A hierarchical process model links behavioral aging and lifespan in C. elegans

Natasha Oswal, Olivier M F Martin, Sofia Stroustrup, Monika Anna Matusiak Bruckner and Nicholas Stroustrup

PLOS Computational Biology, 2022, vol. 18, issue 9, 1-28

Abstract: Aging involves a transition from youthful vigor to geriatric infirmity and death. Individuals who remain vigorous longer tend to live longer, and within isogenic populations of C. elegans the timing of age-associated vigorous movement cessation (VMC) is highly correlated with lifespan. Yet, many mutations and interventions in aging alter the proportion of lifespan spent moving vigorously, appearing to “uncouple” youthful vigor from lifespan. To clarify the relationship between vigorous movement cessation, death, and the physical declines that determine their timing, we developed a new version of the imaging platform called “The Lifespan Machine”. This technology allows us to compare behavioral aging and lifespan at an unprecedented scale. We find that behavioral aging involves a time-dependent increase in the risk of VMC, reminiscent of the risk of death. Furthermore, we find that VMC times are inversely correlated with remaining lifespan across a wide range of genotypes and environmental conditions. Measuring and modelling a variety of lifespan-altering interventions including a new RNA-polymerase II auxin-inducible degron system, we find that vigorous movement and lifespan are best described as emerging from the interplay between at least two distinct physical declines whose rates co-vary between individuals. In this way, we highlight a crucial limitation of predictors of lifespan like VMC—in organisms experiencing multiple, distinct, age-associated physical declines, correlations between mid-life biomarkers and late-life outcomes can arise from the contextual influence of confounding factors rather than a reporting by the biomarker of a robustly predictive biological age.Author summary: Aging produces a variety of outcomes—declines in various measures of health and eventually death. By studying the relationship between two outcomes of aging in the same individual, we can learn about the underlying aging processes that cause them. Here, we consider the relationship between death and an outcome often used to quantify health in C. elegans—vigorous movement cessation which describes the age-associated loss of an individuals’ ability to move long distances. We develop an automated imaging platform that allows us to precisely compare this pair of outcomes in each individual across large populations. We find that individuals who remain vigorous longer subsequently have a shorter remaining lifespan—a pattern that holds even after vigorous movement and lifespan timing are both altered by several different mutations and interventions in aging. Modelling our data using a combination of simulation and analytic studies, we demonstrate how the relative timing of vigorous movement cessation and death suggest that these two outcomes are driven by distinct aging processes. Our data and analyses demonstrate how two outcomes of aging can be correlated across individuals with the timing of one predicting the timing of the other, but nevertheless be driven by mostly distinct underlying physical declines.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1010415

DOI: 10.1371/journal.pcbi.1010415

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