lecture 3 Alternative models Flashcards
advantages of traditional models of aging
-short lifespans
-availability of well-defined strains (many with different longevities)
-genome and transcriptome
-genome editing tools
animal husbandry: controlled management and production of the animals,
negligible Senescence examples
hydra, some jellyfish species, bristlecone pine
animals with unusual lifespans?
naked mole rat
birds
mice and rats (Advantages)
mammalian aging, share (with humans) many aging processes
-cardiomyocyte loss, muscle loss, muscle fiber loss
-available in large numbers, numerous strains (differing longevity)
-environmental control: diet, temperature, monitor activity, lack of infections, parasites
-genetic manipulation (transgenics)
-defined and known lifespan for many of the strains
What animals are not good models for neurodegeneration?
non-transgenic mice and rats are not good models of neurodegeneration because they normally do NOT develop Alzheimer’s disease
-there is considerable use of transgenic mice and rats to model species associated with neurodegeneration
e.g. expression of human amyloid precursor protein (hAPP) and beta-amyloid (AB)
APP/PS1: early-onset AD model
-expressed chimeric mouse/human amyloid precursor protein and a mutant human presenilin 1 (PS1)
is the exclusive use of rodent models the best way to study aging?
would be like attempting to study a broad category on the same two people forever repeating this, so probably not
Greenland shark (Somniosus microcephalus)
lifespan: 272-500 years
sexual maturity (females): approx 150 years
length: 6 metres
slow growth, slow movement only 2.9 km/hr compared to most sharks going 8km/hr
Reasons NOT to study longest lived species
-often have large body mass
-environmental control difficult or impossible to control
-diet, caloric intake, temp, external stress, predation/accidental death, metabolic rate
-rare species- very few animals to study
-longitudinal study often impractical
Reasons to study longest-lived species
makes intuitive sense
-something is allowing for those animals to survive for extended periods
-longitudinal possible for some
-housing (controlled environment) possible
-non-rodent studies needed
Hydra
adults have abundant stocks of adult stem cells–> maintenance of regenerative capacity
Hydra oligactis - when induced to a different temperature of 10 degrees showed signs of aging
-if you change the temperature they go from immortal to senescent
-they are able to do this because of STEM cells
what two things are of greater priority to an organism than repair?
metabolism and reproduction
Bristlecone pines
estimated maximum lifespan: 5000 years
the concept of senescence does not apply to these trees
-longevity is unaccompanied by the deterioration of meristem function in embryos, seedlings or mature trees
Alerce tree, Gran Abuelo (Chile)
known as the great grandfather tree, the oldest living individual on earth
is older than the Methusaleh (bristlecone pine)
new models for aging
animals with an extended lifespan
vertebrates with the short lifespan
animals with unusual aging e.g negligible senescence
mammals with unusually aging - longer lifespan than expected
turquoise killifish
shortest-lived vertebrate in captivity
wide set of aging phenotypes including cancer
sequenced genome
efficient transgenesis
Planarian
-potentially immortal lifespan
-pluripotent adult stem cell
-capable of whole body regeneration
-can perform RNAi screens
-if you chopped it in half, you would have two functioning planaria
naked mole rat
exceptionally long-lived
resistant to cancer, age-related
breeds in captivity, sequenced genome
comparative biogerontology
-raised questions about the rate of living theory
-metabolic rates dictate longevity
-high metabolic->high oxidative stress–> shorter lifespan
e.g. marsupials have 75% metabolic rate of eutherian mammals, yet a shorter lifespan
birds have a higher metabolic rate than mammals of similar size, yet longer lifespan
models of aging: wild vs laboratory rodents
hypothesis
labarotyr mice selected to adapt to lab breeding conditions
-inadvertent selection for rapid maturation and large body size may have resulted in the loss of alleles that retard the aging processes
longer lifespans and delayed maturation in wild-derived mice
3 lines of wild mice (Mus musculus)
Idaho, Pohnpei, and Majuro
-compared with mouse stock representatives of laboratory adapted gene pool
-BALB/c x C57BL/6
-longest lived idaho mouse 48 months
-not aware of a longer lifespan
advantages of laboratory mouse
easier to breed
homogenous genetics
well-recognized and well-characterized
aged mice often available
wild mice
-not selected for lab conditions (rapid breeding, docile, litter size etc)
Naked mole rat
Heterocephalus glaber
-the number of studies and articles on nmr has increased more and more
-extended lifespan
maximum lifepsan: early 30’s (years)
extended healthspan: approx. 75% of lifespan
-Subterranean = limited oxygen, low metabolic rate
live in colonies: several dozen mole rats
queen is dominant: similar to insect colonies
