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

This study investigated the role of the miR-871-5p/proliferator-activated receptor α (PGC1α) pathway in ameliorating hepatic steatosis. We examined miR-871-5p expression in liver tissues of aging mice and AML12 senescent cells co-induced by low serum and palmitic acid (PA). Bioinformatics and multiple experiments were employed to validate the expression level of the target gene PGC1α for miR-871-5p. In this study, we aimed to investigate the potential role of miR-871-5p in regulating hepatic lipid deposition associated with aging. To do so, we performed in vitro transfection of both miR-871-5p mimic and inhibitor into senescent hepatocytes. Our results showed that miR-871-5p could inhibit PGC1α expression and cause lipid deposition in the liver due to aging. miR-871-5p controls this process by regulating PGC1α/fatty acid β-oxidation. H&E staining displayed the appearance of fat vacuoles in the livers of aging mice, and fatty acid β-oxidation-related genes (acyl-coenzyme A oxidase 1 carnitine palmitoyl transferase 1α and peroxisome proliferator-activated receptor α) expression was significantly reduced. Lipogenic genes (sterol regulatory element binding protein 1C and fatty acid synthase) expression level was increased in the livers of aging mice. In AML12 cells co-induced by low serum and PA, miR-871-5p mimics decreased PGC1α expression and increased lipid droplet accumulation in senescent hepatocytes. Conversely, miR-871-5p inhibitor promoted PGC1α expression and reduced lipid deposition in senescent hepatocytes. Our findings suggest that inhibiting miR-871-5p could be crucial in ameliorating aging-associated hepatic steatosis. These findings offer valuable insights into the molecular mechanisms driving hepatic steatosis in aging.

Telomere length (TL) may be a biomarker of aging processes as well as age-related diseases. However, most studies of TL and aging are conducted in high-income countries. Less is known in low- and middle-income countries (LMICs) such as South Africa, where life expectancy remains lower despite population aging. We conducted a descriptive analysis of TL in a cohort of older adults in rural South Africa. TL was assayed from venous blood draws using quantitative polymerase chain reaction (T/S ratio). We examined the correlation between TL and biomarkers, demographic characteristics, mental/cognitive health measures, and physical performance measures in a subsample of the Wave 1 2014-2015 "Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa" (HAALSI) cohort (n = 510). We used logistic regression to measure the association between TL and mortality through Wave 3 (2021-2022). In bivariate analyses, TL was significantly correlated with age (r = -0.29, p < .0001), self-reported female sex (r = 0.13, p = .002), mortality (r = -0.1297, p = .003), diastolic blood pressure (r = 0.09, p = .037), pulse pressure (r = -0.09, p = .045), and being a grandparent (r = -0.17, p = .0001). TL was significantly associated with age (β = -0.003; 95% confidence interval [CI] = -0.005, -0.003). TL was significantly associated in unadjusted multivariate analyses with mortality, but the relationship between TL and mortality was attenuated after adjusting for age (odds ratio [OR] = 0.19; 95% CI = 0.03, 1.27) and other covariates (OR = 0.17; 95% CI = 0.02, 1.19). Our study is the first analysis of TL in an older adult South African population. Our results corroborate existing relationships between TL and age, sex, cardiometabolic disease, and mortality found in higher-income countries.

To deepen the understanding of genetic mechanisms influencing mortality risk, we investigated the impact of genetic predisposition to longevity and APOE-ε4, on all-cause mortality and specific causes of mortality. We further investigated the mediating effects of dementia on these relationships. Using data on 7 131 adults aged ≥50 years (mean = 64.7 years, standard deviation [SD] = 9.5) from the English Longitudinal Study of Aging, genetic predisposition to longevity was calculated using the polygenic score approach (PGSlongevity). APOE-ε4 status was defined according to the absence or presence of ε4 alleles. The causes of death were ascertained from the National Health Service central register, which was classified into cardiovascular diseases, cancers, respiratory illness, and all other causes of mortality. Of the entire sample, 1 234 (17.3%) died during an average 10-year follow-up. One-SD increase in PGSlongevity was associated with a reduced risk for all-cause mortality (hazard ratio [HR] = 0.93, 95% confidence interval [CI]: 0.88-0.98, p = .010) and mortalities due to other causes (HR = 0.81, 95% CI: 0.71-0.93, p = .002) in the following 10 years. In gender-stratified analyses, APOE-ε4 status was associated with a reduced risk for all-cause mortality and mortalities related to cancers in women. Mediation analyses estimated that the percent excess risk of APOE-ε4 on other causes of mortality risk explained by the dementia diagnosis was 24%, which increased to 34% when the sample was restricted to adults who were aged ≤75 years old. To reduce the mortality rate in adults who are aged ≥50 years old, it is essential to prevent dementia onset in the general population.

