Cross-sectional interactive associations of physical activity and sedentary behaviour with physical capacity across adulthood.

BACKGROUND: The way physical activity (PA) and sedentary behaviour (SB) independently and interactively modify the age-related decline in physical capacity remains poorly understood. This cross-sectional study investigated the independent and interactive associations of PA and SB with physical function and performance throughout the adult life course. METHODS: Data from 499 community-dwelling adults (63% female) aged 20-92 years, involved in the INSPIRE Human Translational Cohort, were used in this cross-sectional study. Daily time spent on moderate-to-vigorous PA (MVPA, min/day) and SB (h/day) was measured with activPAL triaxial accelerometers. Physical function and performance were assessed through the measurement of the 4-m usual gait speed (m/s), handgrip strength (kg), lower-limb strength (isokinetic knee extension torque, N·m), estimated lower-limb power (five-time chair-rise test performance, s) and cardiorespiratory fitness (V̇O2max, mL/kg/min). Confounder-adjusted multiple linear and curvilinear regressions were performed to investigate how MVPA, SB and their interactions were associated with the physical outcomes (all square root-transformed except gait speed) throughout the adulthood spectrum. RESULTS: Interaction analyses revealed that the combination of higher levels of MVPA with lower levels of SB favourably reshaped the negative relationship between handgrip strength and age (age2 × SB × MVPA: B = -7E-08, SE = 3E-08, P < 0.05). In addition, higher levels of MVPA were independently associated with an improved age-related profile in gait speed (age2 × MVPA: B = 3E-06, SE = 1E-06, P < 0.05), chair-rise performance (age × MVPA: B = -9E-05, SE = 4E-05, P < 0.05) and V̇O2max (MVPA at 21 years: B = 3E-02, SE = 7E-03, P < 0.05; age × MVPA: B = -5E-04, SE = 2E-04, P < 0.05). Conversely, the detrimental association of age with lower-limb muscle strength (age × SB: B = -1E-04, SE = 6E-05, P < 0.05) and chair-rise performance (age × SB: B = 1E-05, SE = 7E-06, P < 0.05) was exacerbated with increasing duration of SB, independently of MVPA. Supplementary analyses further revealed that some of these associations were age and sex specific. CONCLUSIONS: This cross-sectional study demonstrated that reduced sedentary time and increased activity duration were independently and synergistically associated with an attenuated age-related loss in physical capacity. These findings need to be confirmed with longitudinal data but encourage both adopting an active lifestyle and reducing sedentary time as preventive measures against physical aging.

Predictive Capacity of the Integrated Care for Older People Screening Tool for Intrinsic Capacity Impairments: Results From the INSPIRE-T Cohort.

BACKGROUND: The Integrated Care for Older People (ICOPE) approach was developed by the World Health Organization (WHO) aiming to shift the traditional focus of care based on diseases to a function- and person-centered approach, focused on maintaining and monitoring intrinsic capacity (IC). This study aimed to investigate the ability of the ICOPE screening tool to identify older people with clinically meaningful impairments in IC domains. METHODS: This cross-sectional analysis included 603 older adults, participants (mean age 74.7 [SD = 8.8] years, women 59.0%) of the INSPIRE Translational (INSPIRE-T) cohort. Responses at screening were compared to results of the subsequent in-depth assessment (ie, Mini-Mental State Examination, Mini Nutritional Assessment, Short Physical Performance Battery, Patient Health Questionnaire-9, and clinical investigation of vision problems) to determine its predictive capacity for impairments at the IC domains (ie, cognition, psychological, sensory (vision), vitality, and locomotion). RESULTS: The ICOPE screening items provided very high sensitivity for identifying abnormality in vision (97.2%) and varied from 42.0% to 69.6% for the other domains. High specificity (>70%) was observed for all the IC domains, except for vision (2.7%). CONCLUSIONS: The ICOPE screening tool can be a useful instrument enabling the identification of older people with impairments in IC domains, but studies with different populations are needed. It should be considered as a low-cost and simple screening tool in clinical care.

Association of intrinsic capacity with functional ability, sarcopenia and systemic inflammation in pre-frail older adults.

Background: Decline in intrinsic capacity (IC) has been shown to accelerate progression to disability. The study aims to explore association of IC composite score with functional ability, sarcopenia and systemic inflammation in pre-frail older adults. Methods: Cross-sectional study of pre-frail older adults ≥60 years old recruited from the community and primary care centers. Composite scores of four domains of IC were measured: locomotion, vitality, cognition and psychological. FRAIL scale was used to define pre-frailty. Muscle mass was measured using the bioelectrical impedance analysis. Systemic inflammation biomarkers [Interleukin-6 (IL-6), Interleukin-10 (IL-10), Tumor Necrosis Factor Alpha (TNF-α), and Growth differentiated factor 15 (GDF-15)] were measured. Participants in the lowest tertile (T1) exhibited greater decline in IC. Results: A total of 398 pre-frail older adults were recruited, mean age was 72.7 ± 5.8 years, 60.1% female, education level 7.8 years, and 85.2% were of Chinese ethnicity. A total of 75.1% had decline in locomotion, 40.5% in vitality, 53.2% in cognition and 41.7% in psychological domain. A total of 95% had decline in at least one domain. T1 was significantly associated with ADL impairment (aOR 3.36, 95% CI 1.78-6.32), IADL impairment (aOR 2.37, 95% CI 1.36-4.13), poor perceived health (aOR 0.96, 95% CI 0.95-0.98), fall (aOR 1.63, 95% CI 1.05-2.84), cognitive impairment (aOR 8.21, 95% CI 4.69-14.39), depression (aOR 101.82, 95% CI 33.62-308.37), and sarcopenia (aOR 2.40, 95% CI 1.60-5.45). T1 had significant associations with GDF-15, IL-10, and IL-10 to TNF-α ratio. Conclusion: Decline in IC composite score among pre-frail older adults was associated with functional limitation, sarcopenia, and systemic inflammation.

