Domestic poultry models are particularly well-developed for studies of relatively rapid reproductive and neuroendocrine aging. Although their life spans have been documented at over 15 years, domestic chickens (Gallus domesticus) are short-lived for their size, and hens typically undergo reproductive aging during the first two years of egg production. The smaller, and substantially shorter-lived, domestic Japanese quail (Coturnix japonica) is in many ways an ideal bird model for studies of rapid reproductive and neuroendocrine aging, since its life history is very similar to that of a laboratory rodent. Quail maintained on long days (15L:9D) mature in 8 weeks, maintain peak production for about 10 months, and show fertility declines (30-50%) by 70 weeks of age, with complete ovulatory failure as early as 18 months. Aging females exhibit irregular egg production associated with diminished hypothalamic response to ovarian steroids (Ottinger and Bakst, 1995; Ottinger, 1996). Reproductive aging is relatively rapid (1-2 yrs) in quail hens, yet they have a substantially longer documented postreproductive life span (2-4 yrs) than that of rodents. Quail can be maintained inexpensively and bred in large numbers. The Ottinger lab has used an outbred domestic quail strain for two decades in studies of reproductive physiology and neuroendocrine aspects of aging in male birds (Ottinger et al., 1997; Panzica et al., 1996; Ottinger, 1998; Ottinger, 2001; Ottinger et al., 2004).
Avian reproductive anatomy lends itself well to studies of basic mechanisms controlling female fertility and reproductive aging (Johnson, 2000; Holmes et al., 2003). Most adult female birds have only one functional ovary. Unlike the mammalian ovary, however, in which developing follicles are contained in a capsule, the avian ovary has a lobular structure like a bunch of grapes, with a yolky hierarchy of large preovulatory follicles readily accessible on the outside. This arrangement makes it practical to measure or administer hormones, growth factors or other substances directly from or into individual follicles.
Birds adapted to temperate zones, including poultry and some small cage birds, like finches, often use photoperiod as the primary cue for the timing and onset of reproduction. In these species, manipulation of the photoperiod is a convenient, noninvasive means of shutting down the reproductive neuroendocrine axis. Since some photoperiodic regulation of reproduction occurs in the hypothalamus, the manipulation of photo-period avoids the experimental confound of elevated GnRH and gonadotropins that accompany surgical castration.
In captivity under hospitable conditions, some birds (e.g., quail, budgies) have postreproductive life spans of one-third or more of the total life span (Woodard and Aplanalp, 1971; Holmes et al., 2001). Zebra finch hens exhibit significant declines in egg production after several years (Holmes, unpublished data). Female birds and mammals both produce the vast majority of their primary oocytes, or developing eggs, before or shortly after birth (Tokarz, 1978; Guraya, 1989). This fundamental reproductive trait sets birds and mammals apart from most female fishes, amphibians and reptiles, in which new oocytes are produced as needed throughout reproductive life. For this reason, avian models are particularly relevant for studying the role the finite oocyte pool plays in the timing of reproductive aging. In mammals, fertility loss is generally thought to be correlated with age-related declines in stores of viable primary oocytes. Another advantage of egg-laying is that it facilitates studies of early gonadal development and the examination of primordial oocytes early in life. Domestic birds are excellent models for exploring the effects of early manipulation of embryonic development on health later in life and during aging.
Surprisingly little research has focused on natural variability in ovarian aging in birds of different orders or divergent life-history patterns. Studies of reproductive aging in domestic poultry, however, usually focusing on the heavier poultry breeds, have shown striking differences between strains in fertility, and some aspects of ovarian aging are well documented. For example, Leghorn chickens, referred to as ''layers,'' have been bred for very high, consistent egg production levels (nearly one egg per day). In contrast, the heavier ''broiler'' poultry strains, bred for meat production, may lay under 200 eggs per year. There has been no systematic comparison of ovarian aging in long- and short-lived species in the class Aves as a whole. Moreover, there has been no concerted effort to establish whether common physiological, biochemical or genetic mechanisms are responsible for fertility loss in birds and mammals.
We have begun studies comparing reproductive aging in female quail, budgerigars, and wild terns in an attempt to determine the relative contributions of declining primordial oocyte stores, steroid hormones, gonadotropins and GnRH (gonadotropin-releasing hormone) in short- and long-lived bird species. These bird models are all diurnal, with highly stereotypical, easily identifiable courtship behaviors; egg production and fertility are also readily and noninvasively quantified.
Quail and budgerigars both have a high incidence of ovarian cancers, presumably resulting from the breakdown of normal apoptotic signaling. In species which ovulate frequently, the avian ovary is potentially an excellent model for the ''rupture and repair'' mechanisms implicated in ovarian cancer formation (Giles et al., 2004). To our knowledge, there have been no studies of the molecular basis of aging-related dysregulation of healthy ovarian cellular signaling in longer-lived, non-poultry bird species.
The bones of female birds generally serve as a repository for calcium and other minerals needed for egg production. Female quail develop increasingly fragile bones as they age; these birds are a well-characterized model for the effects of hormones, vitamins and other factors on osteoporosis (see, for example, Keatzel and Soares, 1985).
