Showing papers in "Journals of Gerontology Series A-biological Sciences and Medical Sciences in 2015"

Protein Ingestion to Stimulate Myofibrillar Protein Synthesis Requires Greater Relative Protein Intakes in Healthy Older Versus Younger Men

Abstract: Background Adequate protein ingestion-mediated stimulation of myofibrillar protein synthesis (MPS) is required to maintain skeletal muscle mass. It is currently unknown what per meal protein intake is required to maximally stimulate the response in older men and whether it differs from that of younger men. Methods We retrospectively analyzed data from our laboratories that measured MPS in healthy older (~71 years) and younger (~22 years) men by primed constant infusion of l-ring-[(13)C6]phenylalanine after ingestion of varying amounts (0-40 g) of high-quality dietary protein as a single bolus and normalized to body mass and, where available, lean body mass (LBM). Results There was no difference (p = .53) in basal MPS rates between older (0.027±0.04%/h; means ± 95% CI) and young (0.028 ± 0.03%/h) men. Biphase linear regression and breakpoint analysis revealed the slope of first line segment was lower (p Conclusions This is the first report of the relative (to body weight) protein ingested dose response of MPS in younger and older men. Our data suggest that healthy older men are less sensitive to low protein intakes and require a greater relative protein intake, in a single meal, than young men to maximally stimulate postprandial rates of MPS. These results should be considered when developing nutritional solutions to maximize MPS for the maintenance or enhancement of muscle mass with advancing age.

Frailty in Older Adults: A Nationally Representative Profile in the United States

Abstract: Background Frailty assessment provides a means of identifying older adults most vulnerable to adverse outcomes. Attention to frailty in clinical practice is more likely with better understanding of its prevalence and associations with patient characteristics. We sought to provide national estimates of frailty in older people. Methods A popular, validated frailty phenotype proposed by Fried and colleagues was applied to 7,439 participants in the 2011 baseline of the National Health and Aging Trends Study, a national longitudinal study of persons aged 65 and older. All measures drew on a 2-hour in-person interview. Weighted estimates of frailty prevalence were obtained. Results Fifteen percent (95% CI: 14%, 16%) of the older non-nursing home population is frail, and 45% is prefrail (95% CI: 44%, 47%). Frailty is more prevalent at older ages, among women, racial and ethnic minorities, those in supportive residential settings, and persons of lower income. Independently of these characteristics, frailty prevalence varies substantially across geographic regions. Chronic disease and disability prevalence increase steeply with frailty. Among the frail, 42% were hospitalized in the previous year, compared to 22% of the prefrail and 11% of persons considered robust. Hip, back, and heart surgery in the last year were associated with frailty. Over half of frail persons had a fall in the previous year. Conclusions Our findings support the importance of frailty in late-life health etiology and potential value of frailty as a marker of risk for adverse health outcomes and as a means of identifying opportunities for intervention in clinical practice and public health policy.

Polypharmacy Among Adults Aged 65 Years and Older in the United States: 1988–2010

Abstract: Older adults have a high prevalence of multiple chronic health conditions for which multiple medications are typically recommended as treatment (1,2). Consequently multiple medication use, often referred to as polypharmacy, is common in this population (1). Polypharmacy may be problematic for a number of reasons. For example it may increase the risk of using potentially inappropriate medications (PIMs) (3,4), which have been associated with negative effects on long-term physical and cognitive functioning (5). Polypharmacy also results in medication nonadherence (1,6), increased risk of drug duplication, drug–drug interactions (1) and adverse drug reactions (ADRs) (1,6,7), and higher health care costs (6,8,9). Research has also found that medication use may be associated with poor functional status (6), and decreased cognitive capacity (10). Given the rapidly aging population and the potential negative effects of multiple medication use, it is of interest to characterize trends and correlates of polypharmacy in older adults. A recent National Center for Health Statistics investigation reported that approximately a third of persons over age 60 were on ≥5 prescription medications in 2007–2008 (9). Although other research has examined national trends in polypharmacy among noninstitutionalized U.S. elders, the majority of studies have not included contemporary data (11–13). Additionally, many studies consider older adults as a single group over age 60 or 65, or rely on patient self-report of medication use (9,11). Recent nationally representative estimates of PIM use among community-dwelling older adults are currently unavailable. National rates of PIM prescribing during ambulatory care visits in 1995 and 2000 were estimated at 7.8% (3) but relied on provider report, thus measuring prescribing rather than medication use. Given the association of polypharmacy and PIM use with poor clinical outcomes, more detailed estimates of multiple medication and PIM use are needed. The present study uses data from the National Health & Nutrition Examination Survey (NHANES) between 1988 and 2010 to examine nationally representative time trends in polypharmacy among noninstitutionalized older adults. Trends across age, sex, and select medication classes including PIMs are investigated. To better understand the current needs of this rapidly growing population, we also describe characteristics of prescription medication users in 2009–2010.

