Figure 1. Metabolic resilience — survivability under a variety of extreme conditions.

Certain populations of cavefish have adaptations that cause increased appetite (Aspiras et al., 2015) and increased fat accumulation (Xiong et al., 2018) (in cases where nutrients are plentiful, such as in lab-raised populations). These same populations also exhibit robust health and longevity (Riddle et al., 2018; Xiong et al., 2018) and do not suffer ill-effects due to high levels of visceral fat and hyperglycemia, 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 (Krishnan et al., 2020). 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.