Zebrafish as a Model for Aging

Many species of fish have been used as an experimental model for aging (Woodhead 1978; Patnaik et al., 1994; Woodhead 1998); thus in addition to defining mechanisms of disease, zebrafish may be useful for exploring the process of aging. Recent studies have provided initial evidence that zebrafish have a median lifespan of approximately 36 to 42 months with a maximum lifespan of up to 66 months (Gerhard et al., 2002b), indicating that zebrafish undergo an age-related increase in mortality rate. More recently, a shorter median and maximum lifespan was reported for zebrafish, with 31 and 45 months, respectively (Herrera et al., 2004). The different results in these two studies may be a reflection of strain variation and differences in housing and environmental parameters. These findings, however, set the groundwork for identification of genes that control longevity. Aging zebrafish have been demonstrated to develop several phenotypes similar to aging mammals (Table 27.1), including the

TABLE 27.1 Aging phenotypes recognized in zebrafish

Finding Reference

Phenotype

Median lifespan Maximum lifespan Heat shock protein 70 Heat shock factor 1

Senescence-associated

P-galactosidase staining Protein oxidation Spinal curvature

36-42 months 66 months Decreased with age Increased with age Observed in skin with aging

Increased with age in muscle Observed with aging

(Gerhard et al., 2002b) (Gerhard et al., 2002b) (Murtha et al., 2003a) (Murtha et al., 2003a) (Kishi et al., 2003)

appearance of senescence-associated P-galactosidase staining and oxidized protein (Kishi et al., 2003). Additionally, spinal curvature occurs with age in zebrafish (Gerhard et al., 2002b).

Fish have been said to show three types of senescence: rapid, gradual, and negligible. Teleost fish, of which zebrafish are members, generally undergo gradual senescence, as observed in most vertebrates (Kishi et al., 2003). Whether or not zebrafish undergo gradual senescence as well is not yet fully understood, though they are reported to show increasing senescent morphology with aging, including spinal curvature and muscle degeneration (Gerhard et al., 2002b). It has also been suggested that zebrafish may undergo ''very gradual senescence'' based on molecular changes, including senescence-associated P-galactosidase activity and accumulation of oxidized protein with age in the face of continuously proliferating myocytes and constitutive telomerase activity in adult zebrafish (Kishi et al., 2003). While Kishi et al. (2003) did not find age-related changes in BrdU incorporation, telomerase activity, and lipofuscin accumulation in zebrafish, it is important to note that the oldest fish examined in that study were 24-31 months old, which is less than the median lifespan reported for zebrafish, and may not reflect what occurs in truly ''old'' fish. In many teleost fish, age-related increases in mortality rate, accumulation of lipofuscin, lipid peroxidation, collagen cross-linking and decreases in growth rate, reproductive capacity and protein utilization are clearly observed (Patnaik et al., 1994). Zebrafish demonstrate an age-related increase in mortality rate (Gerhard et al., 2002b; Herrera et al., 2004) though accumulation of lipofuscin (Kishi et al., 2003), and decreases in growth rate (Gerhard et al., 2002b) have not been observed in zebrafish thus far. Other parameters, including lipid peroxidation, collagen cross-linking, reproductive capacity, and protein utilization, have not yet been examined specifically in zebrafish with respect to aging.

Populations of guppies kept under various conditions of culture have shown survival curves similar to those seen in populations of small mammals (Comfort 1960;

Comfort 1961; Comfort 1963; Woodhead 1998). In these studies, guppies showed a median and maximum lifespan of approximately 36-44 and 55-60 months, respectively, which is quite similar to what has been reported in survival curves for zebrafish (Gerhard et al., 2002b). In addition, the tissues of these guppies showed marked aging changes comparable to those seen in the tissues of aging mammals, including senile changes in the gonads, liver, kidneys, and brain (Woodhead et al., 1983; Woodhead 1984; Woodhead et al., 1984). These anatomical changes in various organs during aging have also been noted in other teleost species, confirming an increase in degenerative changes and pathological symptoms with age (Patnaik et al., 1994). One method of manipulating longevity, caloric restriction, has been documented to extend the lifespan of some mammals (Weindruch 1996). Similarly, dietary restriction has been shown to retard the aging processes in several teleost species showing gradual senescence (Patnaik et al., 1994), underscoring the similarities between the biology of aging in fish and mammals. While caloric restriction studies utilizing zebrafish have not yet been reported, preliminary studies are underway to determine its effects in zebrafish (Gerhard et al., 2002a). Taken together, these results support a commonality in mechanism of aging processes in vertebrates.

Fish have several advantages for use as a model for the study of aging (reviewed by Woodhead 1978; Patnaik et al., 1994), including the availability of large cohorts of offspring from single matings, their ectothermic nature which facilitates modulation by external environmental changes, and lower costs for breeding and maintenance. Zebrafish may serve as an excellent model of the biology of aging, particularly allowing for the identification of longevity assurance genes (genes that promote longevity). The zebrafish is readily amenable to large-scale muta-genesis studies which may detect and discover genes involved in pathways of the aging process. Generation of mutations and screening for mutant phenotypes can be achieved faster, on a larger scale, and more cost effectively than in mammalian systems (reviewed in

Gerhard et al., 2002b). Thus, the zebrafish is an experimentally expedient organism similar to invertebrate models such as C. elegans and Drosophila, but with the anatomic and physiological complexities of a vertebrate.

While there are many advantages to the zebrafish as a model of aging, there are also some disadvantages which must be taken into consideration. Much like the mouse, zebrafish have a substantially longer lifespan than invertebrate models of aging such as C. elegans and Drosophila. Thus, while as a vertebrate they are phylogenetically much closer to humans than are these invertebrate models, their generation time is much longer, so aging studies utilizing zebrafish are likely to be more time consuming than with invertebrate models. Physiologically, the respiratory system of the zebrafish is very different from that of mammals, making them a poor model for studies involving respiratory physiology or respiratory diseases. In addition, zebrafish have considerable ability to regenerate tissues such as the heart (Poss et al., 2002), which shows only minimal regeneration in mammals following injury, making the zebrafish a useful model for dissecting the molecular mechanisms of cardiac regeneration and comparative studies of regeneration, but perhaps limiting its usefulness for direct comparisons of regeneration in aging studies. Finally, fish are greatly influenced by their environment (Beverton 1987), and many environment variables, including temperature (Liu et al., 1975), lighting (Raymond et al., 1988), population density (Lorenzen et al., 2002), water quality (Klontz 1995), and nutrition (Comfort 1960; Comfort 1963), must be tightly controlled in order to accurately interpret data obtained from aging studies. Despite these disadvantages, zebrafish still have many advantages and the potential for contributing to our knowledge of aging and complementing what has been learned in other organisms. Information regarding age-related changes specifically in zebrafish is very scarce. It is critical to characterize normal age-related changes in order to understand the effects of mutagenesis and transgenes in mature zebrafish.

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