Functional Linkages for the Pace of Life, Life ... - Semantic Scholar

Integrative and Comparative Biology, volume 50, number 5, pp. 855–868 doi:10.1093/icb/icq024

SYMPOSIUM

Functional Linkages for the Pace of Life, Life-history, and Environment in Birds Joseph B. Williams,1,* Richard A. Miller,†,‡ James M. Harper†,‡ and Popko Wiersma* *Department EEOB, Ohio State University, Columbus, OH 43210, USA; †Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48105-2303, USA; ‡University of Michigan Geriatrics Center and VA Medical Center GRECC, Ann Arbor, MI 48109-2200, USA

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E-mail: [email protected]

Synopsis For vertebrates, body mass underlies much of the variation in metabolism, but among animals of the same body mass, metabolism varies six-fold. Understanding how natural selection can influence variation in metabolism remains a central focus of Physiological Ecologists. Life-history theory postulates that many physiological traits, such as metabolism, may be understood in terms of key maturational and reproductive characteristics over an organism’s life-span. Although it is widely acknowledged that physiological processes serve as a foundation for life-history trade-offs, the physiological mechanisms that underlie the diversification of life-histories remain elusive. Data show that tropical birds have a reduced basal metabolism (BMR), field metabolic rate, and peak metabolic rate compared with temperate counterparts, results consistent with the idea that a low mortality, and therefore increased longevity, and low productivity is associated with low mass-specific metabolic rate. Mass-adjusted BMR of tropical and temperate birds was associated with survival rate, in accordance with the view that animals with a slow pace of life tend to have increased life spans. To understand the mechanisms responsible for a reduced rate of metabolism in tropical birds compared with temperate species, we summarized an unpublished study, based on data from the literature, on organ masses for both groups. Tropical birds had smaller hearts, kidneys, livers, and pectoral muscles than did temperate species of the same body size, but they had a relatively larger skeletal mass. Direct measurements of organ masses for tropical and temperate birds showed that the heart, kidneys, and lungs were significantly smaller in tropical birds, although sample sizes were small. Also from an ongoing study, we summarized results to date on connections between whole-organism metabolism in tropical and temperate birds and attributes of their dermal fibroblasts grown in cell culture. Cells derived from tropical birds had a slower rate of growth, consistent with the hypothesis that these cells have a slower metabolism. We found that dermal fibroblasts from tropical birds resisted chemical agents that induce oxidative and non-oxidative stress better than do cells from temperate species, consistent with the hypothesis that birds that live longer invest more in self-maintenance such as antioxidant properties of cells.

Introduction The rate of metabolism—the fire of life—is the speed at which organisms use energy, an integration of all energy transformations within the body; it governs biological processes that influence rates of cell division, and thus growth and reproduction, and may have a direct or indirect influence on life span (Kleiber 1975; McNab 2003; Brys et al. 2007). Early work found that as species increased in body size, mass-specific metabolism decreased in a non-linear

fashion, best described as a power function (Kleiber 1975). These comparisons also generated awareness that animals of the same body size, such as a mouse, shrew, and bat, could display rates of metabolism that varied as much as six-fold, and therefore, by inference, natural selection must have adjusted aspects of physiological systems, organs, tissues, and cells, that influence whole-organism metabolism in dramatic ways (Calder 1984; Mueller and Diamond 2001). Renewed interest in the underlying causes of variation in metabolic rates of organisms emerged

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From the symposium ‘‘Metabolism, Life History and Aging’’ presented at the annual meeting of the Society for Integrative and Comparative Biology, January 3-7, 2010, at Seattle, Washington.

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Fig. 1 The slow-fast life-history continuum.

