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An organism’s ability to perceive and respond to changes in its environment is crucial for its health and survival. Here we reveal how the most well-studied longevity intervention, dietary restriction, acts in-part through a cell non-autonomous signaling pathway that is inhibited by the presence of attractive smells. Using an intestinal reporter for a key gene induced by dietary restriction but suppressed by attractive smells, we identify three compounds that block food odor effects in C. elegans , thereby increasing longevity as dietary restriction mimetics. These compounds clearly implicate serotonin and dopamine in limiting lifespan in response to food odor. We further identify a chemosensory neuron that likely perceives food odor, an enteric neuron that signals through the serotonin receptor 5-HT1A/SER-4, and a dopaminergic neuron that signals through the dopamine receptor DRD2/DOP-3. Aspects of this pathway are conserved in D. melanogaster . Thus, blocking food odor signaling through antagonism of serotonin or dopamine receptors is a plausible approach to mimic the benefits of dietary restriction. This report finds that dietary restriction, the most extensively studied anti-aging intervention, can be mimicked by blocking food odour signaling and identifies a neural network of food perception that functions through serotonin and dopamine.

Flavin containing monooxygenases (FMOs) are promiscuous enzymes known for metabolizing a wide range of exogenous compounds. In C. elegans , fmo-2 expression increases lifespan and healthspan downstream of multiple longevity-promoting pathways through an unknown mechanism. Here, we report that, beyond its classification as a xenobiotic enzyme, fmo-2 expression leads to rewiring of endogenous metabolism principally through changes in one carbon metabolism (OCM). These changes are likely relevant, as we find that genetically modifying OCM enzyme expression leads to alterations in longevity that interact with fmo-2 expression. Using computer modeling, we identify decreased methylation as the major OCM flux modified by FMO-2 that is sufficient to recapitulate its longevity benefits. We further find that tryptophan is decreased in multiple mammalian FMO overexpression models and is a validated substrate for FMO-2. Our resulting model connects a single enzyme to two previously unconnected key metabolic pathways and provides a framework for the metabolic interconnectivity of longevity-promoting pathways such as dietary restriction. FMOs are well-conserved enzymes that are also induced by lifespan-extending interventions in mice, supporting a conserved and important role in promoting health and longevity through metabolic remodeling. Flavin containing monooxygenase 2 (FMO-2) is known to increase lifespan under dietary restriction through incompletely understood mechanisms. Here the authors report that FMO-2 modifies tryptophan and methionine metabolic pathways to enhance stress resistance and slow aging in C. elegans .

Flavin-containing monooxygenases (FMOs) are a conserved family of xenobiotic enzymes upregulated in multiple longevity interventions, including nematode and mouse models. Previous work supports that promotes longevity, stress resistance, and healthspan by rewiring endogenous metabolism. However, there are five FMOs and five mammalian FMOs, and it is not known whether promoting longevity and health benefits is a conserved role of this gene family. Here, we report that expression of promotes lifespan extension and paraquat stress resistance downstream of both dietary restriction and inhibition of mTOR. We find that overexpression of in just the hypodermis is sufficient for these benefits, and that this expression significantly modifies the transcriptome. By analyzing changes in gene expression, we find that genes related to calcium signaling are significantly altered downstream of expression. Highlighting the importance of calcium homeostasis in this pathway, overexpressing animals are sensitive to thapsigargin, an ER stressor that inhibits calcium flux from the cytosol to the ER lumen. This calcium/ interaction is solidified by data showing that modulating intracellular calcium with either small molecules or genetics can change expression of and/or interact with to affect lifespan and stress resistance. Further analysis supports a pathway where modulates calcium homeostasis downstream of activating transcription factor-6 ( ), whose knockdown induces and requires expression. Together, our data identify as a longevity-promoting gene whose actions interact with known longevity pathways and calcium homeostasis.

