lecture 3 Alternative models

Question 1

advantages of traditional models of aging

Answer 1

-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,

Question 2

negligible Senescence examples

Answer 2

hydra, some jellyfish species, bristlecone pine

Question 3

animals with unusual lifespans?

Answer 3

naked mole rat

birds

Question 4

mice and rats (Advantages)

Answer 4

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

Question 5

What animals are not good models for neurodegeneration?

Answer 5

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)

Question 6

is the exclusive use of rodent models the best way to study aging?

Answer 6

would be like attempting to study a broad category on the same two people forever repeating this, so probably not

Question 7

Greenland shark (Somniosus microcephalus)

Answer 7

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

Question 8

Reasons NOT to study longest lived species

Answer 8

-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

Question 9

Reasons to study longest-lived species

Answer 9

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

Question 10

Hydra

Answer 10

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

Question 11

what two things are of greater priority to an organism than repair?

Answer 11

metabolism and reproduction

Question 12

Bristlecone pines

Answer 12

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

Question 13

Alerce tree, Gran Abuelo (Chile)

Answer 13

known as the great grandfather tree, the oldest living individual on earth

is older than the Methusaleh (bristlecone pine)

Question 14

new models for aging

Answer 14

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

Question 15

turquoise killifish

Answer 15

shortest-lived vertebrate in captivity

wide set of aging phenotypes including cancer

sequenced genome

efficient transgenesis

Question 16

Planarian

Answer 16

-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

Question 17

naked mole rat

Answer 17

exceptionally long-lived

resistant to cancer, age-related

breeds in captivity, sequenced genome

Question 18

comparative biogerontology

Answer 18

-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

Question 19

models of aging: wild vs laboratory rodents

Answer 19

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

Question 20

longer lifespans and delayed maturation in wild-derived mice

3 lines of wild mice (Mus musculus)

Answer 20

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

Question 21

advantages of laboratory mouse

Answer 21

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)

Question 22

Naked mole rat
Heterocephalus glaber

Answer 22

-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

Question 23

censorship

Answer 23

lost from the lifespan dataset due to non death reasons

e.g. animal transferred to another collection animal euthanized for research purposes

Question 24

conclusions from the naked mole rat

Answer 24

identifies them as non-aging mammal

-mortality does not increase with age for them

-they defy Gompertzian laws by not increasing with age

Question 25

problem with naked mole rat conclusion

Answer 25

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

Question 26

naked mole rats health function and disease

Answer 26

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

Question 27

compare skeletal muscle and cardiac mitochondria between mice and naked mole rat

Answer 27

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

Question 28

Carcinogenesis resistance in naked mole rats

Answer 28

key mechanisms in their multi-step carcinogenic pathway are efficient DNA repair pathways, cell-autonomous resistance to transformation, and dampened inflammatory response

Question 29

delayed aging and age-related disease resistance mechanisms in naked mole rats

Answer 29

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

Question 30

negligible senescence examples contd

Answer 30

conifers, hydra, jellyfish, clams, box turtles?

Question 31

long lifespan examples

Answer 31

whales, humans, Galapagos tortoise

Question 32

long lifespan for their size ("longer lifespan")

Answer 32

birds, bats, naked mole rats

Question 33

extended lifespan for species/genera ("longer lived")

Answer 33

Rockfish

Question 34

aging in birds

Answer 34

-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

Question 35

advantages of avian models for studies of basic aging processes

Answer 35

1. birds in general are significantly longer-lived than mammals of comparable body size and lifetime energy expenditures 2. there is a growing body of evidence suggesting that birds have special adaptations for resisting or slowing oxidative damage to cells/tissues 3. many cage and domestic birds are feasible and economical to maintain for aging studies 4. genome sequencing is completed for the domestic chicken, there are well-characterized strains with distinct physiological properties 5. additional data emerging on the genetics underlying important physiological differences between highly specialized strains of domestic poultry 6. many birds exhibit slow or negligible reproductive aging 7. wild birds provide excellent systems for monitoring aging in outbred wild vertebrates subject to natural evolutionary pressures 8. birds are already being utilized in aging studies and reliable biomarkers of avian aging have been identified

Question 36

Disadvantages/drawbacks to avian model studies

Answer 36

1. long-lived animals such as birds can be costly to maintain for longitudinal aging studies 2. best developed domestic avian lab models for studying aging are galliforms (e.g chicken, quail) which are relatively short-lived 3. genetic resources are currently limited for nonpoultry avian models of aging; isogenic inbred lab strains of any bird are currently unavailable 4. studies utilizing songbird models in the lab have focused primarily on neuroethology or nutrition rather than aging 5. studies of aging biomarkers in wild bird populations require monitoring of variables that are difficult to control or monitor over individual life span 6. the development of good avian models and biomarkers, including wild species requires adequate funding and interdisciplinary collaborations

Question 37

Most birds process more ______ tissue in a lifetime than mammals?

Answer 37

oxygen/gram

Question 38

how do birds do it?

Answer 38

-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

Question 39

genomics

Answer 39

-examining species that have exceptionally long lifespans -few animals available

Question 40

tortoise genomics

Answer 40

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

Question 41

Ming the clam

Answer 41

-the oldest animal -ocean quahog -507 years old