A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity

Abstract: BACKGROUND Caloric restriction (CR), energy intake reduced below ad libitum (AL) intake, increases life span in many species. The implications for humans can be clarified by randomized controlled trials of CR. METHODS To determine CR's feasibility, safety, and effects on predictors of longevity, disease risk factors, and quality of life in nonobese humans aged 21-51 years, 218 persons were randomized to a 2-year intervention designed to achieve 25% CR or to AL diet. Outcomes were change from baseline resting metabolic rate adjusted for weight change ("RMR residual") and core temperature (primary); plasma triiodothyronine (T3) and tumor necrosis factor-α (secondary); and exploratory physiological and psychological measures. RESULTS Body mass index averaged 25.1 (range: 21.9-28.0 kg/m(2)). Eighty-two percent of CR and 95% of AL participants completed the protocol. The CR group achieved 11.7±0.7 %CR (mean ± standard error) and maintained 10.4±0.4% weight loss. Weight change in AL was negligible. RMR residual decreased significantly more in CR than AL at 12 months (p = .04) but not 24 months (M24). Core temperature change differed little between groups. T3 decreased more in CR at M12 and M24 (p < .001), while tumor necrosis factor-α decreased significantly more only at M24 (p = .02). CR had larger decreases in cardiometabolic risk factors and in daily energy expenditure adjusted for weight change, without adverse effects on quality of life. CONCLUSIONS Sustained CR is feasible in nonobese humans. The effects of the achieved CR on correlates of human survival and disease risk factors suggest potential benefits for aging-related outcomes that could be elucidated by further human studies.

A Physical Activity Intervention to Treat the Frailty Syndrome in Older Persons—Results From the LIFE-P Study

Abstract: The steady and rapid increase of the absolute and relative number of older persons is a global phenomenon of Western countries. Such demographical changes require immediate actions to render the healthcare systems capable of sustaining the growing number of individuals with multiple age-related conditions. In fact, the prevention of disabling conditions is important because disability severely impacts the quality of life of the individual (1) and is economically burdening for public health (2). Therefore, preventive interventions able to modify the natural history of age-related conditions are urgently needed. During the last two decades, special interest has been devoted by the scientific community to the study of the frailty, a syndrome characterized by reduced homeostatic reserves and resistance to endogenous and exogenous stressors (3). Frailty represents a major risk factor for negative health-related events in the elderly, including disability, falls, hospitalizations, and mortality (4). Consequently, the clinical identification of frailty may play an important role in the development of preventive strategies against age-related conditions. To transfer the theoretical concept of frailty into clinical practice, several operational definitions have been proposed (4). The best known and most commonly used is the one proposed by Fried and colleagues (5) and validated in the Cardiovascular Health Study. It defines the presence of a frailty phenotype when three or more of the following features are simultaneously present: exhaustion, involuntary weight loss, sedentary behavior, slow gait speed, poor muscle strength. Of the most promising preventive interventions for disability, physical activity (PA) is surely one of the most studied and promising (6). Recent findings from the Lifestyle Interventions and Independence for Elders pilot (LIFE-P) study showed the capacity of a PA intervention to improve physical performance in sedentary older persons (7). To our knowledge, no study has yet explored whether PA can modify the frailty status of elders. In this work, we hypothesize that the beneficial effects of PA may positively influence the frailty syndrome, allowing a reduction of its prevalence and severity toward a status of restored robustness. Thus, we conducted analyses aimed at exploring the effects of PA on frailty status in a sample of community-dwelling sedentary elders at initial risk of mobility disability.

GWAS of Longevity in CHARGE Consortium Confirms APOE and FOXO3 Candidacy

Abstract: Background. The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies. Methods. We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity. Results. In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 × 10-7) and GRIK2 (odds ratio = 1.24; p value = 5.09 × 10-8) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85×10-10). Conclusions. We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.

Lifelong Physical Exercise Delays Age-Associated Skeletal Muscle Decline

Abstract: Aging is usually accompanied by a significant reduction in muscle mass and force. To determine the relative contribution of inactivity and aging per se to this decay, we compared muscle function and structure in (a) male participants belonging to a group of well-trained seniors (average of 70 years) who exercised regularly in their previous 30 years and (b) age-matched healthy sedentary seniors with (c) active young men (average of 27 years). The results collected show that relative to their sedentary cohorts, muscle from senior sportsmen have: (a) greater maximal isometric force and function, (b) better preserved fiber morphology and ultrastructure of intracellular organelles involved in Ca(2+) handling and ATP production, (c) preserved muscle fibers size resulting from fiber rescue by reinnervation, and (d) lowered expression of genes related to autophagy and reactive oxygen species detoxification. All together, our results indicate that: (a) skeletal muscle of senior sportsmen is actually more similar to that of adults than to that of age-matched sedentaries and (b) signaling pathways controlling muscle mass and metabolism are differently modulated in senior sportsmen to guarantee maintenance of skeletal muscle structure, function, bioenergetic characteristics, and phenotype. Thus, regular physical activity is a good strategy to attenuate age-related general decay of muscle structure and function (ClinicalTrials.gov: NCT01679977).

