Cardiovascular disease and the risk of incident falls and mortality among adults aged ≥ 65 years presenting to the emergency department: a cohort study from national registry data in Denmark.

BACKGROUND: Falls cause 58% of injury-related Emergency Department (ED) attendances. Previous research has highlighted the potential role of cardiovascular risk factors for falls. This study investigated the impact of cardiovascular disease (CVD) risk on three-year incident falls, with presentation to the ED, and mortality. METHODS: A matched cohort study design was employed using national registry data from 82,292 adults (33% male) aged ≥ 65 years living in Denmark who attended the ED in 2013. We compared age and gender matched ED attendees presenting with a fall versus another reason. The cohort was followed for three-year incident falls, with presentation to the ED, and mortality. The impact of falls-related CVDs was also examined. RESULTS: Three-year incident falls was twofold higher among age and gender matched ED attendees aged ≥ 65 years presenting with a fall versus another reason at baseline. A presentation of falls with hip fracture had the highest percentage of incident falls in the 65-74 age group (22%) and the highest percentage mortality in all age groups (27-62%). CVD was not a significant factor in presenting with a fall at the ED, nor did it contribute significantly to the prediction of three-year incident falls. CVD was strongly associated with mortality risk among the ED fall group (RR = 1.81, 95% CI: 1.67-1.97) and showed interactions with both age and fall history. CONCLUSION: In this large study of adults aged ≥ 65 years attending the ED utilising data from national administrative registers in Denmark, we confirm that older adults attending the ED with a fall, including those with hip fracture, were at greatest risk for future falls. While CVD did not predict incident falls, it increased the risk of mortality in the three-year follow up with advancing age. This may be informative for the provision of care pathways for older adults attending the ED due to a fall.

Frailty on the island of Ireland: evidence from the NICOLA and TILDA studies.

BACKGROUND: Aimed to compare the prevalence, characteristics, and associated mortality risk of frailty in Northern Ireland (NI) and the Republic of Ireland (ROI). METHODS: Secondary analysis of the first wave of two nationally representative cohorts, the Northern Ireland Cohort for the Longitudinal Study of Ageing or NICOLA study (N = 8504) and the Irish Longitudinal Study on Ageing or TILDA study (N = 8504). Frailty was assessed using a harmonized accumulation deficits frailty index (FI) containing 30 items. FI scores classified individuals as non-frail (<0.10), pre-frail (0.10-0.24) and frail (≥0.25). Linkage to respective administrative data sources provided mortality information with a follow-up time of 8 years. RESULTS: The prevalence of frailty was considerably higher in NI compared with the ROI (29.0% compared with 15.0%), though pre-frailty was slightly lower (35.8% and 37.3%, respectively). Age, female sex, and lower socio-economic status were consistently associated with a higher likelihood of both pre-frailty and frailty. In the pooled analysis, both frailty and pre-frailty were higher in NI (RR = 2.68, 95% CIs 2.45, 2.94 and RR = 1.30, 95% CIs 1.21, 1.40, respectively). Frailty was associated with an increased mortality risk in both cohorts, even after full adjustment for all other characteristics, being marginally higher in TILDA than in NICOLA (HR = 2.43, 95% CIs 2.03, 2.91 vs. HR = 2.31, 95% CIs 1.90, 2.79). CONCLUSIONS: Frailty is a major public health concern for both jurisdictions. Further research and monitoring are required to elucidate why there is a higher prevalence in NI and to identify factors in early life that may be driving these differences.

Low vitamin B12 but not folate is associated with incident depressive symptoms in community-dwelling older adults: a 4-year longitudinal study.

