Frailty: a tale of two concepts

Frailty is increasingly relevant for clinicians to improve care for vulnerable older adults. Prominent frailty measures include the frailty phenotype and the frailty index. The frailty phenotype is grounded in a theoretical construct hypothesized to have an underlying biological basis. The frailty index describes frailty as a nonspecific age-associated vulnerability, reflected in an accumulation of medical, social, and functional deficits. Building on this model, Minitski et al. describe the development of a biological index that proves to be a reasonable method to predict mortality when compared to other frailty measurements. Strengths include its ability to import clinical measures, interchangeable components, and its potential ability to identify latent risk factors. Obstacles include the lack of a unifying biological theory related to aging, inclusion of costly research measures, and its inability to provide specific clues to the etiology of frailty according to the frailty index definition. Refinement in measures focused on aging-related biological changes rather than using measures that result from chronic disease states could help provide important biological insights and aid in the development of future treatment and preventive modalities. Please see related article: http://www.biomedcentral.com/1741-7015/13/161

Role of senescence marker p16INK4a measured in peripheral blood T-lymphocytes in predicting length of hospital stay after coronary artery bypass surgery in older adults

Adults older than 65 years undergo more than 120,000 coronary artery bypass (CAB) procedures each year in the United States. Chronological age alone, though commonly used in prediction models of outcomes after CAB, does not alone reflect variability in aging process; thus, the risk of complications in older adults. We performed a prospective study to evaluate a relationship between senescence marker p16INK4a expression in peripheral blood T-lymphocytes (p16 levels in PBTLs) with aging and with perioperative outcomes in older CAB patients. We included 55 patients age 55 and older, who underwent CAB in Johns Hopkins Hospital between September 1st, 2010 and March 25th, 2013. Demographic, clinical and laboratory data following outline of the Society of Thoracic Surgeons data collection form was collected, and p16 mRNA levels in PBTLs were measured using Taqman® qRT-PCR. Associations between p16 mRNA levels in PBTLs with length of hospital stay, frailty status, p16 protein levels in the aortic and left internal mammary artery tissue, cerebral oxygen saturation, and augmentation index as a measure of vascular stiffness were measured using regression analyses. Length of hospital stay was the primary outcome of interest, and major organ morbidity, mortality, and discharge to a skilled nursing facility were secondary outcomes. In secondary analysis, we evaluated associations between p16 mRNA levels in PBTLs and interleukin-6 levels using regression analyses. Median age of enrolled patients was 63.5 years (range 56-81 years), they were predominantly male (74.55%), of Caucasian descent (85.45%). Median log2(p16 levels in PBTLs) were 4.71 (range 1.10-6.82). P16 levels in PBTLs were significantly associated with chronological age (mean difference 0.06 for each year increase in age, 95% CI 0.01-0.11) and interleukin 6 levels (mean difference 0.09 for each pg/ml increase in IL-6 levels, 95% CI 0.01-0.18). There were no significant associations with frailty status, augmentation index, cerebral oxygenation and p16 protein levels in blood vessels. Increasing p16 levels in PBTLs did not predict length of stay in the hospital (HR 1.10, 95% CI 0.87-1.40) or intensive care unit (HR 1.02, 95% CI 0.79-1.32). Additional evaluation of p16 levels in PBTLs as predictor of perioperative outcomes is required and should include additional markers of immune system aging as well as different outcomes after CAB in addition to length of hospital stay

Microbial−mammalian cometabolites dominate the age-associated urinary metabolic phenotype in Taiwanese and American populations

Understanding the metabolic processes associated with aging is key to developing effective management and treatment strategies for age-related diseases. We investigated the metabolic profiles associated with age in a Taiwanese and an American population. 1H NMR spectral profiles were generated for urine specimens collected from the Taiwanese Social Environment and Biomarkers of Aging Study (SEBAS; n = 857; age 54–91 years) and the Mid-Life in the USA study (MIDUS II; n = 1148; age 35–86 years). Multivariate and univariate linear projection methods revealed some common age-related characteristics in urinary metabolite profiles in the American and Taiwanese populations, as well as some distinctive features. In both cases, two metabolites—4-cresyl sulfate (4CS) and phenylacetylglutamine (PAG)—were positively associated with age. In addition, creatine and β-hydroxy-β-methylbutyrate (HMB) were negatively correlated with age in both populations (p < 4 × 10–6). These age-associated gradients in creatine and HMB reflect decreasing muscle mass with age. The systematic increase in PAG and 4CS was confirmed using ultraperformance liquid chromatography–mass spectrometry (UPLC–MS). Both are products of concerted microbial–mammalian host cometabolism and indicate an age-related association with the balance of host–microbiome metabolism

The complex genetics of gait speed:Genome-wide meta-analysis approach

Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging

Interleukin-6 and C-Reactive Protein Levels and 9-Year Cognitive Decline in Community-Dwelling Older Women: The Women’s Health and Aging Study II

Elevated inflammation is a proposed mechanism relating chronic diseases to cognitive dysfunction. The objective of this study was to test the hypothesis that greater levels of inflammation, as measured by the proinflammatory cytokine interleukin-6 (IL-6) and C-reactive protein, are associated with faster rates of cognitive decline among cognitively intact community-dwelling older women

Depressive symptoms, frailty, and adverse outcomes among kidney transplant recipients

