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Studies in mice and cross-sectional studies in humans support the premise that cellular senescence is a contributing mechanism to age-associated deficits in physical function. We tested the hypotheses that circulating proteins secreted by senescent cells are (i) associated with the incidence of major mobility disability (MMD), the development of persistent mobility disability (PMMD), and decrements in physical functioning in older adults, and (ii) influenced by physical activity (PA). Using samples and data obtained longitudinally from the Lifestyle Interventions in Elders Study clinical trial, we measured a panel of 27 proteins secreted by senescent cells. Among 1 377 women and men randomized to either a structured PA intervention or a healthy aging (HA) intervention, we observed significant associations between several senescence biomarkers, most distinctly vascular endothelial growth factor A (VEGFA), tumor necrosis factor receptor 1 (TNFR1), and matrix metallopeptidase 7 (MMP7), and the onset of both MMD and PMMD. Moreover, VEGFA, GDF15, osteopontin, and other senescence biomarkers were associated with reductions in short physical performance battery scores. The change in senescence biomarkers did not differ between PA and HA participants. In the whole cohort, higher levels of PA were associated with significantly greater reductions in 10 senescence-related proteins at 12 and/or 24 months. These data reinforce cellular senescence as a contributing mechanism of age-associated functional decline and the potential for PA to attenuate this hallmark of aging. Clinical Trials Registration Number: NCT01072500 [ABSTRACT FROM AUTHOR]

Cellular senescence is a biological aging process that is exacerbated by obesity and leads to inflammation and age- and obesogenic-driven chronic diseases including type 2 diabetes. Caloric restriction (CR) may improve metabolic function in part by reducing cellular senescence and the pro-inflammatory senescence-associated phenotype (SASP). We conducted an ancillary investigation of an 18-week randomized controlled trial (RCT) of CR (n  = 31) or Control (n  = 27) in 58 middle-aged/older adults (57.6 ± 5.8 years; 75% Women) with obesity and prediabetes. We measured mRNA expression of select senescence and apoptosis genes in blood CD3 + T cells (qRT-PCR) and a panel of 25 plasma SASP proteins (Luminex/multiplex; ELISA). Participants randomized to CR lost −10.8 ± 0.9 kg (−11.3% ± 5.4%) over 18 weeks compared with +0.5 ± 0.9 kg (+0.03% ± 3.5%) in Control group. T-cell expression of senescence biomarkers, p16INK4a and p21CIP1/WAF1, and apoptosis markers, BCL2L1 and BAK1, was not different between CR and Control groups in age, race, and sex-adjusted mixed models (p  > .05, all). Iterative principal axis factor analysis was used to develop composite SASP Factors, and the Factors comprising TNFRI, TNFRII, uPAR, MMP1, GDF15, OPN, Fas, and MPO were significantly altered with CR intervention (age, sex, race-adjusted mixed model time × treatment F  = 4.17, p  ≤ .05) and associated with the degree of weight loss (R 2 = 0.12, p  ≤ .05). Our study provides evidence from an RCT that specific circulating biomarkers of senescent cell burden are changed by CR in middle-aged and older adults with obesity and prediabetes. Future studies compare tissue and circulating levels of p16INK4a and pro-inflammatory SASP biomarkers in other populations, and interventions. [ABSTRACT FROM AUTHOR]

Dynamic measures of resilience—the ability to resist and recover from a challenge—may be informative of the rate of aging before overt manifestations such as chronic disease, disability, and frailty. From this perspective mid-life resilience may predict longevity and late-life health. To test this hypothesis, we developed simple, reproducible, clinically relevant challenges, and outcome measures of physical resilience that revealed differences between and within age groups of genetically heterogeneous mice, and then examined associations between mid-life resilience and both lifespan and late-life measures of physiological function. We demonstrate that time to recovery from isoflurane anesthesia and weight change following a regimen of chemotherapy significantly differed among young, middle-aged, and older mice, and were more variable in older mice. Females that recovered faster than the median time from anesthesia (more resilient) at 12 months of age lived 8% longer than their counterparts, while more resilient males in mid-life exhibited better cardiac (fractional shortening and left ventricular volumes) and metabolic (glucose tolerance) function at 24 months of age. Moreover, female mice with less than the median weight loss at Day 3 of the cisplatin challenge lived 8% longer than those that lost more weight. In contrast, females who had more weight loss between Days 15 and 20 were relatively protected against early death. These data suggest that measures of physical resilience in mid-life may provide information about individual differences in aging, lifespan, and key parameters of late-life health. [ABSTRACT FROM AUTHOR]