Aging is the leading risk factor for chronic diseases, with nearly 95% of adults over the age of 60 affected with at least one chronic condition. As the global population trends older, understanding the mechanisms underlying age-related decline has become increasingly important for public health. Chronic conditions such as heart disease, cancer, and diabetes not only impact individual quality of life, but also place a significant burden on healthcare resources. Therefore, elucidating the biological processes that drive aging is crucial for developing interventions that promote healthier aging and reduce the prevalence of age-related diseases.Because of its fundamental role in cellular function and energy production, metabolism has emerged as a major area of interest in aging research. Broadly, my work centers on understanding how metabolic pathways influence aging, with the ultimate goal of uncovering potential treatments to extend lifespan and enhance healthspan. This dual approach contributes significantly both to our fundamental understanding of the mechanisms of aging and to the development of practical therapeutic interventions.Specifically, my research investigates the role of fmo-4, a gene that promotes longevity, healthspan, and stress resistance in Caenorhabditis elegans. I discovered that fmo-4 functions downstream of multiple nutrient-sensing longevity pathways, including dietary restriction and the inhibition of mTOR signaling, implicating fmo-4 as a major regulator of aging. I also found that fmo-4 is sufficient to extend lifespan when overexpressed either ubiquitously or specifically in the hypodermis. Upon investigation of downstream mechanisms, I established that fmo-4 extends lifespan and promotes resistance to paraquat stress, which increases the formation of free radicals, by interacting with key genes in the endoplasmic reticulum and the mitochondria that regulate calcium signaling between these organelles. These findings highlight the importance of intracellular calcium homeostasis in the aging process as well as the importance of fmo-4 in calcium metabolism.Building on this foundational work, I next explored how fmo-4 influences mitochondrial physiology. Given that fmo-4 plays a critical role in regulating calcium signaling between the endoplasmic reticulum and mitochondria – a process essential for maintaining mitochondrial health – I hypothesized that fmo-4 expression would significantly affect key aspects of mitochondria metabolism. My findings indicate that fmo-4 modulates mitochondrial metabolism to promote longevity and stress resistance by influencing the tricarboxylic acid (TCA) cycle and its metabolites, including malate and fumarate, as well as regulating mitochondrial dynamics, such as fission and fusion. These results reveal an intricate relationship between cellular organelles and metabolic pathways in lifespan extension.In addition to studying fmo-4’s impact on metabolism and longevity, my work also explores its translational potential for human health. I found that fmo-4 expression in C. elegans can serve as a valuable readout for identifying pro-longevity compounds, such as deguelin. Importantly, I confirmed that deguelin requires fmo-4 for its longevity- and healthspan-promoting effects. These data demonstrate the potential for using FMOs as biomarkers to screen for therapeutics that can promote longevity and healthspan in humans. By bridging the gap between basic research and applied science, my research aims to accelerate the development of interventions that mitigate age-related decline and improve quality of life for aging populations.Together, the findings presented in this thesis enhance our understanding of the metabolic mechanisms that regulate aging while supporting the long-term goal of developing therapeutics that promote human health and longevity.

Flavin containing monooxygenases (FMOs) are promiscuous enzymes known for metabolizing a wide range of exogenous compounds. In C. elegans, fmo-2 expression increases lifespan and healthspan downstream of multiple longevity-promoting pathways through an unknown mechanism. Here, we report that, contrary to its classification as a xenobiotic enzyme, fmo-2 expression leads to rewiring of endogenous metabolism principally through changes in one carbon metabolism (OCM). Using computer modeling, we identify decreased methylation as the major OCM flux modified by FMO-2 that is sufficient to recapitulate its longevity benefits. We further find that tryptophan is decreased in multiple mammalian FMO overexpression models and is a validated substrate for FMO enzymes. Our resulting model connects a single enzyme to two previously unconnected key metabolic pathways and provides a framework for the metabolic interconnectivity of longevity-promoting pathways such as dietary restriction. FMOs are well-conserved enzymes that are also induced by lifespan-extending interventions in mice, supporting a conserved and critical role in promoting health and longevity through metabolic remodeling. Competing Interest Statement The authors have declared no competing interest.