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the fast end, rates of reproduction and mortality are high, as in many temperate birds. Although the life-history continuum primarily tracks variation in body size—large animals have a slower pace of life than do small ones—considerable variation remains unexplained by body size. This residual variation is associated with a second axis that has been called ‘‘lifestyles’’ (White and Seymour 2004; Dobson 2007; Sibly and Brown 2007) thought to be the product of a trade-off between rate of mortality and productivity (Williams 1966; Roff 1992). Although it is widely acknowledged that physiological processes serve as a foundation for life-history trade-offs, the physiological mechanisms that underlie the diversification of life-histories remain elusive (Stearns 1992; Ricklefs and Wikelski 2002; Speakman 2008). Because the rate of metabolism of an organism integrates numerous aspects of its physiology and links those internal systems with its ecology, environment, and life-history, investigations into functional linkages between metabolism, at the organismal, tissue, cellular, and molecular level, and key attributes of life-history holds considerable promise in advancing our understanding of the connections between metabolic rate and lifehistory attributes, including longevity (Bartholomew 1972). Researchers have been interested in the possible connection between metabolism and longevity of animals since Pearl (1928) first suggested an inverse relationship between metabolism and longevity, ‘‘the rate-of-living hypothesis’’. Pearl’s theory was expanded when Harman (1956) proffered the ‘‘free radical theory of aging’’, which suggested that free radicals produced during normal aerobic respiration were responsible for the link between metabolic rate and longevity. Aging was thought to be an accumulation of biological damage caused by the production of reactive oxygen species (ROS), an inevitable by-product of aerobic metabolism (Harman 2001). The relationship between metabolism and aging has proven to be more complex than previously envisioned, but links between metabolic rate and longevity remain, despite the lack of a complete unifying framework connecting them (Mockett et al. 2001; Van Voorhies et al. 2003; Speakman et al. 2004; Zhang et al. 2009). For example, birds have high rates of metabolism compared with mammals, so according to the rate-of-living hypothesis, birds should have shorter lives than mammals of similar body mass. Yet, birds live longer than mammals (Holmes et al. 2001). Part of the answer seems to lie in the finding that birds have lower ROS production than mammals, despite their elevated rate of


with the idea that oxygen-delivery systems dictate universal scaling laws (West et al. 2003), but while these attempts to identify such laws have provided new ideas for exploration, they have also failed to explain many key elements of the data (Kurtz and Sandau 1998; Kozlowski and Konarzewski 2005; Demetrius 2006; Chown et al. 2007). Progress toward understanding functional linkages between whole-organism metabolic rate and underlying mechanisms that influence its magnitude has been slow despite the central role this issue plays in evolutionary and physiological ecology (Bennett 1988, 1991; Speakman 2008). A widely used analytical framework in physiological ecology, life-history theory postulates that many physiological traits may be understood in terms of key maturational and reproductive characteristics over an organism’s life-span (Williams 1957; Roff 1992; Stearns 1992). Variation in these characteristics is thought to reflect different patterns of allocation of resources, time and/or energy, to competing vital functions, especially growth, body maintenance, and reproduction (Williams 1957; Charnov 1993; Ghalambor and Martin 2001). Because resources are finite, time and energy used for one purpose diminishes that available for another. For example, the costs of reproduction may be viewed as energy diverted from bodily repair and maintenance, such as reducing energy investment in antioxidant capacity or immunological competence, to energy devoted to production of offspring (Kirkwood 1977; Van Voorhies 1992; Sheldon and Verhulst 1996; Wiersma et al. 2004; Speakman 2008). Animal life-history variables are contained within limited ecological space, lying along a ‘‘slow-fast’’ life-history axis (Fig. 1; Sæther 1988; Promislow and Harvey 1990; Ricklefs 2000). Animals at the slow end of the life-history continuum are characterized by low annual reproductive output and low extrinsic mortality rate, such as in many tropical birds, whereas at

Linkage between metabolism and life-history in birds

agents that induce oxidative and non-oxidative stress better than do cells from temperate species, consistent with the hypothesis that birds that live longer invest more in antioxidant properties of cells. Basal metabolism in tropical and temperate birds Ecological physiologists often measure an individual’s minimum metabolism under a standardized set of laboratory conditions to understand variation in this parameter with respect to body size and the species’ ecology. Measured on fasted animals, at rest, under thermoneutral conditions, and during their sleep phase (King 1974; Kendeigh et al. 1977; Williams 1999), basal metabolism rate (BMR) provides an integrated view of maintenance energy requirements. Although birds only rarely experience basal conditions in the wild, BMR has been a standard for comparison amongst species because it can be relatively easily measured in the laboratory, and because it provides a view of the idling speed for energy turnover (King 1974). After decades of measurements, it now seems clear that BMR of birds is about three times higher than that of mammals of the same body size (Tieleman and Williams 2000; White and Seymour 2003). The ecological significance of BMR is strengthened when one considers that it makes up to 25–40% of a bird’s metabolic rate in the field (Bryant 1997), and, when sample sizes are adequate, it often correlates with field metabolic rate (FMR) (Daan et al. 1991; White and Seymour 2004). For this reason, BMR is sometimes used as a proxy for an individual’s ‘‘pace of life’’. In 619 species of mammals, BMR varied significantly with FMR, and with life-history parameters such as life span and litter size (White and Seymour 2004). For 69 species of birds from lowland tropical habitats in Panama, BMR was significantly lower than for 59 species of temperate birds (Fig. 2; Wiersma et al. 2007a). Analysis of covariance based on conventional least squares regressions and regressions based on phylogenetic independent contrasts each indicated that BMR was lower in tropical species, offering compelling evidence of a connection between the life-history and slow pace of life of tropical birds. Tropical birds had 10–18% lower BMR than did temperate birds, depending on the statistics used. These authors also compared body-mass-adjusted BMR of 13 closely related tropical-temperate species pairs and found that BMR for tropical species was 13% lower than for temperate species: Fig. 3; P50.02).


