Abstract
Animal life-history traits fall within a limited ecological space, a continuum referred to as a “slow-fast” life-history axis. Differences of life-history traits are thought to result from trade-offs between behavioral and physiological aspects in each species as mediated by the biotic and abiotic environment, as well as genetic mechanisms. Domestic animals tend to show inverse relationships between body size and life span. Dogs are a good example of this, with smaller dogs having higher mass-specific metabolic rates and longer lifespans compared with larger dogs. Thus, dogs provide a unique system to examine physiological consequences of life-history trade-offs. I have collected data from the literature to explore implications of these trade-offs at several levels of physiological organization including whole-animal, organ systems, and cells. Small dogs tend to have longer lifespans, fewer pups per litter, faster and shorter developmental trajectories, and higher mass-specific metabolic rates, and in general, larger metabolically active organs compared with large dogs. From work on isolated primary fibroblast cells and telomeres of dogs, I show that selection for body size may influence the attributes of cells that shape proliferative cellular rates and rates of telomere shortening. The potential links between body size, and cellular oxidative stress in dogs as they age are discussed. Furthermore, small size in dogs has been linked to concentrations of reduced insulin growth factor-1 (IGF-1) levels in plasma, a possible metabolic advantage that may provide higher resistance to oxidative stress, a parameter essential to increases in lifespan.
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Introduction
Natural selection has shaped animals to optimize their fitness, so that life-cycle events produce the largest possible number of reproducing progeny (Mitteldorf and Pepper 2009; Longo et al. 2005; Stearns 1992). These concepts are commonly encompassed within the field of life-history evolution. Variation in life-history events is thought to reflect the differential allocation of resources, time, energy, and/or nutrients to competing life functions, such as growth rates, body maintenance, body size, reproduction, and longevity (Charnov 1993; Ghalambor and Martine 2001; Nussey et al. 2009). Trade-offs may include behavioral and physiological traits including growth, reproductive strategies including early vs. late reproduction, size and number of offspring, body storage reserves, life span, aging rates, costs of locomotion, etc. (Charnov 1993; Ghalambor and Martine 2001; Nussey et al. 2009). For example, the cost of reproduction is viewed as energy diverted away from bodily maintenance towards investment in reproduction (Kirkwood 1985; Wiersma et al. 2007). Those animals that expend more energy on reproduction early on in life tend to have shorter lifespans. However, the extent to which physiological traits, such as growth and reproduction, co-vary among species with different life-history characteristics remains unclear. Much of the research to date on life-history trade-offs has explored the evolutionary reasons to expect these trade-offs and physiological mechanisms have elucidated that variation in life-history traits cannot only include negative correlations in the form of trade-offs, but can also involve positive correlations (Dantzer and Swanson 2012; Glazier 2015).
Thousands of years ago, humans unwittingly initiated a large-scale selection experiment that may now allow us to evaluate the effects of artificial selection on life-history traits. The dog, Canis lupus familiaris, is thought to be the first wild species to be domesticated by humans (Galibert et al. 2011). Modern rigid selection practices have shaped this species into more than 400 breeds, with a 44-fold difference in body size ranging from the 2 kg Chihuahua to the 90 kg Great Dane (Galibert et al. 2011; Hawthorne et al. 2004). Humans have not only selected for body size in dogs, but this selection has additionally included phenotypic differences in coat color, leg length, skull shape, bone width, as well as behavioral and temperament differences (Careau et al. 2010; Wayne and Ostrander 2007; Rimbault and Ostrander 2012). Within this phenotypic variation, humans have also selected between breeds for a threefold difference in age-at-maturity, fivefold difference in litter size, and a twofold difference in longevity (Li et al. 1996; Michell 1999; Austad 2005). Thus, dogs constitute an informative group to study connections between life-history and physiology.
In this review, I outline key life-history traits of dogs of different sizes at seemingly opposing ends of the life-history continuum with the intent of linking those traits with their organismal and cellular physiology. Evolutionary theory suggests that developmental trajectories and growth rates can shape the onset and rate of aging (Selman et al. 2013). Lifespan, reproduction (as estimated by litter size) and growth rates are three key life-history traits that influence fitness, and shape the basic physiology of organisms (Russell 2004; Dmitriew 2011). I assembled data from the literature about three key life-history traits, lifespan, reproductive costs in terms of litter size and growth rates, to show that in general, smaller dogs live significantly longer than larger dogs, have smaller litter sizes and seem to grow at faster rates. I explore whole-organism basal and maximal metabolic rates, and further examine how organ size relates to whole-animal metabolic rate. From work on isolated fibroblasts and telomeres of dogs, I show that selection for life-history of smaller dogs has influenced attributes of cells that shape their proliferative capacity, and I speculate on how cellular oxidative stress may play a role in aging between different body sizes of dogs. Then, I discuss the role of IGF-1 signaling in dogs and compare these patterns with cellular phenotypic patterns associated with increased lifespan in other model organisms.