Adherence to the MIND diet and the odds of mild cognitive impairment in generally healthy older adults: The 3-year DO-HEALTH study.

BACKGROUND: The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet may slow cognitive decline in older adults. A potential mechanism could be possible anti-inflammatory properties of the MIND-diet. OBJECTIVE: To examine whether adherence to the MIND diet at baseline is associated with the odds of mild cognitive impairment (MCI) and changes in biomarkers of inflammation (High-sensitivity C-reactive Protein(hsCRP), interleukin-6(IL-6)) over three years in adults ≥70 years. METHODS: Adherence to the MIND diet was assessed by food frequency questionnaire (FFQ) at baseline and after three years. Presence of MCI based on the Montreal Cognitive Assessment (MoCA) was defined as <26 (MCI26), or <24 (MCI24). We performed a minimally adjusted model controlling for sex, prior fall, linear spline at age 85, time, treatment and study site. The fully adjusted model also adjusted for education, BMI, physical activity, depression score, daily energy intake, and comorbidity score. To assess the change in inflammatory markers from baseline, we used linear-mixed-effect models adjusted for the same variables plus the respective baseline concentrations. Sensitivity analyses accounting for practice effects of repeated cognitive tests using the reliable change index for both MoCA cut-offs were done. RESULTS: We included 2028 of 2157 DO-HEALTH participants (60.5% women; mean age 74.88 years) with complete data. Adherence to the MIND diet at baseline was not associated with cognitive decline over three years, neither at MoCA < 26 (OR (95%CI) = 0.99 (0.94-1.04)) nor at MoCA < 24 (OR (95%CI) = 1.03 (0.96-1.1)). Applying the reliable change index to the two cut-offs confirmed the findings. Further, the MIND diet adherence was not associated with the change in MoCA score from baseline in DO-HEALTH. For inflammatory biomarkers MIND-diet baseline adherence was not associated with changes in hsCRP or IL-6. CONCLUSION: Adherence to the MIND-diet was neither associated with the odds of MCI, nor with hsCRP or IL-6 at baseline. Moreover, change in MIND-diet over three years was not associated with changes in hsCRP or IL-6.

Longitudinal Associations Between ATPase Inhibitory Factor 1, Growth Differentiation Factor-15, and Nutritional Status in Older Adults From the MAPT Study.

BACKGROUND: Weight and appetite regulation have been associated with the expression and secretion of ATPase inhibitory factor 1 (IF1) and growth differentiation factor-15 (GDF-15), 2 potential biomarkers for age-related mitochondrial dysfunction. The aim was to explore the associations between these biomarkers and nutritional variables in the Multidomain Alzheimer Preventive Trial study. METHODS: IF1 and GDF-15 plasma levels were quantified at 1-year follow-up. The nutritional status was measured using the Mini Nutritional Assessment (MNA) score variation between baseline and 1- and 2-year visits; appetite loss was extracted from the MNA. Bodyweight was measured every 6 months until the third year and then yearly until the fifth year of follow-up, and weight loss was established if the loss was greater than 5% or 10% within the past 6 or 12 months, respectively. Bidirectional associations of IF1 and GDF-15 levels with malnutrition, appetite, and weight loss were examined. The interactions between individual IF1 and GDF-15 with sex were explored. RESULTS: Four hundred and forty-eight participants had MNA data and 1 045 had weight loss data. All the associations between IF1 levels and the MNA score, appetite loss, and weight loss were nonsignificant. Higher GDF-15 levels were cross-sectionally associated with appetite loss at the first year of follow-up, and the GDF-15 highest quartile was associated with nearly 80% higher risks of weight loss over 4 years. Interactions between IF1 and GDF-15 levels, and between these 2 markers and sex were not significantly associated with the outcomes. CONCLUSIONS: GDF-15 plasma levels were related to key malnutrition criteria.

Associations between physical activity levels and ATPase inhibitory factor 1 concentrations in older adults.