This was a longitudinal study utilising the Irish Longitudinal Study on Ageing (n 3849 aged ≥ 50 years) and investigated the relationship between blood plasma folate and B12 levels at baseline (wave 1) and incident depressive symptoms at 2 and 4 years (waves 2 and 3). A score ≥ 9 on the Center for Epidemiological Studies Depression Scale-8 at wave 2 or 3 was indicative of incident depressive symptoms. B12 status profiles (pmol/l) were defined as < 185, deficient low; 185 to < 258, low normal; > 258-601, normal and > 601 high. Folate status profiles (nmol/l) were defined as ≤ 10·0, deficient low; > 10-23·0, low normal; > 23·0-45·0, normal; >45·0, high. Logistic regression models were used to analyse the longitudinal associations. Both B12 and folate plasma concentrations were lower in the group with incident depressive symptoms v. non-depressed (folate: 21·4 v. 25·1 nmol/l; P = 0·0003; B12:315·7 v. 335·9 pmol/l; P = 0·0148). Regression models demonstrated that participants with deficient-low B12 status at baseline had a significantly higher likelihood of incident depression 4 years later (OR 1·51, 95 % CI 1·01, 2·27, P = 0·043). This finding remained robust after controlling for relevant covariates. No associations of folate status with incident depression were observed. Older adults with deficient-low B12 status had a 51 % increased likelihood of developing depressive symptoms over 4 years. The findings highlight the need to further explore the low-cost benefits of optimising vitamin B12 status for depression in older adults.

The bi-directional association between loneliness and depression among older adults from before to during the COVID-19 pandemic.

BACKGROUND: Older adults have both the highest risk of contracting SARS-CoV-2 and in many jurisdictions have had additional restrictions placed on the social interactions. As a result, the COVID-19 pandemic has led to increased depression and loneliness among older adults. Using data from an established cohort of older adults, the aims of this study was to describe changes in loneliness and depression and to examine the directionality of the association between depression and loneliness over a 5-year period that included the early months of the pandemic. METHODS: Data were from The Irish Longitudinal Study on Ageing (TILDA), a large cohort of community-dwelling adults aged 54+. We applied an auto-regressive cross-lagged panel modelling approach to estimate the effect of depression on loneliness and vice versa over three time points. RESULTS: Both depression and loneliness increased significantly in the early months of the pandemic. While the association between loneliness and depression was bi-directional, loneliness was a stronger predictor of depression. CONCLUSION: The strength and bi-directionality of the association between loneliness and depression suggests that interventions to alleviate loneliness may also help reduce depressive symptoms and vice versa.

Atrial fibrillation and acceleration of frailty: findings from the Irish Longitudinal Study on Ageing.

INTRODUCTION: both atrial fibrillation (AF) and frailty are increasingly prevalent with age. Cross-sectional studies have suggested a relationship between AF and frailty, but longitudinal data are lacking. We explored if the presence of AF was associated with accelerated progression of frailty over 8 years in community-dwelling older adults. METHODS: a longitudinal retrospective case-control study was conducted using data from Waves 1 and 5 of the Irish Longitudinal Study on Ageing (TILDA). Participants with electrocardiographically detected AF at Wave 1 were matched to controls without AF (1:2) based on age and gender. Frailty was assessed using both the frailty phenotype (FP) and a 31-item frailty index (FI). Change in cases' and controls' FP and FI scores from Waves 1 to 5 were modelled using repeated measures analysis of variance (RM-ANOVA). RESULTS: one hundred eighteen TILDA participants with AF at Wave 1 were matched to 236 controls. By FP, participants with AF were not significantly more frail than controls at Wave 1 (P = 0.166) but were at Wave 5 (P = 0.011), and RM-ANOVA suggested that frailty progressed more in participants with AF between Waves 1 and 5 compared with controls (P = 0.033). By FI, participants with AF were significantly more frail at Wave 1 (P < 0.001) and 5 (P = 0.010), and RM-ANOVA did not show a difference in frailty progression between groups (P = 0.955). CONCLUSION: AF may drive the development of the FP. The FP is a pre-disability syndrome and hence may be better than the FI as a focus for disability prevention in adults with AF.

Plasma concentrations of vitamin B12 and folate and global cognitive function in an older population: cross-sectional findings from The Irish Longitudinal Study on Ageing (TILDA).

