Blood Biomarkers from Research Use to Clinical Practice: What Must Be Done? A Report from the EU/US CTAD Task Force.

Timely and accurate diagnosis of Alzheimer's disease (AD) in clinical practice remains challenging. PET and CSF biomarkers are the most widely used biomarkers to aid diagnosis in clinical research but present limitations for clinical practice (i.e., cost, accessibility). Emerging blood-based markers have the potential to be accurate, cost-effective, and easily accessible for widespread clinical use, and could facilitate timely diagnosis. The EU/US CTAD Task Force met in May 2022 in a virtual meeting to discuss pathways to implementation of blood-based markers in clinical practice. Specifically, the CTAD Task Force assessed: the state-of-art for blood-based markers, the current use of blood-based markers in clinical trials, the potential use of blood-based markers in clinical practice, the current challenges with blood-based markers, and the next steps needed for broader adoption in clinical practice.

DNA methylation profile of a rural cohort exposed to early-adversity and malnutrition: An exploratory analysis.

Barker's hypothesis affirms that undernourishment in early-life induces metabolic reprogramming that compromises organism functions later in life, leading to age-related diseases. We are exposed to environmental and social conditions that impact our life trajectories, leading to ageing phenotypes as we grow. Epigenetic mechanisms constitute the link between both external stimuli and genetic programming. Studies have focused on describing the effect of early adverse events such as trauma, famines, or childhood labor on epigenetic markers in adulthood and the elderly. However, we lack information on epigenetic programming in individuals born in rural communities from underdeveloped countries, exposed to negative influences during fetal and postnatal development, particularly chronic malnutrition. Hence, in this exploratory analysis, we characterize the epigenome of individuals and some parents from Tlaltizapan (a rural community in Mexico originally studied almost 50 years ago) and collect anthropometric data on growth and development, as well on the living conditions of the families. Our results help build a biological hypothesis indicating that most of the epigenetic age measures of the subjects are significantly different among them. Interestingly, the most affected methylated regions correspond to pathways involved in neuronal system development, reproductive behaviour, learning and memory regulation.

International Exercise Recommendations in Older Adults (ICFSR): Expert Consensus Guidelines.

The human ageing process is universal, ubiquitous and inevitable. Every physiological function is being continuously diminished. There is a range between two distinct phenotypes of ageing, shaped by patterns of living - experiences and behaviours, and in particular by the presence or absence of physical activity (PA) and structured exercise (i.e., a sedentary lifestyle). Ageing and a sedentary lifestyle are associated with declines in muscle function and cardiorespiratory fitness, resulting in an impaired capacity to perform daily activities and maintain independent functioning. However, in the presence of adequate exercise/PA these changes in muscular and aerobic capacity with age are substantially attenuated. Additionally, both structured exercise and overall PA play important roles as preventive strategies for many chronic diseases, including cardiovascular disease, stroke, diabetes, osteoporosis, and obesity; improvement of mobility, mental health, and quality of life; and reduction in mortality, among other benefits. Notably, exercise intervention programmes improve the hallmarks of frailty (low body mass, strength, mobility, PA level, energy) and cognition, thus optimising functional capacity during ageing. In these pathological conditions exercise is used as a therapeutic agent and follows the precepts of identifying the cause of a disease and then using an agent in an evidence-based dose to eliminate or moderate the disease. Prescription of PA/structured exercise should therefore be based on the intended outcome (e.g., primary prevention, improvement in fitness or functional status or disease treatment), and individualised, adjusted and controlled like any other medical treatment. In addition, in line with other therapeutic agents, exercise shows a dose-response effect and can be individualised using different modalities, volumes and/or intensities as appropriate to the health state or medical condition. Importantly, exercise therapy is often directed at several physiological systems simultaneously, rather than targeted to a single outcome as is generally the case with pharmacological approaches to disease management. There are diseases for which exercise is an alternative to pharmacological treatment (such as depression), thus contributing to the goal of deprescribing of potentially inappropriate medications (PIMS). There are other conditions where no effective drug therapy is currently available (such as sarcopenia or dementia), where it may serve a primary role in prevention and treatment. Therefore, this consensus statement provides an evidence-based rationale for using exercise and PA for health promotion and disease prevention and treatment in older adults. Exercise prescription is discussed in terms of the specific modalities and doses that have been studied in randomised controlled trials for their effectiveness in attenuating physiological changes of ageing, disease prevention, and/or improvement of older adults with chronic disease and disability. Recommendations are proposed to bridge gaps in the current literature and to optimise the use of exercise/PA both as a preventative medicine and as a therapeutic agent.