BACKGROUND: Adenosine triphosphatase inhibitory factor 1 (IF1) is a key protein involved in energy metabolism. IF1 has been linked to various age-related diseases, although its relationship with physical activity (PA) remains unclear. Additionally, the apolipoprotein A-I (apoA-I), a PA-modulated lipoprotein could play a role in this relationship because it shares a binding site with IF1 on the cell-surface ATP synthase. We examined here the associations between chronic PA and plasma IF1 concentrations among older adults, and we investigated whether apoA-I mediated these associations. METHODS: In the present work, 1096 healthy adults (63.8% women) aged 70 years and over who were involved in the Multidomain Alzheimer Prevention Trial study were included. IF1 plasma concentrations (square root of ng/mL) were measured at the 1-year visit of the Multidomain Alzheimer Prevention Trial, while PA levels (square root of metabolic equivalent task min/week) were assessed using questionnaires administered each year from baseline to the 3-year visit. Multiple linear regressions were performed to investigate the associations between the first-year mean PA levels and IF1 concentrations. Mediation analyses were conducted to examine whether apoA-I mediated these associations. Mixed-effect linear regressions were carried out to investigate whether the 1-year visit IF1 concentrations predicted subsequent changes in PA. RESULTS: Multiple linear regressions indicated that first-year mean PA levels were positively associated with IF1 concentrations (B = 0.021; SE = 0.010; p = 0.043). Mediation analyses revealed that about 37.7% of this relationship was mediated by apoA-I (Bab = 0.008; SE = 0.004; p = 0.023). Longitudinal investigations demonstrated that higher concentrations of IF1 at the 1-year visit predicted a faster decline in PA levels over the subsequent 2 years (time × IF1: B = -0.148; SE = 0.066; p = 0.025). CONCLUSION: This study demonstrated that regular PA is associated with plasma IF1 concentrations, and it suggests that apoA-I partly mediates this association. Additionally, this study found that baseline concentrations of IF1 can predict future changes in PA. However, further research is needed to fully understand the mechanisms underlying these observations.

Association between aging-related biomarkers and longitudinal trajectories of intrinsic capacity in older adults.

Intrinsic capacity (IC), the composite of physical and mental capacities, declines with age at different rates and patterns between individuals. We aimed to investigate the association between longitudinal IC trajectories and plasma biomarkers of two hallmarks of aging-chronic inflammation and mitochondrial dysfunction-in older adults. From the Multidomain Alzheimer Preventive Trial (MAPT), we included 1271 community-dwelling older people (mean [SD] age = 76.0 [4.3] years) with IC data over four years. Group-based multi-trajectory modeling was performed to identify clusters of the participants with similar longitudinal patterns across four IC domains: cognition, locomotion, psychology, and vitality. Five IC multi-trajectory groups were determined: low in all domains (8.4%), low locomotion (24.6%), low psychological domain (16.7%), robust (i.e., high in all domains except vitality; 28.3%), and robust with high vitality (22.0%). Compared to the best trajectory group (i.e., robust with high vitality), elevated levels of plasma interleukin-6 (IL-6), tumor necrosis factor receptor-1 (TNFR-1), and growth differentiation factor-15 (GDF-15) were associated with a higher risk of belonging to the "low in all domains" group (IL-6: relative risk ratio (RRR) [95% CI] = 1.42 [1.07 - 1.88]; TNFR-1: RRR = 1.46 [1.09 - 1.96]; GDF-15: RRR = 1.99 [1.45 - 2.73]). Higher IL-6 and GDF-15 also increased the risk of being in the "low locomotion" group. GDF-15 outperformed other biomarkers by showing the strongest associations with IC trajectory groups. Our findings found that plasma biomarkers reflecting inflammation and mitochondrial impairment distinguished older people with multi-impaired IC trajectories from those with high-stable IC.

Current and investigational medications for the treatment of sarcopenia.

Sarcopenia, defined as the loss of muscle mass and function, is a widely prevalent and severe condition in older adults. Since 2016, it is recognized as a disease. Strength exercise training and nutritional support are the frontline treatment of sarcopenia, with no drug currently approved for this indication. However, new therapeutic options are emerging. In this review, we evidenced that only very few trials have focused on sarcopenia/sarcopenic patients. Most drug trials were performed in different clinical older populations (e.g., men with hypogonadism, post-menopausal women at risk for osteoporosis), and their efficacy were tested separately on the components of sarcopenia (muscle mass, muscle strength and physical performances). Results from trials testing the effects of Testosterone, Selective Androgen Receptor Modulators (SARMs), Estrogen, Dehydroepiandrosterone (DHEA), Insulin-like Growth Factor-1 (IGF-1), Growth Hormone (GH), GH Secretagogue (GHS), drug targeting Myostatin and Activin receptor pathway, Vitamin D, Angiotensin Converting Enzyme inhibitors (ACEi) and Angiotensin Receptor Blockers (ARBs), or ß-blockers, were compiled. Although some drugs have been effective in improving muscle mass and/or strength, this was not translated into clinically relevant improvements on physical performance. Finally, some promising molecules investigated in on-going clinical trials and in pre-clinical phase were summarized, including apelin and irisin.

Association between physical activity, growth differentiation factor 15 and bodyweight in older adults: A longitudinal mediation analysis.