Ambulatory Fall-Risk Assessment: Amount and Quality of Daily-Life Gait Predict Falls in Older Adults

Abstract: BACKGROUND: Ambulatory measurements of trunk accelerations can provide valuable information on the amount and quality of daily-life activities and contribute to the identification of individuals at risk of falls. We compared associations between retrospective and prospective falls with potential risk factors as measured by daily-life accelerometry. In addition, we investigated predictive value of these parameters for 6-month prospective falls. METHODS: One week of trunk accelerometry (DynaPort MoveMonitor) was obtained in 169 older adults (mean age 75). The amount of daily activity and quality of gait were determined and validated questionnaires on fall-risk factors, grip strength, and trail making test were obtained. Six-month fall incidence was obtained retrospectively by recall and prospectively by fall diaries and monthly telephone contact. RESULTS: Among all participants, 35.5% had a history of ≥1 falls and 34.9% experienced ≥1 falls during 6-month follow-up. Logistic regressions showed that questionnaires, grip strength, and trail making test, as well as the amount and quality of gait, were significantly associated with falls. Significant associations differed between retrospective and prospective analyses although odds ratios indicated similar patterns. Predictive ability based on questionnaires, grip strength, and trail making test (area under the curve.68) improved substantially by accelerometry-derived parameters of the amount of gait (number of strides), gait quality (complexity, intensity, and smoothness), and their interactions (area under the curve.82). CONCLUSIONS: Daily-life accelerometry contributes substantially to the identification of individuals at risk of falls, and can predict falls in 6 months with good accuracy. Language: en

Reconsidering the Role of Mitochondria in Aging

Abstract: Background: Mitochondrial dysfunction has long been considered a major contributor to aging and age-related diseases. Harman ’s Mitochondrial Free Radical Theory of Aging postulated that somatic mitochondrial DNA mutations that accumulate over the life span cause excessive production of reactive oxygen species that damage macromolecules and impair cell and tissue function. Indeed, studies have shown that maximal oxidative capacity declines with age while reactive oxygen species production increases. Harman’s hypothesis has been seriously challenged by recent studies showing that reactive oxygen species evoke metabolic health and longevity, perhaps through hormetic mechanisms that include autophagy. The purpose of this review is to scan the ever-growing literature on mitochondria from the perspective of aging research and try to identify priority questions that should be addressed in future research. Methods: A systematic search of peer -reviewed studies was performed using PubMed. Search terms included (i) mitochondria or mitochondrial; (ii) aging, ageing, older adults or elderly; and (iii) reactive oxygen species, mitochondria dynamics, mitochondrial proteostasis, cytosol, mitochondrial-associated membranes, redox homeostasis, electron transport chain, electron transport chain efficiency, epigenetic regulation, DNA heteroplasmy. Results: The importance of mitoc hondrial biology as a trait d’union between the basic biology of aging and the pathogenesis of age-related diseases is stronger than ever, although the emphasis has moved from reactive oxygen species production to other aspects of mitochondrial physiology, including mitochondrial biogenesis and turnover, energy sensing, apoptosis, senescence, and calcium dynamics. Conclusions: Mitochondria could play a k ey role in the pathophysiology of aging or in the earlier stages of some events that lead to the aging phenotype. Therefore, mitochondria will increasingly be targeted to prevent and treat chronic diseases and to promote healthy aging.

Aging and the Burden of Multimorbidity: Associations With Inflammatory and Anabolic Hormonal Biomarkers

Abstract: The number of older persons affected by multiple chronic diseases is progressively increasing and caring for them poses a number of scientific and organizational challenges for health care systems around the world (1–3). The coexistence of multiple diseases in the same person is usually referred to as multi morbidity; if one condition is the focus, then the term comorbidity is more often used (4). Because aging is the strongest risk factor for many chronic diseases, including cardiovascular diseases, type 2 diabetes, cancer, and dementia, multimorbidity is considered an important landmark of poor health status in older people, resulting recently increasing interest among gerontology and clinical geriatric researchers in this topic (5). Moreover, it is well-established that multimorbidity increases with age and, independent of age, it is strongly associated with frailty, disability, hospitalization, and mortality (6). However, little is known about risk factors for multimorbidity beyond age. Understanding the nature of such risk factors may shed light on the mechanisms by which some individuals tend to develop multiple and apparently unrelated chronic diseases as they age (7). Epidemiological and clinical studies have found that older persons often show a “low-grade chronic proinflammatory state” (8) and a “multiple hormonal dysregulation” (9) characterized by high levels of serum cytokines and low levels of anabolic hormones, respectively. Both conditions are risk factors for chronic diseases and predict a variety of adverse health outcomes, including frailty, disability, and mortality. Thus, it is reasonable to hypothesize that individuals with chronic inflammation and/or hormonal dysregulation are more likely to be affected by or to develop multimorbidity. Yet, this hypothesis has not been formally tested. This study aims to investigate the relationship of levels of inflammatory markers and anabolic hormones with multimorbidity in the participants of the InCHIANTI study to identify cross-sectional correlates and predictors of future development of multimorbidity over a 9-year follow-up.

Association of Hearing Impairment with Declines in Physical Functioning and the Risk of Disability in Older Adults

Abstract: The prevalence of hearing impairment doubles with every age decade such that nearly two-thirds of adults aged 70 and older in the United States have a clinically significant hearing impairment that hinders daily communication (1). Recent epidemiologic studies have demonstrated that hearing impairment is independently associated with poorer physical functioning (2,3) and falls (4,5) in older adults. These associations may be explained by concomitant vestibular dysfunction, (6,7) a shared pathologic etiology (eg microvascular disease; inflammation), or through the effects of hearing impairment on cognitive load, (8,9) social isolation, (10) and reduced awareness of the auditory environment. Maintaining an optimal level of physical functioning is a critical aspect of healthy aging, and objective physical performance tests predict the onset of dependence and mortality in older adults (11). Currently, there are no longitudinal studies that examine whether hearing impairment is associated with poorer objective physical functioning in older adults. Identifying potentially modifiable risk factors for poorer physical functioning in the elderly is a critical public health priority given the aging of the population. In this study, we investigate whether hearing impairment is independently associated with declines in physical functioning in older adults. We use a well-established physical performance battery to assess objective physical functioning over an 11-year period. To better understand the clinical and public health significance of these results, we also investigate the association of hearing impairment with the risk of incident disability and requirement for nursing care.