Sarcopenia is a geriatric disease associated with increased mortality and disability. Early diagnosis and intervention are required to prevent it. This study investigated biomarkers for sarcopenia by using a combination of comprehensive clinical data and messenger RNA-sequencing (RNA-seq) analysis obtained from peripheral blood mononuclear cells. We enrolled a total of 114 older adults aged 66-94 years (52 sarcopenia diagnosed according to the Asian Working Group for Sarcopenia 2019 consensus and 62 normal older people). We used clinical data which were not included diagnosis criteria of sarcopenia, and stride length showed significance by logistic regression analysis (Bonferroni corrected p = .012, odds ratio = 0.14, 95% confidence interval [CI]: 0.05-0.40). RNA-seq analysis detected 6 differential expressed genes (FAR1, GNL2, HERC5, MRPL47, NUBP2, and S100A11). We also performed gene-set enrichment analysis and detected 2 functional modules (ie, hub genes, MYH9, and FLNA). By using any combination of the 9 candidates and basic information (age and sex), risk-prediction models were constructed. The best model by using a combination of stride length, HERC5, S100A11, and FLNA, achieved a high area under the curve (AUC) of 0.91 in a validation cohort (95% CI: 0.78-0.95). The quantitative PCR results of the 3 genes were consistent with the trend observed in the RNA-seq results. When BMI was added, the model achieved a high AUC of 0.95 (95% CI: 0.84-0.99). We have discovered potential biomarkers for the diagnosis of sarcopenia. Further refinement may lead to their future practical use in clinical use.

Statins are widely used for cardiovascular disease prevention but their effects on cognition remain unclear. Statins reduce cholesterol concentration and have been suggested to provide both beneficial and detrimental effects. Our aim was to investigate the cross-sectional and longitudinal association between statin use and cognitive performance, and whether blood low-density lipoprotein, high-density lipoprotein, triglycerides, glucose, C-reactive protein, and vitamin D biomarkers mediated this association. We used participants from the UK biobank aged 40-69 without neurological and psychiatric disorders (n = 147 502 and n = 24 355, respectively). We performed linear regression to evaluate the association between statin use and cognitive performance and, mediation analysis to quantify the total, direct, indirect effects and the proportion meditated by blood biomarkers. Statin use was associated with lower cognitive performance at baseline (β = -0.40 [-0.53, -0.28], p = <.0001), and this association was mediated by low-density lipoprotein (proportion mediated = 51.4%, p = .002), C-reactive protein (proportion mediated = -11%, p = .006) and blood glucose (proportion mediated = 2.6%, p = .018) concentrations. However, statin use was not associated with cognitive performance, measured 8 years later (β = -0.003 [-0.11, 0.10], p = .96). Our findings suggest that statins are associated with lower short-term cognitive performance by lowering low-density lipoprotein and raising blood glucose concentrations, and better performance by lowering C-reactive protein concentrations. In contrast, statins have no effect on long-term cognition and remain beneficial in reducing cardiovascular risk factors.

Background: Hearing loss is a risk factor for dementia; whether the association is causal or due to a shared pathology is unknown. We estimated the association of brain β-amyloid with hearing, hypothesizing no association. As a positive control, we quantified the association of hearing loss with neurocognitive test performance.

Methods: Cross-sectional analysis of Atherosclerosis Risk in Communities-Positron Emission Tomography study data. Amyloid was measured using global cortical and temporal lobe standardized uptake value ratios (SUVRs) calculated from florbetapir-positron emission tomography scans. Composite global and domain-specific cognitive scores were created from 10 neurocognitive tests. Hearing was measured using an average of better-ear air conduction thresholds (0.5-4 kHz). Multivariable-adjusted linear regression estimated mean differences in hearing by amyloid and mean differences in cognitive scores by hearing, stratified by race.

Results: In 252 dementia-free adults (72-92 years, 37% Black race, and 61% female participants), cortical or temporal lobe SUVR was not associated with hearing (models adjusted for age, sex, education, and APOE ε4). Each 10 dB HL increase in hearing loss was associated with a 0.134 standard deviation lower mean global cognitive factor score (95% CI: -0.248, -0.019), after adjustment for demographic and cardiovascular factors. Observed hearing-cognition associations were stronger in Black versus White participants.

Conclusions: Amyloid is not associated with hearing, suggesting that pathways linking hearing and cognition are independent of this pathognomonic Alzheimer's-related brain change. This is the first study to show that the impact of hearing loss on cognition may be stronger in Black versus White adults.

Background: Dementia severity is unavailable in administrative claims data. We examined whether a claims-based frailty index (CFI) can measure dementia severity in Medicare claims.