Validation of Two Intrinsic Capacity Scales and Its Relationship with Frailty and Other Outcomes in Mexican Community-Dwelling Older Adults.

OBJECTIVES: The aim of this study was to compare a short and a long version of an intrinsic capacity index and test their cross-sectional association with relevant health outcomes in older adults. DESIGN: Cross-sectional analysis of the baseline data of the FraDySMex study. PARTICIPANTS: 543 community-dwelling adults aged 50 years and older living in 2 municipalities in Mexico City, from which 435 had complete data on the variables of interest. METHODS: The intrinsic capacity indices were obtained using principal components analysis. The performance of the indices was tested respective to frailty, IADL and ADL. RESULTS: The short and long versions of the IC index performed well for assessing functional status. Using biometrical variables like the phase angle, grip strength and gait speed measured by the GAIT rite improved the index performance vis a vis IADL disability (Lawton), but not to the other evaluated outcomes. CONCLUSIONS: Both the long and short versions of the intrinsic capacity indices tested were able to classify older adults according to their functional status and were associated with relevant health outcomes.

In the quest of a Standard Index of Intrinsic Capacity. A Critical Literature Review.

OBJECTIVES: Intrinsic capacity is a composite of five domains that summarizes the physical and mental capacities of an individual. Intrinsic capacity is increasing in relevance for adapting health systems to population ageing. Therefore, our objective was to analyse how intrinsic capacity has been assessed in older adults and if these measurements have been validated, as an initial step towards the construction of a standard intrinsic capacity index. DESIGN: Narrative review with electronic searches performed in PubMed and Cochrane databases, including the studies which used the term "intrinsic capacity" in the context of human ageing and health. The full text was then accessed to select studies with at least one operationalised domain of intrinsic capacity. We also looked for information on the validity and reliability of the reported measures of intrinsic capacity. RESULTS: We included ten articles reporting a quantitative measurement of intrinsic capacity. There were two intrinsic capacity scores which combined retrospective data on the intrinsic capacity domains sub-scores, with low concordance among tests chosen to measure each domain. Two studies reported on reliability and validity of the IC scores. The main gaps in the construction and validation process were a) analysis undertaken with each domain separately rather than for the construct of intrinsic capacity, b) lack of a clear conceptual and operational definition of the vitality domain, c) summary score that depends upon the distribution of the study sample. CONCLUSION: Further validation of the intrinsic capacity concept is needed, together with more robust approaches to measure it. A standard index of IC has not been validated for translation into clinical or research purposes.

Promising biomarkers of human aging: In search of a multi-omics panel to understand the aging process from a multidimensional perspective.

The aging process has been linked to the occurrence of chronic diseases and functional impairments, including cancer, sarcopenia, frailty, metabolic, cardiovascular, and neurodegenerative diseases. Nonetheless, aging is highly variable and heterogeneous and represents a challenge for its characterization. In this sense, intrinsic capacity (IC) stands as a novel perspective by the World Health Organization, which integrates the individual wellbeing, environment, and risk factors to understand aging. However, there is a lack of quantitative and qualitative attributes to define it objectively. Therefore, in this review we attempt to summarize the most relevant and promising biomarkers described in clinical studies at date over different molecular levels, including epigenomics, transcriptomics, proteomics, metabolomics, and the microbiome. To aid gerontologists, geriatricians, and biomedical researchers to understand the aging process through the IC. Aging biomarkers reflect the physiological state of individuals and the underlying mechanisms related to homeostatic changes throughout an individual lifespan; they demonstrated that aging could be measured independently of time (that may explain its heterogeneity) and to be helpful to predict age-related syndromes and mortality. In summary, we highlight the areas of opportunity and gaps of knowledge that must be addressed to fully integrate biomedical findings into clinically useful tools and interventions.

