FMO rewires metabolism to promote longevity through tryptophan and one carbon metabolism in C. elegans.

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.

Serotonin and dopamine modulate aging in response to food odor and availability.

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.

An alternative food source for metabolism and longevity studies in Caenorhabditis elegans.

Caenorhabditis elegans is an instrumental research model used to advance our knowledge in areas including development, metabolism, and aging. However, research on metabolism and/or other measures of health/aging are confounded by the nematode's food source in the lab, live E. coli bacteria. Commonly used treatments, including ultraviolet irradiation and antibiotics, are successful in preventing bacterial replication, but the bacteria can remain metabolically active. The purpose of this study is to develop a metabolically inactive food source for the worms that will allow us to minimize the confounding effects of bacterial metabolism on worm metabolism and aging. Our strategy is to use a paraformaldehyde (PFA) treated E. coli food source and to determine its effects on worm health, metabolism and longevity. We initially determine the lowest possible concentrations of PFA necessary to rapidly and reproducibly kill bacteria. We then measure various aspects of worm behavior, healthspan and longevity, including growth rate, food attraction, brood size, lifespan and metabolic assessments, such as oxygen consumption and metabolomics. Our resulting data show that worms eat and grow well on these bacteria and support the use of 0.5% PFA-killed bacteria as a nematode food source for metabolic, drug, and longevity experiments.

Cell non-autonomous regulation of health and longevity.

As the demographics of the modern world skew older, understanding and mitigating the effects of aging is increasingly important within biomedical research. Recent studies in model organisms demonstrate that the aging process is frequently modified by an organism's ability to perceive and respond to changes in its environment. Many well-studied pathways that influence aging involve sensory cells, frequently neurons, that signal to peripheral tissues and promote survival during the presence of stress. Importantly, this activation of stress response pathways is often sufficient to improve health and longevity even in the absence of stress. Here, we review the current landscape of research highlighting the importance of cell non-autonomous signaling in modulating aging from C. elegans to mammals. We also discuss emerging concepts including retrograde signaling, approaches to mapping these networks, and development of potential therapeutics.

Hypoxic response regulators RHY-1 and EGL-9/PHD promote longevity through a VHL-1-independent transcriptional response.

HIF-1-mediated adaptation to changes in oxygen availability is a critical aspect of healthy physiology. HIF is regulated by a conserved mechanism whereby EGLN/PHD family members hydroxylate HIF in an oxygen-dependent manner, targeting it for ubiquitination by Von-Hippel-Lindau (VHL) family members, leading to its proteasomal degradation. The activity of the only C. elegans PHD family member, EGL-9, is also regulated by a hydrogen sulfide sensing cysteine-synthetase-like protein, CYSL-1, which is, in turn, regulated by RHY-1/acyltransferase. Over the last decade, multiple seminal studies have established a role for the hypoxic response in regulating longevity, with mutations in vhl-1 substantially extending C. elegans lifespan through a HIF-1-dependent mechanism. However, studies on other components of the hypoxic signaling pathway that similarly stabilize HIF-1 have shown more mixed results, suggesting that mutations in egl-9 and rhy-1 frequently fail to extend lifespan. Here, we show that egl-9 and rhy-1 mutants suppress the long-lived phenotype of vhl-1 mutants. We also show that RNAi of rhy-1 extends lifespan of wild-type worms while decreasing lifespan of vhl-1 mutant worms. We further identify VHL-1-independent gene expression changes mediated by EGL-9 and RHY-1 and find that a subset of these genes contributes to longevity regulation. The resulting data suggest that changes in HIF-1 activity derived by interactions with EGL-9 likely contribute greatly to its role in regulation of longevity.

A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging.

Many genes that affect replicative lifespan (RLS) in the budding yeast Saccharomyces cerevisiae also affect aging in other organisms such as C. elegans and M. musculus. We performed a systematic analysis of yeast RLS in a set of 4,698 viable single-gene deletion strains. Multiple functional gene clusters were identified, and full genome-to-genome comparison demonstrated a significant conservation in longevity pathways between yeast and C. elegans. Among the mechanisms of aging identified, deletion of tRNA exporter LOS1 robustly extended lifespan. Dietary restriction (DR) and inhibition of mechanistic Target of Rapamycin (mTOR) exclude Los1 from the nucleus in a Rad53-dependent manner. Moreover, lifespan extension from deletion of LOS1 is nonadditive with DR or mTOR inhibition, and results in Gcn4 transcription factor activation. Thus, the DNA damage response and mTOR converge on Los1-mediated nuclear tRNA export to regulate Gcn4 activity and aging.