Mammalian Examples Of Lifeextension

It is well-established that longevity increased in the lineage leading to humans, yet the evolution of longevity occurred in other mammalian lineages as well (Figure 2.3).

Thus it is possible, and even likely, that life-extending strategies vary according to phylogeny. In other words, different mechanisms for long life may have evolved independently in different mammalian lineages. Identifying these mechanisms could potentially allow us to employ them in human medicine.

The best example is certainly the bowhead whale, which has been reported to live over 200 years (George et al., 1999). There is little knowledge of diseases affecting these animals. Still, given that bowhead whales weigh over 75 tons, they must feature some sort of anticancer mechanism(s) to prevent cancer from developing among their huge mass of cells (Austad, 1997b). Other whales too appear to have long lifespans. Animals of the Balaenopteridae family are generally long-lived: examples include the blue whale (Balaenoptera musculus) and the fin whale (Balaenoptera physalus) which may live over a century. Understanding why these species live so long may yield clues about antiaging mechanisms that are absent from humans, such as anticancer mechanisms. Similar examples include elephants (Elephas maximus and Loxodonta africana), which can live up to 80 years, and the dugong (Dugong dugon), which can live up to 70 years. All these mammals feature a long lifespan, a rate of aging, from what we know, comparable to that of humans, and are considerably bigger than us. The hippopotamus (Hippopotamus amphibius), which has a maximum lifespan of 61 years and an MRDT of 7 years, rhinoceros (Ceratotherium simum or Rhinoceros unicornis), which can live up to 50 years, and maybe even horses (Equus caballus), which can live nearly 60 years, may also fit this category. Identifying anticancer mechanisms in these species is thus a promising prospect.

Other specific life-preserving mechanisms may exist in several mammals. For example, the nabarlek (Petrogale concinna), a wallaby from northern Australia, apparently features continuous tooth development, termed poly-phyodonty (Department of the Environment and Heritage, 2000). Elephants also feature an unusual scheduling of tooth eruption and species of the Sirenia order—i.e., manatees (genus: Trichechus) and the dugong—may also feature some form of polyphyodonty (Finch, 1990). While progress in stem cells may allow teeth replacement in humans sooner than later (Ohazama et al., 2004), animals like the nabarlek and manatees demonstrate how numerous species may feature unique mechanisms to cope with nearly universal age-related diseases among mammals that also afflict humans. Even among strains of a given species there may be potentially useful phenotypes,

Figure 2.3. Maximum lifespan phylogentic tree for different mammalian orders. Obtained from AnAge, values represent the average tmax for species of each mammalian order and are expressed in years ± standard deviation. Afrotheria is not an order but rather a clade of mammals proposed, based on DNA analysis, to have a common origin. It includes the following families: Macroscelidea (n = 4), Tubulidentata (n = 1), Sirenia (n = 3), Hyracoidea (n = 3), Proboscidea (n = 2), and Tenrecidae (n = 7). Thus, it is normal for Afrotheria to feature a bigger standard deviation than other taxa. Phylogeny was drawn based on Springer et al. (2003). Branch lengths are not to scale.

Figure 2.3. Maximum lifespan phylogentic tree for different mammalian orders. Obtained from AnAge, values represent the average tmax for species of each mammalian order and are expressed in years ± standard deviation. Afrotheria is not an order but rather a clade of mammals proposed, based on DNA analysis, to have a common origin. It includes the following families: Macroscelidea (n = 4), Tubulidentata (n = 1), Sirenia (n = 3), Hyracoidea (n = 3), Proboscidea (n = 2), and Tenrecidae (n = 7). Thus, it is normal for Afrotheria to feature a bigger standard deviation than other taxa. Phylogeny was drawn based on Springer et al. (2003). Branch lengths are not to scale.

as exemplified in the regeneration capacity observed in the MRL mouse (Heber-Katz et al., 2004).

Potential Nonmammalian Models of Antiaging Strategies

Long-lived nonmammalian species may also feature antiaging mechanisms of potential use in human medicine that obviate, at least, some human age-related pathologies. The best examples are species that appear not to age, such as many types of turtles (order: Testudines). Species like Blanding's turtle (Emydoidea blandingii) and the painted turtle (Chrysemys picta) have been reported not to show signs of aging in studies lasting decades (Congdon et al., 2001, 2003). An increased reproductive output with age was also reported, in accordance with reports of de novo oogenesis in adult reptiles (Finch, 1990; Patnaik, 1994). Understanding the physiological basis of this phenomenon, also termed negligible senescence (Finch, 1990), has tremendous implications for gerontology but has so far been neglected. Further examples include the Aldabra tortoise (Geochelone gigantea) and the Galapagos tortoise (Geochelone elephantopus), which likely live over a century. Anecdotal evidence suggests the Galapagos tortoise reaches sexual maturity only after at least two decades, making it one of the vertebrates with the longest developmental period. Unfortunately, work on turtles is limited. There is some evidence that telomere biology is different in turtles (Girondot and Garcia, 1999), and some results suggest that the brains of turtles have enhanced mechanisms to protect against reactive oxygen species formation and damage (Lutz et al.,

2003). Likewise, neurogenesis may be predominant in reptiles (Font et al., 2001). Since other turtles may feature negligible senescence and oocyte regeneration (Finch, 1990), turtles are promising models for antiaging medicine (de Magalhaes, 2004).

