Proposal to Sequence Genomes of Unique Interest for Research on Aging: Heterocephalus glaber, Cebus capucinus, and Balaena mysticetus

Aging is not only a major puzzle of biology but it has a profound impact on medicine with age-related diseases like heart diseases, type II diabetes, cancer, and neurodegenerative diseases among the leading causes of death in modern societies. Recent research has revealed several gene systems that can regulate longevity in model organisms and appear evolutionary conserved. Nonetheless, the longevity effects of these genes are modest when compared to the lengthening of lifespans during evolution. Among mammals there is at least a 40fold variation in maximum longevity. We still do not know why different species of similar body plan, biochemistry, and physiology can age at such different rates, but these differences must be seated in the genome. In this white paper, we champion the idea that longevity should also be taken into consideration when choosing target organisms for sequencing, and we propose the sequencing of three organisms (in order of priority): the naked mole-rat (Heterocephalus glaber) whose record longevity of 28.3 years makes it the longestlived rodent, the white-faced capuchin monkey (Cebus capucinus) which can live over 50 years, and the bowhead whale (Balaena mysticetus), possibly the longest-lived mammal with an estimated longevity of over 200 years. In particular Heterocephalus and Cebus have a much longer lifespan than expected for their body size. Model organisms have been typically chosen based on their ability to replicate human disease. Heterocephalus is extraordinary because when compared to similar-sized species, such as mice and rats that live up to 4-5 years, it can live >28 years. Therefore, sequencing its genome will provide the molecular biology tools necessary for Heterocephalus to be used not only as another model of human disease but primarily as the first model of resistance to chronic diseases of aging. Interestingly, Heterocephalus is extremely resistant to neoplasia. Cebus is, after humans and apes, the best example of a long-lived primate lineage. The convergence of Cebus and humans in extreme longevity, as well as in other traits such as a large brain, makes Cebus an ideal organism to identify mechanisms and genes that contributed to these convergent traits. Finding clues regarding which genes and mechanisms contributed to the evolution of longevity in primates will increase our knowledge of the biology and genetics of human aging and age-related diseases. Balaena is the only mammal reported to outlive human beings. Due to our inability to conduct in vivo studies in Balaena, obtaining its genome sequence is a first step in uncovering clues about the genetic and molecular mechanisms that allow some organisms to live longer than humans. Overall, these resources will help establish Heterocephalus as the first long-lived model for biomedical research. Because these organisms were chosen to dovetail with existing mammalian sequencing projects, sequencing their genome will also provide researchers with pairs of closely-related species with divergent lifespans that will be powerful tools for studying the evolution of longevity and consequently help guide experiments in more traditional models. If we could understand the genetic basis of differences in longevity between humans and closely-related species, it would open a whole new paradigm for biomedical research on aging and age-related diseases with countless potential applications for improving human health.