Depressive symptoms and frailty are each independently associated with morbidity and mortality in kidney transplant (KT) recipients. We hypothesized that having both depressive symptoms and frailty would be synergistic and worse than the independent effect of each. In a multicenter cohort study of 773 KT recipients, we measured the Fried frailty phenotype and the modified 18â question Center for Epidemiologic Studiesâ Depression Scale (CESâ D). Using adjusted Poisson regression and survival analysis, we tested whether depressive symptoms (CESâ D score > 14) and frailty were associated with KT length of stay (LOS), deathâ censored graft failure (DCGF), and mortality. At KT admission, 10.0% of patients exhibited depressive symptoms, 16.3% were frail, and 3.6% had both. Recipients with depressive symptoms were more likely to be frail (aOR = 3.97, 95% CI: 2.28â 6.91, P < 0.001). Recipients with both depressive symptoms and frailty had a 1.88 times (95% CI: 1.70â 2.08, P < 0.001) longer LOS, 6.20â fold (95% CI:1.67â 22.95, P < 0.01) increased risk of DCGF, and 2.62â fold (95% CI:1.03â 6.70, P = 0.04) increased risk of mortality, compared to those who were nonfrail and without depressive symptoms. There was only evidence of synergistic effect of frailty and depressive symptoms on length of stay (P for interaction < 0.001). Interventions aimed at reducing preâ KT depressive symptoms and frailty should be explored for their impact on postâ KT outcomes.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146305/1/ctr13391_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146305/2/ctr13391.pd

GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium

Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5 × 10−8) and 39 suggestive (P-value< 5 × 10−5) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P-value = 5.20 × 10−10). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength

Thyroid Autoantibodies Are Associated with a Reduced Prevalence of Frailty in Community-Dwelling Older Women

Context: The contribution of autoimmunity to the multisystem dysregulation that characterizes the frailty syndrome in older adults is unknown. Objective: The aim of the study was to investigate the relationship between thyroid antibodies and frailty in older women. Design, Setting, and Participants: We conducted a cross-sectional study nested within the Women’s Health and Aging Studies I and II. Thyroglobulin antibodies (TgAbs), thyroid peroxidase antibodies (TPOAbs), and antinuclear antibodies were measured in the baseline sera of 641 community-dwelling older women. Main Outcome Measure: Frailty was defined using a validated five-component measure. Results: The prevalence of prefrailty and frailty was lower in TgAb-positive than negative older women (37.1 vs. 47.8% and 6.7 vs.11.9%, respectively; P = 0.01 and 0.03). The prevalence of prefrailty, but not frailty, was lower in TPOAb-positive than negative women (38.9 vs. 48.0% and 10.1 vs. 11.3%; P = 0.04 and 0.34). After adjustment for covariates including serum thyroid stimulation hormone concentration and thyroid medication usage in multinomial regression models, TgAb-positive older women had lower odds of prefrailty and frailty compared with TgAb-negative women (odds ratio 0.57 and 0.30; 95% confidence interval 0.34–0.98 and 0.10–0.85, respectively). Similarly, TPOAb-positive older women had lower odds of frailty compared with TPOAb-negative women (odds ratio 0.44; 95% confidence interval 0.20–0.96). These trends were not observed with antinuclear antibodies. Conclusion: Independent of thyroid function status, community-dwelling older women who are seropositive for TgAbs and TPOAbs are less likely to be frail than seronegative women

Racial differences in inflammation and outcomes of aging among kidney transplant candidates

Abstract Background Inflammation is more common among African Americans (AAs), and it is associated with frailty, poor physical performance, and mortality in community-dwelling older adults. Given the elevated inflammation levels among end-stage renal disease (ESRD) patients, inflammation may be associated with adverse health outcomes such as frailty, physical impairment, and poor health-related quality of life (HRQOL), and these associations may differ between AA and non-AA ESRD patients. Methods One thousand three ESRD participants were recruited at kidney transplant evaluation (4/2014–5/2017), and inflammatory markers (interleukin-6 [IL-6], tumor necrosis factor-a receptor-1 [TNFR1], C-reactive protein [CRP]) were measured. We quantified the association with frailty (Fried phenotype), physical impairment (Short Physical Performance Battery [SPPB]), and fair/poor HRQOL at evaluation using adjusted modified Poisson regression and tested whether these associations differed by race (AA vs. non-AA). Results Non-AAs had lower levels of TNFR1 (9.7 ng/ml vs 14.0 ng/ml, p  0.9) and CRP (4.7 μg/ml vs 4.9 μg/ml, p = 0.4). Non-AAs had an increased risk of frailty with elevated IL-6 (RR = 1.58, 95% CI:1.27–1.96, p < 0.001), TNFR1 (RR = 1.60, 95% CI:1.25–2.05, p < 0.001), CRP (RR = 1.41, 95% CI:1.10–1.82, p < 0.01), and inflammatory index (RR = 1.82, 95% CI:1.44–2.31, p < 0.001). The associations between elevated inflammatory markers and frailty were not present among AAs. Similar results were seen with SPPB impairment and poor/fair HRQOL. Conclusions Non-AAs with elevated inflammatory markers may need closer follow-up and may benefit from prehabilitation to improve physical function, reduce frailty burden, and improve quality of life prior to transplant.https://deepblue.lib.umich.edu/bitstream/2027.42/149150/1/12882_2019_Article_1360.pd

Models and Studies of Aging: Executive Summary of a Report from the U13 Conference Series

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148241/1/jgs15788.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148241/2/jgs15780-sup-0001-supinfo.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148241/3/jgs15788_am.pd