Journals of Gerontology Series A-Biological Sciences and Medical Sciences最新文献

Senescent cells that accumulate are regarded as promising therapeutic targets. However, senolytic therapy failed to achieve satisfactory results. We previously discovered that young human plasma improved vascular endothelial cell senescence, and UNC5B might be a novel intervention target. Netrin-1, as a natural ligand of UNC5B, plays roles in multiple age-related vascular disorders, but its involvement in aging is still unclear. Here, we observed a significant decrease in plasma Netrin-1 levels in old healthy subjects compared to the young. In vivo, adeno-associated-virus-mediated delivery of Netrin-1 into aged mice significantly improved functional recovery in a model of hindlimb ischemia, promoted angiogenesis in ischemic tissues, and activated the endothelial nitric oxide synthase. Furthermore, we revealed that low-dose Netrin-1 recombinant protein significantly reduced senescence-associated-β-galactosidase-positive cells, inhibited the P53 pathway, promoted cell migration, increased tubule formation, and elevated nitric oxide production in senescent endothelial cells. However, UNC5B inhibition blocked the pro-angiogenesis effect of low-dose Netrin-1 on senescent cells or aortic rings. In summary, this study depicts that modulating Netrin-1 signaling can result in improved vascular health and Netrin-1 may have therapeutic potential for age-related ischemic diseases.

Background: Hearing loss is linked to loneliness and social isolation, but evidence is typically based on self-reported hearing. This study quantifies the associations of objective and subjective hearing loss with loneliness and social network characteristics among older adults with untreated hearing loss.

Methods: This study uses baseline data (N = 933) from the Aging and Cognitive Health Evaluation in Elders (ACHIEVE) study. Hearing loss was quantified by the better ear, speech-frequency pure tone average (PTA), Quick Speech-in-Noise test, and hearing-related quality of life. Outcomes were validated measures of loneliness and social network characteristics. Associations were assessed by Poisson, negative binomial, and linear regression adjusted for demographic, health, and study design characteristics.

Results: Participants were mean of 76.8 (4.0) years, 54.0% female, and 87.6% White. Prevalence of loneliness was 38%. Worse PTA was associated with a 19% greater prevalence of moderate or greater loneliness (prevalence ration [PR]: 1.19.95% CI: 1.06, 1.33). Better speech-in-noise recognition was associated with greater social network characteristics (eg, larger social network size [IRR: 1.04, 95% CI: 1.00, 1.07]). Worse hearing-related quality of life was associated with a 29% greater prevalence of moderate or greater loneliness (PR: 1.29, 95% CI: 1.19, 1.39) and worse social network characteristics (eg, more constricted social network size [IRR: 0.96, 95% CI: 0.91, 1.00]).

Conclusions: Results suggest the importance of multiple dimensions of hearing to loneliness and social connectedness. Hearing-related quality of life may be a potentially useful, easily administered clinical tool for identifying older adults with hearing loss associated with greater loneliness and social isolation.

Background: Peripheral artery disease (PAD) is associated with lower physical activity but less is known about its association with daily patterns of activity. We examined the cross-sectional association between ankle-brachial index (ABI) and objectively measured patterns of physical activity among Hispanic/Latino adults.

Methods: We analyzed data from 7 688 participants (aged 45-74 years) in the Hispanic Community Health Study/Study of Latinos. ABI was categorized as low (≤0.90, indicating PAD), borderline low (0.91-0.99), normal (1.00-1.40), and high (>1.40, indicating incompressible ankle arteries). Daily physical activity metrics derived from accelerometer data included: log of total activity counts (LTAC), total log-transformed activity counts (TLAC), and active-to-sedentary transition probability (ASTP). Average differences between ABI categories in physical activity, overall and by 4-hour time-of-day intervals, were assessed using linear regression and mixed-effects models, respectively.