mass-specific metabolism (Barja 1998). This pattern agrees with data on mice with high rates of metabolism that lived longer than mice with lower rates of metabolism and in conjunction, mice with high rates of metabolism had increased proton leak in their mitochondria, leading to a decrease in ROS production and attendant longer life (Speakman et al. 2004). Similarly, the rate of H2O2 production from cardiac mitochondria isolated from a wide array of vertebrates with disparate life spans and metabolic rates was negatively correlated with species’ longevity regardless of their metabolic rate. Indeed, bats and birds, despite their high metabolic rates, had some of the lowest rates of H2O2 production (Lambert et al. 2007). Collectively, these findings do not necessarily negate the potential importance of metabolic rate to aging, rather they indicate that the linkages between metabolism and aging are more complex than originally thought (Van Voorhies 2002; Brys et al. 2007). Moreover, we think it is important conceptually to separate studies on laboratory animals, designed to speed up the rate of metabolism and then measure the length of life, from studies on wild animals that have evolved different rates of metabolism. These two views of the metabolic rate of an animal differ and interpretations about their relevance to longevity would be different. In this article we highlight research that demonstrates that tropical birds have a reduced rate of metabolism compared with their temperate counterparts, and connect these differences in metabolism to their disparate life histories. We point out that tropical birds lie on the slow end of the life-history continuum, because they have small clutches (Moreau 1944; Kulesza 1990; Cardillo 2002), slow growth as nestlings (Ricklefs 1976), long post-fledging dependency on parents (Russell et al. 2004; Schaefer et al. 2004), and higher rates of survival of adults (Fogden 1972; Snow and Lill 1974; Ricklefs 1976, 1997; Francis et al. 1999). In a limited dataset for tropical and temperate birds, reduced mass-adjusted BMR was associated with increased survival. Next we present preliminary findings for ongoing research that seeks mechanistic explanations for why tropical birds have a reduced rate of metabolism. We show that tropical birds have, in some cases, smaller central organs than do temperate birds of the same body size. Finally, we explore connections between whole-organism metabolism in tropical and temperate birds and attributes of their dermal fibroblasts grown in cell culture. Cells derived from tropical birds have a slower rate of growth, consistent with the hypothesis that these cells have a lower metabolism, and cells from tropical birds resist chemical

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Fig. 3 Paired comparisons of residual BMR between tropical and temperature species of birds. The line represents equivalency of mass-adjusted BMR between members of the pair of species. Data from Wiersma et al. (2007a).

Body temperature of tropical and temperate birds If tropical birds have a lower rate of metabolism, they could also have a lower set point for body temperature (Tb), but this does not seem to be the case. Prior to measurements of BMR, Wiersma et al. (2007a) measured body temperature (Tb) of birds and found that Tb did not statistically differ between tropical and temperate birds. BMR of migratory versus resident temperate birds Some species of birds over-winter in the tropics but migrate north to temperate areas in spring to breed,