Background Heterochronic parabiosis has identified growth differentiation factor (GDF)-11 as a potential means of cardiac rejuvenation, but findings have been inconsistent. A major barrier has been lack of assay specificity for GDF-11 and its homolog GDF-8. Methods We tested the hypothesis that GDF-11 and GDF-8, and their major antagonists follistatin and follistatin-like (FSTL)-3, are associated with incident heart failure (HF) and its subtypes in elders. Based on validation experiments, we used liquid chromatography–tandem mass spectrometry to measure total serum GDF-11 and GDF-8, along with follistatin and FSTL-3 by immunoassay, in 2 longitudinal cohorts of older adults. Results In 2 599 participants (age 75.2 ± 4.3) followed for 10.8 ± 5.6 years, 721 HF events occurred. After adjustment, neither GDF-11 (HR per doubling: 0.93 [0.67, 1.30]) nor GDF-8 (HR: 1.02 per doubling [0.83, 1.27]) was associated with incident HF or its subtypes. Positive associations with HF were detected for follistatin (HR: 1.15 [1.00, 1.32]) and FLST-3 (HR: 1.38 [1.03, 1.85]), and with HF with preserved ejection fraction for FSTL-3 (HR: 1.77 [1.03, 3.02]). (All HRs per doubling of biomarker.) FSTL-3 associations with HF appeared stronger at higher follistatin levels and vice versa, and also for men, Blacks, and lower kidney function. Conclusions Among older adults, serum follistatin and FSTL-3, but not GDF-11 or GDF-8, were associated with incident HF. These findings do not support the concept that low serum levels of total GDF-11 or GDF-8 contribute to HF late in life, but do implicate transforming growth factor-β superfamily pathways as potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Background Based on studies from animal models, growth differentiation factor-11 (GDF-11) may have rejuvenating effects in humans. GDF-11 has high sequence homology with GDF-8 (also known as myostatin); follistatin and follistatin-like protein-3 (FSTL-3) are inhibitory proteins of both GDF-8 and GDF-11. Methods Using highly specific liquid chromatography with tandem mass spectrometry assays for GDF-11 and GDF-8 and immunoassays for follistatin and FSTL-3, we quantified the association of these factors with muscle size, strength, and physical performance in 2 prospective cohort studies of community-dwelling older adults (Health, Aging, and Body Composition study [Health ABC] and Cardiovascular Health Study [CHS]). Results GDF-8 levels were positively associated with thigh muscle cross-sectional area and density in Health ABC (data not available in CHS). GDF-8 levels were positively associated with lean mass (a surrogate of muscle mass) in Health ABC but not CHS, and grip strength in CHS but not Health ABC. FSTL-3 (and perhaps follistatin) was negatively associated with lean mass and had variable associations with other variables. In contrast, GDF-11 was not significantly associated with strength or performance. Conclusions GDF-8 and its binding proteins, follistatin and FSTL-3, may constitute a counterregulatory system (chalones) to restrain age-related loss of muscle mass and strength. [ABSTRACT FROM AUTHOR]

Background: Delirium is underdiagnosed in clinical practice and is not routinely coded for billing. Manual chart review can be used to identify the occurrence of delirium; however, it is labor-intensive and impractical for large-scale studies. Natural language processing (NLP) has the capability to process raw text in electronic health records (EHRs) and determine the meaning of the information. We developed and validated NLP algorithms to automatically identify the occurrence of delirium from EHRs.Methods: This study used a randomly selected cohort from the population-based Mayo Clinic Biobank (N = 300, age ≥65). We adopted the standardized evidence-based framework confusion assessment method (CAM) to develop and evaluate NLP algorithms to identify the occurrence of delirium using clinical notes in EHRs. Two NLP algorithms were developed based on CAM criteria: one based on the original CAM (NLP-CAM; delirium vs no delirium) and another based on our modified CAM (NLP-mCAM; definite, possible, and no delirium). The sensitivity, specificity, and accuracy were used for concordance in delirium status between NLP algorithms and manual chart review as the gold standard. The prevalence of delirium cases was examined using International Classification of Diseases, 9th Revision (ICD-9), NLP-CAM, and NLP-mCAM.Results: NLP-CAM demonstrated a sensitivity, specificity, and accuracy of 0.919, 1.000, and 0.967, respectively. NLP-mCAM demonstrated sensitivity, specificity, and accuracy of 0.827, 0.913, and 0.827, respectively. The prevalence analysis of delirium showed that the NLP-CAM algorithm identified 12 651 (9.4%) delirium patients, the NLP-mCAM algorithm identified 20 611 (15.3%) definite delirium cases, and 10 762 (8.0%) possible cases.Conclusions: NLP algorithms based on the standardized evidence-based CAM framework demonstrated high performance in delineating delirium status in an expeditious and cost-effective manner. [ABSTRACT FROM AUTHOR]