Apart from turtles, other species with negligible senescence include bullfrogs (Rana catesbeiana), certain fishes such as rockfishes (genus: Sebastes) and sturgeons (family: Acipenseridae), as well as many lower life forms (Finch, 1990). It is possible, of course, that many other species feature negligible senescence, or at least slower rates of aging than humans, of which we know nothing about. Since all studied mammals age, incorporating nonaging species in studies of the biology of aging is auspicious. Species with negligible senescence are also promising models for identifying mechanisms that can be used to fight specific human age-related pathologies. For example, it was shown that the rainbow trout (Oncorhynchus mykiss) features high levels of telomerase and a continuous molting which may be partly responsible for its continuous growth and negligible rate of aging (Klapper et al., 1998). Moreover, species with negligible senescence are important in understanding how the genetic program, the genome, can be optimized for long-term survival. Certainly, there are great difficulties in studying, for instance, an animal that outlives humans and that is probably why most of these species have not been studied in detail. Modern high-throughput technologies, however, give researchers a host of new experimental opportunities (de Magalhaes and Toussaint,

2004). Sequencing the genome of these species should then be a priority.

Turtles are clearly the reptiles with the greatest potential as models of antiaging strategies. Nonetheless, while some short-lived reptiles show signs of aging, other long-lived reptilian species may be of interest. For example, de novo oogenesis has been reported in different reptiles, including alligators and lizards, plus the aforementioned turtles (Patnaik, 1994). The ability to regenerate oocytes in adulthood is crucial to avoid reproductive senescence and, according to evolutionary models, essential for the emergence of negligible senescence. Increased reproductive output with age has also been reported in other reptiles apart from turtles, such as in the northern fence lizard (Sceloporus undulatus) and in king snakes (Lampropeltis getulus), as well as other species (Finch, 1990; Patnaik, 1994). With the exception of turtles, the longest-lived reptile is the tuatara (Sphenodon punctatus), which lives at least 77 years, but possibly much longer (Patnaik, 1994). Tuataras are the only living descendants from the Rhynchocephalia order and thus have no closely related species. They are found only in New Zealand. Even though tuataras rarely exceed one kilogram in weight, they are long-lived, attaining sexual maturity after at least 10 years. Due to their unique evolutionary history and features, the tuatara is a potential model of antiaging strategies.

There are no confirmed birds with negligible senescence, though fulmars and the Andean condor age very slowly, if they age at all. The northern fulmar (Fulmarus glacialis), for example, likely ages more slowly than humans (Gosden, 1996). The longest-lived bird, however, is reported to be the Andean condor (Vultur gryphus), which can live up to 75 years. Senescence has not been described in these animals, though detailed studies are lacking (Finch, 1990). In the arctic tern (Sterna para-disaea) too no senescence has been demonstrated so far (Gosden, 1996). The record longevity for this species is only 34 years, but this particular 34-year-old individual appeared in excellent health and was actually released in the wild (Terres, 1980). Such cases again suggest that there may be many species aging more slowly than humans and about which we know little. The African grey parrot (Psittacus erithacus), the mute swan (Cygnus olor), the southern ground hornbill (Bucorvus cafer), and the Manchurian crane (Grus japonensis) have all been reported as living around 70 years. Interestingly, it has also been suggested that long-lived birds feature enhanced mechanisms of neurogenesis, protection against oxidative damage, and mechanisms against the formation of advanced glycosylation end products (Holmes et al., 2001).

Another bird of potential interest to gerontologists is the raven (Corvus corax), a passerine. Typically, Passer-iformes, corvids, and other species of the genus Corvus are short-lived, but ravens are clearly an exception. In the wild, ravens generally only live a few years, but in captivity their lifespan is likely above 70 years, with anecdotal reports of one raven living up to 80 years in captivity (Boarman and Heinrich, 1999). It would be interesting to know what physiological and genetic mechanisms make ravens live so much longer than their closest relatives. Likewise, more rigorous studies may reveal other long-lived species in the genus Corvus.

