Naturally Longlived Animal Models for the Study of

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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
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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

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The ideal animal model for aging studies

• ___________________________________
• Specificity has specific aging (or anti-aging)
  phenotype of interest
• -e.g. slow aging or other adaptations

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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

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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

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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

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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.
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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.
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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

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Advantages of selecting animal models from among
species with varied aging rates and 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.
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Advantages of selecting animal models from among
species with varied aging rates and 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.
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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

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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

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Six kinds of animals with special potential for
aging studies

• _______________________________________
• Birds
• Bats
• Naked mole-rats
• Turtles
• Fishes
• Insects other than Drosophila

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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
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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

Holmes Austad 1995. J. Gerontol. Biol. Sci.
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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.
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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.
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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 reproductive senescence long
  post-reproductive life spans

Holmes Austad 1995. J. Gerontol. Biol. Sci.
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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.
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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.
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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.
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1. BIRDS, continued

• _________________________________
• Birds have demonstrated exceptional resistance to
  oxidative damage

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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.
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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.
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1. BIRDS, continued

• _________________________________
• Birds are established models for studies of
  neuroendocrine aging

Ottinger 1991. Crit. Rev. Poult. Biol. Ottinger
2001. Exp. Gerontol.
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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.
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1. BIRDS, continued

• Birds are established models for studies of
  reproductive aging

AVIAN OVARY
Exposed yolky follicles

Oviduct
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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
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Some seabirds show apparently negligible
reproductive senescence in the wild
Northern Fulmar
California Gull
Common Tern
Pugesek Diem 1983. Science Finch 1990.
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Some seabirds show apparently negligible
reproductive senescencein the wild
Northern Fulmar
California Gull
INFERTILITY
Common Tern
Pugesek Diem 1983. Science Finch 1990.
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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.
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Birds lay eggs
Parental investment can easily be manipulated to
assess the relationship between reproductive
costs and aging rates
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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

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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.)

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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.
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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.
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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
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Conclusion

• A substantial number of species represent
  unexploited but potentially feasible animal
  models for aging studies,

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Conclusion

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

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Conclusion

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