Background: Ample evidence implicates cellular senescence as a contributor to frailty and functional decline in rodents, but considerable effort remains to translate these findings to human aging.Methods: We quantified senescence biomarker p16INK4a-expressing cells in thigh adipose tissue obtained from older women previously enrolled in a 5-month resistance training intervention, with or without caloric restriction (RT ± CR, n = 11 baseline, 8 pre-post-intervention pairs). Women in this subsample were older (72.9 ± 3.4 y) and overweight/obese (body mass index: 30.6 ± 2.4 kg/m2). p16INK4a+ cells were identified from 12 to 20 random visual fields/sample at 20× magnification (immunohistochemical, nuclear staining) and were present in all adipose samples.Results: Cross-sectional associations were observed between p16INK4a+ cell burden and physical function, including grip strength (r = -0.74), 400-m walk time (r = 0.74), 4-m gait speed (r = -0.73), and self-perceived mobility (r = -0.78) (p ≤ .05). These relationships remained significant after independent adjustments for age and adiposity (p ≤ .05). p16INK4a+ cell abundance was lower following the intervention (pre: 5.47 ± 3.4%, post: 2.17 ± 1.1% count p16INK4a+ cells, p ≤ .05).Conclusions: These results provide proof-of-concept that p16INK4a+ cells in thigh adipose are associated with physical function, and may be sensitive to change with RT ± CR in overweight/obese older women. [ABSTRACT FROM AUTHOR]

Background: Disrupted gait has been associated with an increased risk of frailty, disability, and death, but the causal molecular pathways are not well understood. Sphingolipids, including ceramides, are associated with multiple age-related diseases. Ceramides promote atrophy, necrosis, and proteolysis in cellular and animal models, and ceramide C16:0 levels are negatively correlated with muscle mass in men. However, there is a paucity of evidence examining sphingolipids and physical function.Methods: We examined the cross-sectional association between plasma ceramides, sphingosine-1-phosphate (S1P), and ceramide/S1P ratios and gait, a robust measure of physical function, in 340 clinically normal participants aged 70 years and older enrolled in the Mayo Clinic Study of Aging. GAITRite® instrumentation was used to measure gait speed, cadence, step width, double support time, and intra-individual stride time variability. Based on previous studies, we hypothesized that higher plasma levels of ceramide C16:0 would be associated with worse gait.Results: Multivariable adjusted linear regression models revealed that higher levels of ceramide C16:0 were associated with slower gait speed, decreased cadence, and increased double support time.Conclusions: These results suggest an association between plasma ceramide C16:0 and physical function. Longitudinal studies are needed to determine whether elevated ceramide C16:0 can be utilized as a prognostic marker for functional decline. [ABSTRACT FROM AUTHOR]

