What governs how fast we age? Why do some biological processes stop working earlier than others? And what is happening at the molecular and cellular level as some organisms age while others continue to thrive?
Although seemingly philosophical in nature, these questions address one of the major mysteries of biology, the process of aging. With recent developments in genetics, molecular biology, and genomics, we now have the possibility of addressing these questions at the molecular level. Because our ultimate goal is not simply to extend lifespan, but to improve overall health, we must identify the genes associated with biological functions that we typically associate with quality of life. The goal of our laboratory's work is to understand the molecular mechanisms governing longevity and maintenance of the biological processes that exhibit age-related decline.
Investigating Mechanisms that Control Ubiquitin-Mediated DAF-16/FOXO Protein Turnover.Journal Article
Protein turnover of FOXO family transcription factors is regulated by the ubiquitin-proteasome system. A complex interplay of factors that covalently attach certain types of ubiquitin chains (E3-ubiquitin ligases), and enzymes that are able to remove ubiquitin conjugates (deubiquitylases), regulate the degradation of FOXO proteins by the...
Regulation of reproduction and longevity by nutrient-sensing pathwaysJournal ArticleNutrients are necessary for life, as they are a crucial requirement for biological processes including reproduction, somatic growth, and tissue maintenance. Therefore, signaling systems involved in detecting and interpreting nutrient or energy levels—most notably, the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway, mechanistic...
C. elegans pathogenic learning confers multigenerational pathogen avoidanceJournal ArticleThe ability to pass on learned information to progeny could present an evolutionary advantage for many generations. While apparently evolutionarily conserved, transgenerational epigenetic inheritance (TEI) is not well understood at the molecular or behavioral levels. Here we describe our discovery that C. elegans can pass on a learned pathogenic...
Insulin Signaling Regulates Oocyte Quality Maintenance with Age via Cathepsin B Activity.Journal Article
A decline in female reproduction is one of the earliest hallmarks of aging in many animals, including invertebrates and mammals [1-4]. The insulin/insulin-like growth factor-1 signaling (IIS) pathway has a conserved role in regulating longevity  and also controls reproductive aging [2, 6]. Although IIS transcriptional targets that regulate...
An integrative tissue-network approach to identify and test human disease genes.Journal Article
Effective discovery of causal disease genes must overcome the statistical challenges of quantitative genetics studies and the practical limitations of human biology experiments. Here we developed diseaseQUEST, an integrative approach that combines data from human genome-wide disease studies with in silico network models of tissue- and cell-type...
Caenorhabditis elegans sperm carry a histone-based epigenetic memory of both spermatogenesis and oogenesis.Caenorhabditis elegans sperm carry a histone-based epigenetic memory of both spermatogenesis and oogenesis.Journal Article
Paternal contributions to epigenetic inheritance are not well understood. Paternal contributions via marked nucleosomes are particularly understudied, in part because sperm in some organisms replace the majority of nucleosome packaging with protamine packaging. Here we report that in Caenorhabditis elegans sperm, the genome is packaged in...
Transcriptome analysis of adult Caenorhabditis elegans cells reveals tissue-specific gene and isoform expression.Transcriptome analysis of adult Caenorhabditis elegans cells reveals tissue-specific gene and isoform expression.Journal Article
The biology and behavior of adults differ substantially from those of developing animals, and cell-specific information is critical for deciphering the biology of multicellular animals. Thus, adult tissue-specific transcriptomic data are critical for understanding molecular mechanisms that control their phenotypes. We used adult cell-specific...
Activation of G Signaling Enhances Memory Consolidation and Slows Cognitive Decline.Journal Article
Perhaps the most devastating decline with age is the loss of memory. Therefore, identifying mechanisms to restore memory function with age is critical. Using C. elegans associative learning and memory assays, we identified a gain-of-function G signaling pathway mutant that forms a long-term (cAMP response element binding protein [CREB]-...
Mating and male pheromone kill \textitCaenorhabditis males through distinct mechanismsJournal ArticleDifferences in longevity between sexes is a mysterious yet general phenomenon across great evolutionary distances. To test the roles of responses to environmental cues and sexual behaviors in longevity regulation, we examined \textitCaenorhabditis male lifespan under solitary, grouped, and mated conditions. We find that neurons and the germline...Aging; Caenorhabditis; germline; Male; mating; pheromone
RNA surveillance via nonsense-mediated mRNA decay is crucial for longevity in daf-2/insulin/IGF-1 mutant C. elegans.RNA surveillance via nonsense-mediated mRNA decay is crucial for longevity in daf-2/insulin/IGF-1 mutant C. elegans.Journal Article
Long-lived organisms often feature more stringent protein and DNA quality control. However, whether RNA quality control mechanisms, such as nonsense-mediated mRNA decay (NMD), which degrades both abnormal as well as some normal transcripts, have a role in organismal aging remains unexplored. Here we show that NMD mediates longevity in C....