Homocysteine, Folic Acid, Cyanocobalamin, and Frailty in Older People: Findings From the “Invece. Ab” Study

Frailty is an important age-related syndrome associated with several adverse health outcomes. Its biological basis is undefined. Raised plasma homocysteine (HOcy) is an established risk factor for cardiovascular disease, dementia, cognitive impairment, and mortality, but little is known about the possible role of plasma HOcy, cyanocobalamin (B12), and folate (FO levels in the development of frailty. Our first aim was to explore the possible association between frailty and plasma concentrations of HOcy, FO, and B12 in a cohort of community-dwelling older people. The second was to assess the influence of these metabolic factors on six-year incidence of frailty in the 875 individuals eligible for inclusion in this study (those with a full follow-up dataset). This research is based on data from three waves – 2012 (herein taken as baseline), 2014, and 2018 – of a longitudinal study (InveCe.Ab) in which non-frail men and women born between 1935 and 1939 underwent multidimensional assessments. Frailty was estimated using a deficit accumulation-based frailty index (FI). HOcy concentration was significantly positively correlated with FI at all timepoints, while B12 and FO levels were not. Plasma concentration of HOcy emerged as a predictor of six-year cumulative incidence of frailty, independent of age, sex, and education, while B12 and FO levels showed no relationship with frailty incidence. Individuals with plasma HOcy in the top quintile showed five months less frailty-free survival (HR 1.487; 95% CI: 1.063–2.078), regardless of age, sex, and education. These results demonstrate that higher HOcy is a risk factor for frailty onset in older adults.

Can a Data-Driven Measure of Neuroanatomic Dementia Risk be Considered a Measure of Brain Aging?

There is an increasing interest in identifying aging-related factors which may be permissive of Alzheimer’s Disease (AD) emergence. We previously used machine learning to derive an index of neuroanatomic risk of dementia called AD pattern similarity (AD-PS) score using MRIs obtained in the Atherosclerosis Risk in Communities (ARIC) study. Here, we investigate the potential of the AD-PS scores as a brain-focused measure of biologic age. Among 1970 ARIC participants with MRI collected at ARIC Visit 5, we related AD-PS scores to three measures of aging: mortality (n=356) over 8 years of follow-up; an a priori panel of 32 proteins related to aging (N=1647); and a deficit accumulation index (DAI) based on 38 health-related measures. We found lower AD-PS scores associated with significantly lower mortality (HR=0.58, CI-95%, [0.45 - 0.75], p < 0.001) after adjusting for age, race, smoking and hypertension. Among the 32 proteins, nine were significantly associated to AD-PS scores (p < 0.05) with 4 remaining significant adjusting for multiple comparisons (Growth/differentiation factor 15, Tumor necrosis factor receptor superfamily member 1A and 1B and Collagen alpha-1(XVIII) chain). Finally, in a linear regression model after adjusting for age, race, sex, hypertension and smoking, AD-PS scores were associated with the DAI (p < 0.001). The consistent patterns of associations suggest that a data-driven measure of AD neuroanatomic risk may be capturing aspects of biologic age in older adults.

Frailty and Mortality in a Community-Dwelling Relatively Healthy Older Population

This study examined factors associated with frailty and studied the association between frailty status and mortality in healthy community-dwelling older persons. Participants included 19,114 individuals from the “ASPirin in Reducing Events in the Elderly” (ASPREE) trial. Frailty was defined using modified Fried phenotype comprising exhaustion, body mass index, grip strength, gait speed and physical activity. A deficit accumulation frailty index (FI) using 66 items was also developed. Correlates of frailty were examined using multinomial logistic regression. The association between frailty status at baseline and mortality was analyzed using Cox regression. At baseline, 39.0% (95% CI: 38.3, 39.7) of participants were prefrail, and 2.2% (95% CI: 2.0, 2.4) were frail according to Fried phenotype, while 40.6% (95% CI: 40.0, 41.3) of participants were pre-frail and 8.1% (95% CI: 7.7, 8.5) were frail according to FI. Older age, female sex, lower education, African-American and Hispanic ethno-racial status, smoking, alcohol use, comorbidities, and polypharmacy were associated with frailty status. Pre-frailty increased risk of all-cause mortality significantly (Fried HR: 1.48; 95% CI: 1.28, 1.71; FI HR: 1.54; 95% CI: 1.31, 1.81); and the risk was even higher for frailty (Fried HR: 2.24; 95% CI: 1.67, 3.00; FI HR: 2.34; 95% CI: 1.83, 2.99) after adjustment for covariates. Cardiovascular disease (CVD) and non-CVD-related mortality showed similar trends. These results highlight a considerable burden of pre-frailty among a large group of community-dwelling, initially healthy older adults. Both Fried phenotype and deficit accumulation FI similarly predicted all-cause, CVD and non-CVD-related mortality in relatively healthy older adults.

Frailty in Preclinical Models: Impact of Healthspan on Disease Expression Over the Life Course

People age at different rates. This heterogeneity in aging has led to the concept of “frailty”, a state of heightened vulnerability to adverse health outcomes at any age. Frailty challenges health care providers, as frail patients are more likely than non-frail patients to experience diseases, hospitalization, and death. We showed that frailty occurs not only in humans, but also in aging rodents. It can be measured with a “frailty index” (FI) based on age-related health deficit accumulation as originally established in humans. We found that maladaptive changes in heart structure and function in late life are correlated more so with frailty than age and are closely graded by FI score, especially in male mice. Adverse effects of frailty originate at cellular/subcellular levels and scale up to organ and system levels, predisposing towards cardiovascular disease. Poor overall health, quantified with an FI, may drive maladaptive cardiac remodeling, especially in older males.

