Multimodal cell atlas of the ageing human skeletal muscle.

Muscle atrophy and functional decline (sarcopenia) are common manifestations of frailty and are critical contributors to morbidity and mortality in older people1. Deciphering the molecular mechanisms underlying sarcopenia has major implications for understanding human ageing2. Yet, progress has been slow, partly due to the difficulties of characterizing skeletal muscle niche heterogeneity (whereby myofibres are the most abundant) and obtaining well-characterized human samples3,4. Here we generate a single-cell/single-nucleus transcriptomic and chromatin accessibility map of human limb skeletal muscles encompassing over 387,000 cells/nuclei from individuals aged 15 to 99 years with distinct fitness and frailty levels. We describe how cell populations change during ageing, including the emergence of new populations in older people, and the cell-specific and multicellular network features (at the transcriptomic and epigenetic levels) associated with these changes. On the basis of cross-comparison with genetic data, we also identify key elements of chromatin architecture that mark susceptibility to sarcopenia. Our study provides a basis for identifying targets in the skeletal muscle that are amenable to medical, pharmacological and lifestyle interventions in late life.

iMS-Bmal1-/- mice show evident signs of sarcopenia that are counteracted by exercise and melatonin therapies.

Sarcopenia is an age-related disease characterized by a reduction in muscle mass, strength, and function and, therefore, a deterioration in skeletal muscle health and frailty. Although the cause of sarcopenia is still unknown and, thus, there is no treatment, increasing evidence suggests that chronodisruption, particularly alterations in Bmal1 clock gene, can lead to those deficits culminating in sarcopenia. To gain insight into the cause and mechanism of sarcopenia and the protective effect of a therapeutic intervention with exercise and/or melatonin, the gastrocnemius muscles of male and female skeletal muscle-specific and inducible Bmal1 knockout mice (iMS-Bmal1-/- ) were examined by phenotypic tests and light and electron microscopy. Our results revealed a disruption of the normal activity/rest rhythm, a drop in skeletal muscle function and mass, and increased frailty in male and female iMS-Bmal1-/- animals compared to controls. A reduction in muscle fiber size and increased collagenous tissue were also detected, accompanied by reduced mitochondrial oxidative capacity and a compensatory shift towards a more oxidative fiber type. Electron microscopy further supports mitochondrial impairment in mutant mice. Melatonin and exercise ameliorated the damage caused by loss of Bmal1 in mutant mice, except for mitochondrial damage, which was worsened by the latter. Thus, iMS-Bmal1-/- mice let us to identify Bmal1 deficiency as the responsible for the appearance of sarcopenia in the gastrocnemius muscle. Moreover, the results support the exercise and melatonin as therapeutic tools to counteract sarcopenia, by a mechanism that does not require the presence of Bmal1.

Neurophysiological and Brain Structural Markers of Cognitive Frailty Differ from Alzheimer's Disease.

With increasing life span and prevalence of dementia, it is important to understand the mechanisms of cognitive aging. Here, we focus on a subgroup of the population we term "cognitively frail," defined by reduced cognitive function in the absence of subjective memory complaints, or a clinical diagnosis of dementia. Cognitive frailty is distinct from cognitive impairment caused by physical frailty. It has been proposed to be a precursor to Alzheimer's disease, but may alternatively represent one end of a nonpathologic spectrum of cognitive aging. We test these hypotheses in humans of both sexes, by comparing the structural and neurophysiological properties of a community-based cohort of cognitive frail adults, to people presenting clinically with diagnoses of Alzheimer's disease or mild cognitive impairment, and community-based cognitively typical older adults. Cognitive performance of the cognitively frail was similar to those with mild cognitive impairment. We used a novel cross-modal paired-associates task that presented images followed by sounds, to induce physiological responses of novelty and associative mismatch, recorded by EEG/MEG. Both controls and cognitively frail showed stronger mismatch responses and larger temporal gray matter volume, compared with people with mild cognitive impairment and Alzheimer's disease. Our results suggest that community-based cognitively frail represents a spectrum of normal aging rather than incipient Alzheimer's disease, despite similar cognitive function. Lower lifelong cognitive reserve, hearing impairment, and cardiovascular comorbidities might contribute to the etiology of the cognitive frailty. Critically, community-based cohorts of older adults with low cognitive performance should not be interpreted as representing undiagnosed Alzheimer's disease.SIGNIFICANCE STATEMENT The current study investigates the neural signatures of cognitive frailty in relation to healthy aging and Alzheimer's disease. We focus on the cognitive aspect of frailty and show that, despite performing similarly to the patients with mild cognitive impairment, a cohort of community-based adults with poor cognitive performance do not show structural atrophy or neurophysiological signatures of Alzheimer's disease. Our results call for caution before assuming that cognitive frailty represents latent Alzheimer's disease. Instead, the cognitive underperformance of cognitively frail adults could result in cumulative effects of multiple psychosocial risk factors over the lifespan, and medical comorbidities.

