The journals of gerontology. Series A, Biological sciences and medical sciences最新文献

There is growing interest in the use of molecular features as predictors of age, age-related disease risk and mortality. A major shortcoming of this field, however, is the lack of suitable translational research models to identify and understand the underlying mechanisms of these predictive biomarkers in human populations. In particular, we lack a system which, like humans, is genetically variable, lives in diverse environments, and experiences aging-related chronic conditions treated in the context of a sophisticated health care system. Here, we present results from our analysis of data from the Dog Aging Project (DAP), a long-term longitudinal study of aging in companion dogs. Using longitudinal survival models on data from 937 dogs of the deeply phenotyped Precision Cohort within the DAP, we present the striking finding of a strong, highly significant positive correlation between the effect of individual metabolites on all-cause mortality in humans, and the association of those same metabolites on all-cause mortality in dogs. We also find that across these independent human studies, the biomarkers identified are also highly correlated, strongly suggesting a general signature of mortality within the plasma metabolome across humans, and now in dogs as well. Given the many similarities between dogs and humans with respect to genetics, environment, disease, and disease treatment, and the fact that dogs are so much shorter lived than humans, we argue that dogs represent an extremely valuable translational model in our ongoing effort to understand the underlying molecular causes and consequences of age-related morbidity and mortality in humans.

Background: Peak oxygen consumption during exercise (VO2peak), is a direct measure of cardiorespiratory fitness (CF), a key indicator of physical function and overall health. However, the molecular changes that underpin VO2peak variation are not clear. Our objective is to understand the microRNA (miRNA) signatures that relate to VO2peak variation, which could provide insights to novel mechanisms that contribute to low VO2peak.

Methods: We used small RNA sequencing to analyze baseline, cross-sectional serum samples from 72 participants (70- to 91-year old). We analyzed samples from individuals with low or high VO2peak (N = 18/group) as well as samples from 36 randomly selected participants spanning the entire spectrum of VO2peak. We used LIMMA analysis package for regression analysis and to identify differentially expressed miRNAs.

Results: We identified 1055 miRNAs expressed in all serum samples. Expression of 65 miRNAs differed between participants with low and high VO2peak (P < .05). After P-value adjustment, expression of 5 miRNAs (miR-1301-3p, -431-5p, -501-5p, -519a-3p, and -18a-3p) remained significantly different (FDR = 0.05). The Area Under the Curve for the five miRNAs ranged from 0.77 to 0.84. The optimal sensitivity and specificity ranged from 70% to 80% and 80% to 90%, respectively. After adjustment for age and sex covariates, 46 miRNAs significantly correlated with VO2peak (P < .05) and miR-519a-3p remained significant based on adjusted P-values.

Conclusions: We identified a miRNA signature of VO2peak in older individuals that might provide insights to novel mechanisms that drive low VO2peak. Future studies will validate the findings in a larger, longitudinal study cohort.

With parental age rising around the globe, an increased understanding of the impact on health and longevity is needed. Here, we report how the continuous selection of the last progeny during the Caenorhabditis elegans reproductive span results in a diminishment of multiple age-related health measures. After more than 50 generations of late selection, progeny displayed diminished resistance to acute oxidative stress, disrupted partitioning of stored lipids, reduced movement capacity, and an overall shortening of lifespan (36.84% reduction). In contrast, starvation resistance was improved and late selection had negligible effects on developmental timing and total reproductive output that suggests a reduction in lifespan health to preserve reproductive capacity. The phenotypes of late selection are reminiscent of animals with activation of the cytoprotective transcription factor SKN-1 that may facilitate transcriptional remodeling following late reproductive selection. These findings suggest the existence of a homeostatic mechanism for bookmarking the temporal boundaries of the parental reproductive span that reshapes the way we think about parental age influencing offspring fitness.

Background: Current understanding of the last year of life with dementia is disproportionately informed by studies conducted in western contexts, primarily within long-term care settings. This study examines the last year of life experience for community-dwelling older adults and their caregivers in an Asian setting.

Methods: Using prospective longitudinal cohort data from 125 family caregivers to older adults who have died during the study, we estimate separate random effects regression models to identify factors associated with hospital admissions, medical interventions, care experience, and informal caregiving hours. We also estimate costs associated with informal caregiving hours.

Results: Nearly half (48%) of older adults experienced an inpatient admission, and nearly all (92%) experienced a potentially burdensome intervention. Urinary tract infections were the strongest predictor of hospital admissions (adjusted odds ratio [AOR] = 10.42, p = .00) and medical interventions (AOR = 9.61, p = .02). Pneumonia (AOR = 8.40, p = .05) and febrile episodes (AOR = 3.94, p = .03) were associated with increased odds of intervention, whereas caregivers who prioritized comfort care only were associated with reduced interventions (AOR = 0.28, p = .04) and increased admissions (AOR = 3.20, p = .04). Family caregivers provided 42 hours of care per week on average, and 30% gave up their employment to care for the older adult during the older adult's final year.

Conclusions: Community-dwelling older adults in Singapore experienced similar clinical problems and potentially more burdensome interventions, including feeding tubes and physical restraints, than described previously in other contexts, highlighting the need for a palliative approach not apparent in the frequent acute care utilization, interventions, and caregiving burden observed.

Background: Obesity increases risks for mobility limitations and disability in older adults. We examined the long-term effects of an intensive lifestyle intervention (ILI) versus diabetes support and education (DSE) and body mass index (BMI) on disability.

Methods: Disability was assessed using the Pepper Assessment Tool for Disability (PAT-D) over four post-trial visits in Look AHEAD participants with type 2 diabetes and overweight/obesity. Disability and severe disability were defined as self-reporting "a lot of difficulty" or "unable" to perform ≥1 and ≥3 activities, respectively, on PAT-D subscales for mobility, instrumental, and basic activities of daily living (IADLs and BADLs). Associations between intervention group and BMI with disability prevalence were analyzed with GEE regression models, adjusting for demographics, multimorbidity index, cognition, physical performance, and diabetes control.