Lifespan and body size
Among species, larger organisms live longer than smaller ones (Promislow 1993), as is the case for most of Mammalia (Fig. 1a). However, the opposite seems to be true for dogs and a debated issue in the dog literature is whether all small breeds have significantly longer lifespans than all large breeds (Deeb and Wolf 1994; Michell 1999; Patronek et al. 1997; Proschowsky et al. 2003). To answer this question, several researchers have surveyed multiple dog populations around the world. I have compiled and averaged (where possible) mean lifespan and body weight (Kg) data from all of these datasets including populations from Britain (Michell 1999; Adams et al. 2010), and Denmark (Proschowsky et al. 2003).
I found that smaller dogs do tend to live significantly longer than larger dogs across all breeds surveyed (Fig. 1b), opposing general interspecies trends found across Mammalia. The longest average lifespan was 13.2 years for toy poodles, whereas the shortest was 6.5 and 5.5 years for two larger breeds, the Finnish Lapphund and the Bloodhound, respectively (Michell 1999; Proschowsky et al. 2003). Thus, larger breeds do seem to have a significantly shorter lifespans. Additionally, cross-breed dogs tend to live longer than either of the two parental pure- breed dogs (Comfort 1960; Hayashidani et al. 1988; Proschowsky et al. 2003; Patronek et al. 1997), intact dogs tend to have a shorter lifespans compared with neutered dogs (Hoffman et al. 2013; Michell 1999), and females tend to achieve exceptional longevity more often than males (Waters et al. 2009). It is important to note that within breeds, larger and heavier individuals have similar lifespans to those of smaller individuals (Galis et al. 2007; Jones et al. 2008). For example, standard poodles (26 kg) lived 9.6 years on average, while their miniature poodle counterpart (3.4 kg) had a mean lifespan of 10.2 years. This is an interesting phenomenon that may add variation to this dataset and may be linked to insulin growth factor-1 (IGF-1) signaling and concentration inherent in each breed (read below; Gems and Partridge 2001; Greer et al. 2011). It is important to note, however, that small body size and longer lifespan are not uncommon within a species since mice (Miller et al. 2000), horse and humans (Samaras et al. 2003) seem to correlate small size with longer lives.
Reproduction and body size
There are significant allometric relationships between adult body size and several reproductive parameters in canids, such as, gestation length, birth weight and litter weight (Geffen et al. 1996). I found that litters with the fewest pups tend to come from smaller dog breeds, such as the 2.5 kg Pomeranian with an average litter size of 2.37 pups. Whereas the largest number of pups per litter comes from larger breeds, such as the 29 kg flat-coated retriever with an average litter size of 8.3 pups (Fig. 2) (Fiszdon and Kowalczyk 2009; Geffen et al. 1996; Thomassen et al. 2006; Robinson 1973; Borge et al. 2011), highlighting a positive relationship between litter size and body mass (Scantlebury et al. 2001; Robinson 1973; Kirkwood 1985; Borge et al. 2011). In a study, comparing 30 kg-Labradors and 6 kg-Schnauzers during peak lactation, the energetic demands of the larger longer growing Labrador pups were met by an increase in the intake of metabolizable energy by the mother (Scantlebury et al. 2000). Large Labrador pups compared with schnauzer pups had greater growth and energy requirements (Scantlebury et al. 2001). Hence, larger dogs seem to have an increased investment in reproduction, with large litter sizes, a life-history trade-off that is often associated with shorter lives (Ricklefs 2010).
Growth rates and body size
Species with high adult body mass grow slower than those with low adult body mass across the animal kingdom (Ricklefs 1974; Dmitriew 2011), but whether differences in growth rate between small and large dog breeds are fully explained by adult body size has only begun to be examined. Growth rates are directly related to energy requirement and should be affected by body size (Hawthorne et al. 2004). Data on dog relative growth rates were compiled from the literature (Hawthorne et al. 2004; Posada et al. 2014) and compared to adult dog body weight (Fig. 3). I found that smaller dogs have a significantly faster relative growth rates compared with larger dog breeds, in accordance with others (Hawthorne et al. 2004; Fiszdon and Kowalczyk 2009; Helmsmüller et al. 2013; Posada et al. 2014). For example, Papillons (2 kg) reached 50 % of their adult body mass in 11 weeks, compared with 22 weeks for an English Mastiff (67 kg), a doubling of the time for a smaller dog (Hawthorne et al. 2004; Fig. 3). In even starker contrast, when two populations of differently sized beagles were compared, larger sized beagles reached 50 % of their adult body mass in 14.8 weeks (Helmsmüller et al. 2013), while the smaller sized beagles reached 50 % of their adult body mass in half of the time, 7.1 weeks. Smaller breeds tend to reach 99 % of their adult body mass in about 10 months, whereas larger breeds continue growing until 11–15 months of age (Helmsmüller et al. 2013; Posada et al. 2014; Hawthorne et al. 2004). Some suggest that larger breeds have higher growth rates (Galis et al. 2007), and grow for longer periods of time (Allard et al. 1988). In turn, longer developmental trajectories would amass higher cell turnover, which is required for continual growth, and higher cellular turnover rates may lead to mutations that are not repaired or eliminated leading to early senescence or disease (Greer et al. 2011). Some authors have suggested that longer developmental trajectories are associated with increases in reactive oxygen species (ROS) production. Larger breeds could be burdened with increases in oxidative damage for prolonged periods of time during early life, leading to higher rates of diseases associated with free radical damage, and hence, early mortality (Rollo 2002; Galis et al. 2007; Kraus et al. 2013; more on this below). However, effects of faster growth rates on smaller breeds and the cellular impact these may have on whole-animal physiology have largely been ignored in the literature.