Allostatic Load as a Biological Substrate to Intrinsic Capacity: A Secondary Analysis of CRELES.

OBJECTIVES: Intrinsic capacity (IC) is one of the latest views of positive aging. In its current status lacks a biological substrate amenable to be intervened. The aim of this study was to determine the association of allostatic load (AL) with IC. DESIGN: We present a cross-sectional analysis of the Costa Rican Longevity and Healthy Aging Study. SETTING: This report is from a representative sample of Costa Rican older adults; one of the countries that integrate the Central America region. PARTICIPANTS: 2,827, 60-year or older community-dwelling individuals. METHODS: An IC index was gathered and validated, including different domains: cognitive, psychological, sensory, vitality and locomotion. AL was integrated with: blood pressure, abdominal obesity, body mass index, HDL-cholesterol, glycosylated hemoglobin, DHEAS, cortisol, epinephrine and norepinephrine. AL was grouped in three categories according to the number of abnormal biomarkers (0-1, 2-3 and ≥4). Chronic diseases, socioeconomic level, sex and age were the adjusting variables. Ordinal logistic regression models were estimated in order to test the strength of the association. RESULTS: From a total sample of 1,888 individuals, 51% (n=962) were women, 36.4% were in the 60-69 age category. The mean score of the IC index was of 6.6 (±2.2). Odds ratio (OR) of the adjusted models were significant for the group of those with 2-3 abnormal biomarkers of AL (OR 0.67, p=0.007) and also for those with ≥4 (OR 0.56, p=0.002), when compared to the reference group of AL (0-1 abnormal biomarkers). CONCLUSIONS AND IMPLICATIONS: AL showed an incremental association with IC, even when adjusted for factors such as socioeconomic status and chronic diseases. Targeting therapeutically AL could potentially improve IC in older adults and therefore decreasing the progression to disability or to overt dependency.

Physical Frailty: ICFSR International Clinical Practice Guidelines for Identification and Management.

OBJECTIVE: The task force of the International Conference of Frailty and Sarcopenia Research (ICFSR) developed these clinical practice guidelines to overview the current evidence-base and to provide recommendations for the identification and management of frailty in older adults. METHODS: These recommendations were formed using the GRADE approach, which ranked the strength and certainty (quality) of the supporting evidence behind each recommendation. Where the evidence-base was limited or of low quality, Consensus Based Recommendations (CBRs) were formulated. The recommendations focus on the clinical and practical aspects of care for older people with frailty, and promote person-centred care. Recommendations for Screening and Assessment: The task force recommends that health practitioners case identify/screen all older adults for frailty using a validated instrument suitable for the specific setting or context (strong recommendation). Ideally, the screening instrument should exclude disability as part of the screening process. For individuals screened as positive for frailty, a more comprehensive clinical assessment should be performed to identify signs and underlying mechanisms of frailty (strong recommendation). Recommendations for Management: A comprehensive care plan for frailty should address polypharmacy (whether rational or nonrational), the management of sarcopenia, the treatable causes of weight loss, and the causes of exhaustion (depression, anaemia, hypotension, hypothyroidism, and B12 deficiency) (strong recommendation). All persons with frailty should receive social support as needed to address unmet needs and encourage adherence to a comprehensive care plan (strong recommendation). First-line therapy for the management of frailty should include a multi-component physical activity programme with a resistance-based training component (strong recommendation). Protein/caloric supplementation is recommended when weight loss or undernutrition are present (conditional recommendation). No recommendation was given for systematic additional therapies such as cognitive therapy, problem-solving therapy, vitamin D supplementation, and hormone-based treatment. Pharmacological treatment as presently available is not recommended therapy for the treatment of frailty.

Systems biology and network pharmacology of frailty reveal novel epigenetic targets and mechanisms.