The uncertainty surrounding high intakes of folic acid and associations with cognitive decline in older adults with low vitamin B12 status has been an obstacle to mandatory folic acid fortification for many years. We estimated the prevalence of combinations of low/normal/high vitamin B12 and folate status and compared associations with global cognitive function using two approaches, of individuals in a population-based study of those aged ≥50 years in the Republic of Ireland. Cross-sectional data from 3781 men and women from Wave 1 of The Irish Longitudinal Study on Ageing were analysed. Global cognitive function was assessed by the Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Prevalence estimates for combinations of vitamin B12 (plasma vitamin B12 < or ≥258 pmol/l) and folate (plasma folate ≤ or >45·3 nmol/l) concentrations were generated. Negative binomial regression models were used to investigate the associations of vitamin B12 and folate status with global cognitive function. Of the participants, 1·5 % (n 51) had low vitamin B12 (<258 pmol/l) and high folate (>45·3 nmol/l) status. Global cognitive performance was not significantly reduced in these individuals when compared with those with normal status for both B-vitamins (n 2433). Those with normal vitamin B12/high folate status (7·6 %) had better cognitive performance (MMSE: incidence rate ratio (IRR) 0·82, 95 % CI 0·68, 0·99; P = 0·043, MoCA: IRR 0·89, 95 % CI 0·80, 0·99; P = 0·025). We demonstrated that high folate status was not associated with lower cognitive scores in older adults with low vitamin B12 status. These findings provide important safety information that could guide fortification policy recommendations in Europe.

Tools for Assessing Frailty in Older People: General Concepts.

The general notion of frailty is widely understood to be a state of increased vulnerability to stressors, following age-related declines in function and reserves across multiple physiological systems. Frailty is clinically characterised by slower and/or incomplete recovery from stressors such as infection, injury, surgery or psychosocial distress. There is however no consensus on a single operational definition. Numerous assessment tools and scores are promoted to detect or measure frailty but two have widest research background and acceptance, the Frailty Phenotype and the deficit based Frailty Index. We describe these and other approaches in the context of a description of the psychometric properties, types of scaling, uses and misuses of assessment tools. We advocate the choice of an appropriate measurement tool be based on the population characteristics and the purpose for which it is to be used and illustrate how an understanding of the properties of different tools helps to inform this choice.

Is phenotypical prefrailty all the same? A longitudinal investigation of two prefrailty subtypes in TILDA.

BACKGROUND: Fried's frailty phenotype is defined by five criteria: exhaustion, unexplained weight loss, weakness, slowness and low physical activity. Prefrailty (PF) meets one or two criteria. PF is of interest as a target for preventative interventions, but it is not known if it is a homogenous syndrome. OBJECTIVE: to compare the longitudinal trajectories of two PF groups: one defined by exhaustion and/or unexplained weight loss (PF1) and one defined by one or two of the following: weakness, slowness, low physical activity (PF2). DESIGN AND SETTING: population-based longitudinal study of ageing. SUBJECTS: One-thousand four-hundred seventy-six PF participants aged ≥50 years from wave 1 of the study (2010), followed 2-yearly over four longitudinal waves (2012, 2014, 2016, 2018). METHODS: generalised estimating equations (GEEs) were used to assess the effect of PF type across waves to predict cumulative mortality and disability in basic activities of daily living (ADL) and independent ADL (IADL), adjusting for baseline characteristics (age, sex, education, living alone, self-rated health, comorbidity, body mass index). RESULTS: in wave 1, there were 503 PF1 and 973 PF2 participants. By wave 5, 38 (7.6%) PF1 and 145 (14.9%) PF2 participants had died. In PF1 participants, mean numbers of ADL and IADL disabilities both increased from 0.1 to 0.2 from wave 1 to wave 5, whilst in PF2 increases were from 0.2 to 0.5. Adjusted GEE models suggested significantly divergent trajectories of IADL disability by wave 2, ADL disability by wave 3 and mortality by wave 3. CONCLUSION: PF may not be a homogenous biological syndrome.

Voluntary fortification is ineffective to maintain the vitamin B12 and folate status of older Irish adults: evidence from the Irish Longitudinal Study on Ageing (TILDA).

