Protein catabolites as blood-based biomarkers of aging physiology: Findings from the Dog Aging Project.

Our understanding of age-related physiology and metabolism has grown through the study of systems biology, including transcriptomics, single-cell analysis, proteomics and metabolomics. Studies in lab organisms in controlled environments, while powerful and complex, fall short of capturing the breadth of genetic and environmental variation in nature. Thus, there is now a major effort in geroscience to identify aging biomarkers and to develop aging interventions that might be applied across the diversity of humans and other free-living species.

DNA methylation of transposons pattern aging differences across a diverse cohort of dogs from the Dog Aging Project.

Within a species, larger individuals often have shorter lives and higher rates of age-related disease. Despite this well-known link, we still know little about underlying age-related epigenetic differences, which could help us better understand inter-individual variation in aging and the etiology, onset, and progression of age-associated disease. Dogs exhibit this negative correlation between size, health, and longevity and thus represent an excellent system in which to test the underlying mechanisms.

Tissue-specific metabolomic signatures for a model of reduced sexual dimorphism.

Sex has a major effect on the metabolome. However, we do not yet understand the degree to which these quantitative sex differences in metabolism are associated with anatomical dimorphism and modulated by sex-specific tissues. In the fruit fly, , knocking out the () gene gives rise to adults with intermediate sex characteristics.

Wide-ranging genetic variation in sensitivity to rapamycin in Drosophila melanogaster.

The progress made in aging research using laboratory organisms is undeniable. Yet, with few exceptions, these studies are conducted in a limited number of isogenic strains. The path from laboratory discoveries to treatment in human populations is complicated by the reality of genetic variation in nature.

Selection for early reproduction leads to accelerated aging and extensive metabolic remodeling in .

Experimental evolution studies that feature selection on life-history characters are a proven approach for studying the evolution of aging and variation in rates of senescence. Recently, the incorporation of genomic and transcriptomic approaches into this framework has led to the identification of hundreds of genes associated with different aging patterns. However, our understanding of the specific molecular mechanisms underlying these aging patterns remains limited.

Using Drosophila to identify naturally occurring genetic modifiers of amyloid beta 42- and tau-induced toxicity.

Alzheimer's disease is characterized by 2 pathological proteins, amyloid beta 42 and tau. The majority of Alzheimer's disease cases in the population are sporadic and late-onset Alzheimer's disease, which exhibits high levels of heritability. While several genetic risk factors for late-onset Alzheimer's disease have been identified and replicated in independent studies, including the ApoE ε4 allele, the great majority of the heritability of late-onset Alzheimer's disease remains unexplained, likely due to the aggregate effects of a very large number of genes with small effect size, as well as to biases in sample collection and statistical approaches.

In search of a Drosophila core cellular network with single-cell transcriptome data.

Along with specialized functions, cells of multicellular organisms also perform essential functions common to most if not all cells. Whether diverse cells do this by using the same set of genes, interacting in a fixed coordinated fashion to execute essential functions, or a subset of genes specific to certain cells, remains a central question in biology. Here, we focus on gene coexpression to search for a core cellular network across a whole organism.

Correction: Genetic and metabolomic architecture of variation in diet restriction-mediated lifespan extension in Drosophila.

[This corrects the article DOI: 10.1371/journal.pgen.

The metabolome as a biomarker of aging in Drosophila melanogaster.

Many biomarkers have been shown to be associated not only with chronological age but also with functional measures of biological age. In human populations, it is difficult to show whether variation in biological age is truly predictive of life expectancy, as such research would require longitudinal studies over many years, or even decades. We followed adult cohorts of 20 Drosophila Genetic Reference Panel (DGRP) strains chosen to represent the breadth of lifespan variation, obtain estimates of lifespan, baseline mortality, and rate of aging, and associate these parameters with age-specific functional traits including fecundity and climbing activity and with age-specific targeted metabolomic profiles.

Evolution of natural lifespan variation and molecular strategies of extended lifespan in yeast.

To understand the genetic basis and selective forces acting on longevity, it is useful to examine lifespan variation among closely related species, or ecologically diverse isolates of the same species, within a controlled environment. In particular, this approach may lead to understanding mechanisms underlying natural variation in lifespan. Here, we analyzed 76 ecologically diverse wild yeast isolates and discovered a wide diversity of replicative lifespan (RLS).

Modular Evolution of the Drosophila Metabolome.

