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

Abstract

The Mexican tetra, Astyanax mexicanus, has undergone remarkable physiological and behavioral changes in order to colonize a number of subterranean caves in the Sierra de El Abra region of Mexico. A hallmark of cave-adapted populations is enhanced survival under low-nutrient conditions coupled with hyperglycemia, increased body fat, and insulin resistance, but cavefish appear to avoid the progression of the respective pathologies associated with these conditions and do not exhibit reduced longevity. The metabolic strategies underlying these adaptations are not fully 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 cholesterol esters, urate, intermediates of protein glycation, metabolites associated with hypoxia and longevity, and unexpectedly elevated levels of ascorbate (vitamin C). This work highlights the fact that certain metabolic features associated with human pathologies are not intrinsically harmful in all organisms, and suggests promising avenues for future investigation into the role of certain metabolites 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.

Liver-derived cell lines from cavefish Astyanax mexicanus as an in vitro model for studying metabolic adaptation

“…For instance, genes under the 'lipid catabolic process' such as lipase eb (lipeb), carnitine palmitoyltransferase 1a (cpt1aa), phospholipase D1 (pld1b) are all upregulated in SFL as compared to CFL. These results reflect the biology of these fishes in vivo, as it has been shown that surface fish undergo higher lipid breakdown while cavefish synthesize more lipid and surface fish have an increased innate immune response compared to cavefish (5,7,14).…”

Enhanced lipogenesis through Pparγ helps cavefish adapt to food scarcity

“…In addition to Pparγ, we investigated whether its activators (ligands) are also more abundant in the liver of Pachón cavefish compared to surface fish. Using published lipidomic profiling data (Medley et al, 2020), we found three natural activators (linolenic (C18:3), linoleic (C18:2), and arachidonic acids (C20:4)), to be more abundant in the livers of Pachón cavefish compared to surface fish livers (Fig. 4A).…”

“…2E). Using available lipidomics data (Medley et al, 2020), we compared the abundance of MUFAs in cavefish. We found that both oleic acid and palmitoleic acid were present in higher levels in refed Pachón cavefish livers compared to surface fish samples and cavefish samples starved for 30 days (Fig.…”

“…E) Expression of scd in livers of fasted and refed surface fish and Pachón cavefish (n=3) TPM: transcript per million. F) Fatty acid profiles of two monounsaturated fatty acids (n=6 wilcox test) data from (Medley et al, 2020). G) Refed Pachón cavefish livers have a higher desaturation index (C16:1n7/C16, and C18:1n9/C18) than surface fish (n=6 , wilcox test) data from (Medley et al, 2020) *p<0.05; **p<0.01; ***p<0.001.…”

“…The fatty acid profiling data were extracted from (Medley et al, 2020). In brief: A group of 6 surface and 6 Pachón were starved for 30 days before dissected for liver collection (30d_fasted).…”