Physiological Dysregulation, Frailty, and Impacts on Adverse Health and Functional Outcomes.

Yanxia Lu,Keng Bee Yap,Denise Q L Chua,Tze Pin Ng,Xinyi Gwee,Crystal T Y Tan,Anis Larbi

doi:10.3389/fmed.2021.751022

Abstract

Background: Multi-system physiological dysregulation (PD) may represent a biological endo-phenotype of clinical frailty. We investigated the co-occurrence of PD with physical frailty and its contributions to the known impact of frailty on adverse health outcomes.Methods: Data of 2,725 participants from the Singapore Longitudinal Aging Studies (SLAS-2), included baseline measures of physical frailty and PD derived from Mahalanobis distance (Dm) value of 23 blood biomarkers. We analyzed their concurrent association and their impacts on 9-year mortality, MMSE cognition, GDS depression, number of medications, disability, and hospitalization at baseline and follow up (mean 4.5 years).Results: Global PD (Log10Dm, mean = 1.24, SD = 0.24) was significantly but weakly associated with pre-frailty-and-frailty. Controlling for age, sex and education, pre-frailty-and-frailty (HR = 2.12, 95% CI = 1.51–3.00) and PD (HR = 3.88, 95% CI = 2.15–6.98) predicted mortality. Together in the same model, mortality HR associated with pre-frailty-and-frailty (HR = 1.83, 95% CI = 1.22–2.73) and PD (HR = 3.06, 95% CI = 1.60–5.85) were reduced after additionally adding global PD to the prediction model. The predictive accuracy for mortality were both approximately the same (PD: AUC = 0.62, frailty: AUC = 0.64), but AUC was significantly increased to 0.68 when combined (p < 0.001). Taken into account in the same model, frailty remained significantly associated with all health and functional outcomes, and PD was significantly associated with only MMSE, disability and medications used. In secondary analyses, there were mixed associations of system-specific PDs with frailty and different adverse outcomes.Conclusions: Co-existing PD and physical frailty independently predict mortality and functional and health outcomes, with increased predictive accuracy when combined. PD appears to be a valid representation of a biological endo-phenotype of frailty, and the potential utility of such subclinical measures of frailty could be further studied.

Highlights

IntroductionNumerous studies have shown that it strongly predicts adverse health outcomes, including complications, disability, mortality, hospitalizations, and institutionalization [1, 2] in both community-living older adults and hospitalized patient populations with specific chronic diseases
Frailty is highly prevalent in old age
It is currently theorized that underpinning the development of frailty and age-related diseases in older people is a breakdown with age in the capacity to maintain physiological homeostasis via a complex regulatory network of factors, pathways, or processes which operate independently or inter-dependently in different physiological systems [6,7,8,9,10,11,12]

Summary

Introduction

Numerous studies have shown that it strongly predicts adverse health outcomes, including complications, disability, mortality, hospitalizations, and institutionalization [1, 2] in both community-living older adults and hospitalized patient populations with specific chronic diseases. A conceptual definition of frailty is a diminished capacity (or physiological reserve) to adequately compensate for the effects of stressors, leading to an increased vulnerability to develop chronic diseases and adverse functional, health, and mortality outcomes [1]. There is prima facie evidence that physiological dysregulation (PD) across multiple systems may appropriately represent the underlying biological substrate or endo-phenotype of the clinical frailty syndrome [13,14,15,16]. Multi-system physiological dysregulation (PD) may represent a biological endo-phenotype of clinical frailty. We investigated the co-occurrence of PD with physical frailty and its contributions to the known impact of frailty on adverse health outcomes

Methods

Results

Discussion

Conclusion