BACKGROUND: Late-life aging is often associated with appetite reduction and weight loss. Physical activity (PA) may prevent these processes, but the molecular mechanisms involved remain elusive. The present study investigated the putative mediating aspect of growth differentiation factor 15 (GDF-15), a stress signalling protein involved in aging, exercise and appetite control, on the association between PA and late-life-associated weight loss. METHODS: One thousand eighty-three healthy adults (63.8% women) aged 70 years and over who participated in the Multidomain Alzheimer Preventive Trial were included. Bodyweight (kg) and PA levels (square root of metabolic equivalent of task-min/week) were assessed repeatedly from baseline to the 3-year visit, whereas plasma GDF-15 (pg/mL) was measured at the 1-year visit. Multiple linear regressions were performed to test the association between first-year mean PA level, 1-year visit GDF-15 concentration and subsequent bodyweight changes. Mediation analyses were used to investigate whether GDF-15 mediated the association between first-year mean PA levels and consecutive bodyweight changes. RESULTS: Multiple regression analyses demonstrated that higher first-year mean PA levels significantly predicted lower GDF-15 and bodyweight at 1 year (B = -2.22; SE = 0.79; P = 0.005). In addition, higher 1-year visit GDF-15 levels were associated with faster subsequent bodyweight loss (Time × GDF-15 interaction B = -0.0004; SE = 0.0001; P = 0.003). Mediation analyses confirmed that GDF-15 mediated the association between first-year mean PA levels and subsequent bodyweight changes (mediated effect ab = 0.0018; bootstrap SE = 0.001; P < 0.05) and revealed that mean PA had no direct effect on subsequent bodyweight changes (c' = 0.006; SE = 0.008; P > 0.05). CONCLUSIONS: This study suggests that GDF-15 may be one of the molecules mediating the link between PA and late-life weight loss, but mechanistic studies are necessary to further support the present findings.

Plasma inflammation-related biomarkers are associated with intrinsic capacity in community-dwelling older adults.

BACKGROUND: How inflammation relates to intrinsic capacity (IC), the composite of physical and mental capacities, remains undefined. Our study aimed to investigate the cross-sectional and longitudinal associations between plasma inflammation-related biomarkers and IC in older adults. METHODS: This secondary analysis of the Multidomain Alzheimer Preventive Trial (MAPT) included 1238 community-dwelling older individuals with IC assessments from 12 to 60 months. Plasma C-reactive protein (CRP), interleukin-6 (IL-6), tumour necrosis factor receptor-1 (TNFR-1), monocyte chemoattractant protein-1 (MCP-1) and growth differentiation factor-15 (GDF-15) were measured at 12 months. IC was operationalized as a score ranging from 0 to 100, derived from four domains: cognition, Mini-Mental State Examination; locomotion, Short Physical Performance Battery; psychological, Geriatric Depression Scale; and vitality, handgrip strength. A five-domain IC score (plus sensory) was investigated in a subsample (n = 535) with a 1-year follow-up as an exploratory outcome. RESULTS: The mean age of the 1238 participants was 76.2 years (SD = 4.3); 63.7% were female. Their initial four-domain IC scores averaged 78.9 points (SD = 9.3), with a yearly decline of 1.17 points (95% CI = -1.30 to -1.05; P < 0.001). We observed significant associations of lower baseline IC with higher CRP, IL-6, TNFR-1 and GDF-15, after controlling age, sex, MAPT group allocation and educational level [CRP: adjusted ß (95% CI) = -1.56 (-2.64 to -0.48); P = 0.005; IL-6: adjusted ß = -3.16 (-4.82 to -1.50); P < 0.001; TNFR-1: adjusted ß = -6.86 (-10.25 to -3.47); P < 0.001; GDF-15: adjusted ß = -7.07 (-10.02 to -4.12); P < 0.001]. Higher TNFR-1, MCP-1 and GDF-15 were associated with faster decline in four-domain IC over 4 years [TNFR-1: adjusted ß (95% CI) = -1.28 (-2.29 to -0.27); P = 0.013; MCP-1: adjusted ß = -1.33 (-2.24 to -0.42); P = 0.004; GDF-15: adjusted ß = -1.42 (-2.26 to -0.58); P = 0.001]. None of the biomarkers was significantly associated with the five-domain IC decline. CONCLUSIONS: Inflammation was associated with lower IC in older adults. Among all plasma biomarkers, TNFR-1 and GDF-15 were consistently associated with IC at the cross-sectional and longitudinal levels.

Biomarkers of mitochondrial dysfunction and inflammaging in older adults and blood pressure variability.

