Abstract
Individuals who remain vigorous longer tend to live longer, supporting the design of predictive behavioral biomarkers of aging. In C. elegans, the timing of age-associated vigorous movement cessation (VMC) and lifespan correlate strongly between individuals. However, many genetic and pharmaceutical interventions that alter aging produce disproportional effects on VMC and lifespan, appearing to “uncouple” the rate of behavioral aging and lifespan. To study the causal structure underlying such uncoupling, we developed a high-throughput, automated imaging platform to quantify behavioral aging and lifespan at an unprecedented scale. Our method reveals an inverse correlation between each individuals’ vigorous movement span and their remaining lifespan. Robust across many lifespan-altering interventions including a new RNA-polymerase II auxin-inducible degron system, our data shows that individual C. elegans experience at least two distinct but coupled physical declines—one governing VMC and the other governing lifespan. Through simulations and modeling, we clarify the causal relationship between these two “biological ages” and highlight a crucial but often untested assumption in conventional aging biomarker research: predictive biomarkers may not always report on the same biological age as that which determines long-term health outcomes.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
This revision integrates colleagues' feedback to improve the clarity and focus of the manuscript. Detailed descriptions of the methodological improvements to our imaging technology are transferred into supplementary notes and figures. The theory and modeling supplementary notes are expanded and clarified. Main text figures are simplified and condensed. An additional data table summarizing the effect of interventions is added as "Table 1".