A basic tenet of the rate-of-living theory is that organisms with low rates of metabolism should have increased longevity. In an ongoing study, still incomplete, we have matched estimates of rates of survival for birds that we had measured BMR in the tropics, and for temperate birds that we had measured their BMR or that we could find reliable estimates of BMR. We obtained estimates of survival from a 5-year banding study in Panama (Brawn et al. unpublished) and survival estimates of temperate birds from the north central USA (the Institute for Bird Populations/Monitoring Avian Population and Survival Program) (http://www.birdpop.org/nbii/ NBIIHome.asp), as estimated from modified Cormack-Jolly-Seber mark-recapture analyses. We found that birds with high mass-adjusted BMR also tended to have high apparent survival (Fig. 4). Of course estimates of survival rates of wild birds are fraught with uncertainties, but these survival probabilities are the best estimates available at the moment. This result offers some evidence for the idea that birds with low rates of metabolism have increased longevity. Peak metabolic rate of temperate and tropical birds In birds, sustained high aerobic performance is a fundamental feature of their capacity for powered flight, and for their capacity to produce body heat during bouts of cold (Dawson and Carey 1976). Peak metabolic rate (PMR), the maximum rate of energy


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a journey that requires considerable expenditure of energy. Because tropical migrants developed their itinerant habit relatively recent in geological history (Levy and Stiles 1992; Mila´ et al. 2006), and because they breed in a relatively benign environment, one might predict that their pace of life is more similar to that of resident tropical birds. Some authors have suggested that Neotropical migrants have lower fecundity and higher survival than do temperate residents, life-history patterns consistent with a low rate of expenditure of energy (Cox 1985). When on their temperate breeding grounds, tropical migrants had a significantly lower BMR than did temperate year-round residents measured during the same period (P50.05; Table 1 in Wiersma et al. 2007, Equation (3) in Wiersma et al. 2007a). BMR estimates of marginal means, controlling for body mass and clade in a general linear model, were 0.304 0.008 W (Watts) in tropical birds, 0.329 0.01 W for tropical migrants breeding in temperate areas, and 0.368 0.009 W for temperate residents.

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Fig. 4 Residual BMR as a function of survival in tropical and temperate birds. Data from Wiersma and Williams (unpublished).

expenditure, is typically achieved by forcing animals to exercise (PMRe) or by exposing them to bouts of cold in metabolism chambers (PMRc) (Rosenmann and Morrison 1974). Intuitively, PMR can be linked to fitness in numerous contexts, such as survival during migration, during escape from predators, or during inclement weather (Weibel and Hoppeler 2005). Cold-induced PMRc defines the maximum heat-generating capacity of an endotherm and correlates positively with endurance of cold (Marsh and Dawson 1989; Swanson and Liknes 2006). Unlike BMR, which is influenced by tissues of the central organs such as intestine, heart, and brain, in addition to muscle (Rolf and Brown 1997), in birds, generation of heat during exposure to cold relies primarily on shivering by skeletal muscles (Hohtola et al. 1998; Wiebel et al. 2004), although some data hint at a possible role for uncoupling proteins in muscle for generation of heat (Duchamp et al. 1993; Talbot et al. 2004). Despite the technical challenge of measuring PMRe, it has been quantified in birds trained to fly in wind tunnels (Tucker 1968) to run on treadmills (Brackenbury and el-Sayed 1985), or in ‘‘flight wheels’’ (Chappell et al. 1999). Exposed to decreasing ambient temperature (Ta) in an atmosphere of heliox, tropical birds had a lower PMRc compared with temperate species exposed to the same conditions. PMRC was 34% lower in tropical birds when evaluated using conventional statistics, and 24% lower when assessed by statistics that corrected for phylogeny (Fig. 5). In a subsequent study, Wiersma et al. (2007b) showed that PMRE of tropical birds was 28% lower

compared with estimates from temperate birds. Hence, the maximal power output by the physiological machinery of tropical birds during cold exposure, or during locomotion, is significantly less than that of temperate birds. A reduced PMR in tropical birds is consistent with attributes of their life-history and of their environment. Selection pressures on the upper limits of sustainable power output are apparently reduced because of reduced costs of thermoregulation and attendant costs of foraging, and because smaller brood sizes and slower growth of offspring ameliorate the need for extensive foraging to provision young. For example, tropical house wrens, Troglodytes aedon, lay fewer eggs, make less frequent feeding trips to the nest, and have lower daily energy expenditures, as evaluated by doubly labeled water, than do temperate house wrens (Tieleman et al. 2006, 2008). Conclusions: BMR, PMRC and PMRE are significantly reduced in tropical birds compared with values for temperate birds, results consistent with the idea that a low-mortality-low-productivity lifestyle is associated with low mass-specific metabolic rate. Tropical migrants breeding in the temperate zone have a significantly lower BMR than do temperate residents. There is a significant association between mass-adjusted BMR and survival, although this conclusion is based on a small dataset and our estimates of survival contain significant uncertainty.