Most physiopathological mechanisms underlying blood pressure variability (BPV) are implicated in aging. Vascular aging is associated with chronic low-grade inflammation occurring in late life, known as "inflammaging" and the hallmark "mitochondrial dysfunction" due to age-related stress. We aimed to determine whether plasma levels of the pleiotropic stress-related mitokine growth/differentiation factor 15 (GDF-15) and two inflammatory biomarkers, interleukin 6 (IL-6) and tumor necrosis factor receptor 1 (TNFR-1), are associated with visit-to-visit BPV in a population of community-dwelling older adults. The study population consisted of 1096 community-dwelling participants [median age 75 (72-78) years; 699 females, 63.7%] aged ≥ 70 years from the MAPT study. Plasma blood sample was collected 12 months after enrolment and BP was assessed up to seven times over a 4-year period. Systolic (SBPV) and diastolic BPV (DBPV) were determined through several indicators taking into account BP change over time, the order of measurements and formulas independent of mean BP levels. Higher values of GDF-15 were significantly associated with increased SBPV (all indicators) after adjustment for relevant covariates [adjusted 1-SD increase in GDF-15: ß (SE) = 0.07 (0.04), p < 0.044, for coefficient of variation%]. GDF-15 levels were not associated with DBPV. No significant associations were found between IL-6 and BPV, whereas TNFR1 was only partially related to DBPV. Unlike inflammation biomarkers, higher GDF-15 levels were associated with greater SBPV. Our findings support the age-related process of mitochondrial dysfunction underlying BP instability, suggesting that BPV might be a potential marker of aging.

TNFR-1 and GDF-15 Are Associated With Plasma Neurofilament Light Chain and Progranulin Among Community-Dwelling Older Adults: A Secondary Analysis of the MAPT Study.

There is growing evidence that cognitive decline can be affected by both nutritional aspects and inflammation. Plasma neurodegenerative biomarkers stand out as minimally invasive useful measures to monitor the potential risk of cognitive decline. This study aimed to investigate the associations between biomarkers of neurodegeneration, nutrition, and inflammation among community-dwelling older adults, and to verify if associations differed according to apolipoprotein E (APOE) ε4 status. This cross-sectional analysis included 475 participants ≥70 years old from the Multidomain Alzheimer Preventive Trial (MAPT), mean age 76.8 years (SD = 4.5), 59.4% women. Biomarkers of neurodegeneration (plasma amyloid-ß 42/40-Aß 42/40, neurofilament light chain-NfL, progranulin), nutrition (erythrocyte docosahexaenoic acid, eicosapentaenoic acid, omega-3 index; plasma homocysteine-Hcy, 25 hydroxyvitamin D), inflammation (plasma tumor necrosis factor receptor 1-TNFR-1, monocyte chemoattractant protein 1-MCP-1, interleukin 6-IL-6), and cellular stress (plasma growth differentiation factor 15-GDF-15) were assessed. Linear regression analyses were performed to investigate the associations between nutritional and inflammatory biomarkers (independent variables) and neurodegenerative biomarkers (dependent variables), with adjustments for age, sex, education, body mass index, physical activity, allocation to MAPT groups, and APOE ε4 status. After adjusting for confounders, Aß 42/40 was not associated with nutritional or inflammatory markers. NfL was positively associated with GDF-15, TNFR-1, IL-6, and Hcy. Progranulin was positively associated with GDF-15, TNFR-1, and MCP-1. Analyses restricted to APOE ε4 carriers (n = 116; 26.9%) or noncarriers were mostly similar. Our cross-sectional study with community-dwelling older adults corroborates previous evidence that inflammatory pathways are associated to plasma markers of neurodegeneration. Clinical Trials Registration Number: NCT00672685.

Plasma level of ATPase inhibitory factor 1 (IF1) is associated with type 2 diabetes risk in humans: A prospective cohort study.

AIM: Mitochondrial dysfunction is associated with the development of type 2 diabetes mellitus (T2DM). It is thus of clinical relevance to identify plasma biomarkers of mitochondrial dysfunction associated with the risk of T2DM. ATPase inhibitory factor 1 (IF1) endogenously inhibits mitochondrial ATP synthase activity. Here, we analyzed association of the plasma IF1 level with markers of glucose homeostasis and with the conversion to new-onset diabetes (NOD) in individuals with prediabetes. METHODS: In the IT-DIAB prospective study, the baseline plasma level of IF1 was measured in 307 participants with prediabetes. The primary outcome was the incidence of NOD within five years of follow-up. Cross-sectional analysis of the IF1 level was also done in two independent interventional studies. Correlations between plasma IF1 and metabolic parameters at baseline were assessed by Spearman's correlation coefficients, and the association with the risk of NOD was determined using Cox proportional-hazards models. RESULTS: In IT-DIAB, the mean IF1 plasma level was lower in participants who developed NOD than in those who did not (537 ± 248 versus 621 ± 313 ng/mL, P   = 0.01). The plasma IF1 level negatively correlated with clinical variables associated with obesity and insulin resistance, including the body mass index (r = -0.20, P  = 0.0005) and homeostasis model assessment of insulin resistance (HOMA-IR). (r = -0.37, P < 0.0001). Conversely, IF1 was positively associated with plasma markers of cardiometabolic health, such as HDL-C (r = 0.63, P  <  0.0001) and apoA-I (r = 0.33, P  <  0.0001). These correlations were confirmed in cross-sectional analyses. In IT-DIAB, the IF1 level was significantly associated with a lower risk of T2DM after adjustment for age, sex, and fasting plasma glucose (HR [95% CI] per 1 SD = 0.76 [0.62; 0.94], P   = 0.012). CONCLUSION: We identified for the first time the mitochondrial-related biomarker IF1 as being associated with the risk of T2DM.