Results: In Hispanic/Latino adults, 5.3% and 2.6% had low and high ABIs, respectively. After adjustment, having a low compared to a normal ABI was associated with lower volume (LTAC = -0.13, p < .01; TLAC = -74.4, p = .04) and more fragmented physical activity (ASTP = 1.22%, p < .01). Having a low ABI was linked with more fragmented physical activity after 12 pm (p < .01). Having a high ABI was associated with lower volumes of activity (TLAC = -132.0, p = .03).

Conclusions: Having a low or high ABI is associated with lower and more fragmented physical activity in Hispanic/Latino adults. In adults with low ABI, physical activity is more fragmented in the afternoon to evening. Longitudinal research is warranted to expand these findings to guide targeted interventions for PAD or incompressible ankle arteries.

Background: The relationship between amino acids, B vitamins, and their metabolites with D3-creatine (D3Cr) dilution muscle mass, a more direct measure of skeletal muscle mass, has not been investigated. We aimed to assess associations of plasma metabolites with D3Cr muscle mass, as well as muscle strength and physical performance in older men from the Osteoporotic Fractures in Men cohort study.

Methods: Out of 1 425 men (84.2 ± 4.1 years), men with the lowest D3Cr muscle mass (n = 100), slowest walking speed (n = 100), lowest grip strength (n = 100), and a random sample (n = 200) serving as a comparison group to the low groups were included. Metabolites were analyzed using liquid chromatography-tandem mass spectrometry. Metabolite differences between the low groups and random sample and their relationships with the muscle outcomes adjusted for confounders and multiple comparisons were assessed using t-test/Mann-Whitney-Wilcoxon and partial correlations, respectively.

Results: For D3Cr muscle mass, significant biomarkers (p < .001) with ≥10% fold difference and largest partial correlations were tryptophan (Trp; r = 0.31), kynurenine (Kyn)/Trp; r = -0.27), nicotinamide (Nam)/quinolinic acid (Quin; r = 0.21), and alpha-hydroxy-5-methyl-tetrahydrofolate (hm-THF; r = -0.25). For walking speed, hm-THF, Nam/Quin, and Quin had the largest significance and fold difference, whereas valine (r = 0.17), Trp (r = 0.17), HKyn/Xant (r = -0.20), neopterin (r = -0.17), 5-methyl-THF (r = -0.20), methylated folate (r = -0.21), and thiamine (r = -0.18) had the strongest correlations. Only hm-THF was correlated with grip strength (r = -0.21) and differed between the low group and the random sample.

Conclusions: Future interventions focusing on how the Trp metabolic pathway or hm-THF influences D3Cr muscle mass and physical performance declines in older adults are warranted.

Background: A sizeable proportion of patients with chronic kidney disease (CKD) are reported to be frail. Here we examined the safety and efficacy of dapagliflozin in patients with CKD by frailty level.

Methods: Adults with CKD, with/without type 2 diabetes, with an estimated glomerular filtration rate (eGFR) of 25-75 mL/min/1.73 m2, and urinary albumin-to-creatinine ratio 200-5 000 mg/g were randomized to dapagliflozin (10 mg/day) or placebo. The primary endpoint was a composite of sustained ≥50% eGFR decline, end-stage kidney disease (ESKD), or death from kidney or cardiovascular (CV) causes.

Results: Frailty index (FI), assessed by Rockwood cumulative deficit approach, was calculable in 4 303/4 304 (99.9%) patients: 1 162 (27.0%) in not-to-mildly frail (FI ≤0.210), 1 642 (38.2%) in moderately frail (FI 0.211-0.310), and 1 499 (34.8%) in severely frail categories (FI >0.311). Dapagliflozin reduced the risk of the primary composite endpoint across all FI categories (hazard ratios [95% confidence interval {CI}]: 0.50 [0.33-0.76], 0.62 [0.45-0.85], and 0.64 [0.49--0.83], respectively; p-interaction = 0.67). Results were similar for secondary outcomes including kidney composite outcome (sustained ≥50% eGFR decline, ESKD or death from kidney cause; p-interaction = 0.44), CV endpoint (heart failure hospitalization or CV death; p-interaction = 0.63), and all-cause mortality (p-interaction p = .42). Results were consistent when using FI as a continuous variable. Occurrence of serious adverse events was numerically lower in patients receiving dapagliflozin versus placebo in all FI categories (16.9% vs 20.1%, 26.3% vs 30.7%, and 42.9% vs 47.8%, in not-to-mildly, moderately, and severely frail categories, respectively).

