrocytes, while immunofluorescence (IF) was utilized to evaluate the localization of CRLF1, cleaved-caspase3, MMP13, COL2A1, and ERK.

Results

The expression of CRLF1 was found to be significantly elevated in FJOA tissues compared to normal tissues. Through the use of loss-of-function assays, it was determined that CRLF1 not only enhanced the rate of apoptosis in chondrocytes, but also facilitated the degradation of the extracellular matrix in vitro. Furthermore, CRLF1 was found to activate the ERK1/2 pathways. The pro-arthritic effects elicited by CRLF1 were mitigated by treatment with the MEK inhibitor U0126 in chondrocytes.

Conclusion

These results suggest that CRLF1 enhances chondrocytes apoptosis and extracellular matrix degration in FJOA and thus may therefore be a potential therapeutic target for FJOA.

Cognitive impairment is a common feature in neurodegenerative diseases such as multiple sclerosis (MS). This study aims to explore the potential of enhancing the beneficial effects of fluoxetine (FLX), a neuroprotective agent known for its ability to increase neural plasticity by utilizing nanoparticles. The study specifically focuses on the synthesis and evaluation of PEGylated chitosan nanoparticles of FLX and its effect on demyelination and the subsequent cognitive impairment (CI) in the hippocampus of rats induced by local injection of lysophosphatidylcholine (LPC). Chitosan/polyethylene glycol nanoparticles were synthesized, and their properties were analyzed. Demyelination was induced in rats via hippocampal injections of lysolecithin. Behavioral assessments included open field maze, elevated plus maze, and novel object recognition memory (NORM) tests. Hippocampal levels of insulin-like growth factor (IGF-1) and brain-derived neurotrophic factor (BDNF) were measured using enzyme-linked immunoassay (ELISA). The extent of remyelination was quantified using Luxol fast blue staining. Nanoparticle size measured 240.2 nm with 53 % encapsulation efficacy. Drug release exhibited a slow pattern, with 76 % released within 4 h. Nanoparticle-treated rats displayed reduced anxiety-like behavior, improved memory, increased BDNF levels, and a reduced extent of demyelination, with no change in IGF- levels. In addition, FLX -loaded chitosan nanoparticles had better effect on cognitive improvement, BDNF levels in the hippocampus that FLX. Altering pharmacokinetics and possibly pharmacodynamics. These findings highlight the potential of innovative drug delivery systems, encouraging further research in this direction.