Gantenerumab: an anti-amyloid monoclonal antibody with potential disease-modifying effects in early Alzheimer's disease.

BACKGROUND: This review describes the research and development process of gantenerumab, a fully human anti-amyloid monoclonal antibody in development to treat early symptomatic and asymptomatic Alzheimer's disease (AD). Anti-amyloid monoclonal antibodies can substantially reverse amyloid plaque pathology and may modify the course of the disease by slowing or stopping its clinical progression. Several molecules targeting amyloid have failed in clinical development due to drug-related factors (e.g., treatment-limiting adverse events, low potency, poor brain penetration), study design/methodological issues (e.g., disease stage, lack of AD pathology confirmation), and other factors. The US Food and Drug Administration's approval of aducanumab, an anti-amyloid monoclonal antibody as the first potential disease-modifying therapy for AD, signaled the value of more than 20 years of drug development, adding to the available therapies the first nominal success since cholinesterase inhibitors and memantine were approved. BODY: Here, we review over 2 decades of gantenerumab development in the context of scientific discoveries in the broader AD field. Key learnings from the field were incorporated into the gantenerumab phase 3 program, including confirmed amyloid positivity as an entry criterion, an enriched clinical trial population to ensure measurable clinical decline, data-driven exposure-response models to inform a safe and efficacious dosing regimen, and the use of several blood-based biomarkers. Subcutaneous formulation for more pragmatic implementation was prioritized as a key feature from the beginning of the gantenerumab development program. CONCLUSION: The results from the gantenerumab phase 3 programs are expected by the end of 2022 and will add critical information to the collective knowledge on the search for effective AD treatments.

Implementation of the WHO integrated care for older people (ICOPE) programme in clinical practice: a prospective study.

BACKGROUND: The INSPIRE integrated care for older people (ICOPE)-CARE programme is a public health programme implementing the ICOPE health-care pathway in clinical practice. The primary objective of this study was to describe the large-scale implementation and feasibility of the INSPIRE ICOPE-CARE guidelines in clinical practice. The secondary aims were to describe the characteristics of patients who were identified as positive for abnormalities in intrinsic capacity (ie, locomotion, cognition, psychology, vitality, hearing, and vision) during step 1, and to describe the prevalence of these positive screenings. METHODS: In this prospective study, we evaluated a real-life population of users of primary care services in the Occitania region (France). Participants who were aged 60 years and older and lived in a community were eligible for inclusion in our study. Individuals aged ≥60 years were screened (step 1) by health-care providers or through self-assessments using digital tools (the ICOPE MONITOR app and the ICOPEBOT conversational robot). Our implementation strategy involved raising awareness among health-care professionals about the WHO ICOPE programme, training professionals in the ICOPE-CARE guidelines, and developing a digital infrastructure (ie, digital tools, a database, and a remote ICOPE monitoring platform). The feasibility of implementing the INSPIRE ICOPE-CARE guidelines was determined by the anticipated inclusion of ≥10 000 participants, and having a follow-up rate of over 50%. FINDINGS: Between Jan 1, 2020, and November 18, 2021, 10 903 older people (mean age 76·0, SD 10·5 years; 6627 [60·8%] of whom were women) had a baseline step 1 screening done, and 5185 (70·4%) of 7367 eligible participants had a 6-month follow-up of step 1 screening. 10 285 (94·3%) participants had a positive intrinsic capacity result during screening at baseline. 958 (9·3%) participants were evaluated with step 2 (in-depth assessments). Positive intrinsic capacity was confirmed in 865 (90·3%) participants. Most recommendations in step 3 (care plan) were related to locomotion, vitality, and cognition. INTERPRETATION: The high number of participants included in our study, as well as the high rates of follow-up, provides evidence to suggest that the large-scale implementation of ICOPE in clinical practice is feasible. The very high prevalence of positive screening for impaired intrinsic capacity during step 1, as well as the high rates of confirmed deficits in intrinsic capacity during step 2, suggest that the INSPIRE ICOPE-CARE programme is able to target individuals who are at increased risk for functional loss and disability. FUNDING: Occitania Regional Health Agency, Region Occitanie and Pyrénées-Méditerranée, European Regional Development Fund, and The Interreg Program V-A Spain-France-Andorra.

Frailty biomarkers under the perspective of geroscience: A narrative review.

Cellular and molecular aging biomarkers might contribute to identify at-risk individuals for frailty before overt clinical manifestations appear. Although studies on the associations of aging biomarkers and frailty exist, no investigation has gathered this information using a structured framework for identifying aging biomarkers; as a result, the evidence on frailty and aging biomarkers is diffuse and incomplete. Therefore, this narrative review aimed to gather information on the associations of the hallmarks of aging and frailty under the perspective of geroscience. The literature on human studies on this topic is sparse and mainly composed of cross-sectional investigations performed in small study samples. The main putative aging biomarkers associated to frailty were: mitochondrial DNA copy number (genomic instability and mitochondrial dysfunction), telomere length (telomere attrition), global DNA methylation (epigenetic alterations), Hsp70 and Hsp72 (loss of proteostasis), IGF-1 and SIRT1 (deregulated nutrient-sensing), GDF-15 (mitochondrial dysfunction, cellular senescence and altered intercellular communication), CD4 + and CD8 + cell percentages (cellular senescence), circulating osteogenic progenitor (COP) cells (stem cell exhaustion), and IL-6, CRP and TNF-alpha (altered intercellular communication). IGF-1, SIRT1, GDF-15, IL-6, CRP and TNF-alpha presented more evidence among these biomarkers, highlighting the importance of inflammation and nutrient sensing on frailty. Further longitudinal studies investigating biomarkers across the hallmarks of aging would provide valuable information on this topic.

