Network dynamical stability analysis reveals key "mallostatic" natural variables that erode homeostasis and drive age-related decline of health

TL;DR

This study models aging as a drift in key natural variables affecting homeostasis, revealing how mallostasis contributes to health decline and identifying biomarkers linked to adverse outcomes.

Contribution

It introduces a dynamic network stability analysis to identify natural aging variables and their drift, providing a novel framework for understanding age-related health decline.

Findings

Most natural variables stay near equilibrium over time.

A small subset of variables drift with age, indicating allostasis.

Drift in natural variables correlates with risk of death and dementia.

Abstract

Using longitudinal study data, we dynamically model how aging affects homeostasis in both mice and humans. We operationalize homeostasis as a multivariate mean-reverting stochastic process. We hypothesize that biomarkers have stable equilibrium values, but that deviations from equilibrium of each biomarker affects other biomarkers through an interaction network - this precludes univariate analysis. We therefore looked for age-related changes to homeostasis using dynamic network stability analysis, which transforms observed biomarker data into independent "natural" variables and determines their associated recovery rates. Most natural variables remained near equilibrium and were essentially constant in time. A small number of natural variables were unable to equilibrate due to a gradual drift with age in their homeostatic equilibrium, i.e. allostasis. This drift caused them to accumulate over the lifespan course and makes them natural aging variables. Their rate of accumulation was correlated with risk of adverse outcomes: death or dementia onset. We call this tendency for aging organisms to drift towards an equilibrium position of ever-worsening health "mallostasis". We demonstrate that the effects of mallostasis on observed biomarkers are spread out through the interaction network. This could provide a redundancy mechanism to preserve functioning until multi-system dysfunction emerges at advanced ages.