Mandatory fortification of staple grains with folic acid and/or vitamin B12 (B12) is under debate in many countries including Ireland, which has a liberal, but voluntary, fortification policy. Older adults can be at risk of both deficiency and high folate status, although little is known on the actual prevalence and the major predictors. Population prevalence estimates from older adults (n 5290 ≥50 years) from the Irish Longitudinal Study on Ageing (TILDA) (Wave 1) are presented here. Measures included plasma total vitamin B12 and folate, whereas predictors included detailed demographic, socio-economic, geographic, seasonal and health/lifestyle data. The prevalence of deficient or low B12 status (45 nmol/l) was observed in 8·9 %, whereas high B12 status was observed in 3·1 % (>601 pmol/l). The largest positive predictor of B12 concentration was self-reported B12 injection and/or supplement use (coefficient 51·5 pmol/; 95 % CI 9·4, 93·6; P=0·016) followed by sex and geographic location. The largest negative predictor was metformin use (-33·6; 95 % CI -51·9, -15·4; P<0·0001). The largest positive predictor of folate concentration was folic acid supplement use (6·0; 95 % CI 3·0, 9·0 nmol/l; P<0·001) followed by being female and statin medications. The largest negative predictor was geographic location (-5·7; 95 % CI -6·7, -4·6; P<0·0001) followed by seasonality and smoking. B-vitamin status in older adults is affected by health and lifestyle, medication, sampling period and geographic location. We observed a high prevalence of low B12 and folate status, indicating that the current policy of voluntary fortification is ineffective for older adults.

Cardiovascular risk factors and frailty in a cross-sectional study of older people: implications for prevention.

Objective: to examine the associations of cardiovascular disease (CVD) and cardiovascular risk factors with frailty. Design: a cross-sectional study. Setting: the Irish Longitudinal Study on Ageing (TILDA). Participants: frailty measures were obtained on 5,618 participants and a subset of 4,330 participants with no prior history of CVD. Exposures for observational study: cardiovascular risk factors were combined in three composite CVD risk scores (Systematic Coronary Risk Evaluation [SCORE], Ideal Cardiovascular Health [ICH] and Cardiovascular Health Metrics [CHM]). Main outcome measures: a frailty index (40-items) was used to screen for frailty. Methods: the associations of CVD risk factors with frailty were examined using logistic regression. Results: overall, 16.4% of participants had frailty (7.6% at 50-59 years to 42.5% at 80+ years), and the prevalence was higher in those with versus those without prior CVD (43.0% vs. 10.7%). Among those without prior CVD, mean levels of CVD risk factors were closely correlated with higher frailty index scores. Combined CVD risk factors, assessed using SCORE, were linearly and positively associated with frailty. Compared to low-to-moderate SCOREs, the odds ratio (OR) (95% confidence interval, CI) of frailty for those with very high risk was 3.18 (2.38-4.25). Conversely, ICH was linearly and inversely associated with frailty, with an OR for optimal health of 0.29 (0.21-0.40) compared with inadequate health. Conclusions: the concordant positive associations of SCORE and inverse associations of ICH and CHM with frailty highlight the potential importance of optimum levels of CVD risk factors for prevention of disability in frail older people.

The impact of frailty on healthcare utilisation in Ireland: evidence from the Irish longitudinal study on ageing.

INTRODUCTION: To examine the impact of frailty on medical and social care utilisation among the Irish community-dwelling older population to inform strategies of integrated care for older people with complex needs. METHODS: Participants aged ≥65 years from the Irish Longitudinal Study on Ageing (TILDA) representative of the Irish community-dwelling older population were analysed (n = 3507). The frailty index was used to examine patterns of utilisation across medical and social care services. Multivariate logistic and negative binomial regression models were employed to examine the impact of frailty on service utilisation outcomes after controlling for other factors. RESULTS: The prevalence of frailty and pre-frailty was 24% (95% CI: 23, 26%) and 45% (95% CI: 43, 47%) respectively. Frailty was a significant predictor of utilisation of most social care and medical care services after controlling for the main correlates of frailty and observed individual effects. CONCLUSIONS: Frailty predicts utilisation of many different types of healthcare services rendering it a useful risk stratification tool for targeting strategies of integrated care. The pattern of care is predominantly medical as few of the frail older population use social care prompting questions about sub-groups of the frail older population with unmet care needs.

The lived experience of frailty: beyond classification and towards a holistic understanding of health.