Clinically meaningful change for the chair stand test: monitoring mobility in integrated care for older people.

BACKGROUND: Clinically meaningful changes in the five-repetition chair stand test are essential for monitoring mobility in integrated care for older people. Recommendations for the clinically meaningful change of the chair stand test are not well known. Our study aimed to estimate the absolute and relative clinically meaningful changes for older adults' five-repetition chair stand test. METHODS: We applied distribution-based and anchor-based methods in addition to receiver operator characteristics analyses to a population-based study of community-dwelling adults (SAGE Mexico study, n = 897) to derive the clinically meaningful change in the chair stand test. We used three self-reported clinical anchors: moving around, vigorous activities, and walking 1 km. Our primary outcome was the incidence of disability for basic activities of daily living (ADL). Secondly, we examined our estimates of clinically meaningful change in a clinical trial population of healthy volunteers (MAPT, France, study n = 1575) concerning the risk of incident ADL disability. RESULTS: The age of SAGE Mexico participants ranged from 60 to 96 years; mean (SD) = 69.0 (6.2); 54.4% were female. Their baseline chair stand time averaged 12.1 s (SD = 3 s). Forty-eight participants (5.6%) showed incident disability over 3 years. The absolute and relative clinically meaningful change cut points found over 3 years of follow-up were 2.6 s and 27.7%, respectively. Absolute clinically meaningful change ranged from 0.5 to 4.7 s, depending on the estimation method. Relative clinically meaningful change ranged from 9.6 to 46.2%. SAGE Mexico participants with absolute and relative clinically meaningful declines (increasing 2.6 s and 27.7% from baseline time, respectively) showed an increased risk of ADL disability [aRR = 1.93; P = 0.0381; 95% CI (1.05, 3.46) and aRR = 2.27; P = 0.0157; 95% CI (1.22, 4.10)], respectively, compared with those without a clinically meaningful decline. MAPT participants [age range = 70-94; mean (SD) = 75.3 (4.4); 64.8% female; incident ADL disability over 5 years = 145(14.8%)] with a relative clinically meaningful decline (≥27.7% from baseline over 3 years) had a 74% higher risk of incident ADL disability than their counterparts [aHR = 1.74; P = 0.016; CI95% (1.11, 2.72); mean follow-up of 58 months]. CONCLUSIONS: Community-dwelling older adults with an increase of 3 s or 28% in chair stand test performance over 3 years (approximately 1 s or 10% per year) could be the target of interventions to enhance mobility and prevent incident disability.

Serum neurofilament light levels are predictive of all-cause mortality in late middle-aged individuals.

BACKGROUND: Blood biomarkers can offer valuable and easily accessible indicators of normal biological processes, pathogenic conditions, and responses to therapeutic interventions. Recent studies found that levels of neurofilament light chain (NfL) in the blood are associated with mortality in three European cohorts of older adults (median ages 73, 93, and 100 years). Whether similar associations exist in younger adults and in other ethnic groups is currently not known. METHODS: We utilized a cohort study that included 294 African Americans (baseline ages 49-65). Serum NfL levels were measured using a Meso Scale Discovery-based assay. Vital status was determined by matching through the National Death Index. FINDINGS: Seventy-two participants (24.5%) died during the 14-15 years of follow up (2000-2014). Baseline serum NfL levels were significantly higher in the decedent group (86.1±65.7 pg/ml vs. 50.1±28.0 pg/ml, p < 0·001). In binomial logistic regression models adjusted for age, gender, education, baseline smoking status, BMI, and total comorbidities (0-11), serum NfL levels remained a strong predictor of all-cause mortality, and sensitivity analyses employing multiple additional covariates did not substantively change the relationship. Further, Kaplan-Meier curves based on serum NfL quartiles showed reduced survival in groups with higher serum NfL levels. INTERPRETATION: This study found a positive association between serum NfL levels and mortality in late middle-aged and older individuals. While our findings support that serum NfL levels may be a useful biomarker for all-cause mortality, further studies are needed to understand the biological mechanisms underlying this association. FUNDING: National Institute on Aging, Saint Louis University.

Combined Vitamin D, Omega-3 Fatty Acids, and a Simple Home Exercise Program May Reduce Cancer Risk Among Active Adults Aged 70 and Older: A Randomized Clinical Trial.