do not thermoregulate: thermoforms
form eusocial colonies, a reproductive queen, 1-3 male breeders, and subordinates whose sexual maturation is suppressed - they perform
their adaptation to underground lifestyle and sociality could contribute to their longevity
censorship
lost from the lifespan dataset due to non death reasons
e.g. animal transferred to another collection animal euthanized for research purposes
conclusions from the naked mole rat
identifies them as non-aging mammal
-mortality does not increase with age for them
-they defy Gompertzian laws by not increasing with age
problem with naked mole rat conclusion
there is a very low number of aged animals
-in the study, only 23 animals observed for 18 years or longer
-if similar to other mammals the mortality acceleration would occur after 17 years ( 50% of the lifespan)
-old age cohorts are crucial
-Gompertz mortality acceleration onset: and half of potential lifespan
-cannot calorically restrict them very well in the lab
naked mole rats health function and disease
they maintain cardiovascular function during the aging
-resistance to cardiac aging
young= 2-5 years
middle= 8-13
old age=17-24
-resistance to skeletal muscle aging
-sarcopenia is not seen
rarely develop cancer
compare skeletal muscle and cardiac mitochondria between mice and naked mole rat
comparable levels of H202 generation
capacity of mitochondria to consume H202 greater for NMR in both tissues (2-5x greater in NMR than mice)
** ability to deal with H2O2 was not that MUCH better in naked mole rats
Carcinogenesis resistance in naked mole rats
key mechanisms in their multi-step carcinogenic pathway are efficient DNA repair pathways, cell-autonomous resistance to transformation, and dampened inflammatory response
delayed aging and age-related disease resistance mechanisms in naked mole rats
High DNA repair capacity
genome-epigenome features
cell death/senescence regulation, attenuated inflammation, unique oxidative stress response, high
proteostasis
-they maintain genome stability, protein homeostasis, tissue integrity
negligible senescence examples contd
conifers, hydra, jellyfish, clams, box turtles?
long lifespan examples
whales, humans, Galapagos tortoise
long lifespan for their size (“longer lifespan”)
birds, bats, naked mole rats
extended lifespan for species/genera (“longer lived”)
Rockfish
aging in birds
-many birds live 3x longer than similarly sized mammals
-slow aging despite having a high metabolism
-have a high metabolic rate for their size
-e.g. canary (max lifespan is 24 years)
-cockatiel max lifespan is 20 years
advantages of avian models for studies of basic aging processes
- birds in general are significantly longer-lived than mammals of comparable body size and lifetime energy expenditures
- there is a growing body of evidence suggesting that birds have special adaptations for resisting or slowing oxidative damage to cells/tissues
- many cage and domestic birds are feasible and economical to maintain for aging studies
- genome sequencing is completed for the domestic chicken, there are well-characterized strains with distinct physiological properties
- additional data emerging on the genetics underlying important physiological differences between highly specialized strains of domestic poultry
- many birds exhibit slow or negligible reproductive aging
- wild birds provide excellent systems for monitoring aging in outbred wild vertebrates subject to natural evolutionary pressures
- birds are already being utilized in aging studies and reliable biomarkers of avian aging have been identified
Disadvantages/drawbacks to avian model studies
- long-lived animals such as birds can be costly to maintain for longitudinal aging studies
- best developed domestic avian lab models for studying aging are galliforms (e.g chicken, quail) which are relatively short-lived
- genetic resources are currently limited for nonpoultry avian models of aging; isogenic inbred lab strains of any bird are currently unavailable
- studies utilizing songbird models in the lab have focused primarily on neuroethology or nutrition rather than aging
- studies of aging biomarkers in wild bird populations require monitoring of variables that are difficult to control or monitor over individual life span
- the development of good avian models and biomarkers, including wild species requires adequate funding and interdisciplinary collaborations
Most birds process more ______ tissue in a lifetime than mammals?
oxygen/gram
how do birds do it?
-birds produce fewer ROS/O2 consumed
-H2O2 10x lower in pigeons than rats
birds may have a more efficient anti-oxidant defense system –> studies are contradictory
genomics
-examining species that have exceptionally long lifespans
-few animals available
tortoise genomics
lonesome george = Chelonoidis abingdonii
Aldabra giant tortoise = Aldabrachelys gigantea
identification of gene variants in tortoises
-DNA repair, mitochondrial function, inflammation, and cancer development
-maybe associated with gigantism and longevity
-cancer resistance
Ming the clam
-the oldest animal
-ocean quahog
-507 years old
