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COMMENTARY |
Department of Biological Sciences, University of Idaho, Moscow.
WHY would we possibly need a new vertebrate model for probing genetic mechanisms of aging? After all, we already have two superb invertebrate models (Caenorhabditis elegans, Drosophila melanogaster) that serve that investigative purpose well, plus the mammalian model most useful for genetic studies (laboratory mouse) is exquisitely defined already, genetically tractable, and has proven to be a closer relative to humans than practically anyone suspected (1). So what's the point?
The point is that our current models, for all their usefulness, have certain limitations and leave certain gaps in our scientific tool kit that another, judiciously chosen, vertebrate model might fill nicely. And because there are more species of fishes than all other vertebrate species combined, it would make sense that we might expect to find a particularly useful model among the fishes. In the following article (2), Michael Herrera and Pudur Jagadeeswaran make the case for developing Nothobranchius rachovii (Bluefin Notho), a so-called "annual" killifish of southern African origin, as an additional vertebrate model of aging, and I think their case bears serious consideration.
So what are some limitations of our existing invertebrate models that a fish model might address? First, the invertebrate models have few or no replicative somatic cells in adulthood, and so have little use in investigating the age-related loss of proliferative homeostasis to which all vertebrates are subject. Second, their small size makes establishing normal pathophysiology difficult. In addition, molecular studies have shown them both to be part of the Ecdysozoa superphylum (3), hence evolutionarily related in a way that does not justify assuming that pathways of aging retardation found in both species can be generalized to species such as humans that lie outside that superphylum. Finally, their body organization is vastly different from ours, for instance, lacking bones, capillaries, and immunoglobulins.
Fish, of course, have a body plan reasonably similar to humans especially by invertebrate standards. In addition, given the small size and high fecundity of many fish species, they may be reared and maintained inexpensively in huge numbers compared to mice. A standard mouse room is easily capable of housing more than 100,000 zebrafish, for instance, at a fraction of the mouse cost. The primary disadvantage of developing a fish model for aging studies has always been their longevity. Zebrafish, for instance, live as long, or even longer, than mice!
Here is where the killifish model may solve a key problem. They are very short-lived for a vertebrate. At 4–5 cm in length (i.e., slightly larger than a zebrafish), N. rachovii is here reported to exhibit a mean longevity of 5–6 months with a maximum of just over 9 months. Given that this species reaches reproductive maturity at approximately 1 month and can produce clutches of 20–30 eggs almost daily thereafter, study population sizes in the thousands or tens of thousands are feasible. Thus, in addition to any other advantages, a fish model of this sort would allow the sort of fine-grained demographic analysis of experimental populations that has not previously been possible with vertebrates.
However, some issues of experimental utility remain unresolved with the killifish. First, it needs to be established that the longevities seen under the husbandry conditions described here really represent normal aging and not some sort of unique pathology, associated with those particular husbandry conditions. The survival curve presented lacks a "shoulder" that usually defines healthy, aging populations. On the other hand, some mouse strains, notably DBA/2, also exhibit such linear curves even when maintained in specific pathogen-free conditions (4). Second, although the authors demonstrate that existing genetic reagents from zebrafish and Fugu (pufferfish) can be used to help identify and map some (
40%) genes homologous among the fishes, the ease with which genetic manipulations, such as the production of knock-down, knock-out, or transgenic populations, can be performed has not been established nor has whether this species might be useful (like the zebrafish) for forward mutagenic screening. The intriguing data presented here make these questions well worth pursuing in the near future, however.
Ironically, the authors, as a sidebar, manage to strengthen the case that the zebrafish could also be a vertebrate model worth further development for genetic aging studies. The genetic facility of zebrafish is well known, but the survival study produced here to contrast with the shorter-lived killifish exhibits considerably shorter longevity (mean: 32 months) and a more rectangular survival curve than those previously reported (36–42 months) (5). This may or may not be due to the higher maintenance temperature employed here than in earlier studies, but does suggest that optimal husbandry for studying aging in fishes needs careful attention regardless of the species used.
Acknowledgments
Address correspondence to Steven Austad, PhD, Department of Biological Sciences, Rm. 252, Life Sciences Building, University of Idaho, P.O. Box 443051, Moscow, ID 83844-3051. E-mail: austad{at}uidaho.edu
References
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