Whole-animal metabolism and body size
The rate of metabolism is the speed at which organisms use energy; it governs biological processes that influence rates of growth and reproduction, and may have a direct or indirect influence on lifespan (Kleiber 1947; McNab 1997). The most common index of metabolic rate is basal metabolic rate (BMR), the minimal metabolic rate of a quiescent, post-absorptive animal, in its thermal neutral zone and rest phase (McNab 1997). Over a century ago, Rubner (1883) established empirically that larger animals have lower mass-specific metabolic rates compared with smaller animals. This came after the theoretical assessment that heat dissipation had to be directly proportional to the animal’s surface area: volume (SA:V), so that smaller animals with their relatively larger surface should have a higher rate of heat production (Schmidt-Nielsen 1984). Ironically, Rubner’s first paper on this matter used dogs as his study organism and elucidated that smaller dogs have higher mass-specific metabolic rates. I compiled BMR and maximal metabolic rate (MMR) data for dogs of all sizes from the literature [Heusner 1991 (and references therein); Speakman et al. 2003; Bermingham et al. 2014; Scantlebury et al. 2001; Ahlstrøm et al. 2011; Taylor and Heglund 1982], and found a significant decrease in whole-animal BMR in smaller dogs (Fig. 4). A 2.47-Kg Papillon showed the lowest whole-animal BMR and a 60.7-Kg mixed breed showed the highest whole-animal BMR. Although others have pointed out that in the animal kingdom, the relationship between lifespan and mass-specific metabolism of animals includes all potential patterns of association- positive, negative or not significant (Speakman et al. 2003), in dogs, there is a clear positive relationship.
Dogs participate in a wide range of different forms of physical activity, such as hunting, swimming, working as rescue dogs; and for the elite athletes, there is the Iditarod, which is a 1000-mile sled race across the Alaskan tundra ran by dogs (Larsson et al. 2010). It is generally assumed that 90 % of the energy consumed during exercise is due to muscle performance (Taylor and Heglund 1982). Additionally, it has been suggested that BMR, and MMR are functionally coupled (Bennett and Ruben 1979). MMR sharply increases in comparison to BMR in dogs (Larsson et al. 2010). However, it is remarkable that with the tremendous variation in body size, morphology and breed-specific tasks, we still see significant increases with body size in whole-animal maximal metabolic rate in dogs (Fig. 4). There was a 21-fold increase from BMR to MMR. I should mention here that the BMR and MMR for Alaskan Iditarod race dogs were significantly higher than averages I compiled of hunting dogs or house pets during exercise, and, hence, excluded from my dataset. However, these 23-Kg dogs had a 10,500 kJ/day BMR and 47,100 kJ/day MMR, the highest ever measured in a mammal (Hinchcliff et al. 1997). Variation in MMR can be due to each breed’s physiology and morphology, and also each individual’s performance for the task at hand (Larsson et al. 2010). A hunting dog will work hard to find its goal, but this activity will alternate between sniffing while slowly trotting to get a scent trail and burst running towards its prize. Comparatively, an Iditarod sled dog will be running for 10–12 h of the day, and thus, show a higher MMR compared with the hunting dog (Hinchcliff et al. 1997; Ahlstrom et al. 2011).
Mass-specific metabolic rate significantly decreases across body sizes as dog’s age (Kienzle and Rainbird 1991; Speakman et al. 2003). The cause of age-related decline is not entirely clear, but possible contributors include an age-related decline in organ mass, a decrease in mitochondrial content or mitochondrial function in dog cells as they age, decreases in pumping of ions across membranes and repair mechanisms that are actively shutting down with increases in age (Speakman et al. 2003).
Organ sizes and body size: how do they relate to metabolic rate?
