Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
Universitat Pompeu Fabra (UPF), Barcelona, Spain.
PLoS Comput Biol. 2022 Sep 30;18(9):e1010415. doi: 10.1371/journal.pcbi.1010415. eCollection 2022 Sep.
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.
衰老是一个从年轻活力到老年体弱和死亡的转变过程。长寿的人往往更有活力，在同基因的秀丽隐杆线虫种群中，与年龄相关的剧烈运动停止（VMC）的时间与寿命高度相关。然而，许多衰老的突变和干预改变了活力运动所花费的寿命比例，似乎将年轻活力与寿命“解耦”。为了阐明剧烈运动停止、死亡以及决定它们时间的身体衰退之间的关系，我们开发了一种称为“寿命机器”的新成像平台。这项技术使我们能够以前所未有的规模比较行为衰老和寿命。我们发现，行为衰老涉及 VMC 风险的时间依赖性增加，类似于死亡风险。此外，我们发现 VMC 时间与广泛的基因型和环境条件下的剩余寿命呈反比。通过测量和模拟各种改变寿命的干预措施，包括新的 RNA 聚合酶 II 生长素诱导的去稳定化系统，我们发现剧烈运动和寿命最好被描述为至少两种不同的身体衰退之间相互作用的结果，其速率在个体之间变化。通过这种方式，我们强调了预测寿命的重要限制，例如 VMC-在经历多种不同的与年龄相关的身体衰退的生物体中，中期生物标志物与晚期结果之间的相关性可能源于混杂因素的上下文影响，而不是生物标志物对稳健的预测生物年龄的报告。
