A fascinating case is flatworms, in which reversal of ageing by regeneration is proposed, yet conclusive evidence for this rejuvenation-by-regeneration hypothesis is lacking. We tested this hypothesis by inducing regeneration in the sexual free-living flatworm Macrostomum lignano. We studied survival, fertility, morphology, and gene expression as a function of age. Here, we report that after regeneration, genes expressed in the germline are upregulated at all ages, but no signs of rejuvenation are observed. Instead, the animal appears to be substantially longer lived than previously appreciated, and genes expressed in stem cells are upregulated with age, while germline genes are downregulated. Remarkably, several genes with known beneficial effects on lifespan when overexpressed in mice and C. elegans are naturally upregulated with age in M. lignano, suggesting that molecular mechanism for offsetting negative consequences of ageing has evolved in this animal. We therefore propose that M. lignano represents a novel powerful model for molecular studies of ageing attenuation, and the identified ageing gene expression patterns provide a valuable resource for further exploration of anti-aging strategies.
We showed that the flatworm rejuvenation theory is not valid in the sexual species M. lignano. However, all data taken together reveal that the regulation of fundamentally conserved mechanisms of cellular and organismal health maintenance evolved in M. lignano to efficiently offset negative consequences of ageing. Therefore, we advocate that M. lignano is a novel powerful model toward studies of ageing-related genetic pathways, and we provide temporal gene expression patterns of ageing in M. lignano as a resource to tap the power of this model.
