Transcript Slide 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
Outline
1.
Characteristics of ideal animal models
2. Evolutionary and comparative rationale for
adding some carefully selected long-lived
animals to the biogerontological ‘toolkit’
3. Some specific examples of feasible nontraditional animal models
-Special focus on homeotherms
The ideal animal model for
aging
studies:
___________________________________
1. Specificity: has specific aging (or anti-aging)
phenotype of interest
-e.g. slow aging or other adaptations
The ideal animal model for
aging
studies:
___________________________________
1. Specificity: has specific aging (or anti-aging)
phenotype of interest
-e.g. slow aging or other adaptations
2. Generalizability: phenotype can be generalized
or applied to other species of interest, e.g.,
humans
The ideal animal model for
aging
studies:
___________________________________
1. Specificity: has specific aging (or anti-aging)
phenotype of interest
-e.g. slow aging or other adaptations
2. Generalizability: phenotype can be generalized
or applied to other species of interest, e.g.,
humans
3. Feasibility: must be practical for aging studies
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
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.
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.
EFFECTIVE PROTECTION
Williams 1957. Evolution
Edney & Gill 1966. Science.
LONGEVITY
Rose 1991. Evolutionary
Biology of Aging.
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
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.
Advantages of selecting animal models from
among species with varied aging rates
and from a wide range of taxa:
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• 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.
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
Drawbacks to using “non-traditional”
animals for aging studies:
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• 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
Six kinds of animals with
special potential for aging studies:
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1.
2.
3.
4.
5.
6.
Birds
Bats
Naked mole-rats
Turtles
Fishes
Insects other than Drosophila
Six kinds of animals with
special potential for aging studies:
_______________________________________
1.
2.
3.
4.
5.
6.
Birds
HOMEOTHERMS
Bats
(Naked mole-rats)
Turtles
ECTOTHERMS
Fishes
INVERTEBRATES
(Insects other than Drosophila)
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.
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:
parrots:
MLS 10 yrs
MLS 80+ yrs
High lifetime energy expenditures: up to 8X
times higher than similar-sized mammals
Holmes & Austad 1995. J. Gerontol. Biol. Sci.
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:
parrots:
MLS 10 yrs
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.
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:
parrots:
MLS 10 yrs
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.
1. BIRDS, continued
______________________
•
Domestic bird species with wellestablished 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.
1. BIRDS, continued
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• 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.
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.
1. BIRDS, continued
_________________________________
• Birds have demonstrated exceptional
resistance to oxidative damage
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.
1. BIRDS, continued
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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.
1. BIRDS, continued
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• Birds are established models for studies of
neuroendocrine aging:
Ottinger 1991. Crit. Rev. Poult. Biol.
Ottinger 2001. Exp. Gerontol.
1. BIRDS, continued
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• 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.
1. BIRDS, continued
• Birds are established models for
studies of reproductive aging
AVIAN OVARY
Exposed yolky
follicles
Oviduct
1. BIRDS, continued
• Birds are established models for
studies of reproductive aging:
AVIAN OVARY
– Domestic laying hen is an intensively
used model for study of regulators of
apoptosis and cell signaling in ovarian
granulosa cells
Exposed yolky
follicles
Oviduct
e.g., Johnson 2000. Biol. Signals Recept.;
Bridgham & Johnson 2001. Biol. Reprod.;
Some seabirds show apparently
negligible reproductive senescence
in the wild
Northern Fulmar
California Gull
Common Tern
Pugesek & Diem 1983. Science; Finch 1990.
Some seabirds show apparently
negligible reproductive senescence
in the wild
Northern Fulmar
California Gull
INFERTILITY
Common Tern
Pugesek & Diem 1983. Science; Finch 1990.
Some seabirds show apparently
negligible reproductive senescence
in the wild
Northern Fulmar
California Gull
INFERTILITY
Common Tern
Female birds have
potential as models for
delayed fertility loss
Pugesek & Diem 1983. Science; Finch 1990.
Birds lay eggs:
Parental investment can easily be
manipulated to assess the relationship
between reproductive costs
and aging rates
2. BATS (order Mammalia,
class Chiroptera)
________________________________________
•
•
•
Life spans up to several times longer than
in similar-sized non-flying mammals
-Little brown bat:
-Vampire bat:
-Horseshoe bat:
MLS 34 yrs
MLS 21 yrs
MLS 26 yrs
Significantly higher metabolic rates and
lifetime energy expenditures than nonflying mammals
Can be maintained in captivity; husbandry
practices still being established
2. BATS (order Mammalia,
class Chiroptera)
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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.)
3. Naked Mole-Rat
(class Mammalia, order Rodentia)
______________________________
•
•
•
•
•
“Eusocial”, subterranean with termitelike 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.
3. Naked Mole-Rat
(class Mammalia, order Rodentia)
_______________________________
•
•
•
•
•
•
“Eusocial”, subterranean with termitelike 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.
Six kinds of animals with
special potential for aging studies:
_______________________________________
1.
2.
3.
4.
5.
6.
Birds
HOMEOTHERMS
Bats
(Naked mole-rats)
Turtles
ECTOTHERMS
Fishes
INVERTEBRATES
(Insects other than Drosophila)
Conclusion:
A substantial number of species
represent unexploited but
potentially feasible animal models
for aging studies,
Conclusion:
A substantial number of species
represent unexploited but
potentially feasible animal models
for aging studies,
with specific adaptations for slow
aging,
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.