Methods: This cross-sectional study included the National Health and Aging Trends Study Round 5 participants with possible or probable dementia whose Medicare claims were available. We estimated the Functional Assessment Staging Test (FAST) scale (range: 3 [mild cognitive impairment] to 7 [severe dementia]) using information from the survey. We calculated CFI (range: 0-1, higher scores indicating greater frailty) using Medicare claims 12 months prior to the participants' interview date. We examined C-statistics to evaluate the ability of the CFI in identifying moderate-to-severe dementia (FAST stage 5-7) and determined the optimal CFI cut-point that maximized both sensitivity and specificity.

Results: Of the 814 participants with possible or probable dementia and measurable CFI, 686 (72.2%) patients were ≥75 years old, 448 (50.8%) were female, and 244 (25.9%) had FAST stage 5-7. The C-statistic of CFI to identify FAST stage 5-7 was 0.78 (95% confidence interval: 0.72-0.83), with a CFI cut-point of 0.280, achieving the maximum sensitivity of 76.9% and specificity of 62.8%. Participants with CFI ≥0.280 had a higher prevalence of disability (19.4% vs 58.3%) and dementia medication use (6.0% vs 22.8%) and higher risk of mortality (10.7% vs 26.3%) and nursing home admission (4.5% vs 10.6%) over 2 years than those with CFI <0.280.

Conclusions: Our study suggests that CFI can be useful in identifying moderate-to-severe dementia from administrative claims among older adults with dementia.

Background: Frailty is increasingly recognized as a useful measure of vulnerability in older adults. Multiple claims-based frailty indices (CFIs) can readily identify individuals with frailty, but whether 1 CFI improves prediction over another is unknown. We sought to assess the ability of 5 distinct CFIs to predict long-term institutionalization (LTI) and mortality in older Veterans.

Methods: Retrospective study conducted in U.S. Veterans ≥65 years without prior LTI or hospice use in 2014. Five CFIs were compared: Kim, Orkaby (Veteran Affairs Frailty Index [VAFI]), Segal, Figueroa, and the JEN-FI, grounded in different theories of frailty: Rockwood cumulative deficit (Kim and VAFI), Fried physical phenotype (Segal), or expert opinion (Figueroa and JFI). The prevalence of frailty according to each CFI was compared. CFI performance for the coprimary outcomes of any LTI or mortality from 2015 to 2017 was examined. Because Segal and Kim include age, sex, or prior utilization, these variables were added to regression models to compare all 5 CFIs. Logistic regression was used to calculate model discrimination and calibration for both outcomes.

Results: A total of 3 million Veterans were included (mean age 75, 98% male participants, 80% White, and 9% Black). Frailty was identified for between 6.8% and 25.7% of the cohort with 2.6% identified as frail by all 5 CFIs. There was no meaningful difference between CFIs in the area under the receiver operating characteristic curve for LTI (0.78-0.80) or mortality (0.77-0.79).

Conclusions: Based on different frailty constructs, and identifying different subsets of the population, all 5 CFIs similarly predicted LTI or death, suggesting each could be used for prediction or analytics.

Background: The Study of Muscle, Mobility and Aging (SOMMA) aims to understand the biological basis of many facets of human aging, with a focus on mobility decline, by creating a unique platform of data, tissues, and images.

Methods: The multidisciplinary SOMMA team includes 2 clinical centers (University of Pittsburgh and Wake Forest University), a biorepository (Translational Research Institute at Advent Health), and the San Francisco Coordinating Center (California Pacific Medical Center Research Institute). Enrollees were age ≥70 years, able to walk ≥0.6 m/s (4 m); able to complete 400 m walk, free of life-threatening disease, and had no contraindications to magnetic resonance or tissue collection. Participants are followed with 6-month phone contacts and annual in-person exams. At baseline, SOMMA collected biospecimens (muscle and adipose tissue, blood, urine, fecal samples); a variety of questionnaires; physical and cognitive assessments; whole-body imaging (magnetic resonance and computed tomography); accelerometry; and cardiopulmonary exercise testing. Primary outcomes include change in walking speed, change in fitness, and objective mobility disability (able to walk 400 m in 15 minutes and change in 400 m speed). Incident events, including hospitalizations, cancer diagnoses, fractures, and mortality are collected and centrally adjudicated by study physicians.

Results: SOMMA exceeded its goals by enrolling 879 participants, despite being slowed by the COVID-19 pandemic: 59.2% women; mean age 76.3 ± 5.0 years (range 70-94); mean walking speed 1.04 ± 0.20 m/s; 15.8% identify as other than Non-Hispanic White. Over 97% had data for key measurements.

Conclusions: SOMMA will provide the foundation for discoveries in the biology of human aging and mobility.