Frailty is an age-associated condition, characterized by an inappropriate response to stress that results in a higher frequency of adverse outcomes (e.g., mortality, institutionalization and disability). Some light has been shed over its genetic background, but this is still a matter of debate. In the present study, we used network biology to analyze the interactome of frailty-related genes at different levels to relate them with pathways, clinical deficits and drugs with potential therapeutic implications. Significant pathways involved in frailty: apoptosis, proteolysis, muscle proliferation, and inflammation; genes as FN1, APP, CREBBP, EGFR playing a role as hubs and bottlenecks in the interactome network and epigenetic factors as HIST1H3 cluster and miR200 family were also involved. When connecting clinical deficits and genes, we identified five clusters that give insights into the biology of frailty: cancer, glucocorticoid receptor, TNF-α, myostatin, angiotensin converter enzyme, ApoE, interleukine-12 and -18. Finally, when performing network pharmacology analysis of the target nodes, some compounds were identified as potentially therapeutic (e.g., epigallocatechin gallate and antirheumatic agents); while some other substances appeared to be toxicants that may be involved in the development of this condition.

International Clinical Practice Guidelines for Sarcopenia (ICFSR): Screening, Diagnosis and Management.

OBJECTIVES: Sarcopenia, defined as an age-associated loss of skeletal muscle function and muscle mass, occurs in approximately 6 - 22 % of older adults. This paper presents evidence-based clinical practice guidelines for screening, diagnosis and management of sarcopenia from the task force of the International Conference on Sarcopenia and Frailty Research (ICSFR). METHODS: To develop the guidelines, we drew upon the best available evidence from two systematic reviews paired with consensus statements by international working groups on sarcopenia. Eight topics were selected for the recommendations: (i) defining sarcopenia; (ii) screening and diagnosis; (iii) physical activity prescription; (iv) protein supplementation; (v) vitamin D supplementation; (vi) anabolic hormone prescription; (vii) medications under development; and (viii) research. The ICSFR task force evaluated the evidence behind each topic including the quality of evidence, the benefit-harm balance of treatment, patient preferences/values, and cost-effectiveness. Recommendations were graded as either strong or conditional (weak) as per the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Consensus was achieved via one face-to-face workshop and a modified Delphi process. RECOMMENDATIONS: We make a conditional recommendation for the use of an internationally accepted measurement tool for the diagnosis of sarcopenia including the EWGSOP and FNIH definitions, and advocate for rapid screening using gait speed or the SARC-F. To treat sarcopenia, we strongly recommend the prescription of resistance-based physical activity, and conditionally recommend protein supplementation/a protein-rich diet. No recommendation is given for Vitamin D supplementation or for anabolic hormone prescription. There is a lack of robust evidence to assess the strength of other treatment options.

Calf circumference predicts mobility disability: A secondary analysis of the Mexican health and ageing study.

INTRODUCTION: Calf circumference is a surrogate measurement of muscle mass. However, there is scarce evidence on its validity in predicting adverse outcomes such as mobility disability. The aim of this report is to determine if calf circumference could predict incident mobility disability in Mexican 60-year or older adults. METHODS: This is a secondary analysis of the Mexican Health and Aging Study and in particular of its two first waves. Sixty-year or older adults without mobility disability in the first assessment were included and followed-up for two years. Calf circumference quartile groups were compared to test the difference of incident mobility disability. Logistic regression models were fitted to test the independent association when including confounding variables. RESULTS: A total of 745 older adults were assessed, from which 24.4% of the older adults developed mobility disability at follow-up. A calf circumference > 38 cm was associated with a higher risk of developing mobility disability, even after adjustment in the multivariate model, with an odds ratio 0.55 (95% confidence interval 0.31-0.99, P = 0.049). CONCLUSIONS: High calf circumference in Mexican older adults is independently associated with incident mobility disability. This could reflect the impact of adverse health conditions such as obesity (with high fat tissue) or edema. Further research should aim at testing these results in different populations.

Frailty Across Age Groups.