Comparative phylogenetic studies offer a powerful approach to study the evolution of complex traits. Although much effort has been devoted to the evolution of the genome and to organismal phenotypes, until now relatively little work has been done on the evolution of the metabolome, despite the fact that it is composed of the basic structural and functional building blocks of all organisms. Here we explore variation in metabolite levels across 50 My of evolution in the genus Drosophila, employing a common garden design to measure the metabolome within and among 11 species of Drosophila.

Genetic and metabolomic architecture of variation in diet restriction-mediated lifespan extension in Drosophila.

In most organisms, dietary restriction (DR) increases lifespan. However, several studies have found that genotypes within the same species vary widely in how they respond to DR. To explore the mechanisms underlying this variation, we exposed 178 inbred Drosophila melanogaster lines to a DR or ad libitum (AL) diet, and measured a panel of 105 metabolites under both diets.

The metabolome as a link in the genotype-phenotype map for peroxide resistance in the fruit fly, Drosophila melanogaster.

Background: Genetic association studies that seek to explain the inheritance of complex traits typically fail to explain a majority of the heritability of the trait under study. Thus, we are left with a gap in the map from genotype to phenotype. Several approaches have been used to fill this gap, including those that attempt to map endophenotype such as the transcriptome, proteome or metabolome, that underlie complex traits.

Persons with essential tremor can adapt to new walking patterns.

Essential tremor (ET) is a common movement disorder that causes motor deficits similar to those seen in cerebellar disorders. These include kinetic tremor, gait ataxia, and impaired motor adaptation. Previous studies of motor adaptation in ET have focused on reaching while the effects of ET on gait adaptation are currently unknown.

Immunohistochemistry relative to gravity: a simple method to retain information about gravity for immunolocalization and histochemistry.

We describe a simple method to preserve information about a plant organ's orientation relative to the direction of the gravity vector during sample processing for immunolocalization or histochemical analysis of cell biological processes. This approach has been used in gravity stimulated roots of Arabidopsis thaliana and Zea mays to study PIN3 relocalization, study the asymmetrical remodeling of the actin network and the cortical microtubule array, and to reveal the asymmetrical expression of the auxin signaling reporter DR5::GUS. This method enables the rapid analysis of a large number of samples from a variety of genotypes, as well as from tissue that may be too thick for microscopy in live plants.

Life without RNAi: noncoding RNAs and their functions in Saccharomyces cerevisiae.

There are a number of well-characterized and fundamental roles for noncoding RNAs (ncRNAs) in gene regulation in all kingdoms of life. ncRNAs, such as ribosomal RNAs, transfer RNAs, small nuclear RNAs, small nucleolar RNAs, and small interfering RNAs, can serve catalytic and scaffolding functions in transcription, messenger RNA processing, translation, and RNA degradation. Recently, our understanding of gene expression has been dramatically challenged by the identification of large and diverse populations of novel ncRNAs in the eukaryotic genomes surveyed thus far.

ARL2, ARG1 and PIN3 define a gravity signal transduction pathway in root statocytes.

ALTERED RESPONSE TO GRAVITY1 (ARG1) and its paralog ARG1-LIKE2 (ARL2) are J-domain proteins that are required for normal root and hypocotyl gravitropism. In this paper, we show that both ARL2 and ARG1 function in a gravity signal transduction pathway with PIN3, an auxin efflux facilitator that is expressed in the statocytes. In gravi-stimulated roots, PIN3 relocalizes to the lower side of statocytes, a process that is thought to, in part, drive the asymmetrical redistribution of auxin toward the lower flank of the root.

Adenosine kinase modulates root gravitropism and cap morphogenesis in Arabidopsis.

Adenosine kinase (ADK) is a key enzyme that regulates intra- and extracellular levels of adenosine, thereby modulating methyltransferase reactions, production of polyamines and secondary compounds, and cell signaling in animals. Unfortunately, little is known about ADK's contribution to the regulation of plant growth and development. Here, we show that ADK is a modulator of root cap morphogenesis and gravitropism.

Gravity signal transduction in primary roots.

Aims: The molecular mechanisms that correlate with gravity perception and signal transduction in the tip of angiosperm primary roots are discussed.

Scope: Gravity provides a cue for downward orientation of plant roots, allowing anchorage of the plant and uptake of the water and nutrients needed for growth and development. Root gravitropism involves a succession of physiological steps: gravity perception and signal transduction (mainly mediated by the columella cells of the root cap); signal transmission to the elongation zone; and curvature response.