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Naturally Long-lived Animal Models for the Study of Slow Aging and Longevity Donna J. Holmes

Naturally Long-lived Animal Models for the Study of Slow Aging and Longevity Donna J. Holmes University of Idaho Moscow, Idaho, USA. IABG10 Cambridge 2003. Outline. Characteristics of ideal animal models

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Naturally Long-lived Animal Models for the Study of Slow Aging and Longevity Donna J. Holmes

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  1. Naturally Long-lived Animal Models for the Study of Slow Aging and Longevity Donna J. Holmes University of Idaho Moscow, Idaho, USA IABG10 Cambridge 2003

  2. Outline • Characteristics of ideal animal models • Evolutionary and comparative rationale for adding some carefully selected long-lived animals to the biogerontological ‘toolkit’ • Some specific examples of feasible non-traditional animal models -Special focus on homeotherms

  3. The ideal animal model for aging studies: ___________________________________ • Specificity: has specific aging (or anti-aging) phenotype of interest -e.g. slow aging or other adaptations

  4. The ideal animal model for aging studies: ___________________________________ • Specificity: has specific aging (or anti-aging) phenotype of interest -e.g. slow aging or other adaptations • Generalizability: phenotype can be generalized or applied to other species of interest, e.g., humans

  5. The ideal animal model for aging studies: ___________________________________ • Specificity: has specific aging (or anti-aging) phenotype of interest -e.g. slow aging or other adaptations • Generalizability: phenotype can be generalized or applied to other species of interest, e.g., humans • Feasibility: must be practical for aging studies

  6. Rationale for using long-lived animal models to understand basic aging mechanisms is based in ‘evolutionary gerontology’: _____________________________________________ • Aging is understood to be a consequence of declining force of natural selection with waning reproductive potential • Basic biochemical aging (and anti-aging) mechanisms due to antagonistic pleiotropy are expected to be shared by a wide range of species • Aging (and anti-aging) mechanisms resulting from mutation accumulation expected to be idiosyncratic

  7. Evolutionary senescence theory predicts:In the absence of selection from high mortality rates, organims will evolve long life spans with adaptations for long-term somatic maintenance. Williams 1957. Evolution Edney & Gill 1966. Science. Rose 1991. Evolutionary Biology of Aging.

  8. Evolutionary senescence theory predicts:In the absence of selection from high mortality rates, organims will evolve long life spans with adaptations for long-term somatic maintenance. LONGEVITY EFFECTIVE PROTECTION Williams 1957. Evolution Edney & Gill 1966. Science. Rose 1991. Evolutionary Biology of Aging.

  9. Potential pitfalls of using only short-lived animal models from a narrow range of taxa: _____________________________________________ • Basic aging mechanisms in short-lived animals may differ qualitatively, as well as quantitatively, from those in long-lived species • Possibility of phylogenetic confounds: • Basic aging mechanisms in closely related species, like rats and mice, could result from common ancestry, rather than being generalizable to mammals

  10. Advantages of selecting animal models from among species with varied aging ratesand from a wide range of taxa: _________________________________________ • Common molecular bases for longevity are less likely to be confounded by common genetic ancestry (advantages of proper phylogenetic controls) • Distantly related species may have evolved different molecular solutions to problem of prolonged somatic maintenance • Or, distantly related species may prove to have common anti-aging mechanisms. Austad & Holmes. 1991. In B.P. Yu: Methods in Aging Research.

  11. Advantages of selecting animal models from among species with varied aging ratesand from a wide range of taxa: _________________________________________ • Common molecular bases for longevity are less likely to be confounded by common genetic ancestry (advantages of proper phylogenetic controls) • Distantly related species may have evolved different molecular solutions to problem of prolonged somatic maintenance • Or, distantly related species may prove to have common anti-aging mechanisms. = RULES FOR JUDICIOUS APPLICATION OF COMPARATIVE METHOD Austad & Holmes. 1991. In B.P. Yu: Methods in Aging Research.

