Mechanisms of beneficial transgenerational plasticity to improve offspring aging
Therapies to improve health and increase longevity rely on plasticity--or changeability in phenotype--in age- related traits and lifespan. There is growing awareness that phenotypic plasticity may occur not only in an individual, but also across generations. Such transgenerational phenotypic plasticity, known as "maternal effects," occurs when the maternal response to the environment causes a change in offspring phenotype without a corresponding change in the genome. Previous studies have focused on detrimental maternal effects like smoking and alcohol consumption, but little is known about the role of beneficial maternal effects on aging. This project will characterize the effects of maternal age and maternal caloric restriction, also known as food limitation, on offspring aging, and will uncover the transcriptional and epigenetic mechanisms behind maternal effects that improve offspring health and longevity. The central hypothesis is that interventions to improve maternal health and longevity will benefit offspring, and that therapeutic interventions to mothers will offset the negative effects on offspring of advanced maternal age. These maternal effects will be driven by epigenetic mechanisms causing changes in gene expression. The goal of the proposed research is to understand the mechanisms of beneficial maternal effects on aging and health in offspring in order to identify potential gene targets for therapies to improve human health during aging. Dr. Gribble will determine the effect of maternal age and caloric restriction on the health, fecundity, and longevity of offspring, and the persistence of maternal effects through multiple generations using life table experiments and stress-resistance assays (Aim 1);characterize the molecular genetic mechanisms underlying maternal caloric restriction effects, and determine whether this intervention works through the same mechanisms in maternal and filial generations using RNA- Seq, qPCR and RNAi (Aim 2);and define how epigenetic mechanisms are employed transgenerationally to regulate offspring health and longevity in response to maternal environment, using assays for epigenetic histone modifications and ChIP-qPCR (Aim 3). In keeping with the NIA's goal of increasing the variety of model systems available to investigate questions of human health, this project will advance the development of invertebrate monogonont rotifers as a modern model system for the study of aging. Rotifers provide many advantages as models in aging research, including a century of aging-related and maternal effects research;a three-week lifespan enabling high replication and rapid experimentation;asexual (clonal) and sexual propagation;and genetic resources including draft genomes, transcriptomes, and protocols for transgenics and RNAi. The combination of coursework, professional meetings, and direct work with mentors outlined in this Mentored Research Scientist Development Award (K01) will provide Dr. Gribble with the additional training she needs for a successful research career in the biology of aging. This research will form the basis for future investigation of specific genetic and epigenetic factors involved in beneficial maternal effects.