8-Year Changes in Frailty in Adults: Links to Cognitive and Physical Function and Mortality

Deficit accumulation frailty indices are being evaluated as clinical markers of biological aging. In this context, it is to be expected that changes over time in such indices should be predictive of downstream changes in cognition, physical function, and mortality. We derived a frailty index (FI) based on deficit accumulation in 38 functional, behavioral, and clinical characteristics and examined associations between 8-year changes in FI and subsequent standardized measures of cognitive and physical function and mortality collected over years 8-18. We drew data from the Look AHEAD clinical trial of a multidomain intensive lifestyle intervention (ILI) in 3841 adults, aged 45-76 years at baseline with overweight/obesity and type 2 diabetes mellitus. Greater FI increases tended to occur among individuals who were older, non-Hispanic White, heavier, and who had greater baseline multimorbidity. Greater increases in FI were associated with subsequently worse levels of composite cognitive function and 400m walk speed (all p<0.001). Additionally, compared with the lowest tertile of FI change, hazard ratios [95% confidence intervals] for 10-year mortality for the middle and highest tertiles of FI change were 1.28 [1.03.1.58] and 1.56 [1.24,1.96], respectively. While assignment to ILI was associated with smaller 8-year increases in FI, this did not translate overall to better cognitive functioning compared to the Diabetes Support and Education control condition across years 8-18. Increase in FI over 8 years predicts subsequent reduced function and greater mortality. However, whether interventions generally targeting FI reduce risks for downstream outcomes remains to be seen.

Operationalizing Healthspan as an Outcome for Clinical Trials in Geroscience

Efforts targeting biological aging pathways are advancing interventions which could extend healthy lifespan. Design of clinical trials to test such interventions necessitates an operational definition of healthspan, such as slowed accumulation or progression of multiple chronic diseases, functional decline, and disability. In this talk we explore these composite measures of healthspan proposed as outcomes for clinical trials in aging. This will be examined in example cases including multimorbidity and deficit accumulation frailty indices in an 8-Year intensive lifestyle intervention trial, and an update on multimordbity, functional, and biomarker endpoints in the trial Targeting Aging with MEtformin (TAME). Through these examples we will explore issues related to effect sizes and statistical challenges related to composite endpoints. Finally, we will discuss the role existing and emerging biomarkers of aging in clinical trials in geroscience and summarize evidence linking biomarkers to clinically meaningful outcomes.

The Effect of Low-Dose Aspirin on Frailty in Older Adults in the Aspirin in Reducing Events in the Elderly Study

There are no widely accepted pharmacologic treatments for frailty prevention. Since frailty is associated with inflammation, aspirin has the potential to reduce frailty. We investigated whether low-dose aspirin reduces incident frailty in participants of the ASPirin in Reducing Events in the Elderly (ASPREE) trial. In the U.S and Australia, 19,114 healthy community-dwelling individuals aged ≥70 years (U.S. minorities ≥65 years) were enrolled in ASPREE, a double-blind, placebo-controlled trial of 100mg daily low-dose aspirin vs. placebo. Frailty was defined according to a modified Fried frailty definition, and a frailty index which used a deficit accumulation model. Competing risk Cox proportional hazards models were used to compare time to incident frailty for aspirin vs. placebo. At baseline, 2.2% and 8.1% met criteria for frailty by Fried and frailty index criteria, respectively. Over a median of 4.7 years of follow-up, 2252 participants developed incident frailty according to Fried classification, and 4376 according to the frailty deficit accumulation index. There was no difference in the risk of incident frailty between individuals randomized to aspirin versus placebo according to either criteria (Fried frailty HR: 1.03, 95% CI 0.97-1.09, p=0.41; frailty index HR: 1.03, 95% CI 0.97-1.10, p=0.29). Change in frailty over time was not different between the aspirin and placebo treatment arms. The results were consistent across a series of sub-groups, including baseline frailty status. Based on these results, aspirin use in healthy older adults does not reduce incident frailty.

Frailty and Functional Status improvement after Skilled Nursing Facility based Post-Acute Care

People admitted to a skilled nursing facility (SNF) for post-acute care undergo comprehensive evaluation and rehabilitation, potentially enabling prediction of future functional recovery. We identified the first SNF admission per beneficiary (n=250,159) between 07/01/2014 – 06/30/2016 in a 5% Medicare sample, using the Minimum Data Set (MDS) and the Outcome and Assessment Information Set (OASIS). Episodes were excluded for non-community discharge (n=43,397) or no OASIS admission assessment within 14 days of SNF discharge (n=77,989). A deficit accumulation Frailty Index (FI) was measured on admission MDS assessment and categorized into robust (MDS-FI<0.15), pre-frailty (MDS-FI0.15-0.24), mild frailty (MDS-FI0.25-0.34), and moderate or worse frailty (MDS-FI≥0.35). Outcomes were functional decline obtained from OASIS, readmission, or death after initiation of home care. Functional status was measured by activities of daily living from OASIS assessments. A total of 135,310 SNF episodes were matched to OASIS episodes. Of these, there were 6,472 (4.8%) robust patients, 38,923 (28.8%) pre-frail, 63,727 (47.1%) mildly frail and 26,053 (19.3%) moderately frail or worse. In a logistic regression after adjustment for OASIS admission function, compared to robust status, frailty was associated with hospital readmission or death within 30 days of OASIS admission, (mild frailty OR1.33 [95%CI 1.23-1.45] and moderate or worse OR1.81 [95%CI 1.66-1.97]). Frailty was also associated with functional decline at OASIS discharge, after adjustment for OASIS admission function (mild frailty OR1.50 [95%CI 1.38-1.63] and moderate or worse OR2.30 [95%CI 2.11-2.50]). Among those discharged from SNF with home services, a SNF-based MDS-FI is associated with increased likelihood of poor community outcomes.