Linkages between organ masses and metabolism of tropical birds After Brody and Proctor (1932) and Kleiber (1941) described how resting metabolism scaled allometrically with body mass raised to the exponent 0.64–0.75 in birds and mammals, numerous researchers have extended data on body-mass scaling


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Fig. 5 Peak metabolic rate as elicited by exposure to cold in tropical and temperate birds. Data from Wiersma et al. (2007b).

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and with mass of the heart in some studies (Chappell et al. 1999; Dohm et al. 1994; Ve´zina et al. 2006), but not in others (Chappell et al. 2007). Combining estimates of metabolic output of liver, brain, kidneys, and heart, in rats, rabbits, dogs, cats, and humans, Wang et al. (2001) showed that the collective metabolic output of these organs scaled with an exponent of 0.76 in mammals, a value indistinguishable from the exponent for whole body metabolism as found by Kleiber. This finding emphasizes the importance of the metabolism of some organs in explaining variation in the rate of metabolism between species. Data on masses of organs from the literature revealed that the reduced BMR in tropical birds could be explained, at least in part, by a reduction in the size of some central organs with high tissue-specific metabolism (Wiersma and Williams, unpublished). These authors collated data on masses of organs of tropical and temperate birds from the literature (n ¼ 35–400 species/organ) and then, using a General Linear Model with log-transformed mass of the organ as the dependent variable, climate as the independent variable, and log-body mass as a covariate, they discovered that the heart, liver, kidneys, and intestines, were significantly smaller, by 13–34%, in tropical birds (P50.02 in all cases). This finding implies a possible link between a slow pace of life and smaller central organs, and suggests that animals with markedly different life histories, such as tropical and temperate birds, might have organs that differ in relative size. If some organs are disproportionately smaller in tropical birds compared with those in temperate species, then some body components must be larger for a tropical bird of the same body mass. Using data gathered on skeletal masses of museum specimens for 26 temperate species and 34 lowland tropical species, Wiersma and Williams (unpublished) found that the mass of the skeleton was significantly larger in tropical birds (P50.001). Because predation on nests in the tropics is high, forcing females to lay multiple clutches throughout the breeding season, it could be that selection has increased the size of some of the bones in tropical birds as a storage mechanism for calcium required during egg laying. One might question results from a literature survey on organ masses because multiple authors collected the data, thereby adding to uncertainty about conclusions. As a remedy, Wierma and Williams (unpublished) have initiated a study to directly measure organ masses of phylogenetically paired tropical and temperate birds, a powerful method because it eliminates any potential bias due to phylogeny and to differences in body mass.


exponents and how they vary with respect to phylogeny, climate, and phase of the daily cycle (Aschoff and Pohl 1970; King 1974; Bennett and Harvey 1987; Tieleman and Williams 2000). Intense debate has been, and continues to be, a feature of these studies, with arguments that suggest BMR should scale with an exponent of 0.67 based on the notion that heat loss occurs at the surface of an animal and therefore surface area to volume ratios should dictate scaling phenomena (Dodds et al. 2001; White and Seymour 2003), or should scale with an exponent of 0.75 based on mathematical reasoning that involves derivation of this exponent from fractal geometry, which is thought to describe supply networks such as the blood-vascular system (West et al. 1999, 2002), or, alternatively, should scale with multiple values for exponents as predicted by allometric cascade models (Darveau et al. 2002). As interesting as these discussions tend to be, they provide only a modest step in our understanding of how natural selection has brought about major differences in metabolism of animals, especially for animals of similar body size. A major challenge facing Ecological Physiologists in the next decade will be to establish linkages between life-history evolution and attributes of an organism’s physiology, such as its rate of metabolism. Rather than treat animal energetics as a black box, it will be important to understand connections between rates of whole-organism metabolism and constituents of an organism’s internal milieu such as size- and mass-specific metabolism of body components, organs, tissues, and cells, and to understand how variation in these has been impacted by natural selection (Savage et al. 2007). For mammals, consumption of energy by internal organs equals 70% of BMR, even though the mass of organs equals only 8% of body mass (Elia 1992; Rolfe and Brown 1997; Wang et al. 2001). Indeed, in humans, metabolism of the brain, kidneys, liver, and heart account for 60% of resting metabolism, but 56% of body mass (Wang et al. 2001). As a result, some investigators have argued that studies of the contribution of organs to whole-organism BMR should be emphasized as we search for underlying causes of resting metabolism (Elia 1992). Among studies that have attempted to relate variation in BMR to the relative size of central organs of endotherms, results are mixed. Some researchers have shown strong correlations with some central organs and BMR (Daan et al. 1990; Piersma et al. 1996; Hammond et al. 2000; Nespolo et al. 2002; Brzek et al. 2007), whereas others have failed to find associations (Tieleman et al. 2003). Variation in PMR coincides with variation in skeletal muscle


