Molecular signatures of longevity: Insights from cross-species comparative studies

Abstract

Much of the current research on longevity focuses on the aging process within a single species. Several molecular players (e.g. IGF1 and MTOR), pharmacological compounds (e.g. rapamycin and metformin), and dietary approaches (e.g. calorie restriction and methionine restriction) have been shown to be important in regulating and modestly extending lifespan in model organisms. On the other hand, natural lifespan varies much more significantly across species. Within mammals alone, maximum lifespan differs more than 100 fold, but the underlying regulatory mechanisms remain poorly understood. Recent comparative studies are beginning to shed light on the molecular signatures associated with exceptional longevity. These include genome sequencing of microbats, naked mole rat, blind mole rat, bowhead whale and African turquoise killifish, and comparative analyses of gene expression, metabolites, lipids and ions across multiple mammalian species. Together, they point towards several putative strategies for lifespan regulation and cancer resistance, as well as the pathways and metabolites associated with longevity variation. In particular, longevity may be achieved by both lineage-specific adaptations and common mechanisms that apply across the species. Comparing the resulting cross-species molecular signatures with the within-species lifespan extension strategies will improve our understanding of mechanisms of longevity control and provide a starting point for novel and effective interventions.

Figure 1. Aging process within a single species

(A) Hallmarks of aging. The hallmarks are as in (Lopez-Otin et al., 2013). (B) A typical survival curve. A successful lifespan extension strategy shifts or scales the black curve to the red. (C) Major pathways implicated in lifespan extension. Only selected components of the pathways are shown. Cross-talks among the pathways are omitted. Caloric restriction is used as an example for illustrative purposes.

Figure 2. Lifespan variation across different species

(A) Maximum lifespan correlates positively with adult weight. Individual points correspond to individual species and are colored by taxonomic orders. Selected species were labeled. Adult body mass and maximum lifespan records of 995 mammalian species used to make the figure are from AnAge Database (Tacutu et al., 2013). (B) Some recently sequenced species with remarkable longevity. Animal sketches are not drawn to scale. (C) Comparative omics studies across mammalian species. Animal sketches are not drawn to scale.