Heteroplasmy of Wild-Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty.

BACKGROUND: In most eukaryotic cells, the mitochondrial DNA (mtDNA) is transmitted uniparentally and present in multiple copies derived from the clonal expansion of maternally inherited mtDNA. All copies are therefore near-identical, or homoplasmic. The presence of >1 mtDNA variant in the same cytoplasm can arise naturally or result from new medical technologies aimed at preventing mitochondrial genetic diseases and improving fertility. The latter is called divergent nonpathologic mtDNA heteroplasmy (DNPH). We hypothesized that DNPH is maladaptive and usually prevented by the cell. METHODS: We engineered and characterized DNPH mice throughout their lifespan using transcriptomic, metabolomic, biochemical, physiologic, and phenotyping techniques. We focused on in vivo imaging techniques for noninvasive assessment of cardiac and pulmonary energy metabolism. RESULTS: We show that DNPH impairs mitochondrial function, with profound consequences in critical tissues that cannot resolve heteroplasmy, particularly cardiac and skeletal muscle. Progressive metabolic stress in these tissues leads to severe pathology in adulthood, including pulmonary hypertension and heart failure, skeletal muscle wasting, frailty, and premature death. Symptom severity is strongly modulated by the nuclear context. CONCLUSIONS: Medical interventions that may generate DNPH should address potential incompatibilities between donor and recipient mtDNA.

Identifying an Optimal Liver Frailty Index Cutoff to Predict Waitlist Mortality in Liver Transplant Candidates.

BACKGROUND AND AIMS: Frailty, as measured by the Liver Frailty Index (LFI), is associated with liver transplant (LT) waitlist mortality. We sought to identify an optimal LFI cutoff that predicts waitlist mortality. APPROACH AND RESULTS: Adults with cirrhosis awaiting LT without hepatocellular carcinoma at nine LT centers in the United States with LFI assessments were included. Multivariable competing risk analysis assessed the relationship between LFI and waitlist mortality. We identified a single LFI cutoff by evaluating the fit of the competing risk models, searching for the cutoff that gave the best model fit (as judged by the pseudo-log-likelihood). We ascertained the area under the curve (AUC) in an analysis of waitlist mortality to find optimal cutoffs at 3, 6, or 12 months. We used the AUC to compare the discriminative ability of LFI+Model for End Stage Liver Disease-sodium (MELDNa) versus MELDNa alone in 3-month waitlist mortality prediction. Of 1,405 patients, 37 (3%), 82 (6%), and 135 (10%) experienced waitlist mortality at 3, 6, and 12 months, respectively. LFI was predictive of waitlist mortality across a broad LFI range: 3.7-5.2. We identified an optimal LFI cutoff of 4.4 (95% confidence interval [CI], 4.0-4.8) for 3-month mortality, 4.2 (95% CI, 4.1-4.4) for 6-month mortality, and 4.2 (95% CI, 4.1-4.4) for 12-month mortality. The AUC for prediction of 3-month mortality for MELDNa was 0.73; the addition of LFI to MELDNa improved the AUC to 0.79. CONCLUSIONS: LFI is predictive of waitlist mortality across a wide spectrum of LFI values. The optimal LFI cutoff for waitlist mortality was 4.4 at 3 months and 4.2 at 6 and 12 months. The discriminative performance of LFI+MELDNa was greater than MELDNa alone. Our data suggest that incorporating LFI with MELDNa can more accurately represent waitlist mortality in LT candidates.

