Naturally Long-lived Animal Naturally Long-lived Animal Models for the Study of Models for the Study of

Slow Aging and LongevitySlow Aging and LongevityDonna J. Holmes

University of IdahoMoscow, Idaho, USA

IABG10Cambridge

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 non-traditional 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’evolutionary gerontology’:

_____________________________________________

• Aging is understood to be a consequence of declining force declining force of natural selection with waning reproductive potentialof natural selection with waning reproductive potential

• Basic biochemical aging (and anti-aging) mechanisms due to antagonistic pleiotropyantagonistic pleiotropy are expected to be shared by a wide range of species

• Aging (and anti-aging) mechanisms resulting from mutation mutation accumulationaccumulation 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.

Williams 1957. Evolution Edney & Gill 1966. Science.

Rose 1991. Evolutionary Biology of Aging.

EFFECTIVE PROTECTION LONGEVITY

Potential pitfalls of using only short-livedshort-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 ratesvaried aging rates

and from a wide range of taxawide 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 ratesvaried aging rates

and from a wide range of taxawide 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.

= RULES FOR JUDICIOUS APPLICATION OF COMPARATIVE METHOD

Advantages to using tractable long-livedlong-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:

_______________________________________

• 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:_______________________________________

1. Birds2. Bats3. Naked mole-rats4. Turtles5. Fishes6. Insects other than Drosophila

Six kinds of animals with special potential for aging studies:_______________________________________

1.1. BirdsBirds2.2. BatsBats3.3. (Naked mole-rats)(Naked mole-rats)4. Turtles5. Fishes6. (Insects other than Drosophila)

HOMEOTHERMS

ECTOTHERMS

VE

RTE

BR

ATE

S

INVERTEBRATES

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: 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.

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.

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.

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.

1. BIRDS, continued_________________________________• An extensive demographic literature is

available from mark-recapture studies of wild bird populations

Sparrowhawk

California Gull

Newton (Ed.) 1989. Lifetime Reproduction in Birds; Holmes & Austad 1995. Amer. Zool.

males

females

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

_________________________________

Birds are well established as animal models in neurobiologyneurobiology:– 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_________________________________• Birds are established models for studies of

neuroendocrine agingneuroendocrine aging:

Ottinger 1991. Crit. Rev. Poult. Biol.Ottinger 2001. Exp. Gerontol.

1. BIRDS, continued_________________________________• Birds are established models for studies of

neuroendocrine agingneuroendocrine 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 agingreproductive aging

AVIAN OVARY

Oviduct

Exposed yolkyfollicles

1. BIRDS, continued

• Birds are established models for studies of reproductive agingreproductive aging:

– Domestic laying hen is an intensively used model for study of regulators of apoptosis and cell signaling in ovarian granulosa cells

AVIAN OVARY

Oviduct

Exposed yolkyfollicles

e.g., Johnson 2000. Biol. Signals Recept.; Bridgham & Johnson 2001. Biol. Reprod.;

Some seabirds show apparently negligible reproductive senescence

in the wild

Northern Fulmar

Common Tern

California Gull

Pugesek & Diem 1983. Science; Finch 1990.

Some seabirds show apparently negligible reproductive senescence

in the wild

Northern Fulmar

Common Tern

California Gull

Pugesek & Diem 1983. Science; Finch 1990.

INFERTILITYINFERTILITY

Some seabirds show apparently negligible reproductive senescence

in the wild

Northern Fulmar

Common Tern

California Gull

Pugesek & Diem 1983. Science; Finch 1990.

Female birds have potential as models for delayed fertility loss

INFERTILITYINFERTILITY

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: 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

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.)

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.

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.

Six kinds of animals with special potential for aging studies:_______________________________________

1.1. BirdsBirds2.2. BatsBats3.3. (Naked mole-rats)(Naked mole-rats)4. Turtles5. Fishes6. (Insects other than Drosophila)

HOMEOTHERMS

ECTOTHERMS

VE

RTE

BR

ATE

S

INVERTEBRATES

Conclusion:

A substantial number of species represent unexploited but

potentially feasiblefeasible animal models for aging studies,

Conclusion:

A substantial number of species represent unexploited but

potentially feasiblefeasible animal models for aging studies,

with specificspecific adaptations for slow aging,

Conclusion:

A substantial number of species represent unexploited but

potentially feasiblefeasible animal models for aging studies,

with specificspecific adaptations for slow aging,

and—in many cases--more generalizablegeneralizable to humans than standard laboratory animals.