Objective: The aim of this study was to test the individual and combined benefit of vitamin D, omega-3, and a simple home strength exercise program on the risk of any invasive cancer. Design: The DO-HEALTH trial is a three-year, multicenter, 2 × 2 × 2 factorial design double-blind, randomized-controlled trial to test the individual and combined benefit of three public health interventions. Setting: The trial was conducted between December 2012 and December 2017 in five European countries. Participants: Generally healthy community-dwelling adults ≥70 years were recruited. Interventions: Supplemental 2000 IU/day of vitamin D3, and/or 1 g/day of marine omega-3s, and/or a simple home strength exercise (SHEP) programme compared to placebo and control exercise. Main outcome: In this pre-defined exploratory analysis, time-to-development of any verified invasive cancer was the primary outcome in an adjusted, intent-to-treat analysis. Results: In total, 2,157 participants (mean age 74.9 years; 61.7% women; 40.7% with 25-OH vitamin D below 20 /ml, 83% at least moderately physically active) were randomized. Over a median follow-up of 2.99 years, 81 invasive cancer cases were diagnosed and verified. For the three individual treatments, the adjusted hazard ratios (HRs, 95% CI, cases intervention versus control) were 0.76 (0.49-1.18; 36 vs. 45) for vitamin D3, 0.70 (0.44-1.09, 32 vs. 49) for omega-3s, and 0.74 (0.48-1.15, 35 vs. 46) for SHEP. For combinations of two treatments, adjusted HRs were 0.53 (0.28-1.00; 15 vs. 28 cases) for omega-3s plus vitamin D3; 0.56 (0.30-1.04; 11 vs. 21) for vitamin D3 plus SHEP; and 0.52 (0.28-0.97; 12 vs. 26 cases) for omega-3s plus SHEP. For all three treatments combined, the adjusted HR was 0.39 (0.18-0.85; 4 vs. 12 cases). Conclusion: Supplementation with daily high-dose vitamin D3 plus omega-3s, combined with SHEP, showed cumulative reduction in the cancer risk in generally healthy and active and largely vitamin D-replete adults ≥70 years. Clinical Trial Registration: ClinicalTrials.gov, Identifier: NCT01745263.

The ability of eight frailty instruments to identify adverse outcomes across different settings: the FRAILTOOLS project.

BACKGROUND: To compare the performance of eight frailty instruments to identify relevant adverse outcomes for older people across different settings over a 12 month follow-up. METHODS: Observational longitudinal prospective study of people aged 75 + years enrolled in different settings (acute geriatric wards, geriatric clinic, primary care clinics, and nursing homes) across five European cities. Frailty was assessed using the following: Frailty Phenotype, SHARE-FI, 5-item Frailty Trait Scale (FTS-5), 3-item FTS (FTS-3), FRAIL scale, 35-item Frailty Index (FI-35), Gérontopôle Frailty Screening Tool, and Clinical Frailty Scale. Adverse outcomes ascertained at follow-up were as follows: falls, hospitalization, increase in limitation in basic (BADL) and instrumental activities of daily living (IADL), and mortality. Sensitivity, specificity, and capacity to predict adverse outcomes in logistic regressions by each instrument above age, gender, and multimorbidity were calculated. RESULTS: A total of 996 individuals were followed (mean age 82.2 SD 5.5 years, 61.3% female). In geriatric wards, the FI-35 (69.1%) and the FTS-5 (67.9%) showed good sensitivity to predict death and good specificity to predict BADL worsening (70.3% and 69.8%, respectively). The FI-35 also showed good sensitivity to predict BADL worsening (74.6%). In nursing homes, the FI-35 and the FTSs predicted mortality and BADL worsening with a sensitivity > 73.9%. In geriatric clinic, the FI-35, the FTS-5, and the FRAIL scale obtained specificities > 85% to predict BADL worsening. No instrument achieved high enough sensitivity nor specificity in primary care. All the instruments predict the risk for all the outcomes in the whole sample after adjusting for age, gender, and multimorbidity. The associations of these instruments that remained significant by setting were for BADL worsening in geriatric wards [FI-35 OR = 5.94 (2.69-13.14), FTS-3 = 3.87 (1.76-8.48)], nursing homes [FI-35 = 4.88 (1.54-15.44), FTS-5 = 3.20 (1.61-6.38), FTS-3 = 2.31 (1.27-4.21), FRAIL scale = 1.91 (1.05-3.48)], and geriatric clinic [FRAIL scale = 4.48 (1.73-11.58), FI-35 = 3.30 (1.55-7.00)]; for IADL worsening in primary care [FTS-5 = 3.99 (1.14-13.89)] and geriatric clinic [FI-35 = 3.42 (1.56-7.49), FRAIL scale = 3.27 (1.21-8.86)]; for hospitalizations in primary care [FI-35 = 3.04 (1.25-7.39)]; and for falls in geriatric clinic [FI-35 = 2.21 (1.01-4.84)]. CONCLUSIONS: No single assessment instrument performs the best for all settings and outcomes. While in inpatients several commonly used frailty instruments showed good sensitivities (mainly for mortality and BADL worsening) but usually poor specificities, the contrary happened in geriatric clinic. None of the instruments showed a good performance in primary care. The FI-35 and the FTS-5 showed the best profile among the instruments assessed.