Abstract An organism’s ability to perceive and respond to changes in its environment is crucial for its health and survival. Here we reveal how the most well-studied longevity intervention, dietary restriction (DR), acts in-part through a cell non-autonomous signaling pathway that is inhibited by the perception of attractive smells. Using an intestinal reporter for a key gene induced by DR but suppressed by attractive smells, we identify three compounds that block food perception in C. elegans, thereby increasing longevity as DR mimetics. These compounds clearly implicate serotonin and dopamine in limiting lifespan in response to food perception. We further identify an enteric neuron in this pathway that signals through the serotonin receptor 5-HT1A/ser-4 and dopamine receptor DRD2/dop-3. Aspects of this pathway are conserved in D. melanogaster and mammalian cells. Thus, blocking food perception through antagonism of serotonin or dopamine receptors is a plausible approach to mimic the benefits of dietary restriction. Competing Interest Statement The authors have declared no competing interest.

Flavin-containing monooxygenases (FMOs) are a conserved family of xenobiotic enzymes upregulated in multiple longevity interventions, including nematode and mouse models. Previous work supports that C. elegans fmo-2 promotes longevity, stress resistance, and healthspan by rewiring endogenous metabolism. However, there are five C. elegans FMOs and five mammalian FMOs, and it is not known whether promoting longevity and health benefits is a conserved role of this gene family. Here, we report that expression of C. elegans fmo-4 promotes lifespan extension and paraquat stress resistance downstream of both dietary restriction and inhibition of mTOR. We find that overexpression of fmo-4 in just the hypodermis is sufficient for these benefits, and that this expression significantly modifies the transcriptome. By analyzing changes in gene expression, we find that genes related to calcium signaling are significantly altered downstream of fmo-4 expression. Highlighting the importance of calcium homeostasis in this pathway, fmo-4 overexpressing animals are sensitive to thapsigargin, an ER stressor that inhibits calcium flux from the cytosol to the ER lumen. This calcium/fmo-4 interaction is solidified by data showing that modulating intracellular calcium with either small molecules or genetics can change expression of fmo-4 and/or interact with fmo-4 to affect lifespan and stress resistance. Further analysis supports a pathway where fmo-4 modulates calcium homeostasis downstream of activating transcription factor-6 (atf-6), whose knockdown induces and requires fmo-4 expression. Together, our data identify fmo-4 as a longevity-promoting gene whose actions interact with known longevity pathways and calcium homeostasis.

Dietary restriction (DR) and hypoxia (low oxygen) extend lifespan in Caenorhabditis elegans through the induction of a convergent downstream longevity gene, fmo-2 . Flavin-containing monooxygenases (FMOs) are highly conserved xenobiotic-metabolizing enzymes with a clear role in promoting longevity in nematodes and a plausible similar role in mammals. This makes them an attractive potential target of small molecule drugs to stimulate the health-promoting effects of longevity pathways. Here, we utilize an fmo-2 fluorescent transcriptional reporter in C. elegans to screen a set of 80 compounds previously shown to improve stress resistance in mouse fibroblasts. Our data show that 19 compounds significantly induce fmo-2 , and 10 of the compounds induce fmo-2 more than twofold. Interestingly, 9 of the 10 high fmo-2 inducers also extend lifespan in C. elegans . Two of these drugs, mitochondrial respiration chain complex inhibitors, interact with the hypoxia pathway to induce fmo-2 , whereas two dopamine receptor type 2 (DRD2) antagonists interact with the DR pathway to induce fmo-2 , indicating that dopamine signaling is involved in DR-mediated fmo-2 induction. Together, our data identify nine drugs that each (1) increase stress resistance in mouse fibroblasts, (2) induce fmo-2 in C. elegans , and (3) extend nematode lifespan, some through known longevity pathways. These results define fmo-2 induction as a viable approach to identifying and understanding mechanisms of putative longevity compounds.