BACKGROUND: The implementation of an aging biomarker into clinical practice is under debate. The Frailty Index is a model of deficit accumulation and has shown to accurately capture frailty in older adults, thus bridging biological with clinical practice. OBJECTIVES: To describe the association of socio-demographic characteristics and the Frailty Index in different age groups (from 20 to over one hundred years) in a representative sample of Mexican subjects. DESIGN: Cross-sectional analysis. SETTING: Nationwide and population-representative survey. PARTICIPANTS: Adults 20-years and older interviewed during the last Mexican National Health and Nutrition Survey (2012). MEASUREMENTS: A 30-item Frailty Index following standard construction was developed. Multi-level regression models were performed to test the associations of the Frailty Index with multiple socio-demographic characteristics across age groups. RESULTS: A total of 29,504 subjects was analyzed. The 30-item Frailty Index showed the highest scores in the older age groups, especially in women. No sociodemographic variable was associated with the Frailty Index in all the studied age groups. However, employment, economic income, and smoking status were more consistently found across age groups. CONCLUSIONS: To our knowledge, this is the first report describing the Frailty Index in a representative large sample of a Latin American country. Increasing age and gender were closely associated with a higher score.

Sarcopenia prevalence using simple measurements and population-based cutoff values.

OBJECTIVE: To estimate the prevalence of sarcopenia in Mexican older adults using simple measurements and tailored cutoff values for the components of the European Working Group on Sarcopenia in Older People algorithm. MATERIAL AND METHODS: This study used cross-sectional data from the third wave (2012) of the Mexican Health and Aging Study. Gait speed and handgrip strength cutoff values were tailored for Mexican older adults. Muscle mass was estimated by a formula, which uses simple anthropometry and demographic characteristics. RESULTS: From the total of 1,238 older adults included in our study, sarcopenia prevalence was 11% (n = 137). When categorizing sarcopenia, 39.1% (n = 484) had pre-sarcopenia, 8.3% (n = 103) moderate sarcopenia, and 2.75% (n = 34) had severe sarcopenia. CONCLUSIONS: Sarcopenia is a common problem in Mexican older adults, and its frequency along with its severity increases with age. Tailored cutoff values could help in identifying those subjects that could have benefited from intervention.

RISK FACTORS FOR SLOW GAIT SPEED: A NESTED CASE-CONTROL SECONDARY ANALYSIS OF THE MEXICAN HEALTH AND AGING STUDY.

BACKGROUND: Physical performance tests play a major role in the geriatric assessment. In particular, gait speed has shown to be useful for predicting adverse outcomes. However, risk factors for slow gait speed (slowness) are not clearly described. OBJECTIVES: To determine risk factors associated with slowness in Mexican older adults. DESIGN: A two-step process was adopted for exploring the antecedent risk factors of slow gait speed. First, the cut-off values for gait speed were determined in a representative sample of Mexican older adults. Then, antecedent risk factors of slow gait speed (defined using the identified cut-points) were explored in a nested, cohort case-control study. SETTING PARTICIPANTS: One representative sample of a cross-sectional survey for the first step and the Mexican Health and Aging Study (a cohort characterized by a 10-year follow-up). MEASUREMENTS: A 4-meter usual gait speed test was conducted. Lowest gender and height-stratified groups were considered as defining slow gait speed. Sociodemographic characteristics, comorbidities, psychological and health-care related variables were explored to find those associated with the subsequent development of slow gait speed. Unadjusted and adjusted logistic regression models were performed. RESULTS: In the final model, age, diabetes, hypertension, and history of fractures were associated with the development of slow gait speed. CONCLUSIONS: Early identification of subjects at risk of developing slow gait speed may halt the path to disability due to the robust association of this physical performance test with functional decline.

Gait Speed and Handgrip Strength as Predictors of Incident Disability in Mexican Older Adults.

Physical performance tests are associated with different adverse outcomes in older people. The objective of this study was to test the association between handgrip strength and gait speed with incident disability in community-dwelling, well-functioning, Mexican older adults (age ≥70 years). Incident disability was defined as the onset of any difficulty in basic or instrumental activities of daily living. Of a total of 133 participants, 52.6% (n=70) experienced incident disability during one year of follow-up. Significant associations of handgrip strength (odds ratio [OR] 0.96, 95% confidence interval [95%CI] 0.93-0.99) and gait speed (OR 0.27, 95%CI 0.07-0.99) with incident disability were reported. The inclusion of covariates in the models reduced the statistical significance of the associations without substantially modifying the magnitude of them. Handgrip strength and gait speed are independently associated with incident disability in Mexican older adults.

Mortality as an adverse outcome of sarcopenia.

