Resilience in a Natural Model of Metabolic Dysfunction Through Changes in Longevity and Ageing-Related Metabolites

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. Cave-dwelling populations of Mexican 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 cavefish 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.