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Fig. 6 Paired comparisons of residuals of heart mass between tropical and temperate species of birds. Data from Wiersma and Williams (unpublished).

Alhough incomplete, results thus far show that the mass of the heart, kidney, and lungs, is significantly smaller in tropical birds (Fig. 6). Conclusions: Tropical birds have different proportions of central organs than do temperate species, and this may explain, in part, their reduced rate of maintenance metabolism. Linkages between whole-organism metabolism and attributes of their cells Multicellular organisms have cells that are strikingly similar in the mechanisms by which they execute basic cellular processes such as energy metabolism (Campisi 2001). Among mammals, for most cell types, including erythrocytes, fibroblasts, and hepatocytes, cell size remains invariate as body size increases, but in vivo metabolic rate of cells decreases (Savage et al. 2007). A number of studies of mammals have assessed in vivo energy consumption of organs by measuring arterio-venous differences in oxygen concentration of blood plasma, together with simultaneous blood-flow measurements across the organ (Elia 1992; McCully and Prosner 1995). These studies show that mass-specific metabolism of the liver, relative to body size, for rats, rabbits, cats, dogs, and humans decreased with increased body size (Wang et al. 2001). These data suggest that mammals of larger body size have cells that have a lower rate of energy turnover than do mammals of smaller body mass; the mass-specific metabolism of liver cells varied with body mass with an exponent of 0.25, remarkably similar to the


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allometric relationship for intact mammals (see also Krebs 1950; Porter and Brand 1995). Most studies that have attempted to relate how cellular processes translate into whole-organism physiology, such as the rate of metabolism or the length of life, have done so over a range of body masses. As in our analysis above, large animals, with their longer length of life and lower rates of mass-specific oxygen consumption, are composed of cells that appear to have lower rates of metabolism. A corollary to this finding would be that larger animals would be expected to have lower rates of cell division because the rate of cell metabolism is directly related to the rate of cell division (Rose 1991). Whether animals of the same body size, but different rates of metabolism, also have cells with different intrisic rates of cell metabolism remains a contested issue. Moreover, researchers disagree on whether cells removed from the organism and grown in culture catabolize fuels at the same rate as in vivo. Whereas the theoretical model of West et al. (1997), based on the mathematics of branching patterns of blood vessels, predicts that cells will lose their in situ characteristics of scaling when they are grown in culture, the quantum-metabolism theory, which attempts to infer whole-organism metabolic rates from metabolic activities of component cells, predicts the opposite (Demetrius 2006). In an attempt to resolve whether cultured cells from animals of different body sizes have different intrinsic rates of energy turnover, Brown et al. (2007) measured metabolic rate of dermal fibroblasts for 10 species of mammals including laboratory mice, humans, cows, and horses. They did not find a statistically significant relationship between metabolic rate of dermal fibroblasts, from long-term culture, and body size. However, their results have been criticized because they did not measure metabolism of primary cell cultures, but rather of cells acquired from commercial facilities and other laboratories (Wheatley 2007). Thus, the length of time that cells had been dividing in culture was unknown and likely varied among species. Moreover, slight differences in culture conditions among sources of the fibroblasts could have impacted results. Given that two allometric models make opposite predictions about intrinsic rates of cellular metabolism in vitro, more studies are needed to examine the metabolic rate of primary cultured cells for animals of different sizes (Wheatley 2007). If the rate at which cells divide is closely tied to cellular metabolic rate, assuming sufficient availability of nutrients, as is the case for cancer cells with

