Changes in body temperature can profoundly affect survival. The dramatic longevity-enhancing effect of cold has long been known in organisms ranging from invertebrates to mammals, yet the underlying mechanisms have only recently begun to be uncovered. In the nematode Caenorhabditis elegans, this process is regulated by a thermosensitive membrane TRP channel and the DAF-16/FOXO transcription factor, but in more complex organisms the underpinnings of cold-induced longevity remain largely mysterious. We report that, in Drosophila melanogaster, variation in ambient temperature triggers metabolic changes in protein translation, mitochondrial protein synthesis, and posttranslational regulation of the translation repressor, 4E-BP (eukaryotic translation initiation factor 4E-binding protein). We show that 4E-BP determines Drosophila lifespan in the context of temperature changes, revealing a genetic mechanism for cold-induced longevity in this model organism. Our results suggest that the 4E-BP pathway, chiefly thought of as a nutrient sensor, may represent a master metabolic switch responding to diverse environmental factors.S tudies on the biological underpinnings of aging have uncovered numerous genetic and environmental factors regulating animal lifespan. Longevity-promoting genes include components of the insulin-like signaling pathway, the histone deacetylase Sir2, the GTPase Ras, TRP membrane channels, and transcription factors, among many others (1, 2). Environmental manipulations extending life include changes in nutrition (often referred to as caloric or dietary restriction), sexual/reproductive history, and ambient temperature (3-5).Of the factors known to impact aging, temperature is arguably the most promising. Lifespan extension by cold is evolutionarily conserved-documented in poikilotherms, such as worms and flies, and homeotherms, including mammals (4, 6-11)-and more robust than well-studied interventions such as dietary restriction (12, 13). However, the underlying mechanisms remain incompletely understood (10,14,15). In Caenorhabditis elegans, the effect of cold on survival involves the thermosensitive membrane channel TRPA-1 acting upstream of the DAF-16/FOXO transcription factor (14,15). This seminal finding countered the notion that longevity is the passive result of general thermodynamic changes, and favored instead the view that genetic pathways actively control lifespan in response to ambient temperature. However, these results have to date not been extended or replicated in other model organisms. Explanatory theories for the effect of cold on longevity include a reduction in reactive oxygen species generated by mitochondrial uncoupling proteins, suppression of autoimmune response, and changes in neuroendocrine factors (6,16,17), but these views remain largely speculative given the lack of further mechanistic insight into lifespan extension by cold in model organisms.We report that, in Drosophila, changes in temperature trigger a metabolic program impacting protein translation, mitochondrial prot...