Breaking-up Sedentary Time Is Associated With Physical Function in Older Adults

Abstract: Background. Ph ysical function is a key determinant that corresponds to the physiological capacity of older adults to perform normal everyday activities, safely and independently, without undue fatigue. We examined the associations of sedentary behavior (SB), breaks in sedentary time (BST), and moderate-to-vigorous physical activity (MVPA) with physical function in older adults. Methods. Ph ysical activity and SB were assessed with accelerometers (ActiGraph, GT1M) and physical function with the Senior Fitness Test battery, among 87 males and 128 females aged between 65 and 94 years. A composite Z-score was created based on the individual scores for each Senior Fitness Test battery item. Associations of SB, BST, and MVPA with physical function were examined, adjusting for demographic attributes, physical independence, and medical status. Results. A significant positive association was found between BST and the composite physical function Z-score, after adjusting for total SB, MVPA, and potential confounders. MVPA was also positively associated with physical function, after adjusting for SB, BST, and potential confounders. Those with low BST in conjunction with performing less than 30 min/d of MVP A had lower physical function. Conclusions. Breaking-up sedentary time is associated with bet ter physical function in older adults; and, it may have an important place in future guidelines on preserving older adults’ physical function to support activities of daily living.

Bed Rest Promotes Reductions in Walking Speed, Functional Parameters, and Aerobic Fitness in Older, Healthy Adults

Abstract: Several studies have highlighted the detrimental influence of bed rest on metabolism and muscle protein synthesis (1–4). Additional studies have demonstrated that chronic bed rest may result in the loss of postural muscles, leading to increased risk of falls and disability (5). Realizing the high incidence of anorexia in the geriatric population (6), our group has studied the influence of bed rest in the elderly under eucaloric conditions and still observed reductions in strength in healthy older individuals despite the lack of deficiencies in macronutrient intake or caloric balance (7). Walking speed has been confirmed as a clear predictor for adverse health-related events (8). In addition, the findings from Health Aging and Body Composition study demonstrated that age-related reductions in thigh and grip strength were closely correlated with increased mortality (9). These changes in lean mass were consistent in earlier reports, and changes in physical function were not evaluated in these studies. Recently, Drummond and coworkers (10) demonstrated significant bed rest-induced reductions in total lean mass that were linked to impairment in the response to amino acids. Even small reductions in physical activity in older adults have also resulted in changes altered muscle protein synthesis associated with reductions in insulin sensitivity (11). In addition, we recently demonstrated significant reductions in hepatic and peripheral insulin sensitivity with short-term bed rest in older adults (12). Therefore, bed rest might promote tissue lipid accumulation and aggravated insulin resistance in the elderly that has been linked to detrimental reductions in muscle mass and strength (13). Therefore, we hypothesized that short-term bed rest would promote reductions in muscle strength and physical function, and that these changes would be related to the reduction of lean mass. We also sought to examine the relationships between changes in lean mass and muscle strength and physical function.

Comorbidity and Functional Trajectories From Midlife to Old Age: The Health and Retirement Study

Abstract: BACKGROUND: The number of diseases and physical functioning difficulties tend to increase with age. The aim of this study was to examine the trajectories of physical functioning across age groups and whether the trajectories differ according to disease status in different population subgroups.METHODS: Repeat data from a nationally representative population sample, the Health and Retirement Study, was used. Participants were 10,709 men and 13,477 women aged 60-107 years at baseline with biennial surveys from 1992 to 2010. Average length of follow-up was 10.3 years ranging from 0 to 18 years. Disease status and physical functioning was asked about at all study phases and 10 items were summed to obtain a physical functioning score (0-10).RESULTS: Age modified the relationship between number of chronic diseases and physical functioning with older participants having more physical functioning difficulties with increasing number of diseases. An average 70-year-old participant with no diseases had 0.89 (95% CI: 0.85-0.93) physical functioning difficulties, with one disease 1.72 (95% CI: 1.69-1.76) difficulties, with two diseases 2.57 (95% CI: 2.52-2.62) difficulties, and with three or more diseases 3.82 (95% CI: 3.76-3.88) difficulties. Of the individual diseases memory-related diseases, stroke, pulmonary diseases, and arthritis were associated with significantly higher physical functioning difficulties compared with other diseases.CONCLUSIONS: Comorbidity is associated with greater burden of physical functioning difficulties. Of the studied diseases, memory-related diseases, stroke, pulmonary diseases, and arthritis alone or in combination limit most physical functioning.