Results: Among 1191 participants at the first post-trial visit, mean (±SD) age was 68.7 ± 5.7 years, BMI was 34.4 ± 6.1 kg/m2; 61% were female, 69% White, and 52% assigned to ILI. Over nine years of follow-up, odds of severe mobility disability were higher for ILI participants aged ≥70 years (OR [95% CI]): 1.50 [1.02-2.20]) but lower for those in ILI <70 years (0.69 [0.48-0.99]) compared to controls (interaction P = 0.0043). Participants with BMI ≥35 kg/m2 had higher odds of mobility disability (2.06 [1.57-2.70]), severe mobility disability (2.52 [1.79-3.56]), and IADL disability (OR [95% CI]: 2.15 [1.53-3.02]) compared to those with BMI <30 kg/m2.

Conclusion: ILI was associated with greater severe mobility disability in participants ≥70. Regardless of age, those with higher BMI had increased late-life mobility and IADL disability.

Background: Preoperative frailty assessment is crucial for surgical risk stratification in older adults. Traditional frailty measurements are often too time-consuming and resource-intensive in preoperative settings. This study aimed to externally validate an artificial intelligence (AI)-based frailty index developed using electronic health records (EHR).

Methods: We externally validated an AI-based frailty index, previously developed by our team, on a cohort of 1 52 364 surgical patients aged 65+ years from the OneFlorida+ Clinical Research Consortium. We examined the association between the predicted frailty and three postoperative outcomes: 30-day mortality, length of hospital stay, and discharge disposition. We also compared the predictive performance of general and service-specific frailty indices (the latter developed using data from patients undergoing specific surgeries) in predicting postoperative outcomes.

Results: The AI-based frailty index demonstrated a strong and stepwise association with adverse postoperative outcomes. Patients in the highest frailty level (top 20%) had significantly higher odds of 30-day mortality (OR 4.33, 95% CI 3.91-4.80), longer hospital stays (2.53 times longer, 95% CI 2.47-2.60), and a higher likelihood of unfavorable discharge dispositions compared to the lowest frailty level, after adjusting for demographics and comorbidities. The general frailty index performed comparably to or slightly better than service-specific indices across surgical specialties.

Conclusion: The developed preoperative frailty index effectively predicts postoperative outcomes in a large and diverse external cohort. The index's efficiency and predictive performance in stratifying surgical risk can potentially improve surgical care and outcomes.

Background: Intrinsic capacity (IC) is a multidimensional concept within the World Health Organization framework for healthy aging. It refers to the composite of an individual's physical and mental capacities that enable them to maintain well-being, functional ability, and engagement in valued activities throughout life. While substantial evidence supports the biological basis of IC and its subdomains, the extent to which genetic factors influence IC remains largely unexplored, with no studies currently available.

Methods: Using datasets from the UK Biobank (UKB; N = 44 631) and the Canadian Longitudinal Study on Aging (CLSA; N = 13 085), we implemented the restricted maximum likelihood method to estimate SNP-based heritability (h2snp), followed by a Genome-Wide Association Study (GWAS) to identify genetic variants associated with IC, and post-GWAS analyses to pinpoint biological implications.

Results: The h2snp for IC was estimated at 25.2% in UKB and 19.5% in CLSA. Our GWAS identified 38 independent SNPs for IC across 10 genomic loci and 4289 candidate SNPs, mapped to 197 genes. Post-GWAS analysis revealed the role of these genes in cellular processes such as cell proliferation, immune function, metabolism, and neurodegeneration, with high expression in muscle, heart, brain, adipose, and nerve tissues. Of the 52 traits tested, 23 showed significant genetic correlations with IC, and a higher genetic loading for IC was associated with higher IC scores.

Conclusions: Overall, this study provides comprehensive evidence on the genetic architecture of IC, identifying novel genetic variants and biological pathways, advancing our current knowledge and laying the foundation for ongoing and future research on healthy aging.

Background: Poor olfaction may be associated with incident heart failure (HF) in older adults, but empirical evidence is scant.

Methods: We included 5217 participants free of clinical HF and with a smell assessment in 2011-2013 from the Atherosclerosis Risk in Communities Study. Olfaction was measured by the 12-item Sniffin' Sticks odor identification test and defined as good (score 11-12), moderate (9-10), or poor (≤8). Participants were followed until the first HF hospitalization, death, last contact, or December 31, 2020, whichever happened first. We estimated adjusted risk ratios (aRR) for associations of olfaction with incident HF and its subtypes, and cross-sectional associations of olfaction with subclinical HF markers, including N-terminal pro-B-type natriuretic peptides (NT-proBNP), high-sensitive cardiac troponin T (hs-cTnT), and echocardiogram-defined structural heart disease.

Results: During a median 8.4-year follow-up, we identified 622 incident HF, including 212 with reduced ejection fraction (HFrEF) and 250 with preserved EF (HFpEF). Comparing poor with good olfaction, the aRR of HF was 1.24 (95% confidence interval (CI): 1.03,1.51) at year 8. Moderate olfaction showed a similar association pattern with HF risk, with the corresponding aRR of 1.23 (95% CI, 1.00-1.50). Poor olfaction appeared to have an evident association with HFrEF but not with HFpEF. Poor olfaction was associated with higher median levels of NT-proBNP and hs-cTnT, and higher odds of having structural heart disease than good olfaction.

Conclusions: In older adults, poor olfaction identified by a single smell test was associated with a modestly higher risk of HF, especially HFrEF, and with known subclinical HF biomarkers.