Variation in BMR has been shown to be related to the relative size of central organs in some studies (Daan et al. 1990; Piersma et al. 1996; Nespolo et al. 2002; Brzek et al. 2007), but not others (Tieleman et al. 2003). Relative organ size data for puppy and adult dogs were divided into three size classes, small (up to 10 kg for adult BM), medium (10–20 kg for adult BM), and large (20 kg and upwards for adult BM). Relative organ size data for puppies revealed that bone mass was significantly higher for the larger breeds compared with the smaller breeds, and fat mass was significantly higher in the smaller breeds compared with the larger (Fig. 5a). However, this data set was largely sample size limited. For adult dogs, I was not able to find bone mass data for the small size class to draw comparisons with developmental puppy data (Fig. 5b). Relative skeletal muscle mass was significantly higher in the larger breeds compared with the smaller breeds (Fig. 5b). This result is not entirely surprising since functional demands in different body shapes in mixed-breeds, hound-type and beagles gave rise to differing proportions of muscle mass to body weight in these three types of dogs (Kuzon et al. 1989). Athletes also have a different functional demand than sedentary dogs. For example, Greyhounds have undergone intense artificial selection for maximal running speed and, thus, contain the highest proportion of muscle to body mass at 57 %, while in other dog breeds (mixed breed and purebred) this proportion is approximately 44 % (Gunn 1978). Comparatively, another breed that has been intensely selected for fighting, the Pit bull, demonstrated different functional trade-offs for optimal performance by having more muscle mass in their distal limbs and stronger muscles in their forelimbs, and their hind limb (Pasi and Carrier 2003).
Although skeletal muscle has a relatively low tissue-specific metabolism at rest, it makes up the largest fraction of body mass, and therefore, contributes more to BMR than any other tissue (Martin and Fuhrman 1955; Rolfe and Brown 1997). Skeletal muscle accounted for 61.5 % of BMR in dogs (Martin and Fuhrman 1955); the percentage of BMR devoted to muscle mass doubles from a small dog to a larger dog. Thus, a proportional increase in muscle mass in larger dogs may be a metabolic sink for energy, and tend to increase the individual’s BMR. But larger dogs have significantly lower mass-specific metabolic rates compared with smaller breeds (Fig. 4). Thus, there must be a physiological adaptation that allows larger breeds to have proportionally more muscle mass and lower mass-specific metabolic rates. Mammalian muscle fiber size tends to be ~10–100 µm in diameter, a size that seems to be largely dictated by diffusion limitations (Kinsey et al. 2007). Nonetheless, there is a trade-off between optimal diffusion distances in muscle fibers and the cost of maintaining the membrane potential in this tissue. Large muscle fibers compared with small muscle fibers had a decreased cost of basal maintenance via a decrease in cost of Na+-K+-ATPase pumping, and provided metabolic cost savings to animals with larger muscle fiber diameters (Jimenez et al. 2013; Jimenez and Williams 2014). So, another functional difference in larger breeds could be the percentage of different muscle fiber types and muscle fiber sizes across breeds.
Relative size of liver, kidney and brain size were significantly smaller in larger breeds compared with smaller breeds (Fig. 5b), in agreement with previous studies (Kirkwood 1985). The central organs like the liver and kidneys are thought to be major contributors to BMR (Daan et al. 1991). Thus, a decrease in metabolically active organs in larger breeds may support their decreased mass-specific metabolic rate (Porter 2001). Liver was the second-highest consumer of metabolic rate in dogs at 11.9 % of total BMR (Martin and Fuhrman 1955).
Aging, in general, comes with a progressive reduction in the ability of an organism to meet the demands of its environment: a decreased metabolic rate, reduced activity, increased fat content, a decreased number of liver cells with a related increase in fibrous tissue in the liver, decline in kidney function, decreased secretion of growth hormone, loss of muscle and bone mass, and decreased cardiac output (Mosier 1989). As dogs age, organ masses may decrease. For example, Great Danes progressively gained body fat as they aged, hypothetically due to a decrease in resting metabolic rate with age (Speakman et al. 2003), but Labradors and Papillons did not. Metabolic intensity of tissues is thought to vary due to differences in numbers of mitochondria within cells (Else and Hulbert 1985; Moyes 2003; Porter 2001; Suarez 1996), concentrations of metabolic enzymes (Garrido et al. 1996), activity or quantity of the membrane sodium–potassium ATPase pump (Wu et al. 2004; Jimenez et al. 2013), and the number of double bonds in fatty acids of cell membranes (Brzek et al. 2007; Hulbert and Else 2005). All of these aging patterns may occur at different rates in small dogs compared with larger dogs, giving rise to the differences in aging rates and lifespan. Dog size influences metabolic rate which, in turn, may influence cellular phenotypes and the rate at which tissues are bombarded by ROS production (Austad 2005), a potential determinant in the rate of aging (read below). For the rest of this review, I will examine cellular consequences and possible phenotypes of dog size and their potential relationship to metabolic rate.