Sarcopenia has an important impact in elderly. Recently the European Working Group on Sarcopenia in Older People (EWGSOP) defined sarcopenia as the loss of muscle mass plus low muscle strength or low physical performance. Lack of clinical sounding outcomes (ie external validity), is one of the flaws of this algorithm. The aim of our study was to determine the association of sarcopenia and mortality in a group of Mexican elderly. A total of 345 elderly were recruited in Mexico City, and followed up for three years. The EWGSOP algorithm was integrated by: gait speed, grip strength and calf circumference. Other covariates were assessed in order to test the independent association of sarcopenia with mortality. Of the 345 subjects, 53.3% were women; with a mean age of 78.5 (SD 7) years. During the three year follow-up a total of 43 (12.4%) subjects died. Age, cognition, ADL, IADL, health self-perception, ischemic heart disease and sarcopenia were associated in the bivariate analysis with survival. Negative predictive value for sarcopenia regarding mortality was of 90%. Kaplan-Meier curves along with their respective log-rank test were significant for sarcopenia. The components of the final Cox-regression multivariate model were age, ischemic heart disease, ADL and sarcopenia. Adjusted HR for age was 3.24 (CI 95% 1.55-6.78 p 0.002), IHD 5.07 (CI 95% 1.89-13.59 p 0.001), health self-perception 5.07 (CI 95% 1.9-13.6 p 0.001), ADL 0.75 (CI 95% 0.56-0.99 p 0.048) and sarcopenia 2.39 (CI 95% 1.05-5.43 p 0.037).

The Coyoacán Cohort Study: Design, Methodology, and Participants' Characteristics of a Mexican Study on Nutritional and Psychosocial Markers of Frailty.

BACKGROUND: "Frailty" has emerged as a condition associated with an increased risk of functional decline among the elderly, which may be differentiated from aging, disability, and co-morbidities. OBJECTIVE: The Mexican Study of Nutritional and Psychosocial Markers of Frailty among Community-Dwelling Elderly has emerged to help answer many questions about frailty among the older adults. This report presents the design of the study and baseline data of its participants. DESIGN: The "Coyoacan cohort" is a longitudinal observational study developed in Mexico City. PARTICIPANTS: A representative sample of 1,294 non-institutionalized men and women aged 70 years and older were randomly recruited to undergo a face-to-face interview and a comprehensive geriatric assessment (including clinical evaluations and blood samples) between 2008 and 2009. MEASUREMENTS: Data collected included socio-demographic and economic characteristics, medical history, oral health, drug use, cognitive function and mood, nutritional status, physical performance and functional status, physical activity, quality of life, social networks, and biological data. Frailty was defined as the presence of ≥3 of the following components: slowness, poor muscle strength, low physical activity, exhaustion and unintentional weight loss. RESULTS: A total of 1,124 participants completed the interview. The mean age was 79.5 ± 7.1 years, and 55.9% were female. Nine hundred and forty-five subjects completed the clinical evaluation and 743 blood samples were collected. The baseline prevalence of frailty was 14.1%. CONCLUSIONS: Understanding the medical, biological, and environmental factors that contribute to the phenomenon of frailty is the goal of the current research in the field.

Self-reported reading and writing skills in elderly who never attended school influence cognitive performances: results from the Coyoacán cohort study.

OBJECTIVES: Beyond the well-known effect of educational level on cognitive performances, the present study investigates the specific effect of literacy acquisition independently of education. DESIGN: A sample of 175 unschooled elderly participants was selected from a larger Mexican population-based cohort study. PARTICIPANTS: The sample of 175 subjects who never went to school was divided in two groups: 109 who never acquired literacy skills and 66 who declared having acquired reading and writing abilities. MEASUREMENTS: Cognitive performances on commonly used tests (mini mental state examination, Isaacs set test, free and cued selective reminding test and clock-drawing test) were compared between the two groups taking into account several potentially confounding factors. RESULTS: The participants with reading and writing skills performed better than their counterparts in most tests, even though no difference was observed for the Isaacs Set Test and the delayed recall of the free and cued selective reminding test. CONCLUSION: Writing and reading skills in elderly people with no formal education influence performances in very commonly used test. Not only educational level but also literacy acquisition should be taken into account when conducting cognitive assessment in very low educated elderly people.