Celeganser: Automated Analysis of Nematode Morphology and Age

The nematode Caenorhabditis elegans (C. elegans) serves as an important model organism in a wide variety of biological studies. In this paper we introduce a pipeline for automated analysis of C. elegans imagery for the purpose of studying life-span, health-span and the underlying genetic determinants of aging. Our system detects and segments the worm, and predicts body coordinates at each pixel location inside the worm. These coordinates provide dense correspondence across individual animals to allow for meaningful comparative analysis. We show that a model pre-trained to perform body-coordinate regression extracts rich features that can be used to predict the age of individual worms with high accuracy. This lays the ground for future research in quantifying the relation between organs' physiologic and biochemical state, and individual life/health-span.Comment: Computer Vision for Microscopy Image Analysis (CVMI) 202

Predicting all-cause mortality from basic physiology in the Framingham Heart Study

Using longitudinal data from a cohort of 1349 participants in the Framingham Heart Study, we show that as early as 28–38 years of age, almost 10% of variation in future lifespan can be predicted from simple clinical parameters. Specifically, we found diastolic and systolic blood pressure, blood glucose, weight, and body mass index (BMI) to be relevant to lifespan. These and similar parameters have been well‐characterized as risk factors in the relatively narrow context of cardiovascular disease and mortality in middle to old age. In contrast, we demonstrate here that such measures can be used to predict all‐cause mortality from mid‐adulthood onward. Further, we find that different clinical measurements are predictive of lifespan in different age regimes. Specifically, blood pressure and BMI are predictive of all‐cause mortality from ages 35 to 60, while blood glucose is predictive from ages 57 to 73. Moreover, we find that several of these parameters are best considered as measures of a rate of ‘damage accrual’, such that total historical exposure, rather than current measurement values, is the most relevant risk factor (as with pack‐years of cigarette smoking). In short, we show that simple physiological measurements have broader lifespan‐predictive value than indicated by previous work and that incorporating information from multiple time points can significantly increase that predictive capacity. In general, our results apply equally to both men and women, although some differences exist

A microRNA feedback loop regulates global microRNA abundance during aging

Expression levels of many microRNAs (miRNAs) change during aging, notably declining globally in a number of organisms and tissues across taxa. However, little is known about the mechanisms or the biological relevance for this change. We investigated the network of genes that controls miRNA transcription and processing during C. elegans aging. We found that miRNA biogenesis genes are highly networked with transcription factors and aging-associated miRNAs. In particular, miR-71, known to influence life span and itself up-regulated during aging, represses alg-1/Argonaute expression post-transcriptionally during aging. Increased ALG-1 abundance in mir-71 loss-of-function mutants led to globally increased miRNA expression. Interestingly, these mutants demonstrated widespread mRNA expression dysregulation and diminished levels of variability both in gene expression and in overall life span. Thus, the progressive molecular decline often thought to be the result of accumulated damage over an organism's life may be partially explained by a miRNA-directed mechanism of age-associated decline.</jats:p

Transcriptional (dys)regulation and aging in Caenorhabditis elegans

New work could link laboratory-defined longevity pathways to the process of normal aging

High temporal resolution measurements of movement reveal novel early-life physiological decline in C. elegans

Age-related physiological changes are most notable and best-studied late in life, while the nature of aging in early- or middle-aged individuals has not been explored as thoroughly. In C. elegans, many studies of movement vs. age generally focus on three distinct phases: sustained, youthful movement; onset of rapidly progressing impairment; and gross immobility. We investigated whether this first period of early-life adult movement is a sustained healthy level of high function followed by a discrete movement catastrophe -or whether there are early-life changes in movement that precede future physiological declines. To determine how movement varies during early adult life, we followed isolated individuals throughout life with a previously unachieved combination of duration and temporal resolution. By tracking individuals across the first six days of adulthood, we observed declines in movement starting as early as the first two days of adult life, as well as high interindividual variability in total daily movement. These findings suggest that movement is a highly dynamic behavior early in life, and that factors driving movement decline may begin acting as early as the first day of adulthood. Using simulation studies based on acquired data, we suggest that too-infrequent sampling in common movement assays limits observation of early-adult changes in motility, and we propose feasible strategies and a framework for designing assays with increased sensitivity for early movement declines