  12. Advantages to using tractable long-lived animal models for aging studies: _______________________________________________ • Naturally long-lived animals are actually good at aging slowly • Genetic heterogeneity (raw material of natural selection) has been maintained • Many domestic species with established husbandry are available • Data from wild populations can elucidate the evolutionary basis for longevity

  13. Drawbacks to using “non-traditional” animals for aging studies: _______________________________________ • Possible lack of information on husbandry, including diet, medicine, breeding • No isogenic strains • Far less information available on genetics • Species of interest may be intimidating to handle or manage in captivity • Data from wild animal populations lacks internal controls; may be difficult to interpret

  14. Six kinds of animals with special potential for aging studies: _______________________________________ • Birds • Bats • Naked mole-rats • Turtles • Fishes • Insects other than Drosophila

  15. Six kinds of animals with special potential for aging studies: _______________________________________ • Birds • Bats • (Naked mole-rats) • Turtles • Fishes • (Insects other than Drosophila) HOMEOTHERMS VERTEBRATES ECTOTHERMS INVERTEBRATES

  16. 1. BIRDS(Class Aves) _______________________ • Remarkably long-lived: maximum recorded life spans generally 2-3 timesthose of mammals of similar body size -e.g., hummingbirds: MLS 10+ yrs songbirds: MLS 10 yrs parrots: MLS 80+ yrs Holmes & Austad 1995. J. Gerontol. Biol. Sci.

  17. 1. BIRDS(Class Aves) _______________________ • Remarkably long-lived: maximum recorded life spans generally 2-3 times those of mammals of similar body size -e.g., hummingbirds: MLS 10+ yrs songbirds: MLS 10 yrs parrots: MLS 80+ yrs • High lifetime energy expenditures: up to 8X times higher than similar-sized mammals Holmes & Austad 1995. J. Gerontol. Biol. Sci.

  18. 1. BIRDS(Class Aves) _______________________ • Remarkably long-lived: maximum recorded life spans generally 2-3 times those of mammals of similar body size -e.g., hummingbirds: MLS 10+ yrs songbirds: MLS 10 yrs parrots: MLS 80+ yrs • High lifetime energy expenditures: up to 8X times higher than similar-sized mammals • High plasma glucose levels (equivalent to diabetic levels for mammals) Holmes & Austad 1995. J. Gerontol. Biol. Sci.

  19. 1. BIRDS(Class Aves) _______________________ • Remarkably long-lived: maximum recorded life spans generally 2-3 times those of mammals of similar body size -e.g., hummingbirds: MLS 10+ yrs songbirds: MLS 10 yrs parrots: MLS 80+ yrs • High lifetime energy expenditures: up to 8X times higher than similar-sized mammals • High plasma glucose levels (equivalent to diabetic levels for mammals) +Slow reproductivesenescence; long post-reproductive life spans Holmes & Austad 1995. J. Gerontol. Biol. Sci.

  20. 1. BIRDS, continued ______________________ • Domestic bird species with well-established husbandry available -Small parrots, finches, pigeons, domestic poultry species • Small cage birds and quail breed readily in captivity; cost-effective maintenance, comparable to that of laboratory rodents Austad 1997. ILAR Journal; Holmes, et al. Exp. Gerontol. in press.

  21. 1. BIRDS, continued _________________________________ • An extensive demographic literature is available from mark-recapture studies of wild bird populations California Gull Sparrowhawk females males Newton (Ed.) 1989. Lifetime Reproduction in Birds; Holmes & Austad 1995. Amer. Zool.

  22. 1. BIRDS, continued _________________________________ • Bird tissues examined thus far show lower accumulation of AGEs (advanced glycoxidation end-products), including pentosidine Monnier 2001, In B.P. Yu (Ed.) Methods in Aging Research; Chaney & Klandorf 2003, Auk, etc.

  23. 1. BIRDS, continued _________________________________ • Birds have demonstrated exceptional resistance to oxidative damage

  24. 1. BIRDS, continued _________________________________ • Birds have demonstrated exceptional resistance to oxidative damage, probably including: • More efficient mitochondrial metabolism • Superior molecular protection • Better DNA repair • Both constitutive and inducible defenses, including peroxidation-resistant membranes and antioxidant enzymes Barja, et al. 1994. Free Rad. Res.; Barja 1998. Ann. N.Y. Acad. Sci.; Herrero & Barja 1998. Mech. Age. Dev.; Jaensch 2001. ; Ogburn, et al., 1998, 2001. J. Gerontol. Biol. Sci.

