A Platform for Rapid Exploration of Aging and Diseases in a Naturally Short-Lived Vertebrate

作者：Harel Itamar; Benayoun Berenice A; Machado Ben; Singh Param Priya; Hu Chi Kuo; Pech Matthew F; Valenzano Dario Riccardo; Zhang Elisa; Sharp Sabrina C; Artandi Steven E; Brunet Anne^*

来源：Cell, 2015, 160(5): 1013-1026.

DOI：10.1016/j.cell.2015.01.038

Aging is a complex process that affects multiple organs. Modeling aging and age-related diseases in the lab is challenging because classical vertebrate models have relatively long lifespans. Here, we develop the first platform for rapid exploration of age-dependent traits and diseases in vertebrates, using the naturally short-lived African turquoise killifish. We provide an integrative genomic and genome-editing toolkit in this organism using our de-novo-assembled genome and the CRISPR/Cas9 technology. We mutate many genes encompassing the hallmarks of aging, and for a subset, we produce stable lines within 2-3 months. As a proof of principle, we show that fish deficient for the protein subunit of telomerase exhibit the fastest onset of telomere-related pathologies among vertebrates. We further demonstrate the feasibility of creating specific genetic variants. This genome-to-phenotype platform represents a unique resource for studying vertebrate aging and disease in a high-throughput manner and for investigating candidates arising from human genome-wide studies.