Cytokines and Postoperative Delirium in Older Patients Undergoing Major Elective Surgery

Abstract: available at http://www.ncbi.nlm.nih.gov/pubmed/25838546 Editorial Comment: Frailty is a geriatric syndrome that is associated with increased vulnerability in multiple clinical domains. The causes of frailty are complex and multifactorial. This study examined the potential link between nutritional status and frailty with an emphasis on dietary polyphenols. These compounds include carotenoids, vitamins E and D and bioflavonoids, and appear to have antioxidant and anti-inflammatory properties. Using a large, cross-sectional, population based study cohort, the levels of urinary polyphenols were compared with measures of frailty in 811 community dwelling people 65 years or older in Italy. The Mediterranean diet tends to be rich in polyphenols, and this group provided a unique population in which to study this question. The results demonstrated an inverse relationship between urinary polyphenol levels and degree of frailty. Sense of physical exhaustion and slowed gait were the frailty parameters most closely linked to decreased measured levels of urinary polyphenols. The cross-sectional study design precluded determination of absolute causality but the results raise interesting questions about the relationship between these variables. Future prospective nutritional research targeting this question will be required to enhance our understanding of this process, including the potential benefits of polyphenol rich foods as a mechanism to slow progression of the frailty phenotype. Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26215633 Editorial Comment: Delirium is a serious potential complication that often occurs postoperatively in geriatric patients. The etiology is generally thought to be multifactorial, and prevention is considered a key element in care of older adults. This study examined the potential relationship between inflammatory cytokines as biomarkers for risk of delirium in a cohort of 566 older adults undergoing major surgery. A nested, matched control study was performed to account for variables such as patient age and gender, type of surgery, baseline cognitive status, vascular comorbidity and apolipoprotein E, which is a genetic risk factor for dementia. The overall incidence of delirium was 24%, and those who demonstrated this condition by postoperative day 2 had significantly increased levels of interleukin-6 compared to controls. Patients with delirium also had increased interleukin-2 levels in the immediate postoperative period compared to controls, and this finding continued longitudinally through multiple subsequent time points. With time levels of other cytokines, including vascular endothelial growth factor and tumor necrosis factor-alpha, also differed between those who did and did not show delirium. These data suggest that there is a link between inflam- matory cytokines and the risk of delirium in the elderly surgical population. This finding may help lead to future development of preoperative or perioperative screening tests using these biomarkers to help reduce the incidence or severity of delirium postoperatively in older adults.

Comparative Effects of Light or Heavy Resistance Power Training for Improving Lower Extremity Power and Physical Performance in Mobility-Limited Older Adults

Abstract: Background. We compared the effects of two uniquely different lower extremity power training interventions on changes in muscle power, physical performance, neuromuscular activation, and muscle cross sectional area in mobility-limited older adults.

Association Between the Mediterranean Diet and Cognitive Decline in a Biracial Population

Abstract: Background. Results from numerous studies suggest protective effects of the Mediterranean diet for cardiovascular disease, cancer, and mortality. Evidence for an association with a decreased risk of cognitive decline is less consistent and studies are limited by a lack of diversity in their populations.

Longevity GWAS Using the Drosophila Genetic Reference Panel

Abstract: We used 197 Drosophila melanogaster Genetic Reference Panel (DGRP) lines to perform a genome-wide association analysis for virgin female lifespan, using ~2M common single nucleotide polymorphisms (SNPs). We found considerable genetic variation in lifespan in the DGRP, with a broad-sense heritability of 0.413. There was little power to detect signals at a genome-wide level in single-SNP and gene-based analyses. Polygenic score analysis revealed that a small proportion of the variation in lifespan (~4.7%) was explicable in terms of additive effects of common SNPs (≥2% minor allele frequency). However, several of the top associated genes are involved in the processes previously shown to impact ageing (eg, carbohydrate-related metabolism, regulation of cell death, proteolysis). Other top-ranked genes are of unknown function and provide promising candidates for experimental examination. Genes in the target of rapamycin pathway (TOR; Chrb, slif, mipp2, dredd, RpS9, dm) contributed to the significant enrichment of this pathway among the top-ranked 100 genes (p = 4.79×10(-06)). Gene Ontology analysis suggested that genes involved in carbohydrate metabolism are important for lifespan; including the InterPro term DUF227, which has been previously associated with lifespan determination. This analysis suggests that our understanding of the genetic basis of natural variation in lifespan from induced mutations is incomplete.

Association of Hearing Impairment and Mortality in Older Adults

Abstract: Hearing impairment (HI) affects 16.1 million or nearly two of every three adults aged 70 and older in the United States (1). Epidemiologic studies have demonstrated that HI is independently associated with poorer hearing-related quality of life (2), depression (3), cognitive decline (4), incident dementia (5), impaired activities of daily living (6), increased falls (7), and increased hospitalizations (8). Hypothesized mechanisms to explain these observed associations include residual confounding from shared pathologies (eg, microvascular disease), cognitive load from increased auditory central processing required to decode degraded auditory signals (9), or social isolation (10). Importantly, these mechanisms are not mutually exclusive, and multiple pathways likely coexist and contribute to poorer cognitive and social functioning in older adults with HI. Whether HI is associated with mortality, possibly through similar pathways, is unclear. Previous studies have examined an association of HI with mortality but with inconsistent results (11–17). Most previous studies (12–15) subjectively measured hearing through self-report, and this imprecision in diagnostic assessment might have resulted in decreased sensitivity to detect associations. However, two Australian studies (16,18) determined hearing objectively through audiometric testing, with one finding an association between HI and mortality that was mediated through cognitive impairment and walking disability (16). Additionally, a study of older adults in Iceland demonstrated that HI was independently associated with increased cardiovascular mortality (17). In the present study, we investigated whether HI defined according to World Health Organization criteria (19) was associated with mortality in a longitudinal sample of community-dwelling older adults living in the United States followed in the Health, Aging, and Body Composition study. We hypothesized that greater HI is associated with increased mortality, independent of demographics and cardiovascular risk factors.