Dynamic expression of small non-coding RNAs, including novel microRNAs and piRNAs/21U-RNAs, during Caenorhabditis elegans development

A deep-sequencing approach to profiling gender-specific developmental regulation of small non-coding RNA expression in C. elegans reveals dynamic temporal expression and novel miRNAs and 21U RNAs

Global, cell non-autonomous gene regulation drives individual lifespan among isogenic C. elegans

Across species, lifespan is highly variable among individuals within a population. Even genetically identica

Functional trajectories during innate spinal cord repair

Adult zebrafish are capable of anatomical and functional recovery following severe spinal cord injury. Axon growth, glial bridging and adult neurogenesis are hallmarks of cellular regeneration during spinal cord repair. However, the correlation between these cellular regenerative processes and functional recovery remains to be elucidated. Whereas the majority of established functional regeneration metrics measure swim capacity, we hypothesize that gait quality is more directly related to neurological health. Here, we performed a longitudinal swim tracking study for 60 individual zebrafish spanning 8 weeks of spinal cord regeneration. Multiple swim parameters as well as axonal and glial bridging were integrated. We established rostral compensation as a new gait quality metric that highly correlates with functional recovery. Tensor component analysis of longitudinal data supports a correspondence between functional recovery trajectories and neurological outcomes. Moreover, our studies predicted and validated that a subset of functional regeneration parameters measured 1 to 2 weeks post-injury is sufficient to predict the regenerative outcomes of individual animals at 8 weeks post-injury. Our findings established new functional regeneration parameters and generated a comprehensive correlative database between various functional and cellular regeneration outputs

Emergence of Large-Scale Cell Morphology and Movement from Local Actin Filament Growth Dynamics

Variations in cell migration and morphology are consequences of changes in underlying cytoskeletal organization and dynamics. We investigated how these large-scale cellular events emerge as direct consequences of small-scale cytoskeletal molecular activities. Because the properties of the actin cytoskeleton can be modulated by actin-remodeling proteins, we quantitatively examined how one such family of proteins, enabled/vasodilator-stimulated phosphoprotein (Ena/VASP), affects the migration and morphology of epithelial fish keratocytes. Keratocytes generally migrate persistently while exhibiting a characteristic smooth-edged “canoe” shape, but may also exhibit less regular morphologies and less persistent movement. When we observed that the smooth-edged canoe keratocyte morphology correlated with enrichment of Ena/VASP at the leading edge, we mislocalized and overexpressed Ena/VASP proteins and found that this led to changes in the morphology and movement persistence of cells within a population. Thus, local changes in actin filament dynamics due to Ena/VASP activity directly caused changes in cell morphology, which is coupled to the motile behavior of keratocytes. We also characterized the range of natural cell-to-cell variation within a population by using measurable morphological and behavioral features—cell shape, leading-edge shape, filamentous actin (F-actin) distribution, cell speed, and directional persistence—that we have found to correlate with each other to describe a spectrum of coordinated phenotypes based on Ena/VASP enrichment at the leading edge. This spectrum stretched from smooth-edged, canoe-shaped keratocytes—which had VASP highly enriched at their leading edges and migrated fast with straight trajectories—to more irregular, rounder cells migrating slower with less directional persistence and low levels of VASP at their leading edges. We developed a mathematical model that accounts for these coordinated cell-shape and behavior phenotypes as large-scale consequences of kinetic contributions of VASP to actin filament growth and protection from capping at the leading edge. This work shows that the local effects of actin-remodeling proteins on cytoskeletal dynamics and organization can manifest as global modifications of the shape and behavior of migrating cells and that mathematical modeling can elucidate these large-scale cell behaviors from knowledge of detailed multiscale protein interactions