Reproductive aging in the domestic hen The domestic chicken is one of the classical models for developmental and reproductive biology, and many fundamental physiological correlates of ovarian aging in hens are thoroughly documented (Johnson et al., 1986; Bahr and Palmer, 1989; Ottinger and Bakst, 1995). As egg production declines (between about 30 to 90 weeks of age), the normal recruitment of small white follicles into the preovulatory hierarchy slows, as does follicular maturation. Yolky preovulatory follicles become less sensitive to the surge of luteinizing hormone (LH) that normally stimulates ovulation. Administration of LH or gonadotropin-releasing hormone (GnRH), has been shown to stimulate arian response in aged hens, with older hens responding more slowly than young ones (Ottinger and Soares, 1988; Wu and Ottinger, unpublished data). Old hens are also less sensitive to progesterone and may require more to trigger a preovulatory LH surge (Williams and Sharp, 1978; Ottinger and Soares, 1988). Granulosa cells from old hens have been shown to have more follicle-stimulating hormone (FSH) receptors and to produce more progesterone (P4) in response to FSH administration than those of younger hens (Johnson et al., 1986; Bahr and Palmer, 1989; Johnson, 2000a, 2000b). This has been attributed to membrane-level changes, rather than actual P4 secretion in response to the cyclic AMP stimulation that normally triggers P4 production.
Estrogen production in birds occurs primarily in small white prehierarchal follicles, and therefore may play a minor role in loss of ovulatory competence. While estrogen is less dominant in the bird than in the mammal ovary, declines in estrogen may be partly responsible for declining follicular responsiveness. Decreased responsiveness of granulosa cells of hierarchal follicles could be attributable to lower estrogen secretion by a declining pool of small follicles, as well as altered responsiveness to gonadotropins and GnRH (Bahr and Palmer, 1989). The proportion of the original follicular pool that is required for ovulation to occur, however, is unknown.
While age-related changes in follicular populations have not been quantified over the reproductive life span of any bird, follicular atresia rates have been shown to increase with age in domestic hens. Approximately 20 percent of smaller (<8 mm) prehierarchal follicles undergo atresia in younger hens; this rate increases as fertility declines. Atresia rate increases have been attributed to declines in FSH, which normally inhibits atresia. Atresia and its regulation, however, may be expected to vary a great deal between poultry and exotic bird species.
Apoptosis, the programmed cell death that is a normal part of development and aging, has been intensively studied in the ovary of the chicken and, to a lesser extent, in the Japanese quail (Yak et al., 1998; Volentine et al., 1998; Johnson, 2000a,b; Bridgham and Johnson, 2001; Johnson et al., 2002). Changes in populations of mitotic and apoptotic cells in prehierarchal follicles have been quantified during chicken development and during a significant portion of the reproductive life of chickens and quail (Waddington et al., 1985; Waddington and Walker, 1988; Kitamura et al., 2002; Johnson, 2000). Many of the same molecules involved in mammalian apoptotic signaling and follicular development have also been shown to function in the ovaries of chickens and quail.
The Japanese quail as a model for male neuroendocrine aging and neuroplasticity
Over the past 20 years, the Ottinger laboratory has used the Japanese quail extensively as a model for aging-related declines in reproduction, focusing on a variety of changes in behavioral, gonadal, metabolic, sensory and central neuroendocrine function (for reviews, see Ottinger, 1991; 1996; 1998; 2001). Male quail mirror many aspects ofmam-malian neuroendocrine aging, but they offer some important advantages over laboratory rodent models. Unlike that of most mammals studied, the male hypothalamic-gonadal system retains plasticity during aging. This plasticity is most obvious in the recovery of male courtship and mating behavior in studies in which males were given exogenous testosterone (Ottinger et al., 1997; Ottinger, 1998). Even very aged, infertile males respond to testosterone replacement and recover full reproductive behavior, including restored immunoreactivity of cells containing aromatase enzyme (AROM-ir) in the preoptic region of the hypothalamus. Furthermore, the critical role of AROM-ir for the expression of male courtship and mating behavior is seen in aging males that remain reproductively active without exogenous testosterone treatment. These males have significantly larger AROM-ir cells in the preoptic region (Ottinger et al., 2004). Age-related declines in male reproductive function are also reflected in the function of the GnRH-1 system, including reduced hypothalamic GnRH-1 content, fewer GnRH-1 immunoreactive cells, and lower-amplitude GnRH-1 pulses in vitro (Ottinger et al., 2004). These age-related hypothalamic changes provide a platform for identifying the sequence of neuroendocrinological events eventually culminating in loss of reproductive function. The retention of neuroplasticity in quail hypothalamic systems also offers the opportunity to examine and manipulate age-sensitive signals that appear to decline selectively during reproductive senescence.
Caloric restriction improves reproductive performance in poultry
Caloric restriction (CR) is a well-established experimental paradigm in biogerontology, and the beneficial effects of long-term CR have been documented for a broad range of animal taxa, including invertebrates. Reliable effects of CR typically include extended life span, delayed onset of aging-related diseases, sustained healthy metabolic and endocrine function, and delayed loss of reproductive capacity (for reviews, see Weindruch and Walford, 1988; Finch, 1990; Masoro, 1993, 2001). Shorter-term caloric
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