Unit 7 - Introduction to Aging Flashcards Preview

Molecular and Cellular Princples of Medicine > Unit 7 - Introduction to Aging > Flashcards

Flashcards in Unit 7 - Introduction to Aging Deck (34):

how is aging related to disease?

overall progressive impairment of organ/tissue function, which predisposes to disease
-physiological process after reproductive phase of life, whose ultimate consequence is death
-but NOT a disease


what is sarcopenia? is it aging?

it is not aging, but a progressive loss of skeletal muscle mass from 1.5 to 1% per year after age 25
-aging "process" that causes frailty, but not necessarily disease and death


what is the Gompertz law of human mortality?

death rate increases exponentially with age in a protected environment, where external causes of death (famine, disease) are negligible
-after age of mid-20s, probability of dying doubles every 8 years
-shows mean lifespan (age at which 50% of population has died) and max lifespan (age at which oldest known member of a species has died, or mean lifespan of most long-lived 10% of the population)


how is life expectancy calculated?

average number of hears of life remaining in a given age, and uses number of births to calculate
-life expectancy is decreased due to childhood death and aging


what is the more accepted of the "programmed" theory of aging?

aging and death result from a decline in the force of natural selection on traits acting in late life
-so genes that have ill effeccts only at a later age are not exposed to presence of natural selection (b/c prior to reproductive age)
-thus the principal determinant in evolution of longevity is level of extrinsic mortality


what is the mutation accumulation theory of aging?

due to the extrinsic mortality and rarity of aged animals in a natural population, the force of selection is too weak to oppose accumulation of germ line mutations with late-acting deleterious effects
-"selection shadow" allows for a wide range of alleles with late deleterious effects to accumulate over generations with little or no check (dementia, osteoporosis, cataracts, etc.)


what is the disposal soma theory of aging?

somatic organism is maintained only for reproductive success, and that the soma becomes disposable after that
-limited amount of metabolic recourses that have to be divided between reproductive activities and maintenance of non-reproductive aspects of organism
-aging is the result of natural accumulation of damage, that can be repaired by organism at expense of reproductive effort (IOW: longevity has its cost)


what is lifespan determined by?

balance of resources invested in longevity VS reproductive fitness in a specific natural environment
-carries evolutionary trade-off that reduces reproductive fitness
-function of reproductive strategies in a specific environment
-shaped as a result of selective pressures to optimize reproductive fitness of organisms that die from predation and environmental hazards in specific environments


what does evolution act to do, and when is the longevity trait chosen for?

evolution primarily maximizes reproductive fitness, and longevity is only selected for if it's beneficial for reproductive success


what is the antagonistic pleiotropy theory of aging?

some genes may be selected for beneficial effects on reproductive and survival successes early in life, but the same genes have unselected deleterious effects with age, which contribute directly to aging
-so if extrinsic hazards are high, investment in reproductive success becomes high, and deleterious genes accumulate at earlier ages, so there is a short life expectancy, and vice versa
-best example: rats (4 year lifespan; high reproduction) VS naked molerats (30 year lifespan; higher soma maintenance)


what is compression of morbidity?

age-associated diseases are compressed in last 5% of life
-slowing down aging process may delay onset of aging-related degenerative disorders
-may improve "healthspan"


what is one known way to increase healthspan?

in people with early onset degenerative diseases
-manipulating aging process could be used to treat this disease to extend BOTH lifespan and healthspan


what are the 9 hallmark/theories of aging?

1. genome instability
2. telomere attrition
3. epigenetic alterations
4. proteostatic stress
5. deregulated nutrient sensing
6. mitochondrial dysfunction
7. cellular senescence
8. stem cell exhaustion
9. altered intercellular communication


what does the free radical (oxidative stress) theory of aging require to be valid?

