Molecular Genetics of Aging Laboratory

Aging is accompanied by a progressive decline in the ability of cells and organisms to maintain homeostasis. Why do biological systems gradually lose this ability? Our laboratory addresses this question from the perspective of RNA biology, viewing aging as a progressive loss of biological information integrity. Using the nematode Caenorhabditis elegans together with mammalian systems, we investigate how RNA quality control, translation, metabolism, and stress responses interact to regulate aging and healthspan. We have shown that mechanisms maintaining the fidelity of gene expression, including nonsense-mediated mRNA decay, pre-mRNA splicing, and ribosome-associated quality control, change with age and directly regulate lifespan. We are now studying how errors in RNA processing and translation arise during aging, how stalled and collided ribosomes are resolved, and how failures in these systems cause dysfunctions in RNA and protein homeostasis, subsequently reducing healthspan. Circular RNAs, tRNA-derived RNAs, double-stranded RNAs (dsRNAs), and other non-canonical RNA species change with age. We have identified ribonucleases that limit the age-associated accumulation of circular and tRNA-derived RNAs, as well as mechanisms that prevent the buildup of mitochondrial dsRNAs and innate immune activation. We are now asking how cells selectively eliminate harmful RNAs while preserving functional ones, and whether age-associated RNA structures and condensates represent new hallmarks of aging. Defects in RNA homeostasis affect mitochondrial function, innate immunity, proteostasis, and metabolism, while metabolic states in turn reshape RNA processing and translation. Building on our previous work on mitochondrial signaling, autophagy, and neuroendocrine control of lifespan, we