Molecular and physiological manifestations and measurement of aging in humans

Abstract

Biological aging is associated with a reduction in the reparative and regenerative potential in tissues and organs. This reduction manifests as a decreased physiological reserve in response to stress (termed homeostenosis) and a time-dependent failure of complex molecular mechanisms that cumulatively create disorder. Aging inevitably occurs with time in all organisms and emerges on a molecular, cellular, organ, and organismal level with genetic, epigenetic, and environmental modulators. Individuals with the same chronological age exhibit differential trajectories of age-related decline, and it follows that we should assess biological age distinctly from chronological age. In this review, we outline mechanisms of aging with attention to well-described molecular and cellular hallmarks and discuss physiological changes of aging at the organ-system level. We suggest methods to measure aging with attention to both molecular biology (e.g., telomere length and epigenetic marks) and physiological function (e.g., lung function and echocardiographic measurements). Finally, we propose a framework to integrate these molecular and physiological data into a composite score that measures biological aging in humans. Understanding the molecular and physiological phenomena that drive the complex and multifactorial processes underlying the variable pace of biological aging in humans will inform how researchers assess and investigate health and disease over the life course. This composite biological age score could be of use to researchers seeking to characterize normal, accelerated, and exceptionally successful aging as well as to assess the effect of interventions aimed at modulating human aging.

Keywords: aging; biological age; biomarkers; score; senescence.

Figure 1

Biological aging is a multifactorial process. The molecular hallmarks of aging and organ‐specific physiological function are both influenced by genetic, epigenetic, and environmental factors. Metastatic aging may contribute to differential aging in remote tissues through a paracrine mechanism.

Figure 2

Conceptual derivation of a biological age score (BAS) that combines molecular markers derived from measures of the molecular hallmarks of aging (represented here in blue, e.g., telomere length and gene‐specific DNA methylation) and measures of physiological function (represented here in red, e.g., FEV ₁ and e’ velocity) that are longitudinally assessed throughout the life course. Potential mathematical modeling approaches for integrating individual components into a composite BAS include multiple linear regression, principal component analysis, and Klemera and Doubal's method with derivation and validation in population‐based data sets. The BAS graph depicts three hypothetical aging trajectories: 1) normal ager, 2) super ager, and 3) accelerated ager with colored areas representing confidence intervals and demonstrating overlap at young ages. The aging lines are depicted hypothetically as straight lines, but the trajectory of biological aging is not known.

Figure 3

Relative rates of decline of organ‐specific physiological function. Different organ systems may carry a specific vulnerability to age (i.e., the cardiovascular system appears to suffer biological aging more rapidly than the gastrointestinal system).