Linkages between whole-organism physiology and cell biology
Cellular parameters, such as rates of proliferation or length of telomeres, may be involved in determining maximal lifespan in dogs. Primary fibroblasts have been established as a useful model system for many animals because of their ease of use in tissue culture and abundance in the body (Morell and Froesch 1973). Fibroblast cells orchestrate the synthesis of extracellular matrix constituents in connective tissue, and in the presence of tissue injury, these cells promote wound closure and tissue repair (Sorrell and Caplan 2004). Although, cellular work in dogs is limited, primary dermal fibroblasts growth potential was inversely associated with mortality, with the exception of Chihuahuas, Great Danes and Irish Wolfhounds (Li et al. 1996). However, growth rate of primary dermal fibroblasts in cell culture may be inversely proportional to the age of the animal they were isolated from (Mosier 1989), and Li and co-authors did not control for the age of the dog from which they isolated primary fibroblast cells, thus potentially confounding the results of this study.
Another component of cellular physiology that may be linked to the rate of aging is telomere length and rate of shortening. Telomeres maintain genomic integrity by protecting chromosome ends and tend to shorten with each cell division (Nasir et al. 2001). Since cellular division increases with age, we would expect a decrease in telomere length as animals increase in age, but at possibly different rates according to body mass. We know that telomere lengths decrease with age for certain breeds of dogs (McKevitt et al. 2002; Fick et al. 2012), but not others (Nasir et al. 2001). The retriever group, a larger bodied breed, seems to trend towards a decrease in telomere length with increasing age (Nasir et al. 2001). Oxidative stress plays a major role in telomere loss in different species (Fick et al. 2012). For example, replicative senescence in murine fibroblast cells was found to increase as a function of oxidative stress severely increasing DNA damage, so that cells at 20 % oxygen concentration had more DNA damage and stop replicating sooner than cells at 3 % oxygen concentration (Parrinello et al. 2003). Thus, chronic mild oxidative stress accelerates telomere shortening and shortens replicative lifespan of cells (von Zglinicki et al. 2003). If oxidative stress increases in larger dog breeds, we may see a more pronounced association between telomere shortening and lifespan, as is the case for the retriever group (Nasir et al. 2001).
How are reactive oxygen species (ROS) production and cellular metabolic rate linked?
Dog breeds provide a particularly valuable model for the “rate of living” theory of aging, among other theories (Speakman et al. 2003). Mitochondrial function is important for aging since it is the main source of energy in cells, and its byproducts are the main culprits of oxidative damage, in the form of ROS species. As a byproduct of normal oxidative phosphorylation, errant electrons form free radicals, such as O2 −, OH−, or H2O2 (Harman 2001), which can attack DNA, proteins, and lipids, causing impairment of function and ultimately cell death, if the damage cannot be repaired. At low levels, these ROS species are known to be essential for cell survival because of their role in gene regulation, cell signaling, and apoptosis (Sohal and Orr 2012; Dowling and Simmons 2009; Monaghan et al. 2009). However, at high levels, ROS production can potentially overwhelm the antioxidant capacity of the cell and exert oxidative stress changing gene expression, and causing structural damage (Dowling and Simmons 2009; Monaghan et al. 2009). Cells inherently contain molecules to combat damage from ROS production, broadly termed the antioxidant system, which includes enzymatic antioxidants, such as glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT), which function by catalyzing the oxidation of less biologically insulting molecules. Other antioxidant molecules, such as vitamin E and C, act as chain-breaking antioxidants, which can scavenge for ROS, remove them once they are formed, and further halt propagation of peroxidation (Nemec et al. 2000). The “oxidative stress” theory of aging states that aging is not a genetically programmed phenomenon, but it happens because of the deleterious damage of oxidative stress on the genetic machinery, successfully linking the balance between the accumulation of cellular damage and pro-oxidant concentration over time to give rise to the process of aging (Sohal and Allen 1990; Speakman et al. 2015). Gerontologists have turned their attention to whether oxidative stress is the principal, generalized mechanism in aging (Speakman et al. 2015). It has been suggested that ROS-induced oxidative damage is a key mechanism that acts to mediate life-history trade-offs in animals, as may be the case in dogs (Speakman and Selman 2011; Dowling and Simmons 2009; Halliwell and Gutteridge 1999).
High BMR should lead to elevated ROS production, but the literature is divergent on this matter (Barja et al. 1994). Previous work proposes that when respiration is high, proton flow across the inner mitochondrial membrane is maximized, and more ROS species are produced (Selman et al. 2012; Costantini et al. 2010). This implies that animals with higher BMR (larger dogs) would have higher ROS production by their mitochondria (Perez-Campo et al. 1998), and that these individuals should show high levels of tissue antioxidants to combat their high rates of ROS production (Barja et al. 1994; Herrero and Barja 1997; Lopez-Torres et al. 1993; Perez-Campo et al. 1998). In opposition, it has been suggested that when respiration slows, electrons accumulate in the electron transport chain instead of rapidly passing through the complexes. This would increase the amount of errant electrons available for ROS production, thus, ROS production would be highest when animals have low basal energy expenditure (smaller dogs) (Selman et al. 2012). The discrepancy between ROS production with inherent high or low BMR likely lays on the specific mitochondrial pathway responsible for energy expenditure, whether it is mitochondrial proton leak or ATP synthesis (Speakman et al. 2015). Furthermore, there are other mitochondrial transporters that may alter the rate of ROS production and increase BMR, such as uncoupling proteins (UCPs).