Conclusions: The relative benefit of dapagliflozin for all outcomes was consistent across all frailty categories, with no difference in associated safety.

Vascular aging is directly related to several major diseases including clinical primary hypertension. Conversely, elevated blood pressure itself accelerates vascular senescence. However, the interaction between vascular aging and hypertension has not been characterized during hypertensive aging. To depict the interconnectedness of complex mechanisms between hypertension and aging, we performed single-cell RNA sequencing of aorta, femoral and mesentery arteries, respectively, from male Wistar Kyoto rats and male spontaneously hypertensive rats aging 16 or 72 weeks. We integrated 12 data sets to map the blood vessels of senile hypertension from 3 perspective: vascular aging, hypertension, and vascular type. We found that aging and hypertension independently exerted a significant impact on the alteration of cellular composition and artery remodeling, even greater when superimposed. Consistently, smooth muscle cells (SMCs) underwent phenotypic switching from contractile toward synthetic, apoptotic, and senescent SMCs with aging/hypertension. Furthermore, we identified 3 subclusters of Spp1high, encoding protein osteopontin (OPN), synthetic SMCs, Spp1high matrix activated fibroblasts, and Spp1high scar-associated macrophage involved in hypertensive aging. Spp1high scar-associated macrophage enriched for reactive oxygen species metabolic process and cell migration-associated function. Cell-cell communication analysis revealed Spp1-Cd44 receptor pairing was markedly aggravated in the hypertensive aging condition. Importantly, the concentration of serum OPN significantly potentiated in aged hypertensive patients compared with the normal group. Thus, we provide a comprehensive cell atlas to systematically resolve the cellular diversity and dynamic cellular communication changes of the vessel wall during hypertensive aging, identifying a protein marker OPN as a potential regulator of vascular remodeling during hypertensive aging.

Background: Little is known about the current prevalence and management of hypertension among older Filipinos. To address this gap, we examined the prevalence, awareness, treatment, and control of hypertension, as well as their correlates, among older Filipinos.

Methods: We analyzed a nationally representative survey of Filipinos aged 60 years and older (N = 5 985) in the Philippines. Blood pressure (BP) measurements were taken using a digital BP apparatus. People with hypertension included those with a systolic BP ≥ 140 mmHg or a diastolic BP ≥ 90 mmHg, or those who reported current use of antihypertensive medication. People with undiagnosed hypertension were those who had measured hypertension but had not been diagnosed by a doctor as having hypertension, while people with untreated hypertension were those who had measured hypertension but not taking medication. Among those who were taking antihypertensive medication, respondents with measured hypertension were considered to have uncontrolled BP.

Results: Results showed that 69.1% of older Filipinos had hypertension, but only 61.6% of people with hypertension were aware of their hypertension and 51.5% were untreated. Sociodemographic factors, such as age, sex, education, and living arrangements, were significantly associated with hypertension prevalence, hypertension awareness, lack of treatment for hypertension, and/or suboptimal BP control.

Conclusion: We observed a high prevalence of hypertension among older Filipinos and a relatively low level of awareness and treatment of hypertension among them. While there are government efforts to address the growing prevalence of hypertension in the country, more efforts should be made to bring these government programs to older Filipinos.

Background: Sarcopenia and bone loss are both common in older individuals. However, the association between sarcopenia and bone fractures has not been evaluated longitudinally. In this study, we evaluated the association between computed tomography (CT)-based erector spinae muscle area and attenuation and vertebral compression fracture (VCF) in elderly individuals in a longitudinal study.