Progression in Physical Frailty in Peritoneal Dialysis Patients.

BACKGROUND: Physical frailty contributes to adverse clinical outcomes in peritoneal dialysis (PD) patients. Little has been reported about frailty transitions in this population. We aimed to describe the transitions of frailty in PD patients and identify factors that predicted changes in frailty state. METHODS: In a prospective observational study, we recruited 267 PD patients. Frailty was assessed by a validated frailty score. Depression was graded by PHQ-9 score, and nutritional status was evaluated by serum albumin, Subjective Global Assessment (SGA), and comprehensive Malnutrition Inflammation Score (MIS). The primary outcome was the change in frailty score at follow-up compared to baseline. RESULTS: At baseline, 194 (72.7%) patients were classified as frail. With time, their frailty scores significantly increased (p < 0.001), and 93 of the surviving subjects (78.2%) were classified as frail. There was a modest significant correlation between change in MIS (p < 0.001), change in SGA score (p < 0.001), and change in PHQ-9 score (p < 0.001) with change in frailty score. An increase in PHQ-9 score (p < 0.001) and MIS (p = 0.001), as well as longer duration of hospitalization (p = 0.001), was independently associated with a greater change in frailty score after adjustment for confounding factors. Frailty score was also improved in patients who were converted to hemodialysis (p = 0.048) and received renal transplantation (p = 0.005). CONCLUSION: Our findings suggested that frailty transitions were common in PD patients. Worsening in nutrition and depression, together with a longer duration of hospitalization, were associated with worsening in frailty.

Basic Science of Frailty-Biological Mechanisms of Age-Related Sarcopenia.

Aging is associated with loss of function across organ systems, contributing to systemic frailty. Loss of skeletal muscle mass and function, in particular, is a major source of frailty in older adults, severely impacting quality of life. Some loss of muscle mass and strength with aging is inevitable, and sarcopenia, the severe loss of muscle mass with aging, is common. Sarcopenia is determined in part by genetics but can be modified by lifestyle choices. The pathophysiologic underpinnings of sarcopenia are complex and multifactorial. In this review, the causes of sarcopenia are surveyed at the systems, cell, subcellular, and molecular levels with emphasis on the interplay between these various causes of this degenerative disease process.

The immense heterogeneity of frailty in neurosurgery: a systematic literature review.

The aim of this study was to review and analyze the neurosurgery body of literature to document the current knowledge of frailty within neurosurgery, standardizing terminology and how frailty is defined, including the different levels of frailty, while determining what conclusions can be drawn about frailty's impact on neurosurgical outcomes. While multiple studies on frailty in neurosurgery exist, no literature reviews have been conducted. Therefore, we performed a literature review in order to organize, tabulate, and present findings from the data to broaden the understanding about what we know from frailty and neurosurgery. We performed a PubMed search to identify studies that evaluated frailty and neurosurgery. The terms "frail," "frailty," "neurosurgery," "spine surgery," "craniotomy," and "neurological surgery" were all used in the query. We then organized, analyzed, and summarized the comprehensive frailty and neurosurgical literature. The literature contained 25 published studies analyzing frailty in neurosurgery between December 2015 and December 2018. Five of these studies were cranial neurosurgical studies, the remaining studies focused on spinal neurosurgery. Over 100,000 surgical cases were analyzed among the 25 studies. Of these, 18 studies demonstrated that increasing frailty was associated with increased rate of complications, 10 studies showed that frailty was associated with higher mortality rates, 11 studies demonstrated an association between frailty and increased hospital length of stay, and 5 studies noted that higher frailty was associated with discharge to a higher level of care. The current body of literature repeatedly demonstrates that frailty is associated with worse outcomes across the neurosurgical subspecialties.

The Importance of Cellular Senescence in Frailty and Cardiovascular Diseases.