Much of the thermoregulatory energy to produce heat comes from the action of UCPs. UCPs are members of a mitochondrial transporter family that serves to dissipate the mitochondrial proton gradient as heat rather than ATP production (Palmieri 1994). There are three isoforms of this transporter, each with a different function within the mitochondria. UCP1 exists in brown adipose tissue and serves as a regulator for thermogenesis; UCP2 may serve to regulate hydrogen peroxide (H2O2) formation and modulate cellular events that may lead to cellular damage; and UCP3 is mainly expressed in skeletal muscle in mammals and is thought to also have thermoregulatory properties (Ishioka et al. 2002). UCP2 is ubiquitously expressed in all canine tissues, and UCP3 is expressed in heart and skeletal muscle of dogs. Every canine UCP has uncoupling activity (Ishioka et al. 2002). Increases in concentration of UCPs within cells, could decrease mitochondrial efficiency, thus, increasing oxygen consumption to meet ATP demand (Speakman 2005). BMR in smaller dogs may be associated with more uncoupled mitochondria because of their need to be ready for increased energy demands during cold exposure (Speakman et al. 2003). Additionally, since mitochondria are less efficient when UCPs are present, there may be a decrease in ROS production (Speakman 2005), and hence, less oxidative damage and a longer lifespan. It would be informative and exciting to define functional differences in UCPs in different dog breeds.
Oxidative damage has many key players and may be highly variable among tissues and different among breeds, so it is unsurprising that oxidative stress is not an easily predictable biological parameter (Glazier 2015; Speakman et al. 2015). Ultimately, the rate of oxidative damage is dictated not just by the rate of mitochondrial ROS production, but also by the amount of unsaturation in biological membranes adjacent to the site of ROS production (Hulbert et al. 2007). Polyunsaturated fatty acids (PUFA) exhibit highest sensitivity to oxidative damage, as these membranes contain a greater number of double bonds with an available electron to propagate damage across membranes (Pamplona et al. 1998). Membrane composition seems to be body size dependent, where large mammalian species have membranes that are less vulnerable to oxidative stress (Hulbert et al. 2007; Niitepold and Hanski 2013). On the other hand, mitochondrial membranes with a lower degree of unsaturation are negatively correlated with maximum lifespan; a low degree of fatty acid unsaturation could protect tissues against oxidative damage (Pamplona et al. 1998; Hulbert et al. 2007). Thus, hypothetically, an alteration of mitochondrial density, mitochondrial efficiency (UCP proteins), and saturation level in membranes are all important parameters in determining any possible damage caused by ROS production. Thus, the existing balance between ROS production and mechanisms that perpetuate and thwart oxidative damage in different dog breeds, and sizes may give us a clue as to how high mass-specific metabolic rates and long lifespans are biologically possible in this species.
Cellular resistance to oxidative stress in aging and other life-history traits
An age-related increase in mitochondrial formation of ROS is the basis of the free radical theory of aging. Mitochondrial DNA is continually exposed to ROS production. Increases in age are also associated with a concomitant decrease in antioxidant capacity, resulting in higher oxidative damage in older individuals (McMichael 2007). The oxidative status in dogs is variable and can be changed with diet or exercise (Todorova et al. 2005). Normally, lipid peroxidation increased and reduced glutathione decreased with age in dogs, leading to an imbalance between antioxidants and pro-oxidants and potential increases in oxidative stress (Gaal et al. 1996; Vajdovich et al. 1997; Todorova et al. 2005; Stowe et al. 2006). In contrast, Labrador retrievers’ total antioxidant potential in blood plasma in aging dogs did not alter with age although there was also an accumulation of DNA damage in older dogs in some studies (Blount et al. 2004), but when specific antioxidants in blood plasma, such as vitamin E, were examined, there seems to be a decrease with age (Stowe et al. 2006). Additionally, sex-differences in the level of enzymatic antioxidant activity in the blood exist so that older females had higher reduced glutathione and SOD activity (Vajdovich et al. 1997), a finding that may explain why female dogs tend to live longer than male dogs (Waters et al. 2009). In the dog brain, there are age-related increases in oxidative damage to lipids and proteins although reduced glutathione also increased (Head et al. 2002). Thus, we know that cellular damage may increase with age in dogs due to imbalances in oxidative stress in brain and in serum, but we do not know if this damage accumulation is different between differently sized dog breeds.
