BioAge: toward a multi-determined, mechanistic account of cognitive aging

Abstract

The search for reliable early indicators of age-related cognitive decline represents a critical avenue for progress in aging research. Chronological age is a commonly used developmental index; however, it offers little insight into the mechanisms underlying cognitive decline. In contrast, biological age (BioAge), reflecting the vitality of essential biological systems, represents a promising operationalization of developmental time. Current BioAge models have successfully predicted age-related cognitive deficits. Research on aging-related cognitive function indicates that the interaction of multiple risk and protective factors across the human lifespan confers individual risk for late-life cognitive decline, implicating a multi-causal explanation. In this review, we explore current BioAge models, describe three broad yet pathologically relevant biological processes linked to cognitive decline, and propose a novel operationalization of BioAge accounting for both moderating and causal mechanisms of cognitive decline and dementia. We argue that a multivariate and mechanistic BioAge approach will lead to a greater understanding of disease pathology as well as more accurate prediction and early identification of late-life cognitive decline.

Keywords: Biological age; Cognitive aging; Early identification; Inflammation; Oxidative stress; Vascular health.

Figure 1. An interaction model of possible moderating and causal mechanisms contributing to aging, cognitive function and brain neurodegeneration

Both moderators (i.e., epigenetics, disease comorbidity, DNA repair mechanisms, etc.) and theoretical causal influences (i.e., inflammation, oxidative stress, etc.) are thought to interact with each other over the lifespan, resulting in a unique individual susceptibility to age-related diseases such as cognitive decline or more severe neurodegenerative disorders.