Frailty is a complex clinical syndrome, progressively described in the last thirty years, resulting from multiple impairments across many organs and systems and characterized by a reduction in physiological reserves and increased vulnerability to stressors, as well. Cardiovascular diseases (CVDs) are a common health problem in very old populations. Age-related changes occur throughout the body and in all organs, including the cardiovascular system. Cellular senescence links age-related CVDs and frailty by many mechanisms of particular interest in the aging biology and geriatric syndromes. Cellular senescence may represent the pivotal factor with its senescence-associated secretory phenotype (SASP) leading to systemic inflammation. In this context, SASP may represent the key element in the association between aging, frailty and the development of age-related CVDs.

Inflammation, Frailty and Cardiovascular Disease.

Chronic inflammation, which is called "inflamm-aging" , is characterized by an increased level of inflammatory cytokines in response to physiological and environmental stressors, and causes the immune system to function consistently at a low level, even though it is not effective. Possible causes of inflammaging include genetic susceptibility, visceral obesity, changes in gut microbiota and permeability, chronic infections and cellular senescence. Inflammation has a role in the development of many age-related diseases, such as frailty. Low grade chronic inflammation can also increase the risk of atherosclerosis and insulin resistance which are the leading mechanisms in the development of cardiovascular diseases (CVD). As it is well known that the risk of CVD is higher in older people with frailty and the risk of frailty is higher in patients with CVD, there may be relationship between inflammation and the development of CVD and frailty. Therefore, this important issue will be discussed in this chapter.

Oxidative Stress, Frailty and Cardiovascular Diseases: Current Evidence.

The aim of this chapter is to review the results of recent studies analyzing the role of oxidative stress and systemic inflammation as potential contributors to frailty and CVD, and to explain a possible pathogenic relationship between the latter two conditions. Available evidence suggests that frail patients have elevated levels of oxidative stress biomarkers and proinflammatory cytokines, as well as with reduced concentrations of endogenous antioxidants. This implies that oxidative stress and systemic inflammation might play a role in the pathogenesis of frailty, but an underlying mechanism of this relationship is still mostly hypothetical. Oxidative stress and systemic inflammation are also involved in the pathogenesis of CVD. Cardiovascular conditions are established risk factor for frailty and in turn, presence of frailty constitutes an unfavorable prognostic factor in cardiac patients. Finally, some cardiovascular risk factors, such as lack of physical activity, smoking, obesity and inappropriate diet, are also involved in the etiology of oxidative stress, chronic inflammation and frailty. This complex interplay between intrinsic and extrinsic elements should be considered during holistic management of older persons with frailty and/or cardiovascular conditions.

Frailty and Comprehensive Geriatric Assessment.

Frailty is defined as a reduced physiologic reserve vulnerable to external stressors. For older individuals, frailty plays a decisive role in increasing adverse health outcomes in most clinical situations. Many tools or criteria have been introduced to define frailty in recent years, and the definition of frailty has gradually converged into several consensuses. Frail older adults often have multi-domain risk factors in terms of physical, psychological, and social health. Comprehensive geriatric assessment (CGA) is the process of identifying and quantifying frailty by examining various risky domains and body functions, which is the basis for geriatric medicine and research. CGA provides physicians with information on the reversible area of frailty and the leading cause of deterioration in frail older adults. Therefore frailty assessment based on understanding CGA and its relationship with frailty, can help establish treatment strategies and intervention in frail older adults. This review article summarizes the recent consensus and evidence of frailty and CGA.

Association between Timed Up and Go Test and Subsequent Functional Dependency.