Elevated Muscle TLR4 Expression and Metabolic Endotoxemia in Human Aging

Abstract: Aging is associated with alterations in glucose metabolism and sarcopenia that jointly contribute to a higher risk of developing type 2 diabetes. Because aging is considered as a state of low-grade inflammation, in this study we examined whether older, healthy (lean, community-dwelling) participants have altered signaling flux through toll-like receptor 4 (TLR4), a key mediator of innate and adaptive immune responses. We also examined whether a 4-month aerobic exercise program would have an anti-inflammatory effect by reducing TLR4 expression and signaling. At baseline, muscle TLR4, nuclear factor κB p50 and nuclear factor κB p65 protein content, and c-Jun N-terminal kinase phosphorylation were significantly elevated in older versus young participants. The plasma concentration of the TLR4 agonist lipopolysaccharide and its binding protein also were significantly elevated in older participants, indicative of metabolic endotoxemia, which is a recently described phenomenon of increased plasma endotoxin level in metabolic disease. These alterations in older participants were accompanied by decreased insulin sensitivity, quadriceps muscle volume, and muscle strength. The exercise training program increased insulin sensitivity, without affecting quadriceps muscle volume or strength. Muscle TLR4, nuclear factor κB, and c-Jun N-terminal kinase, and plasma lipopolysaccharide and lipopolysaccharide binding protein were not changed by exercise. In conclusion, insulin resistance and sarcopenia of aging are associated with increased TLR4 expression/signaling, which may be secondary to metabolic endotoxemia.

MicroRNA-34a Induces Vascular Smooth Muscle Cells Senescence by SIRT1 Downregulation and Promotes the Expression of Age-Associated Pro-inflammatory Secretory Factors

Abstract: Arterial aging is a major risk factor for the occurrence of cardiovascular diseases. The aged artery is characterized by endothelial dysfunction and vascular smooth muscle cells altered physiology together with low-grade chronic inflammation. MicroRNA-34a (miR-34a) has been recently implicated in cardiac, endothelial, and endothelial progenitor cell senescence; however, its contribution to aging-associated vascular smooth muscle cells phenotype has not been explored so far. We found that miR-34a was highly expressed in aortas isolated from old mice. Moreover, its well-known target, the longevity-associated protein SIRT1, was significantly downregulated during aging in both endothelial cells and vascular smooth muscle cells. Increased miR-34a as well as decreased SIRT1 expression was also observed in replicative-senescent human aortic smooth muscle cells. miR-34a overexpression in proliferative human aortic smooth muscle cells caused cell cycle arrest along with enhanced p21 protein levels and evidence of cell senescence. Furthermore, miR-34a ectopic expression induced pro-inflammatory senescence-associated secretory phenotype molecules. Finally, SIRT1 protein significantly decreased upon miR-34a overexpression and restoration of its levels rescued miR-34a-dependent human aortic smooth muscle cells senescence, but not senescence-associated secretory phenotype factors upregulation. Taken together, our findings suggest that aging-associated increase of miR-34a expression levels, by promoting vascular smooth muscle cells senescence and inflammation through SIRT1 downregulation and senescence-associated secretory phenotype factors induction, respectively, may lead to arterial dysfunctions.

Circulating Proteomic Signatures of Chronological Age

Abstract: To elucidate the proteomic features of aging in plasma, the subproteome targeted by the SOMAscan assay was profiled in blood samples from 202 females from the TwinsUK cohort. Findings were replicated in 677 independent individuals from the AddNeuroMed, Alzheimer's Research UK, and Dementia Case Registry cohorts. Results were further validated using RNAseq data from whole blood in TwinsUK and the most significant proteins were tested for association with aging-related phenotypes after adjustment for age. Eleven proteins were associated with chronological age and were replicated at protein level in an independent population. These were further investigated at gene expression level in 384 females from the TwinsUK cohort. The two most strongly associated proteins were chordin-like protein 1 (meta-analysis β [SE] = 0.013 [0.001], p = 3.66 × 10(-46)) and pleiotrophin (0.012 [0.005], p = 3.88 × 10(-41)). Chordin-like protein 1 was also significantly correlated with birthweight (0.06 [0.02], p = 0.005) and with the individual Framingham 10-years cardiovascular risk scores in TwinsUK (0.71 [0.18], p = 9.9 × 10(-5)). Pleiotrophin is a secreted growth factor with a plethora of functions in multiple tissues and known to be a marker for cardiovascular risk and osteoporosis. Our study highlights the importance of proteomics to identify some molecular mechanisms involved in human health and aging.

Greater Skeletal Muscle Fat Infiltration Is Associated With Higher All-Cause and Cardiovascular Mortality in Older Men

