Untargeted Metabolomics of the Cavefish Astyanax mexicanus Reveals the Basis of Metabolic Strategies in Adaptation to Extreme Conditions
Insights from extreme-adapted organisms, which have evolved natural strategies for promoting survivability under severe environmental pressures, may help guide future research into novel approaches for enhancing human longevity. The cave-adapted Mexican tetra,Astyanax mexicanus, has attracted interest as a model system for metabolic resilience, a term we use to denote the property of maintaining robust health and longevity under conditions that would have highly deleterious effects in other organisms (Fig 1). Cave-dwelling populations of Mexi-can tetra exhibit elevated blood glucose and possess a mutation in the insulin receptor that in humans has been linked to Rabson-Mendenhall syndrome, a condition characterized by severe insulin resistance that causes numerous developmental abnormalities, is highly associated with debilitating progression, and drastically reduces lifespan. In addition, cavefish develop large numbers of hypertrophic visceral adipocytes and possess vastly enriched stores of body fat compared to surface-dwelling counterparts. However, cavefish appear to avoid the progression of the respective pathologies typically associated with these conditions, such as accumulation of advanced glycation end products (AGEs), chronic tissue inflammation, impaired growth due to insulin dysregulation, and low survivability due to arterial disease. The metabolic strategies underlying the resilience properties of A. mexicanus cavefish, and how they relate to environmental challenges of the cave environment, are poorly understood. Here, we provide an untargeted metabolomics study of long- and short-term fasting in two A. mexicanus cave populations and one surface population. We find that, although cave-fish share many similarities with metabolic syndrome normally associated with the human state of obesity, important differences emerge, including a reduction in cholesteryl esters and intermediates of protein glycation, and an increase in antioxidants and metabolites associated with hypoxia and longevity. We find important overlaps between metabolic alterations in cave-dwelling Mexican tetra and other models of resilience and extreme longevity, such as naked mole-rats, including enhanced reliance on sugars as an energy source and a trend toward more potent antioxidant activity. This work suggests that certain metabolic features associated with human pathologies are not intrinsically harmful, but are rather consequences of suboptimal adaptation of humans to survival under adverse metabolic conditions, and suggests promising avenues for future investigation into the role of metabolic strategies in evolutionary adaptation and health. We provide a transparent pipeline for reproducing our analysis and a Shiny app for other researchers to explore and visualize our dataset. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/358077v3_fig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@bcaff5org.highwire.dtl.DTLVardef@1c40b89org.highwire.dtl.DTLVardef@1d17d69org.highwire.dtl.DTLVardef@80a483_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFig. 1.C_FLOATNO Metabolic resilience survivability under a variety of extreme conditions. Certain populations of cavefish have adaptations that cause increased appetite (1) and increased fat accumulation (2) (in cases where nutrients are plentiful, such as in lab-raised populations). These same populations also exhibit robust health and longevity (2, 3) and do not suffer ill-effects due to high levels of visceral fat and hyper-glycemia, both of which are features of most cave populations. However, visceral fat accumulation in cave populations is highly dependent on nutrient availability and is not displayed in wild-caught specimens (4). Thus, cavefish paradoxically appear to tolerate both extremely low and extremely high levels of triglycerides, glucose, and other energy storage metabolites. We argue that these differences can be reconciled under a hypothesis whereby the cave environment selects not for resistance to nutrient deprivation per se, but rather resilience to a variety of nutrient availability states (such as seasonal floods). Survival under such challenging conditions ostensibly favors the ability to tolerate extreme metabolic states, including not only starvation but also high levels of potentially deleterious metabolites such as triglycerides and reactive oxygen species (ROS). We find evidence for elevated antioxidant levels and altered cholesterol / cholesteryl ester homeostasis in cavefish, suggesting that cavefish may use these mechanisms to offset potentially harmful metabolites and tolerate a broad range of metabolic conditions. C_FIG