PURPOSE: Frailty is characterised by decreased physiological reserves and vulnerability to stressors. Although scales, such as the Fried's Frailty Phenotype (FP), Frailty Index (FI), and Clinical Frailty Scale (CFS), are used to identify frailty, the lived experience of frailty remains understudied. METHODS: This cross-sectional observational research involved participants aged 65 years and older from Wave 1 of The Irish Longitudinal Study on Ageing (TILDA). Participants were categorised into four independent groups: three frail groups based on the aforementioned scales and a non-frail group. Quantitative variables, including self-rated health, CASP-19 quality-of-life score, and frequency of social activities, were analysed and described. RESULTS: The study encompassed 1999 participants with an average age of 72 years, of whom 51% were women. FP exclusively identified 1.6% as frail (n = 32), FI 11.7% (n = 233), and CFS 6.8% (n = 135). More than 60% of all those classified as frail reported their health as good, very good, or excellent, with the lowest proportion (64%) being among frail by FI participants. Frail by FI participants exhibited the lowest mean average CASP-19 score, yet it remained relatively high at 39 out of 57 points. Over 77% of all frail individuals engaged in active leisure activities at least once a month. CONCLUSION: This study underscores the need to comprehend frailty holistically beyond its mere identification. It challenges the prevailing belief that frailty inevitably leads to impaired quality of life and limited social engagement. The findings advocate for a reassessment of how both the general public and healthcare professionals perceive frailty.

Association between metabolic syndrome and risk of both prevalent and incident frailty in older adults: Findings from The Irish Longitudinal Study on Ageing (TILDA).

OBJECTIVES: Metabolic syndrome (MetS) is a risk factor for cardiovascular disease, diabetes, and all-cause mortality. Frailty is a condition of decreased multi-system physiological reserve where one has increased vulnerability to stressors. This study aimed to examine if MetS is associated with prevalent and incident frailty over a 4-year follow-up period in an aged population. METHODS: This study used data from waves 1 (2009-2011) and 3 (2014-2015) of The Irish Longitudinal Study on Ageing. Those aged <50 years or without baseline health assessment data were excluded. Baseline MetS status was determined using the National Cholesterol Education Program Third Adult Treatment Panel criteria. Frailty status was identified at both waves, operationalised using Fried's frailty phenotype (FP) and Rockwood's frailty index (FI). Ordinal logistic regression examined the cross-sectional association between MetS and prevalent frailty status. Those with prevalent pre-frailty or frailty were excluded and ordinal logistic regression models examined the association between MetS and incident frailty. Lastly, MetS' longitudinal associations with the five individual components of Fried's FP were examined. Models were adjusted for age, sex, education, smoking, chronic disease history and renal function. RESULTS: Ordinal logistic regression models (n > 5100), showed MetS was associated with prevalent frailty as assessed by both FP (odds ratio (OR) 1.29, p < 0.001) and FI (OR 1.65, p < 0.001). Of those who were non-frail at baseline, 2247 participants had longitudinal FP data, while 3546 participants had longitudinal FI data. Models demonstrated that MetS was associated with an increased likelihood of incident frailty for both FP (OR 1.57, p < 0.001) and FI (OR 1.29, p = 0.014). MetS was found to be associated with incident low physical activity (OR 1.57, p = 0.001) and incident unintentional weight loss (OR 1.59, p = 0.025). CONCLUSIONS: MetS in those ≥50 years was found to be associated with an increased likelihood of incident frailty over a 4-year period, by 57 % when measured by FP and 29 % by FI. MetS should be considered a risk factor for frailty and be taken into considered in any comprehensive geriatric assessment given frailty's dynamic nature and MetS being potentially modifiable.

Sustaining an ageing population: the role of micronutrients in frailty and cognitive impairment.

Age-related frailty and cognitive decline are complex multidimensional conditions that significantly impact the ability of older adults to sustain functional capacity and independence. While underlying causes remain poorly understood, nutrition continually emerges as one associated risk element. Many studies have addressed the importance of adequate nutrition in delaying the onset of these conditions, but the specific role of micronutrients is not well established. The consideration of pre-frailty as an outcome variable is also limited in the current literature. In this review, we focus on the potential value of maintaining micronutrient sufficiency to sustaining the health of the ageing population. Using data from the Irish longitudinal study on ageing, we consider several vitamins known to have a high prevalence of low status in older adults and their impact on pre-frailty, frailty and cognitive impairment. They include vitamin B12 and folate, both of which are associated with multiple biological mechanisms involved in long-term health, in particular in cognitive function; vitamin D, which has been associated with increased risk of musculoskeletal disorders, depression and other chronic diseases; and the carotenoids, lutein and zeaxanthin, that may help mitigate the risk of frailty and cognitive decline via their antioxidant and anti-inflammatory properties. We show that low concentrations of folate and carotenoids are implicated in poorer cognitive health and that the co-occurrence of multiple nutrient deficiencies confers greatest risk for frailty and pre-frailty in the Irish longitudinal study on ageing cohort. These health associations contribute to evidence needed to optimise micronutrient status for health in the older adult population.