Although amphibians are not reported to be as long-lived as reptiles or mammals, they may prove useful for gerontology. The longest-lived amphibian is the Japanese giant salamander (Andrias japonicus), which reportedly can live up to 55 years. While this pales in comparison to whales and tortoises, amphibians do have some unique traits of potential use to medicine. One of them is how regenerative mechanisms in amphibians are more advanced than those of mammals. For example, amphibians can regenerate entire limbs while mammalian tissues, such as muscle, can regenerate only as isolated entities (Carlson, 2003). Limb regeneration has been particularly well-studied in newts, and it may have future applications in antiaging research. In one study, protein extracts derived from newts were able to dedifferentiate mouse muscle cells into stem cells. This process of dedifferentiation of adult cells appears then to be modulated by appropriate factors that can be potentially isolated in newts (McGann et al., 2001). Future studies to implement the regenerative capacity of some amphibians to humans are of great medical interest. Furthermore, while short-lived amphibians show signs of aging, long-lived amphibians may feature negligible senescence, polyphyodonty, and oocyte regeneration (Kara, 1994).

Among the large diversity of animals in the world there are certainly multiple processes that can be useful to prevent age-related pathologies in humans. For example, loss of auditory hair cells (AHCs) is a major cause of deafness in people and hence regeneration of these cells has considerable medical interest (Hawkins and Lovett, 2004). It is interesting to note that most mammals, contrary to most birds and amphibians and maybe even some bats (Kirkegaard and Jorgensen, 2002), lose the capacity to regenerate AHCs early in life. Therefore, it has been suggested that genomic tools may be used to understand the basis of this regenerative capacity and eventually apply it to mammals (Hawkins and Lovett, 2004). Another example is heart regeneration. Mammals and amphibians typically have a limited regenerative capacity of the heart muscle. The zebrafish (Danio rerio) heart, however, appears to have a robust capacity for regeneration based on the proliferation of cardiomyocytes which can avoid scar formation and allow cardiac regeneration (Poss et al. 2002). Thus, zebrafish may also be a powerful system to study antiaging or life-prolonging strategies of specific human age-related diseases (see chapters 27 and 28 in this book about the zebrafish). With the emerging age of genomics, it may soon be possible to employ genomic tools to identify life-extending genes and pathways absent from humans. For example, mammals appear to have lost the CPD-photolyase DNA-repair enzyme (Thoma, 1999). Certainly, other such genes exist and some may turn out to have life-extending functions.

These examples are only the tip of the iceberg. Among the extraordinary diversity of life forms on earth, including the thousands of vertebrates, we are likely to find many novel antiaging strategies. In Table 2.2 I present the examples cited above plus the longest-lived species for a number of vertebrate classes and selected mammalian orders. These represent species in which longevity likely evolved and hence may feature antiaging mechanisms. In theory, the longest-lived animals in each mammalian family are capable of delaying aging in relation to similar species, and thus studying these animals may allow us to identify not only genetic factors regulating aging rates but even life-extending mechanisms.

Conclusion

Maximum lifespan will likely continue to be used as the measure of aging in animal species. Even though other measures exist and should be implemented, tmax does give an estimate of rate of aging; it is the easiest method presently at our disposal, and tmax data are widely available—including in AnAge—making comparisons straightforward. It is not a perfect measure for comparing aging across species, but it is arguably the best.

More animal diversity is necessary in comparative studies of aging. Implementing novel models of aging should be welcomed independently of the species used. In the context of comparative studies of aging, though, there is no need to drift away from primates and rodents and certainly not from mammals. With sequencing technology becoming cheaper, in a near future it will become possible to sequence the genome of multiple species, and I predict comparative genomics to become the predominant tool in comparative studies of aging (de Magalhaes and Toussaint, 2004). Choosing which species to investigate will then become crucial. My rationale is that the best way to perform comparative genomics studies of aging is by focusing on primates plus a few rodents (Table 2.2).

Mammalian species, with a major bias toward primates and rodents, may allow us to understand the genetic factors that determine the pace of aging. Yet numerous other species, including long-lived mammals, reptiles, amphibians, fishes, and birds, may hold secrets to delay human age-related pathologies and maybe even the aging process itself. From species that appear to have escaped senescence, to animals featuring extreme forms of regeneration, passing by animals possessing specific traits that may be used to delay human age-related pathologies, multiple species may feature applications to antiaging research.

Recommended Resources

Readers are encouraged to visit the Human Ageing Genomic Resources (http://genomics.senescence.info), which features the AnAge database (http://genomics. senescence.info/species/).

How To Add Ten Years To Your Life

How To Add Ten Years To Your Life

When over eighty years of age, the poet Bryant said that he had added more than ten years to his life by taking a simple exercise while dressing in the morning. Those who knew Bryant and the facts of his life never doubted the truth of this statement.

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