Smaller breeds are suggested to be able to delay age-related diseases, whereas larger breeds are battered with age-related diseases early on in life (Kraus et al. 2013). The onset of senescence occurs somewhat earlier in breeds over 50 kg, suggesting physiological frailty in large dogs (Kraus et al. 2013). In Rottweilers with exceptional longevity, there was a decrease in the likelihood that the dog would die of cancer after 10 years of age. This phenomenon could be linked to the universal resistance of cells to DNA damage and increased repair mechanisms (Cooley et al. 2003). DNA damage in peripheral blood leukocytes correlated with prostatic DNA damage, which designated dogs to be at higher risk of developing prostate cancer (Waters 2011). There may be some evidence that extreme aged Rottweilers experienced a delayed onset of major life-threatening diseases, but the biological mechanism underlying this pattern remains understudied. That “large dogs die young” has been a contested statement in the dog literature. Mortality data have been used to attest that larger breeds “die young,” an approach prone to a number of unavoidable biases (Galis et al. 2007; Kraus et al. 2013). So, functional data about oxidative stress in cells from different sized dogs need to be gathered to test this hypothesis and unveil any biological mechanisms that underlie these differences (Selman et al. 2013).
Costs of raised investment in growth and reproduction have traditionally been considered a diversion of limited somatic resources away from maintenance functions (Nussey et al. 2009). Biologists have argued that increased investment in growth and reproduction, comparable with larger dogs should result in an increased metabolic rate with a possible increase in ROS production and cellular damage (Monaghan et al. 2009). This question of increases in ROS damage with different absolute growth rates has been studied in a population of Soay sheep. Sheep that grew more rapidly in the first 4 months of life had increased levels of oxidative damage to phospholipids in their plasma (Nussey et al. 2009) as seems to be the case for smaller dogs. Thus, here is where life-history trade-offs for dogs start to become convoluted. Between species, slower growth rates that lead to larger body sizes imply a reduction in ROS damage, allowing for longer lifespan (Rollo 2002). However, the opposite is true for dogs: slower relative growth rates that lead to larger body sizes have a shorter lifespan and the underlying physiological mechanism for this is largely unexplored.
Comparison with other model organisms
Release of growth hormone (GH) from the pituitary increases the cellular production of insulin growth factor 1 (IGF-1) in tissues (Dantzer and Swanson 2012). In vertebrates, the insulin receptor regulates energy metabolism, whereas insulin growth factor type I receptor (IGF-1R) promotes growth (Holzenberger et al. 2003). Moreover, the GH/IGF-1 system is involved in body composition and maintenance of adult tissues as well as in gonadal function and regulation of puberty (Bartke 2005). IGF-1 is a major determinant of small body size in mice (Dantzer and Swanson 2012), humans (Dantzer and Swanson 2012), and dogs (Sutter et al. 2007; Rimbault and Ostrander 2012). As puppies, toy poodles, Great Danes, and Beagles seem to have similar plasma IGF-1 levels regardless of size (Nap et al. 1993; Favier et al. 2001). This may be the reason why within breed lifespan, as in the case of poodles, is similar despite body size. However, as dogs age, an increase in IGF-1 concentration has been linked to increased body mass in dogs (Gems and Partridge 2001; Greer et al. 2011). More recently, small dog skeletal size was closely associated with a IGF-1R gene substitution (Hoopes et al. 2012). Presumably, small size is a phenotypic marker of some developmental and/or metabolic characteristic that is predisposed to increased lifespan, but small size per se is unlikely linked to increases in lifespan (Bartke 2005).
Genetic alterations to the growth hormone (GH) pathway appear to regulate longevity, and body size in model organisms; providing a genotype that depicts a precise effect on cellular phenotypes (Bartke and Westbrook 2012). Progress has been made using model organisms to understand the role that the IGF signaling pathway and cellular resistance play in the aging. For example, some yeast strains and smaller bodied long-lived mice mutants, such as the Ames and Snell Dwarf strains, have reduced insulin signaling, enhanced sensitivity to insulin, and reduced IGF-1 plasma levels. These cellular differences come with further metabolic advantages in that long-lived mutants tend to have higher resistance to oxidative stress, a parameter essential to increased lifespan (Barbieri et al. 2003; Holzenberger et al. 2003). Reduced levels of GH, and IGF-1 are expected to reduce oxidative metabolism via a decrease in oxygen consumption (smaller breeds), and decrease in generation of mitochondrial ROS production, two plausible mechanisms that can be beneficial at the cellular level to delay aging (Bartke 2005). Increases in ROS production, however, can also be quenched if there is a strong antioxidant system, so as to not propagate cellular damage. Studies in the fruit fly, Drosophila melanogaster, demonstrate that there are beneficial effects of antioxidant enzymes with respect to increases in lifespan. For example, flies that showed an over-expression of the enzymes Cu–Zn SOD, and CAT had increased lifespans, and experiments injecting Caenorhabditis elegans with synthetic SOD and CAT also extended lifespan. In Ames dwarf mice, Cu–Zn SOD and CAT were significantly higher in the liver, kidney and hypothalamus compared with age- and sex-matched normal mice and showed significantly reduced oxidative DNA damage and protein carbonyl content (Bartke et al. 2001; Butler et al. 2003; Kuningas et al. 2008), an increased activity of these enzymes may provide this strain of mice with increased protection from ROS production and contribute to their longevity. Although, other studies have also found that Ames dwarf mice generate fewer ROS compared with wild-type mice (Brown-Borg et al. 2001). Additionally, younger mice had comparatively higher activities of these enzymes than adult mice, suggesting that younger mice had increased protection from ROS damage in early life which may also contribute to increases in lifespan (Bartke et al. 2001). Primary fibroblasts from Snell and Ames dwarf mice are more resistant to oxidative stress compared with normal mice, a correlation that may imply that extended lifespan comes with an increase potential for dealing with oxidative stress (Sun et al. 2009; Bartke 2005). Some of these cellular phenotypes may also play a role in the relationship between metabolism and aging found in dogs.