Vitamin D status & associations with inflammation in older adults.

Research studies have observed associations of vitamin D with inflammation but data in representative older adult studies is lacking. We aimed to investigate the association of C-reactive protein (CRP) with vitamin D status in a representative sample of the older Irish population. The concentrations of 25-hydroxyvitamin D (25(OH)D) and CRP was measured in 5,381 community dwelling Irish adults aged ≥50 years from the Irish Longitudinal Study on Ageing (TILDA). Demographic, health and lifestyle variables were assessed by questionnaire and categorical proportions of CRP were generated by vitamin D status and age. Multi-nominal logistic regression was used to investigate the association of 25(OH)D and CRP status. The prevalence (mean; 95% confidence interval (95% CI)) of normal CRP status (0-5 mg/dL) was 83.9% (82.6-85.0%), elevated status (5-10 mg/dL) 11.0% (9.9-12.0%) and high status (>10 mg/dL) was 5.1% (4.5-5.8%). Mean (95% CI) CRP concentrations were lower in those with normal vs. deficient 25(OH)D status (2.02 mg/dL (1.95-2.08) vs. 2.60 mg/dL (2.41-2.82); p<0.0001). In a logistic regression analysis, those with insufficient or sufficient 25(OH)D status were less likely to have a high CRP status compared to those with deficient 25(OH)D status (insufficient: coefficient (CE) -0.732, 95% CI -1.12-0.33, p<0.0001; sufficient: CE -0.599, 95% CI -0.95-0.24, p = 0.001). In conclusion older adults with deficient vitamin D status had higher levels of inflammation as measured by CRP. Given that inflammation is an important pathological driver of chronic diseases of ageing, and that emerging evidence suggests that vitamin D therapy can reduce inflammation in some disease settings, optimising vitamin D status could represent an effective low risk/low-cost pathway to modulate inflammation in community dwelling older adults.

Metabolic syndrome accelerates epigenetic ageing in older adults: Findings from The Irish Longitudinal Study on Ageing (TILDA).

Metabolic syndrome (MetS) is a risk factor for the development of diabetes, cardiovascular disease, and all-cause mortality. It has an estimated prevalence of 40 % among older adults. Epigenetic clocks, which measure biological age based on DNA methylation (DNAm) patterns, are a candidate biomarker for ageing. GrimAge is one such clock which is based on levels of DNAm at 100 Cytosine-phosphate-Guanine (CpG) sites. This study hypothesised that those with MetS have 'accelerated ageing' (biological age greater than their chronological age) as indexed by GrimAge. This study examined MetS's association with GrimAge age acceleration (AA) using data from a subsample of 469 participants of the Irish Longitudinal Study on Ageing (TILDA). MetS was defined by National Cholesterol Education Program Third Adult Treatment Panel (ATP III) and International Diabetes Foundation (IDF) criteria, operationalised using the conventional binary cut-off, and as a count variable ranging from 0 to 5, based on the presence of individual components. This study also explored inflammation (as measured by C reactive protein) and metabolic dysfunction (as measured by adiponectin) as possible mediating factors between MetS and GrimAge AA. We found that MetS as defined by IDF criteria was associated with GrimAge AA of 0.63 years. When MetS was treated as a count, each unit increase in MetS score was associated with over 0.3 years GrimAge AA for both ATP III and IDF criteria. Inflammation mediated approximately one third of the association between MetS and GrimAge AA, suggesting that chronic subclinical inflammation observed in MetS has a relationship with DNAm changes consistent with a faster pace of ageing. Metabolic dysfunction mediated the association between MetS and GrimAge AA to a lesser extent (16 %). These data suggest that chronic subclinical inflammation observed in MetS has a relationship with DNAm changes consistent with a greater pace of ageing.

Differential Associations Between Two Markers of Probable Sarcopenia and Continuous Orthostatic Hemodynamics in The Irish Longitudinal Study on Ageing.