BACKGROUND: This study aimed to evaluate the association between baseline results of the Timed Up and Go (TUG) test and subsequent functional dependency occurrence. METHODS: From the National Health Insurance Service-Senior Cohort database, we identified 39,519 people who participated in the National Screening Program for Transitional Ages at the age of 66 during 2007-2008. Impaired mobility was defined as taking 10 seconds or longer to perform the TUG test. Functional dependency occurrence was defined as the initiation of receiving national Long-Term Care Insurance services-home care or admission to long-term care facilities. Cox proportional hazard regression models were used to assess the hazard ratios (HRs) for dependency occurrence according to baseline TUG test results. RESULTS: The mean follow-up period was 5.7 years. Occurrence rates of dependency were 2.0 and 3.4 cases per 1,000 person-years in the normal and impaired TUG groups, respectively. Impaired mobility was associated with a higher risk of functional dependency occurrence (adjusted HR [aHR], 1.65; 95% confidence interval [CI], 1.40-1.95; P < 0.001). Additionally, in the subgroup analysis for the participants with intact baseline activities of daily living, impaired mobility was associated with a higher risk of dependency occurrence (aHR, 1.65; 95% CI, 1.33-2.04; P < 0.001). CONCLUSION: The TUG test might be a useful predictive marker of subsequent functional dependency occurrence. Intervention to prevent functional dependency may be helpful for older adults with impairment on the TUG test.

HIV serostatus, inflammatory biomarkers and the frailty phenotype among older people in rural KwaZulu-Natal, South Africa.

Objective: We compared the prevalence of frailty by HIV serostatus and related biomarkers to the modified frailty phenotype among older individuals in a rural population in South Africa. Methods: Questionnaire data were from a cohort of people living with HIV (PWH) on antiretroviral therapy (ART) and HIV-uninfected people aged 50 years and older sampled from the Africa Health Research Institute Demographic Health and Surveillance area in northern KwaZulu-Natal. The prevalence of frailty was compared using five categories: (1) physical activity; (2) mobility; (3) fatigue; (4) gait speed; and (5) grip strength, and assessed for demographic, clinical, and inflammatory correlates of frailty. Results: Among 614 individuals in the study, 384 (62.5%) were women. The median age at study enrolment was 64 years [Interquartile range (IQR) (58.6-72.0)]. 292 (47.6%) were PWH. 499 (81%) were classified as either pre-frail or frail. 43 (7%) were frail and HIV positive, 185 (30%) were pre-frail and HIV positive, 57 were frail and HIV negative and 214 (35%) were pre-frail and HIV negative. Frailty was similar for HIV negative and PWH (17.7% vs 14.7%, p = 0.72). Women were more likely to be frail (18.3% vs 13.04%, p = 0.16). The prevalence of frailty increased with age for both HIV groups. In the multivariable analysis, the odds of being frail were higher in those aged 70 years and above than those aged between 50 and 59 years (p < 0.001). Females were less likely to be pre-frail than males (p < 0.001). There was no association between any of the inflammatory biomarkers and frailty and pre-frailty. Conclusion: In this population, the prevalence of frailty is similar for PWH and people without HIV, but higher for women than men. These data suggest that the odds of developing frailty is similar for PWH over the age of 50 years, who survive into older age, as for people without HIV.

Frailty, Neurocognitive Impairment, or Both in Predicting Poor Health Outcomes Among Adults Living With Human Immunodeficiency Virus.

Background: Neurocognitive impairment (NCI) is strongly associated with frailty in people living with human immunodeficiency virus (PLWH); the overlap of frailty and NCI and the impact on health outcomes in PLWH are unknown. Methods: PLWH in a longitudinal, observational study of aging completed entry evaluations for frailty and NCI. Outcomes of falls (recurrent) increased limitations in independent activities of daily living (IADL), or mortality were combined. Poisson regression models estimated prevalence ratios (PR) for ≥1 outcome over 2 years. Results: Among 987 participants, the median age at entry was 51 years; 19% were female; the median CD4 count was 616 cells/µL; and HIV-1 RNA was <200 copies/mL in 94%. Most (79%) participants had neither frailty nor NCI; 2% had both; 4% frailty only; and 15% NCI only. Over 2 years of observation, 100 (10%) participants experienced recurrent falls; 175 (18%) had worsening IADL limitations; 17 (2%) died; and 254 (26%) experienced ≥1 poor health outcome. In adjusted models, frailty with NCI was associated with more than double the risk of a poor health outcome (PR 2.65; 95% CI 1.98, 3.54); a significant association was also seen with frailty alone (PR 2.26; 95%CI 1.71, 2.99) and NCI alone (PR 1.73; 95% CI 1.36, 2.20). Conclusions: The presence of frailty with NCI was associated with a greater risk of falls, disability, or death in PLWH than NCI alone. Interventions that target prevention or reversal of both frailty and NCI (such as increased physical activity) may significantly limit poor health outcomes among PLWH.