Abstract: Increased accumulation of fat around and within nonadipose tissue organs that normally contain only small amounts of fat, such as in liver, heart, and skeletal muscle, can impair the normal physiological function of those organs (1). This “ectopic fat” storage is now recognized as a risk factor for several chronic diseases, in particular type 2 diabetes (T2D) and cardiovascular disease (CVD), independent of general obesity (2–9). Some propose that the tendency to accumulate adipose tissue in ectopic depots may be explained by inadequate function and capacity of subcutaneous depot to store excess fat (10,11), increased fatty acid transport, uptake and storage, and reduced fatty acid oxidation (2,12,13), and/or increased macrophage infiltration which inhibits adipocyte differentiation (14). Ectopic fat within and around skeletal muscle (known as myosteatosis) is a unique ectopic fat depot that is associated with poor metabolic and musculoskeletal health, and with accelerated aging (1,5,9,15–22). Specifically, myosteatosis has been identified as a risk factor for insulin resistance and T2D (16,22), increased risk of osteoporotic fractures (18,21), decreased muscle strength and mobility loss (15,19), reduced physical performance (23), and impaired longevity (20). Previous studies showed that skeletal muscle fat infiltration increases with advancing age (24), and that elderly individuals have greater myosteatosis (25,26) compared to younger individuals. Despite the emerging role of myosteatosis as an independent risk factor for metabolic dysfunction and other aging-related disorders, no previous studies have examined its association with mortality among older populations recruited without regard to their health status. Thus, in the current study, we evaluated the relationship between myosteatosis and mortality in a cohort of community-dwelling older men. We tested if this relationship was independent of total body and trunk fat, muscle size, lifestyle factors, comorbidities, frailty, and medications that may influence skeletal muscle metabolism. Given its important role in cardio-metabolic health, we hypothesized that increased myosteatosis would be associated with a greater risk of all-cause and CVD mortality.

Moderate-Intensity Physical Activity, Hippocampal Volume, and Memory in Older Adults With Mild Cognitive Impairment

Abstract: Background Greater physical activity (PA) is associated with better memory performance and greater hippocampal volume in older adults. However, most studies to date assessed PA via questionnaires and thereby lacked objective characterization of PA (eg, intensity, duration, etc.). Thus, we currently do not have a comprehensive understanding of PA characteristics that are important for neuroprotection, especially among older adults with mild cognitive impairment (MCI). Thus, using triaxial accelerometers, we examined the association between light- and moderate-intensity PA, total duration of PA, hippocampal volume, and memory in older adults with MCI. Methods This cross-sectional study involved 310 older adults with MCI who completed neuropsychological tests of memory, and structural magnetic resonance imaging. Participants were instructed to wear the accelerometer on an elastic band on their hip at all times for 2 weeks. Average daily duration of light, moderate, and total PA (min/day) was calculated. Results Moderate PA was associated with hippocampal volume (β = .167, p = .003) after controlling for age, but light PA (β = -.021, p = .713) and total PA (β = .011, p = .844) were not. Both light and moderate PAs were not associated with memory performance. Structural equation modeling demonstrated that moderate PA was not directly associated with memory but significantly contributed to hippocampal volume; hippocampal volume loss was significantly and directly associated with poor memory performance. Conclusions Our results suggest that the benefits of moderate PA on memory among older adults with MCI are mediated by hippocampal volume. Furthermore, light PA may not reduce dementia risk among older adults with MCI.

Investigation of MicroRNA Expression in Human Serum During the Aging Process

Abstract: eases, molecular and cellular functions, and participated pathways were further analyzed. Conclusions. The measurement of miRNAs in serum provides a novel, noninvasive approach for the identification of the aging process. Our bioinformatic analyses could form a useful knowledge base for the potential future development of novel therapeutic treatments.

Predictors of 1-Year Mortality in a Prospective Cohort of Elderly Patients With Cancer

Abstract: BACKGROUND Mortality prediction is crucial to select the optimal treatment in elderly cancer patients. Our objective was to identify cancer-related factors and Comprehensive Geriatric Assessment (CGA) findings associated with 1-year mortality in elderly inpatients and outpatients with cancer. METHODS We prospectively included patients aged ≥70 years who had solid or hematologic malignancies and in whom the CGA was performed by geriatricians in two French teaching hospitals. We identified independent predictors of 1-year mortality after study inclusion, using multivariate Cox models stratified on inpatient/outpatient status. We built three multivariate Cox models, since strong correlations linked activities of daily living (ADL), Eastern Cooperative Oncology Group Performance Status (ECOG-PS), and timed get-up-and-go test (GUG) results; and since physicians' preferences for these three assessments vary. A sensitivity analysis was performed using multiple imputation. RESULTS Of the 993 patients (mean age, 80.2 years; 51.2% men), 58.2% were outpatients and 46% had metastatic disease. Colorectal cancer was the most common malignancy (21.4%). Mortality rates after 6 and 12 months were 30.1% and 41.2%, respectively. In all models, tumor site and metastatic status (p 80 years (p < .05), higher number of severe comorbidities (p < .05), and malnutrition (p < .001) were associated with death independently from impaired ECOG-PS (p < .001), ADL (p < .001), and GUG (p < .001). The adverse effect of metastatic status differed significantly across tumor sites, being greatest for breast and prostate cancer (p < .001). Multiple imputation produced similar results. CONCLUSION The predictors of 1-year mortality identified in our study may help physicians select the optimal cancer-treatment strategy in elderly patients.