BACKGROUND: Sarcopenia and orthostatic hypotension are growing age-related health burdens associated with adverse outcomes, including falls. Despite a possible pathophysiological link, the association between the 2 disorders is not well elucidated. We sought to investigate this relationship in The Irish Longitudinal Study on Ageing (TILDA). METHODS: Data from 2 858 participants at wave 3 of TILDA were analyzed. Probable sarcopenia was defined as per the European Working Group on Sarcopenia in Older People revised definition cutoffs (hand grip strength [HGS] <27 kg in men, <16 kg in women, and/or 5-chair stand test [5CST] time >15 seconds). Participants underwent an active stand orthostatic test with continuous blood pressure (BP) monitoring. Multilevel mixed-effects models, controlling for possible confounders, were used to assess the effect of probable sarcopenia by HGS and 5CST criteria on the change in BP after standing. RESULTS: HGS- and 5CST-defined probable sarcopenia were independently associated with an attenuated BP recovery at 10-20 seconds poststand (systolic BP: ß -0.54, p < .001; ß -0.25, p < .001). On average, those meeting HGS probable sarcopenia criteria had a significantly lower BP at 20, 30, and 40 seconds (differences in systolic BP: -5.01 mmHg, -3.68 mmHg, -2.32 mmHg, p < .05 for all). Those meeting 5CST probable sarcopenia criteria had a significant difference in systolic BP at 20 seconds (-1.94 mmHg, p = .002) but not at 30 or 40 seconds. CONCLUSION: Probable sarcopenia had a significant association with delayed orthostatic BP recovery, with HGS-defined probable sarcopenia having a stronger association than 5CST-defined probable sarcopenia. Results support a modest but significant pathophysiological link between probable sarcopenia and orthostatic hypotension.

Plasma lutein and zeaxanthin concentrations associated with musculoskeletal health and incident frailty in The Irish Longitudinal Study on Ageing (TILDA).

INTRODUCTION: Lutein and zeaxanthin are diet-derived carotenoids that are proposed to help mitigate frailty risk and age-related declines in musculoskeletal health via their anti-oxidant and anti-inflammatory properties. Therefore, this study aimed to investigate the association between lutein and zeaxanthin status and indices of musculoskeletal health and incident frailty among community-dwelling adults aged ≥50 years in the Irish Longitudinal Study on Ageing (TILDA). METHODS: Cross-sectional analyses (n = 4513) of plasma lutein and zeaxanthin concentrations and grip strength, usual gait speed, timed up-and-go (TUG), probable sarcopenia (defined as grip strength <27 kg in men, <16 kg in women), and bone mass (assessed using calcaneal broadband ultrasound stiffness index) were performed at Wave 1 (2009-2011; baseline). In the longitudinal analyses (n = 1425-3100), changes in usual gait speed (at Wave 3, 2014-2015), grip strength (Wave 4, 2016) and TUG (at Wave 5, 2018), incident probable sarcopenia (at Wave 4) and incident frailty (Fried's phenotype, Frailty Index, FRAIL Scale, Clinical Frailty Scale-classification tree, at Wave 5) were determined. Data were analysed using linear and ordinal logistic regression, adjusted for confounders. RESULTS: Cross-sectionally, plasma lutein and zeaxanthin concentrations were positively associated with usual gait speed (B [95 % CI] per 100-nmol/L higher concentration: Lutein 0.59 [0.18, 1.00], Zeaxanthin 1.46 [0.37, 2.55] cm/s) and inversely associated with TUG time (Lutein -0.07 [-0.11, -0.03], Zeaxanthin -0.14 [-0.25, -0.04] s; all p < 0.01), but not with grip strength or probable sarcopenia (p > 0.05). Plasma lutein concentration was positively associated with bone stiffness index (0.54 [0.15, 0.93], p < 0.01). Longitudinally, among participants who were non-frail at Wave 1, higher plasma lutein and zeaxanthin concentrations were associated lower odds of progressing to a higher frailty category (e.g. prefrailty or frailty) by Wave 5 (ORs 0.57-0.89, p < 0.05) based on the Fried's phenotype, FRAIL Scale and the Clinical Frailty Scale, and in the case of zeaxanthin, Frailty Index. Neither plasma lutein nor zeaxanthin concentrations were associated with changes in musculoskeletal indices or incident probable sarcopenia (p > 0.05). CONCLUSION: Higher plasma lutein and zeaxanthin concentrations at baseline were associated with a reduced likelihood of incident frailty after ~8 years of follow up. Baseline plasma lutein and zeaxanthin concentrations were also positively associated with several indices of musculoskeletal health cross-sectionally but were not predictive of longitudinal changes in these outcomes over 4-8 years.

