The role of shingolipids in stress response and healthy aging.hips - While lifespans are increasing, so is age-related loss of cardiovascular, immune and cognitive
functions. It is necessary to better understand the biology of healthy aging that focuses on
increasing the number of years one remains healthy and free of age-related disorders. These
years, termed health span, often associate with the ability to maintain youthful stress response,
motor function, and cognition. This project examines the role of a bioactive lipid pathway –
sphingolipid metabolism – on increasing health span. For this, we analyze lifespan, oxidative
stress, and locomotor function using the model organism C. elegans. First, this project
examines whether reducing mRNA expression of sphingolipid enzymes, specifically at older
ages, affects lifespan, survival to oxidative stressors, and neuromuscular function. We use
physiological and cellular experiments, RNA interference, and gene expression analyses to
examine a panel of sphingolipid genes. In particular, the proposal examines whether one
sphingolipid, sphingosine- 1-phosphate (S1P), can promote improved health span and whether
another, ceramide, worsens healthspan. Secondly, the project examines how sphingolipids
mediate bacteria-host interactions, specifically to modulate innate immune responses. For this,
we determine whether mutations in sphingolipid genes affect the induction of innate immunity
signaling pathways following stress. We also examine the gene expression of sphingolipid
metabolism enzymes and sphingolipid content in known aging mutant models, including the
insulin signaling, dietary restriction, and mitochondrial respiration pathways. In addition, we
analyze bacterial gene expression in these models of aging, to elucidate how microbial gene
expression dynamics differ in aging hosts. Sphingolipids are major players in the intestinal tract
and function in stress response; using mutants with altered sphingolipid signaling, gene
expression analysis of sphingolipid enzymes, and bacterial transcriptomics, we might gain
insight into how sphingolipids mediate stress responses and host physiology during aging.
Together, the project aims to generate invaluable datasets that interrelates host sphingolipids,
the gut microbiome, and age to identify novel players in promoting healthy aging.
