Aging of a eukaryotic organism is affected by its nutrition state and by its ability to prevent or repair oxidative damage. Consequently, signal transduction systems that control metabolism and oxidative stress responses influence life span. When nutrients are abundant, the insulin/IGF signaling (IIS) pathway promotes growth and energy storage but shortens life span. The transcription factor Foxo, which is inhibited by IIS, extends life span in conditions of low IIS activity. Life span can also be increased by activating the stress-responsive Jun-N-terminal kinase (JNK) pathway. Here we show that JNK requires Foxo to extend life span in Drosophila. JNK antagonizes IIS, causing nuclear localization of Foxo and inducing its targets, including growth control and stress defense genes. JNK and Foxo also restrict IIS activity systemically by repressing IIS ligand expression in neuroendocrine cells. The convergence of JNK signaling and IIS on Foxo provides a model to explain the effects of stress and nutrition on longevity.

Functional small biomolecules play indispensable roles inside cells. However, sensitive and specific visualization of these molecules in living systems has proven to be highly challenging. Herein, we report stimulated Raman scattering imaging of alkyne tags as a general strategy for studying a broad spectrum of small biomolecules in live cells and animals. We demonstrate this technique by tracking alkyne-bearing drugs in mouse tissues, and visualizing de novo synthesis of DNA, RNA, proteomes, phospholipids and triglycerides, respectively, through metabolic incorporation of alkyne-tagged small precursors.

SummaryFat metabolism, reproduction, and aging are intertwined regulatory axes; however, the mechanism by which they are coupled remains poorly understood. We found that germline stem cells (GSCs) actively modulate lipid hydrolysis in Caenorhabditis elegans, which in turn regulates longevity. GSC arrest promotes systemic lipolysis via induction of a specific fat lipase. Subsequently, fat mobilization is promoted and life span is prolonged. Constitutive expression of this lipase in fat storage tissue generates lean and long-lived animals. This lipase is a key factor in the lipid hydrolysis and increased longevity that are induced by decreased insulin signaling. These results suggest a link between C. elegans fat metabolism and longevity.Abalance of fat storage and mobilization is a universal feature of animal physiology (1). Reproduction is an energy-intensive process, which is modulated by the availability of nutrients and in turn influences lipid metabolism (2). Reproductive ability declines with age, and many organisms undergo reproductive senescence (3). Obesity increases with age and is also associated with the transition to menopause in women (4). Genetic studies have suggested endocrine roles of adipose tissue and the reproductive system in regulation of life span (5-8). Thus, understanding the mechanisms by which fat metabolism is coupled to reproductive cues may reveal systemic regulation of fat metabolism and provide insights into the control of aging.In C. elegans, the energetic demands of progeny production are profound. The gonad undergoes many more mitoses than does somatic tissue, and the biomass of the oocytes produced is approximately equal to the biomass increase from egg to adult. Thus, in the absence of reproduction, a surfeit of available energy could lead to an increase in fat storage. To test this idea, we ablated the precursor cells of the germ line in C. elegans with the use of a laser microbeam. The vital dye Nile Red was used to visualize fat storage droplets in living animals (9). Opposite to the expected increase in fat storage, germ line-ablated animals stored 50% as much fat as untreated animals (Fig. 1, A to C). This finding suggested a regulatory mechanism coupling reproduction and fat metabolism.Fat storage is also aberrant in the sterile mutants glp-1(e2141ts) and glp-4(bn2ts), which are defective in germline proliferation (10,11). The glp mutants showed a 50% decrease in fat storage at the nonpermissive temperature relative to the wild type (N2) (Fig. 1, D to G). A similar decrease was observed by staining with a BODIPY-labeled fatty acid analog ( fig. S1)

Changes in the genetic makeup of an organism can extend lifespan significantly if they promote tolerance to environmental insults and thus prevent the general deterioration of cellular function that is associated with aging. Here, we introduce the Jun N-terminal kinase (JNK) signaling pathway as a genetic determinant of aging in Drosophila melanogaster. Based on expression profiling experiments, we demonstrate that JNK functions at the center of a signal transduction network that coordinates the induction of protective genes in response to oxidative challenge. JNK signaling activity thus alleviates the toxic effects of reactive oxygen species (ROS). In addition, we show that flies with mutations that augment JNK signaling accumulate less oxidative damage and live dramatically longer than wild-type flies. Our work thus identifies the evolutionarily conserved JNK signaling pathway as a major genetic factor in the control of longevity.