  25. 1. BIRDS, continued _________________________________ Birds are well established as animal models in neurobiology: • Male finches (zebra finch, canary) undergo seasonal regeneration of neurons in brain regions involved in song learning Nottebohm et al. 1994. PNAS; Scharff et al. 2000. Neuron.

  26. 1. BIRDS, continued _________________________________ • Birds are established models for studies of neuroendocrine aging: Ottinger 1991. Crit. Rev. Poult. Biol. Ottinger 2001. Exp. Gerontol.

  27. 1. BIRDS, continued _________________________________ • Birds are established models for studies of neuroendocrine aging: • Male Japanese quail retains hypothalamic neuroplasticity during aging CNS aging is primary (vs. gonadal aging); reproduction is restored in aged males with testosterone replacement; GnRH cells in hypothalamus remain responsive Ottinger 1991. Crit. Rev. Poult. Biol. Ottinger 2001. Exp. Gerontol.

  28. 1. BIRDS, continued • Birds are established models for studies of reproductive aging AVIAN OVARY Exposed yolky follicles Oviduct

  29. 1. BIRDS, continued • Birds are established models for studies of reproductive aging: • Domestic laying hen is an intensively used model for study of regulators of apoptosis and cell signaling in ovarian granulosa cells AVIAN OVARY Exposed yolky follicles e.g., Johnson 2000. Biol. Signals Recept.; Bridgham & Johnson 2001. Biol. Reprod.; Oviduct

  30. Some seabirds show apparently negligible reproductive senescence in the wild Northern Fulmar California Gull Common Tern Pugesek & Diem 1983. Science; Finch 1990.

  31. Some seabirds show apparently negligible reproductive senescencein the wild Northern Fulmar California Gull INFERTILITY Common Tern Pugesek & Diem 1983. Science; Finch 1990.

  32. Some seabirds show apparently negligible reproductive senescencein the wild Northern Fulmar California Gull INFERTILITY Female birds have potential as models for delayed fertility loss Common Tern Pugesek & Diem 1983. Science; Finch 1990.

  33. Birds lay eggs: Parental investment can easily be manipulated to assess the relationship between reproductive costs and aging rates

  34. 2. BATS(order Mammalia, class Chiroptera) ________________________________________ • Life spans up to several times longer than in similar-sized non-flying mammals -Little brown bat: MLS 34 yrs -Vampire bat: MLS 21 yrs -Horseshoe bat: MLS 26 yrs • Significantly higher metabolic rates and lifetime energy expenditures than non-flying mammals • Can be maintained in captivity; husbandry practices still being established

  35. 2. BATS(order Mammalia, class Chiroptera) ________________________________________ New work with bats supports the free radical theory of aging: • Adult little brown bats (Myotis lucifugus) have been shown to produce similar amounts of oxygen, but less • than half the hydrogen peroxide, produced by short-tailed shrews (Blarina brevicauda) • (A. Brunet Rossinni, in review, Exp. Gerontol.)

  36. 3. Naked Mole-Rat (class Mammalia, order Rodentia) ______________________________ • “Eusocial”, subterranean with termite-like caste system • One reproductive “queen”, tended by non-reproductive “workers” • Low metabolic rates for body size • Life spans of 25+ years • Numbers of established captive colonies Sherman, 2002. Proc. Roy. Acad. Sci. London. Biol. Sci.

  37. 3. Naked Mole-Rat (class Mammalia, order Rodentia) _______________________________ • “Eusocial”, subterranean with termite-like caste system • One reproductive “queen”, tended by non-reproductive “workers” • Low metabolic rates for body size • Life spans of 25+ years • Numbers of established captive colonies • No aging studies to date Sherman, 2002. Proc. Roy. Acad. Sci. London. Biol. Sci.

  38. Six kinds of animals with special potential for aging studies: _______________________________________ • Birds • Bats • (Naked mole-rats) • Turtles • Fishes • (Insects other than Drosophila) HOMEOTHERMS VERTEBRATES ECTOTHERMS INVERTEBRATES

  39. Conclusion: A substantial number of species represent unexploited but potentially feasible animal models for aging studies,

  40. Conclusion: A substantial number of species represent unexploited but potentially feasible animal models for aging studies, with specific adaptations for slow aging,

  41. Conclusion: A substantial number of species represent unexploited but potentially feasible animal models for aging studies, with specific adaptations for slow aging, and—in many cases--more generalizable to humans than standard laboratory animals.

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