Towards a consensus definition of allostatic load: a multi-cohort, multi-system, multi-biomarker individual participant data (IPD) meta-analysis.

BACKGROUND: Allostatic load (AL) is a multi-system composite index for quantifying physiological dysregulation caused by life course stressors. For over 30 years, an extensive body of research has drawn on the AL framework but has been hampered by the lack of a consistent definition. METHODS: This study analyses data for 67,126 individuals aged 40-111 years participating in 13 different cohort studies and 40 biomarkers across 12 physiological systems: hypothalamic-pituitary-adrenal (HPA) axis, sympathetic-adrenal-medullary (SAM) axis, parasympathetic nervous system functioning, oxidative stress, immunological/inflammatory, cardiovascular, respiratory, lipidemia, anthropometric, glucose metabolism, kidney, and liver. We use individual-participant-data meta-analysis and exploit natural heterogeneity in the number and type of biomarkers that have been used across studies, but a common set of health outcomes (grip strength, walking speed, and self-rated health), to determine the optimal configuration of parameters to define the concept. RESULTS: There was at least one biomarker within 9/12 physiological systems that was reliably and consistently associated in the hypothesised direction with the three health outcomes in the meta-analysis of these cohorts: dehydroepiandrosterone sulfate (DHEAS), low frequency-heart rate variability (LF-HRV), C-reactive protein (CRP), resting heart rate (RHR), peak expiratory flow (PEF), high density lipoprotein cholesterol (HDL-C), waist-to-height ratio (WtHR), HbA1c, and cystatin C. An index based on five biomarkers (CRP, RHR, HDL-C, WtHR and HbA1c) available in every study was found to predict an independent outcome - mortality - as well or better than more elaborate sets of biomarkers. DISCUSSION: This study has identified a brief 5-item measure of AL that arguably represents a universal and efficient set of biomarkers for capturing physiological 'wear and tear' and a further biomarker (PEF) that could usefully be included in future data collection.

Characterisation of the pro-inflammatory cytokine signature in severe COVID-19.

Clinical outcomes from infection with SARS-CoV-2, the cause of the COVID-19 pandemic, are remarkably variable ranging from asymptomatic infection to severe pneumonia and death. One of the key drivers of this variability is differing trajectories in the immune response to SARS-CoV-2 infection. Many studies have noted markedly elevated cytokine levels in severe COVID-19, although results vary by cohort, cytokine studied and sensitivity of assay used. We assessed the immune response in acute COVID-19 by measuring 20 inflammatory markers in 118 unvaccinated patients with acute COVID-19 (median age: 70, IQR: 58-79 years; 48.3% female) recruited during the first year of the pandemic and 44 SARS-CoV-2 naïve healthy controls. Acute COVID-19 was associated with marked elevations in nearly all pro-inflammatory markers, whilst eleven markers (namely IL-1ß, IL-2, IL-6, IL-10, IL-18, IL-23, IL-33, TNF-α, IP-10, G-CSF and YKL-40) were associated with disease severity. We observed significant correlations between nearly all markers elevated in those infected with SARS-CoV-2 consistent with widespread immune dysregulation. Principal component analysis highlighted a pro-inflammatory cytokine signature (with strongest contributions from IL-1ß, IL-2, IL-6, IL-10, IL-33, G-CSF, TNF-α and IP-10) which was independently associated with severe COVID-19 (aOR: 1.40, 1.11-1.76, p=0.005), invasive mechanical ventilation (aOR: 1.61, 1.19-2.20, p=0.001) and mortality (aOR 1.57, 1.06-2.32, p = 0.02). Our findings demonstrate elevated cytokines and widespread immune dysregulation in severe COVID-19, adding further evidence for the role of a pro-inflammatory cytokine signature in severe and critical COVID-19.