The African killifish: A short‐lived vertebrate model to study the biology of sarcopenia and longevity

Abstract Sarcopenia, the age‐related decline in muscle function, places a considerable burden on health‐care systems. While the stereotypic hallmarks of sarcopenia are well characterized, their contribution to muscle wasting remains elusive, which is partly due to the limited availability of animal models. Here, we have performed cellular and molecular characterization of skeletal muscle from the African killifish—an extremely short‐lived vertebrate—revealing that while many characteristics deteriorate with increasing age, supporting the use of killifish as a model for sarcopenia research, some features surprisingly reverse to an “early‐life” state in the extremely old stages. This suggests that in extremely old animals, there may be mechanisms that prevent further deterioration of skeletal muscle, contributing to an extension of life span. In line with this, we report a reduction in mortality rates in extremely old killifish. To identify mechanisms for this phenomenon, we used a systems metabolomics approach, which revealed that during aging there is a striking depletion of triglycerides, mimicking a state of calorie restriction. This results in the activation of mitohormesis, increasing Sirt1 levels, which improves lipid metabolism and maintains nutrient homeostasis in extremely old animals. Pharmacological induction of Sirt1 in aged animals was sufficient to induce a late life‐like metabolic profile, supporting its role in life span extension in vertebrate populations that are naturally long‐lived. Collectively, our results demonstrate that killifish are not only a novel model to study the biological processes that govern sarcopenia, but they also provide a unique vertebrate system to dissect the regulation of longevity.

Extended Data Fig. 2: Schematic of trends presented by metabolites.Metabolites statistically fall in one of five broad groups covering 17 possible trend types.Trend type 1 covers metabolites that are unaltered with age; metabolites in group two are upregulated with age and within this group they follow one of four patterns (trend 2-5).Similarly, metabolites in group three are downregulated with age covering trends 6-9.The fourth group of metabolites, consisting of trends 10-13, show a bell-shaped inversion where by the abundance of the metabolite at 37-week is higher than 22-week-week and 52-week.The final set of metabolites display a U-shaped inversion in that the abundance of the metabolite at 37-week is lower than 22-week-week and 52-week, covering trends 14-17.22-week-week samples displayed in blue, 37-week cohort in red, and 52-week fish shown in green.Dashed lines represent non-significant changes with p>0.05, and solid lines reflect significant alterations with p<0.05.

Extended Data Table 1 :
List of the top 15 most influential putative metabolites determined using our "Integrated Value of Significance" (IVI) algorithm.The IVI score reflects the authoritative position the metabolite holds within the network, with larger scores reflecting a more influential position.The trend column is based on the ANOVA analyses and highlights how the metabolite is altered with across the lifespan of the fish.

Glycolysis Pathway Metabolotie Fructose and Mannose metabolism Pentose Phosphate pathway Tricarboxylic acid cycle Trend 22 week 37 week 52 week Extended DataTable 3 :
Sequences of all primers used in the study

Table 4 :
Number of samples examined for each experiment

Table 7 :
Statistical tests for experiments in presented Fig.5

Table 9 :
Statistical tests for experiments in presented Fig.7

Table 10 :
Statistical tests for experiments in presented Extended Data Figures