Background: Frailty confers risk for surgical morbidity and mortality. Whether patient-reported measures of health, well-being, or quality of life respond differently to surgery in non-frail and frail individuals is unknown.Methods: Older adults with severe aortic stenosis presenting for surgery were assessed for frailty using Cardiovascular Health Study Criteria. Patient-reported measures of functional capacity (Duke Activity Status Index [DASI]), physical and mental health (Medical Outcomes Study Short Form-Physical and Mental Component Scales [SF-12 PCS and SF-12 MCS, respectively]), well-being (linear analogue self-assessment [LASA]), and quality of life (LASA) were administered before and 3 months after surgery.Results: Of 103 participants (mean age of 80.6 years), 54 were frail. Frail participants had lower baseline DASI, SF-12 PCS, SF-12 MCS, physical well-being, and quality of life scores than non-frail participants. At follow-up, frail participants showed significant improvement in physical function, with DASI and SF-12 PCS scores improving by 50% and 14%, respectively. Non-frail subjects did not significantly improve in these measures. SF-12 MCS scores also improved to a greater extent in frail compared to non-frail participants (3.6 vs < 1 point). Furthermore, the frail participants improved to a greater extent than non-frail participants in physical well-being (21.6 vs 7.1 points) and quality of life measures (25.1 vs 8.7 points).Conclusions: Frailty is prevalent in older adults with severe aortic stenosis and is associated with poor physical and mental function, physical well-being, and quality of life. In response to surgery, frail participants exhibited greater improvement in these patient-centered outcomes than non-frail peers. [ABSTRACT FROM AUTHOR]

Aging is associated with visceral adiposity, metabolic disorders, and chronic low-grade inflammation. 17α-estradiol (17α-E2), a naturally occurring enantiomer of 17β-estradiol (17β-E2), extends life span in male mice through unresolved mechanisms. We tested whether 17α-E2 could alleviate age-related metabolic dysfunction and inflammation. 17α-E2 reduced body mass, visceral adiposity, and ectopic lipid deposition without decreasing lean mass. These declines were associated with reductions in energy intake due to the activation of hypothalamic anorexigenic pathways and direct effects of 17α-E2 on nutrient-sensing pathways in visceral adipose tissue. 17α-E2 did not alter energy expenditure or excretion. Fasting glucose, insulin, and glycosylated hemoglobin were also reduced by 17α-E2, and hyperinsulinemic-euglycemic clamps revealed improvements in peripheral glucose disposal and hepatic glucose production. Inflammatory mediators in visceral adipose tissue and the circulation were reduced by 17α-E2. 17α-E2 increased AMPKα and reduced mTOR complex 1 activity in visceral adipose tissue but not in liver or quadriceps muscle, which is in contrast to the generalized systemic effects of caloric restriction. These beneficial phenotypic changes occurred in the absence of feminization or cardiac dysfunction, two commonly observed deleterious effects of exogenous estrogen administration. Thus, 17α-E2 holds potential as a novel therapeutic for alleviating age-related metabolic dysfunction through tissue-specific effects. [ABSTRACT FROM AUTHOR]

The objective of this study was to examine the effects of short-term exercise training, myostatin inhibition (PF-354), and exercise + PF-354, all relative to a vehicle control, on performance and metabolic measures in 24-month-old mice. At study termination, PF-354–treated mice exhibited significantly greater muscle weights. Performance measures revealed that exercise + PF-354 increased treadmill running time and distance to exhaustion (more than twofold) and increased habitual activity. Measures of strength were not different; however, all treatment groups demonstrated more than 30% reductions in muscle fatigue. Metabolic measures showed that basal metabolic rates were higher in PF-354– and exercise + PF-354–treated mice, and exercise and exercise + PF-354 groups exhibited significantly greater insulin sensitivity. PF-354 was associated with decreased Smad3 phosphorylation and increased peroxisome proliferator-activated receptor gamma coactivator-1α expression and, similar to exercise, decreased MuRF-1. The data suggest that the combination of exercise training and myostatin blockade may significantly improve physical function and whole-body metabolism in older individuals. [ABSTRACT FROM PUBLISHER]

The author looks at four studies that examined gait, its determinants, and its associated sequelae. Highlights include spatial and temporal parameters of gait as endpoints in preclinical and clinical trials of interventions targeting the biology of aging, unobstructed and obstructed walking in older women and men classified as nonfallers or fallers, and comparison of study participants' reaction time to two independent unisensory stimuli and a multisensory stimulus.

An editorial is presented on the opportunities and challenges associated with physical resilience, focusing on a study by Hadley, Kuchel and Newman within the issue of the "Journal of Gerontology," which offers a summary of the National Institute on Aging (NIA) Workshop on Measures of Physiologic Resiliencies in Human Aging. Topics include physical resilience research, gaps in understanding physical resilience across translational continuum, and multidisciplinary approach.

A correction to the article "Physical Resilience: Opportunities and Challenges in Translation" in the May 2017 issue of the periodical is presented.