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Fig. 7 Cell growth as determined by staining of DNA as a function of time for three paired comparisons of tropical and temperate birds. Data from Harper et al. (unpublished).

their high rate of metabolism and consequent high rate of growth (Jorgensen and Tyers 2004; Hall et al. 2004), then we predict that cell division will be slower in tropical birds compared with temperate species of the same body mass. In a preliminary set of experiments, we followed the rate of cell growth in fibroblasts from three phylogenetically matched pairs of temperate and tropical birds American Robin— clay colored Robin, Ruby-throated Hummingbirdwhite necked Jacobin, Barn Swallow-Mangrove Swallow (Fig. 7). In multi-well plates, we initially seeded 3000 cells in each of six-wells for each species, and then counted cells in successive wells at 24 h intervals until day 5, then again at day 9, using a fluorescence assay based on binding of Hoescht 33258 to DNA. The number of cells in each well is directly proportional to the intensity of the fluorescent signal. In each case, rate of cell growth was statistically lower as judged by ANCOVA (P50.001) in cultured fibroblasts from the tropical member of the couplet, indicating the possibility that cell growth is slower in tropical species. This finding may also hint that the rate of metabolism of fibroblasts from tropical birds is reduced.


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The membrane-pacemaker theory holds that cellular membranes of animals with high rates of mass-specific metabolism, such as temperate birds, have more polyunsaturated fatty acids in their cell membranes (PUFA) (Hulbert and Else 2005). The idea posits that such high levels of PUFAs result in physical properties of membrane bilayers that speed up the activity of membrane-associated proteins and consequently the metabolic rate of cells. This theory is buoyed by correlational evidence (Couture and Hulbert 1995; Hulbert et al. 2007; Buttemer et al. 2008), and some experimental evidence (Else and Wu 1999; Wu et al. 2004), but other studies failed to support the idea (Brookes et al. 1997; Valencak and Ruf 2007). The theory also posits that membranes with high levels of PUFA are more susceptible to oxidative stress, which may be related to species’ longevity (Mitchell et al. 2007). This idea postulates that tropical birds have low levels of PUFA in their cell membranes, and that those membranes would be less susceptible to oxidative stress. Birds are thought to be highly resistant to cellular damage wrought by reactive oxygen species (ROS) and other forms of stress, perhaps because of the lipid composition of their cell membranes (Miller et al. 2010). Cultures of fibroblasts of budgerigars, with a maximum life span of 20 years, showed greater cellular resistance to oxidative damage than did cells from Japanense quail, with a maximum life span of 5 years (Ogburn et al. 1998). To test this hypothesis on wild birds, we initiated a series of experiments designed to examine the resistance of dermal fibroblasts of birds to various forms of chemical insult, including exposure to cadmium, H2O2, paraquat, rotenone, thapsigargin, tunicamycin, and methane methylsulfonate (MMS), a DNA alkylating agent (Harper et al. unpublished). H2O2 causes OH radical formation, paraquat is an herbicide that induces O2 formation, rotenone blocks the plasma membrane redox system, thapsigargin inhibits Caþþ pumping in the endoplasmic reticulum, and tunicamycin is an antibiotic that interferes with the processing of protein in the endoplasmic reticulum. Our first experiment evaluated cell lines from 27 temperate bird species for resistance to these chemicals that induce metabolic stress or lead to cell death. Initially we compared results from temperate birds with those from ten species of mammals [wild and laboratory house mice, deer mice, rats, red squirrels, white-footed mice, fox squirrels, porcupines, beavers, and bats (Harper et al. 2006)]. The cells were tested after sub-culturing them three times or at passage 3. As judged by values for the dose required to kill 50% of the cells (LD50), cells from