1. oxidative damage increases with size
2. extended lifespan should correlate with attenuated age-related oxidative damage
3. genetic or nutritional manipulations that increase oxidative stress should shorten lifespan and those reducing ROS production should extend lifespan


what happens in animals that are deficient in, or overexpress antioxidant enzymes?

don't support oxidative stress theory of aging
-they have no shortened or increased lifespan, even though all the activity increased/decreased


what is the mitochondrial theory of aging?

mitochondrial damage during aging is well documented, and dysfunctional mitochondria may contribute to aging by affecting the following in manner independent to ROS:
1. energy depletion
2. increase propensity of mitochondrial permeability transition (MPT) in response to stress, which increases apoptotic or necrotic cell death
3. defective Fe-S biosynthesis that can have effects on global cellular function
4. alters redox balance and ROS signaling, that has effects on global cellular function
5. affects global protein homeostasis


what does the cell senescence/telomere theory of aging predict?

replicative cellular senescence contributes to aging, and is consistent with antagonistic pleiotropy theory of aging (cell senescence would be beneficial in early life by suppressing cancer, but is detrimental later on by causing frailty in somatic tissues)
-predicts animals with longer telomeres have longer lifespan, but this theory is poorly conserved (mice have longer telomeres)


what is the somatic mutation theory of aging?

DNA damage is primary cause of aging
-supported by evidence in human and mouse that inherited deficiencies in DNA repair and genome maintenance genes often cause premature aging (progeroid syndromes)


what is the proteostatic stress theory of aging?

stress induced by protein homeostasis leads to protein dysfunction, disruption of cell membranes, formation of toxic protein aggregates, and apoptotic or non-apoptotic cell death


how is proteostatic signaling important in proteostasis?

molecular strategies like reducing PRo synthesis and increasing expression of molecular chaperones
-ex: heat shock response and ER unfolded protein response


why do dwarf mice life longer?

they are a third of the size, look younger, are less susceptible to cancer, with low insulin levels (less diabetes)
-due to defective GH and mutations in inuslin/IGF-1 receptor


what effect does insulin and IGF-1 usually have on aging? how can this be inhibited?

GH --> IGF-1 --> P13 kinase --> Akt --> mTOR --> aging
-PTEN inhibits P13 kinase
-FOXO inhibits aging, but is inhibited by Akt


what is the effect of FOXO proteins?

protect undamaged cells in energy-utilizing tissues in response to stress stimuli by entering self-preservation state


what does mTOR do?

participates in complexes mTORC1 and mTORC2
-1 has critical roles in promoting cell growth by stimulating protein synthesis, energy metabolism, and lipogenesis and by inhibiting autophagy


how much of longevity is attributable to hereditary factors?



FOXO3A function?

variations in trascriptional factor forkhead box O3A is linked to longevity in diverse populations of humans
-component of signaling pathways that control growth, metabolism, and stress resistance
-human counterpart of DAF-16


CETP function?

cholesteryl ester transfer protein is plasma protein that facilitates transport of cholesteryl esters and triglycerides between lipoproteins


APOC3 function?

component of VLDL that inhibits LPL and hepatic uptake of TG-rich particles


TOMM40 function?

encodes translocase on OMM, such that variation may contribute to lifespan differences


what are cellular defects associated with Hutchinson Gilford Progeria syndrome? why is it "segmental"?

-elevated DNA damage
-epigenetic alterations
-chronic p53 signaling
-metabolic alterations
-autophagy deregulation
-stem cell dysfunction
-protein dyshomeostasis
it's segmental because it recapitulates cardiovascular aging, but no cancer or neurodegeneration


why may caloric restriction increase lifespan?

decreased insulin/IGF and mTOR, with increased FOXO and AMPK causes decreased translation, and increased autophagy, stress response, and energy homeostasis, which all leads to longevity


what are 4 potential downstream effectors that explain beneficial effect of caloric restriction?

1. activation of FOXo transcriptional factor increases stress resistance
2. reduced mTOR signaling, which decreases PRO translation and improves PRO homeostasis
3. activation of AMPK pathway to remodel metabolism and improve energy homeostasis
4. increased autophagy due to FOXo and AMPK activation and TOR suppression removes damaged organelles and msifolded PRO


why does exercise decrease aging and by how much?

extends life expectancy by 4.5 years (obesity decreases by 5-7 years)
-increased ATP syntehsis and O2 consumption --> increased hormetic response and stress signaling --> increased mitochondrial density, metabolic capacity, and resistance to oxidative stress --> increased bioenergetic reserve --> increased ATP...
-the biogenic reserve and resistance to oxidative stress decrease aging


rapamycin pill?

in mice, it increased lifespan 15-20% if given at mid-life
-however, it's an immunosuppressant for cancer patients, so dangerous to keep taking