T-cell immunity against cytomegalovirus in HIV infection and aging: relationships with inflammation, immune activation, and frailty.

Both aging and treated human immunodeficiency virus (HIV) infection are characterized by low-level chronic inflammation and immune activation which contribute to the development of age-related diseases, frailty, and early mortality. Chronic cytomegalovirus (CMV) infection is highly prevalent in older adults and HIV-infected populations. A number of studies have shown that CMV induces broad and strong T-cell responses in CMV-seropositive older adults and HIV-infected individuals. CMV infection rarely develops into clinical disease in immunocompetent individuals. However, a large body of literature has shown adverse effects of chronic CMV infection on the health and longevity of these populations. It has been hypothesized that chronic CMV infection may be a driver of chronic inflammation and immune activation, and may further contribute to the development of frailty. Thus, there is a need to better understand the extent of the impact of chronic CMV infection on T-cell immunity and health in aging and HIV infection. In this review, we will address important considerations and challenges in the assessment of chronic CMV infection and CMV-specific T-cell responses. We will then review recent data on relationships between T-cell responses to CMV and levels of inflammatory markers and immune activation, as well as the onset of frailty.

Indicators of stress and their association with frailty in the precontact Southwestern United States.

OBJECTIVES: Physiological disturbances in early life have been shown to increase individual mortality risk and impact health in adulthood. This study examines frailty through analysis of lesion status of two commonly collected skeletal indicators of stress (cribra orbitalia [CO] and porotic hyperostosis [PH]) and their association with mortality risk in the precontact U.S. Southwest. Several predictions are addressed: (a) individuals with active skeletal lesions are the frailest; (b) individuals with healed lesions are the least frail; (c) CO lesions, regardless of status, are associated with increased mortality risk. MATERIALS AND METHODS: Odds ratios and Kaplan-Meier survival analysis are used to examine the association between stress indicators and mortality in the U.S. Southwest. This study includes 335 individuals (75 females, 81 males, 20 adults of unknown sex, and 159 juveniles) from precontact New Mexico archaeological sites dating to A.D. 1,000-1,400. RESULTS: Active CO and PH lesions are associated with lower survivorship and greater mortality risk than healed or absent lesions. Only juvenile individuals have active CO and PH lesions, as is expected given their physiology. CO lesions in any state are associated with greater mortality risk and earlier ages of death. DISCUSSION: Individuals with active lesions are the frailest; while individuals with healed lesions are the least frail. CO and PH likely have different etiologies: CO lesions are associated with increased mortality risk and decreased individual longevity. These results indicate that CO's presence suggests a more severe underlying condition than PH lesions alone.

The intersections of industrialization: Variation in skeletal indicators of frailty by age, sex, and socioeconomic status in 18th- and 19th-century England.

OBJECTIVES: Intersectionality theory argues that various categories of identity and forms of systemic oppression interact and produce inequalities in resource access, economic opportunities, and health outcomes. However, there has been little explicit engagement with this theory by bioarchaeologists examining disparate health outcomes in the past. This study examines the associations among frailty, age at death, sex, and socioeconomic status (SES) in 18th- and 19th-century England. MATERIALS AND METHODS: The sample for this study comes from four industrial-era cemeteries from England, ca. 1711-1857. The associations among adult age (18+ years), SES, sex, and three skeletal indicators of stress (dental enamel hypoplasia [DEH, n = 293], cribra orbitalia [CO, n = 457], periosteal lesions [PNB, n = 436]) are examined using hierarchical log-linear analysis. RESULTS: Significant interactions existed among the variables examined for two skeletal indicators: high SES females had lower frequencies of CO relative to other groups and males between ages 30-45 years exhibited higher frequencies of PNB compared to females or males of older or younger ages, regardless of SES. Additionally, sex and SES were consistently associated with age at death. CONCLUSIONS: These results suggest that patterns of stress indicators cannot be examined solely across unilateral axes of age, SES, or sex. Intersecting axes of privilege, marginalization, and structural oppression may have buffered high SES females from some negative health outcomes (CO) while predisposing them to others (risk of maternal mortality). Likewise, the hazardous working conditions relegated to adult males may have heightened the risk of injury, infection, and death for middle-aged men in industrial-era England.