Effects of Low-Load, Elastic Band Resistance Training Combined With Blood Flow Restriction on Muscle Size and Arterial Stiffness in Older Adults

Abstract: We examined the effect of low-load, elastic band resistance training with blood flow restriction (BFR) on muscle size and arterial stiffness in older adults. Healthy older adults (aged 61-85 years) were divided into BFR training (BFR-T, n = 9) or non-BFR training (CON-T, n = 8) groups. Both groups performed low-load arm curl and triceps down exercises (four sets, total 75 repetitions for each) using an elastic band, 2 d/wk for 12 weeks. The BFR-T group wore inflated pneumatic elastic cuffs (120-270 mm Hg) on both arms during training. Magnetic resonance imaging-measured muscle cross-sectional area of the upper arm, maximum voluntary isometric contraction of the elbow flexors and extensors, cardio-ankle vascular index testing, and ankle-brachial pressure index were measured before and 3-5 days after the final training session. Muscle cross-sectional area of the elbow flexors (17.6%) and extensors (17.4%) increased, as did elbow flexion and elbow extension maximum voluntary isometric contraction (7.8% and 16.1%, respectively) improved (p < .05) in the BFR-T group, but not in the CON-T group. In cardio-ankle vascular index and ankle-brachial pressure index testing, there were no changes between pre- and post-results in either group. In conclusion, elastic band BFR-T improves muscle cross-sectional area as well as maximal muscle strength but does not negatively affect arterial stiffness in older adults.

Skeletal muscle lipid content and oxidative activity in relation to muscle fiber type in aging and metabolic syndrome

Abstract: One of the most noticeable effects of aging is the reduction in skeletal muscle mass and strength (sarcopenia). The metabolic syndrome (MS) is also prevalent in old subjects, but its relevance to skeletal muscle characteristics has poorly been investigated. Immunohistochemical studies were performed with muscle biopsies from young (22 years) and old (73 years) men with and without MS to reveal age-dependent and MS-associated modifications of fiber-type characteristics. Atrophy of type II fibers and altered fiber shape characterized muscle aging in lean healthy men. In contrast, increased cross-sectional area of the most abundant type I and type IIA fibers, and reduced cytochrome c oxidase content in all fiber types, characterized MS. Aging and particularly MS were associated with accumulation of intramyocellular lipid droplets. Although lipids mostly accumulated in type I fibers, matrix-assisted laser desorption/ionization-mass spectrometry imaging of intramyocellular lipids did not distinguish fiber types, but clearly separated young, old, and MS subjects. In conclusion, our study suggests that MS in the elderly persons is associated with alterations in skeletal muscle at a fiber-type specific level. Overall, these fiber type-specific modifications may be important both for the age-related loss of muscle mass and strength and for the increased prevalence of MS in elderly subjects.

Aging, the Central Nervous System, and Mobility in Older Adults: Neural Mechanisms of Mobility Impairment

Abstract: Background Mobility is crucial for successful aging and is impaired in many older adults. We know very little about the subtle, subclinical age-related changes in the central nervous system (CNS) that mediate mobility impairment. Methods A conference series focused on aging, the CNS, and mobility was launched. The second conference addressed major age-associated mechanisms of CNS-mediated mobility impairment. Speakers and conference attendees recommended key areas for future research, identified barriers to progress, and proposed strategies to overcome them. Results Priorities identified for future research include (a) studying interactions among different mechanisms; (b) examining effects of interventions targeting these mechanisms; (c) evaluating the effect of genetic polymorphisms on risks and course of age-related mobility impairment; and (d) examining the effect of age on CNS repair processes, neuroplasticity, and neuronal compensatory mechanisms. Key strategies to promote research include (a) establish standard measures of mobility across species; (b) evaluate the effect of aging in the absence of disease on CNS and mobility; and (c) use advanced computational methods to better evaluate the interactions between CNS and other systems involved in mobility. Conclusions CNS is a major player in the process, leading to mobility decline with aging. Future research in this area has the potential to prolong independence in older persons. Better interactions among disciplines and shared research paradigms are needed to make progress. Research priorities include the development of innovative approaches to integrate research on aging, cognition, and movement with attention to neurovascular function, neuroplasticity, and neurophysiological reserve.

Day-to-Day Changes in Muscle Protein Synthesis in Recovery From Resistance, Aerobic, and High-Intensity Interval Exercise in Older Men

Abstract: Background Resistance exercise (RE) and aerobic exercise are recommended for older adults for fitness and strength. High-intensity interval exercise (HIIT) is an understudied but potent potential alternative to aerobic exercise. This study aimed to determine how each mode of exercise affected the integrated day-to-day response of muscle protein synthesis. Methods Sedentary men (n = 22; 67±4 years; body mass index: 27.0±2.6 kg m(-) (2) [mean ± SEM]) were randomly assigned to perform RE, aerobic exercise, or HIIT. Participants consumed a stable isotope tracer (D2O) for 9 days. Daily saliva samples were taken to measure tracer incorporation in body water. Muscle biopsies were obtained on Days 5-8 of D2O consumption to measure tracer incorporation into muscle at rest, 24 hours, and 48 hours following each exercise bout: RE (3 × 10 repetitions: leg extensor and press, 95% 10RM), HIIT (10 × 1 minute, 95% maximal heart rate [HRmax]), or aerobic exercise (30 minutes, 55%-60% HRmax). Results Myofibrillar protein fractional synthetic rate was elevated, relative to rest, at 24 and 48 hours following RE and HIIT. The increase in myofibrillar fractional synthetic rate was greater following RE versus HIIT at both time points. HIIT was the only mode of exercise to increase sarcoplasmic protein fractional synthetic rate 24-hour postexercise (2.30±0.34% d(-) (1) vs 1.83±0.21% d(-) (1)). Conclusions This study shows that in older men, changes in muscle protein synthesis in response to certain exercises are long lasting and that HIIT significantly increases myofibrillar and sarcoplasmic fractional synthetic rate in this population.