Methods: This study recruited individuals 50 years of age and older, who did not have VCF and underwent CT imaging for lung cancer screening during January 2016 to December 2019. Participants were followed up annually until January 2021. Muscle CT value and muscle area of the erector spinae were determined for muscle assessment. Genant score was used to define new-onset VCF. Cox proportional hazards models were used to assess the association between muscle area/attenuation and VCF.

Results: Of the 7 906 included participants, 72 developed new VCF over a median follow-up of 2 years. Large area of the erector spinae (adjusted hazard ratio [HR] = 0.2, 95% confidence interval [CI]: 0.1-0.7) and high bone attenuation (adjusted HR = 0.2, 95% CI: 0.1-0.5) were independently associated with VCF. High muscle attenuation was associated with severe VCF (adjusted HR = 0.46, 95% CI: 0.24-0.86). The addition of muscle area improved the area under the curve of bone attenuation from 0.79 (95% CI: 0.74-0.86) to 0.86 (95% CI: 0.82-0.91; p = .001).

Conclusions: CT-based muscle area/attenuation of the erector spinae was associated with VCF in elderly individuals, independently of bone attenuation. The addition of muscle area improved the performance of bone attenuation in predicting VCF.

Background: Hearing and vision difficulties are some of the most common deficits experienced by older adults. Having either visual or hearing difficulties increases the risk of comorbidity, disability, and poor quality of life. So far, however, few studies have examined the association between vision and hearing difficulties on life expectancy without activities of daily living (ADL) or instrumental ADL (IADL) limitations (LEWL).

Methods: Data came from the English Longitudinal Study of Ageing and the Health and Retirement Study in the United States from 2002 to 2013. The outcome was defined as reporting 2+ limitations with ADL/IADL. Life expectancy was estimated by discrete-time multistate life table models for hearing and vision difficulties separately as well as for combined vision and hearing difficulties by sex and age.

Results: Thirteen percent of men in England and the United States had ADL/IADL limitations, whereas, for women, it was 16% and 19% in England and the United States. At all ages, either vision or hearing difficulty was associated with shorter LEWL compared to no difficulties. Dual sensory difficulty (vision and hearing) reduced LEWL by up to 12 years in both countries. At the ages of 50 and 60 in England, hearing difficulty was associated with fewer years lived without ADL/IADL limitations than vision difficulty. In contrast, in the United States, vision difficulty led to fewer years lived without ADL/IADL limitations than hearing difficulty.

Conclusions: The implementation of strategies to reduce the prevalence and incidence of vision and hearing difficulties has the potential to increase the number of years spent without ADL/IADL limitations.

Background: The current study aims to examine association of dietary live microbes and nondietary prebiotic/probiotic intake with cognitive function among older U.S. adults, examining heterogeneity across demographic characteristics and diseases.

Methods: Participants from the National Health and Nutrition Examination Survey 2011-2014 cycles were selected and administered 3 cognitive function tests: the Consortium to Establish a Registry for Alzheimer's Disease Word Learning subtest (CERAD W-L, including immediate [CERAD-IRT] and delayed [CERAD-DRT] memory), the Animal Fluency Test (AFT), and the Digit Symbol Substitution Test (DSST). Test-specific and global cognition z-score was created. Based on their estimated dietary live microbes intake, participants were categorized into three groups: low, medium, and high. Text mining was employed to identify nondietary prebiotic/probiotic usage by examining the names and ingredients of dietary supplements or drugs.

Results: Participants in the medium (including AFT) and high (including global cognition, AFT, DSST, and CERAD-IRT) dietary live microbes intake group had significantly higher z-score of cognitive function compared to those in the low intake group. Among participants with cardiovascular disease history, nondietary prebiotic intake was associated with higher z-score in global cognition and CERAD-DRT compared to those who did not consume prebiotic. Additionally, probiotic intake was linked to higher z-score in global cognition, AFT, and DSST, particularly in participants with diabetes mellitus or hypertension.

Conclusions: Our study suggests that the intake of dietary live microbes and nondietary probiotic/prebiotic was associated with better cognitive function in older adults, particularly in specific disease states.