Metabolism, life-history, and insights into aging In 1951, Peter Medawar presented a lecture on aging in animals that was entitled ‘‘An Unsolved Problem in Biology’’ in which he lamented that we did not know the biological reasons for aging. Since that time researchers have gathered a wealth of information about the aging process (Finch 1990, Austad 1999), success that led Holliday (2006) to assert that the problem identified by Medawar had been solved. Yet most who study this phenomenon would likely say that many problems in aging remain unsolved, that our progress has been slow, and that many theories of aging, such as the

rate-of-living theory, oxidative-stress theory, and lipid-membrane theory (Promislow and Pletcher 2002), have failed to provide infallible or complete explanations (Pe´rez et al. 2009; Zhang et al. 2009). A small coterie would also point out that approaches to studying the aging process have lacked an evolutionary perspective (Rose 1991; Vleck et al. 2007). Many in the medical community doubt that evolutionary biology can yield substantive answers to understanding the aging process (Lane 2009). Studies by biogerontologists, for the most part, have focused on laboratory organisms, nematode worms, fruit flies, yeast, and laboratory mice, all artificially selected for short-generation times and for early reproduction, which can, in turn, shorten life span (Sgro` and Partridge 2000), thereby raising the insidious possibility that ‘‘longevity genes’’ isolated from laboratory populations may simply be extending the life of organisms artificially selected for short lives with high reproductive potential (Promislow and Pletcher 2002; Harper et al. 2006). Selection for rapid growth and early reproduction in the laboratory is likely to result in the accumulation of genes causing early aging, but of little importance in natural populations (Miller et al. 2002). Wild-caught fruit flies have survival rates equivalent to laboratory strains of flies that have been selected for longevity for 20 years (Linnen et al. 2001). The wealth of information available to us about how natural selection has altered rates of aging in the natural world lies untapped. Here we argue that mapping of demography, life-history, and environment of wild birds on to physiological traits such as metabolism and its component parts can yield new insight into the aging process and elucidate patterns undetectable in laboratory animals. Comparative studies provide a powerful tool for identifying which of the candidate mechanisms of aging have been of evolutionary importance because they can take advantage of the long-term natural experiments that have produced an array of species with different life-spans. These studies require analyses that incorporate evolutionary thinking in them (Felsenstein 1985; Haussmann 2005; Garland et al. 2005; Speakman 2005), but we caution against wholesale acceptance of statistics that incorporate phylogenetic information without careful scrutiny of the underlying assumptions in the models (Westoby 1995; Price 1997; Munoz-Garcia and Williams 2005). An especially powerful method that does not assume an infallible topology, does not require information about branch lengths of a phylogeny, and does not make assumptions about the model of evolution throughout the tree, is the


birds were remarkably more resistant to all of the above stress agents than were those of mammals; these differences were statistically significant by ANCOVA (P50.05 in all cases). The avian cells were also found to be remarkably resistant to rotenone, which inhibits the plasma membrane redox system: although LD50 values for cells from mammals exposed to rotenone are between 10 and 150 mM, avian cells were resistant to rotenone at concentrations as high as 1000 mM. The first of their kind on wild birds, these exciting results suggest that cells from many wild avian species may prove to be more resistant, in vitro, to heavy metals and oxidant stresses compared with cells from similarly sized wild mammals. We performed a second series of pilot studies to evaluate whether fibroblasts from tropical and temperate birds differ in resistance to chemical stress. Cells were developed from one to three individuals from each of our 27 species of temperate birds and from 10 species of tropical birds, including Goldencollared Manakin, Clay Colored Robin, Palm Tanager, Social Flycatcher, Mangrove Swallow, Red-crowned Woodpecker, Common Paraque, Ruddy Ground Dove, White-necked Jacobin, and Tropical House Wren. The cells were then tested for resistance to cadmium, H2O2, UV light, paraquat, MMS, thapsagargin, and tunicamycin. By ANCOVA, fibroblasts from tropical birds had significantly higher LD50 for cadmium, H2O2, paraquat, MMS, and thapsigargin. For these analyses, Mangrove Swallows, Social Flycatchers, Palm Tanagers, Clay-colored Robins, and Golden-collared Manakins consistently had higher resistances to stress. Conclusions: Fibroblasts from long-lived tropical bird species differ systematically from short-lived temperate species in their characteristics, including their rate of division and resistance to death induced by oxidant or non-oxidant injury.

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Funding This work was supported by a grant from the National Science Foundation (grant IBN 0212587 to J.B.W.) and by grants from the National Institute for Aging (grants AG024824 and AG023122 to R.A.M.).

Acknowledgments We would like to thank participants in the symposium ‘‘Metabolism, Life History, and Aging’’, held on January 3, 2010, at the meeting of the Society for Integrative and Comparative Biology, for stimulating discussion and insightful comments. J. Brawn kindly supplied unpublished data on survival of tropical birds.

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