In mammals, body size is dictated by many factors, but it is primarily the result of number of cells in the body and aging may be directly related to how many times these cells divide (de Magalhães and Faragher 2008). Ultimately, a larger number of cell divisions will result in a bigger organism. Snell dwarf mice have provided evidence that the number of cells in different organs is significantly reduced compared with wild-type mice. Since IGF-1 is mitogenic, and its concentration is reduced in Snell dwarf mice (as is the case with smaller dogs), it suggests that the number of cell divisions in Snell dwarf mice is lower compared with normal mice (Bartke et al. 2001). Ames dwarf mice are born the same size as their normal siblings, but their growth rate lags behind allowing for a smaller body size in adulthood (Bartke et al. 2001). Although smaller dogs have faster growth rates compared with larger dogs, their developmental growth trajectory is shorter. Thus, cellular proliferation rates due to development are shorter in smaller dogs, which may be a metabolic advantage and a commonality in pathways to increase lifespan.
In summary, the regulation of lifespan of C. elegans and D. melanogaster can be influenced by three pathways: the insulin signaling pathway, and oxidative stress resistance (Butler et al. 2003). Dwarf mice, such as Ames or Snell mice with growth hormone related mutations also show an increase in lifespan (Butler et al. 2003). In the example of Snell and Ames dwarf mice, extended mean and maximal longevity maybe directly linked to increased cellular resistance to oxidative stress, though speculative, a similar mechanism could be present in smaller dogs compared with larger ones (Vergara et al. 2004); providing evidence that IGF-1 signaling may have an evolutionarily conserved role in regulating cellular ROS production, oxidative stress resistance, and in turn, animal lifespan (Fig. 6).
Conclusions and future perspectives
The advantage of the dog as a model organism in aging and metabolism is as it highlights that lifespan is not a simple function of metabolic rate, and that longevity can be related to other biological processes that may be associated with body size (Glazier 2015). For example, high peak metabolic rates are positively correlated with lifespan in the butterfly, Melitaea cinxia (Niitepold and Hanski 2013), showing high energy requirements leading to increases in ROS production, higher oxidative damage and shortened lifespan may not be universally true, as may be the case for dogs.
The number of genes that control each trait in dogs, such as morphometric diversity, is small; a fact that likely reflects canine population structure (Rimbault and Ostrander 2012). Each dog breed is possibly a descendant from a small number of founders, and many breeds have undergone bottlenecks early in their development leading reduced gene diversity to control major traits (Rimbault and Ostrander 2012; Boyko et al. 2010). The GH/IGF-1 pathway is involved in the regulation of some key aspects of life-history evolution, such as puberty, gonadal function, body composition and maintenance of adult tissues. In fact, body composition changes during aging, such as increases in adipose tissue, and decreases in skeletal muscle mass have been linked to a decrease in pituitary GH secretion (Bartke 2005). Thus, that the dog is a metabolic anomaly may be simply due to this link between IGF-1 concentration and body size. Additionally, there is also a link between IGF-1 and the activation of hypertrophic muscle growth (Stitt et al. 2004), increases in IGF-1 with body size (Greer et al. 2011), could lead to increases in muscle fiber size and mass in larger dogs, a potential metabolic energetic saving (Jimenez et al. 2011, 2013).
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Acknowledgments
I would like to thank Dr. Elisabeth Huynh for her direction with organ size data from the veterinary literature. I am grateful to Drs. George Somero, Joe Williams and Ms. Clara Cooper-Mullin for their suggestions and insights on an earlier draft of this manuscript. The comments of three anonymous reviewers greatly improved this manuscript. And undoubtedly, I am grateful to my own dog, Emma, for inspiring me to wonder about the factors that may influence her lifespan.
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Communicated by I. D. Hume.
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Jimenez, A.G. Physiological underpinnings in life-history trade-offs in man’s most popular selection experiment: the dog. J Comp Physiol B 186, 813–827 (2016). https://doi.org/10.1007/s00360-016-1002-4
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DOI: https://doi.org/10.1007/s00360-016-1002-4