Cellular Thermogenesis and Lifespan Modulation: Mechanisms of Cold-Temperature Aging in Drosophila

/ ABSTRACT Exposure to low temperature robustly extends lifespan across a myriad of animal species. In Drosophila melanogaster, we find that adults maintained at 18°C exhibit a dramatic extension of lifespan often exceeding 200 days, more than double that of flies housed at 25°C. This represents the most robust lifespan extension reported in Drosophila under a single environmental intervention. Despite the dramatic nature of this extension, the underlying mechanisms are poorly understood and appear to differ markedly from mechanisms previously characterized in Caenorhabditis elegans. We hypothesize that cold exposure in Drosophila activates a coordinated cell-autonomous intracellular program involving: (1) thermogenic-like mitochondrial remodeling, (2) suppression of O-GlcNAcylation and associated nutrient signaling pathways, and (3) translational reprogramming that enhances proteostasis. Each of these mechanisms is independently supported by robust pilot data and we hypothesize contributes to the longevity phenotype through improved metabolic function, stress resistance, and protein quality control. Aim 1 examines the role of mitochondrial remodeling and metabolic signaling. We show that cold- exposed flies upregulate the mitochondrial uncoupling protein UCP4b and display sustained metabolic shifts, including altered glucose and triglyceride utilization. We will determine whether UCP4b is required and sufficient for mitochondrial activation, redox homeostasis, and lifespan extension. In parallel, we investigate cold-induced suppression of O-GlcNAcylation as a regulator of mTOR and GSK3β signaling, using genetic and pharmacologic modulation of OGA and OGT enzymes. Aim 2 interrogates a role for cold-induced translational remodeling to promote proteostasis and slow aging trajectories. Our data shows cold suppresses global protein synthesis while preserving IRES-mediated translation of stress-responsive proteins, including proteasome subunits. We will assess translation dynamics with bicistronic IRES-reporter constructs and RiboTag RNA-seq. We further hypothesize that enhanced proteasome activity, driven by NRF2/CNC-C signaling, is a key effector of proteostatic maintenance and cold- induced longevity. Using RNAi, overexpression, and small molecules, we will determine whether proteasome activation is necessary and sufficient for these effects. This work establishes a novel framework for how cold exposure modulates aging in Drosophila. It identifies new, independently testable mechanisms involving mitochondrial metabolism, nutrient signaling, and protein homeostasis, and provides a rigorous dissection of cold-adaptive responses. Beyond revealing how ectotherms respond to environmental stress, this research may uncover conserved regulators of aging that could be targeted to promote healthy lifespan in broader biological contexts. Project Number: 1R21AG094596-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Andrew Pickering | Institution: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON, HOUSTON, TX | Award Amount: $429,000 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 CDB-H (90)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11380150