Is there a role for new invertebrate models for aging research?

OUR current major invertebrate models for research on the biology of aging, the worm, Caenorhabditis elegans, and the fruit fly, Drosophila melanogaster, have been, and will continue to be, major sources of insight for the field. However, these models have certain shortcomings that make the development of additional invertebrate models worthwhile. Foremost among these shortcomings is that worms and flies belong to the same superphylum, the Ecdysozoa, and both species have undergone extensive gene loss since their divergence from their common ancestor with humans (Figure 1). This is clearly shown by the discovery that more than 10% of the genes identified in a more distantly related phylum, the Cnidaria, have clear human homologs, which are not found in worm or fly genomes (1). Thus, there remains a substantial genomic universe of potential relevance to humans that has not yet been screened for longevity genes. Both the Cnidaria and the Lophotrochozoa, which also share unique genetic orthologues with humans, offer potentially rewarding model species. Second, worms and flies both have limited (or no) somatic cell division in adulthood and have virtually no regenerative potential. Third, both worms and flies use special nonaging life history stages in times of environmental stress (dauer in worms, reproductive diapause in flies), which may be partially induced by genetic or environmental manipulations that extend life (2,3). Humans have no apparent equivalent of these stages, and it would be unfortunate if successes in extending life in these model species were due to a phenomenon not reproducible in humans. Additional invertebrate models with proliferating cells in the adult as well as extensive regenerative potential might be informative for learning how to manage the perils of lifelong cell division, coupled with the potential for tissue regeneration. Figure 1. The major groups of multicellular animals (yeast and protozoa as out-group). Note that genetic screening for longevity mutants has not yet been performed for any Cnidarian or Lophotrochozoan species, although they share with humans orthologous genes that . To be most useful in screening for new genes, prospective new invertebrate models would ideally possess three features: (i) the ability to be mass cultured in the laboratory, (ii) reasonably short life span, and (iii) tractable genetics. It is important that large numbers of healthy individuals can be produced and maintained, so that life span studies of a large number of mutants is possible. Other things being equal, the shorter the life span, the better, although as with any aging study, it is important that the animals in the study be healthy, that is, not short lived because their laboratory husbandry is so poor that they are unhealthy throughout their short lives. Finally, tractable genetics makes mutant screening possible and implies that manipulation of gene expression will be reasonably straightforward. Clearly, species that combine all these features at present would likely already be used extensively in aging research, so we focused our attention on species that appear to possess two of the three (mass culturing, short life span), with indications that tractable genetics might be fairly easily developed. Given this background, we believe that the following animals bear consideration for development as new invertebrate models for aging research.