Relationship Between T-Cell Responses to CMV, Markers of Inflammation, and Frailty in HIV-uninfected and HIV-infected Men in the Multicenter AIDS Cohort Study.

Background: Both aging and treated human immunodeficiency virus (HIV)-infected populations exhibit low-level chronic immune activation of unknown etiology, which correlates with morbidity and mortality. Cytomegalovirus (CMV) infection is common in both populations, but its relation to immune activation is unknown. Methods: T cells from men who have sex with men (22 virologically suppressed HIV+, 20 HIV-) were stimulated with peptides spanning 19 CMV open reading frames, and intracellular cytokine responses were assessed. Soluble and cellular inflammatory markers were assessed by multiplex electrochemiluminescence and flow cytometry, respectively. Frailty was assessed by the Fried criteria. Results: All men had responses to CMV. Proportions of CMV-responsive T cells correlated strongly (r ≥ 0.6 or ≤ -0.6; P < .05) with immunologic markers, depending on donor HIV and frailty status. Markers significantly correlated in some groups after adjustment for multiple comparisons included interferon-γ, tumor necrosis factor-α, interleukin-6, and several chemokines in serum, and the proportion of activated T cells. The magnitude of the CD4 IL-2 response significantly predicted onset of frailty in HIV- nonfrail men, but not in HIV+ nonfrail men. Conclusions: T-cell responses to CMV may strongly influence chronic immune activation in HIV-uninfected and virologically suppressed HIV-infected men, and may predict frailty in HIV-uninfected men.

Frailty, nutrition-related parameters, and mortality across the adult age spectrum.

BACKGROUND: Nutritional status and individual nutrients have been associated with frailty in older adults. The extent to which these associations hold in younger people, by type of malnutrition or grades of frailty, is unclear. Our objectives were to (1) evaluate the relationship between individual nutrition-related parameters and frailty, (2) investigate the association between individual nutrition-related parameters and mortality across frailty levels, and (3) examine whether combining nutrition-related parameters in an index predicts mortality risk across frailty levels. METHODS: This observational study assembled 9030 participants aged ≥ 20 years from the 2003-2006 cohorts of the National Health and Nutrition Examination Survey who had complete frailty data. A 36-item frailty index (FI) was constructed excluding items related to nutritional status. We examined 62 nutrition-related parameters with established cut points: 34 nutrient intake items, 5 anthropometric measurements, and 23 relevant blood tests. The 41 nutrition-related parameters which were associated with frailty were combined into a nutrition index (NI). All-cause mortality data until 2011 were identified from death certificates. RESULTS: All 5 anthropometric measurements, 21/23 blood tests, and 19/34 nutrient intake items were significantly related to frailty. Although most nutrition-related parameters were directly related to frailty, high alcohol consumption and high levels of serum alpha-carotene, beta-carotene, beta-cryptoxanthin, total cholesterol, and LDL-c were associated with lower frailty scores. Only low vitamin D was associated with increased mortality risk across all frailty levels. Seventeen nutrition-related parameters were associated with mortality in the 0.1-0.2 FI group, 11 in the 0.2-0.3 group, and 16 in the > 0.3 group. Overall, 393 (5.8%) of the participants had an NI score less than 0.1 (abnormality in ≤ 4 of the 41 parameters examined). Higher levels of NI were associated with higher mortality risk after adjusting for frailty and other covariates (HR per 0.1: 1.19 [95%CI 1.133-1.257]). CONCLUSIONS: Most nutrition-related parameters were correlated to frailty, but only low vitamin D was associated with higher risk for mortality across levels of frailty. As has been observed with other age-related phenomena, even though many nutrition-related parameters were not significantly associated with mortality individually, when combined in an index, they strongly predicted mortality risk.