MCP Lecture 11

Question 1

What is aging?

Answer 1

overall progressive impairment of the functions of organs and tissue with an increasing risk of illness

Question 2

What is the Gompertz law of human mortality?

Answer 2

death rate increases exponentially with age in a protected environment where external causes of death become negligible (starting in mid 20s)

Question 3

How does evolution influence aging?

Answer 3

evolution selects genes that promote aging in order to limit population size or accelerate the turnover of generations - helps adapting to changing environments and available resources - aging results from a decline in the force of natural selection on traits acting in late life

Question 4

What is the mutation accumulation theory of aging? Example?

Answer 4

the force of selection is too weak to oppose the accumulation of germ-line mutations with late-acting deleterious effects
-Example: Huntington’s disease - avoids the force of selection

Question 5

What is the antagonistic pleiotropy theory of aging? Example?

Answer 5

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

• aging is a trade off of reproductive and survival success
• Example: bone calcification important for fitness in young - causes calcification of arteries and myocardiac infarction in old

Question 6

What is the disposal soma theory of aging? Example?

Answer 6

evolution acts primarily to maximize reproductive fitness
-soma (non-reproductive aspects) is maintained only for reproductive success and becomes disposable after reproductive success - aging = natural accumulation of damage to the stroma
Example: reduced pressure for reproductive success and increased resources for stroma = longer lifespan (different species of mice)

Question 7

What is aging a branch of study of?

Answer 7

gerontology - hope to develop interventions that possible modulate the rate of aging

Question 8

What is compression of morbidity?

Answer 8

the idea that slowing down the aging process may delay the onset of aging-related degenerative disorders (address the building blocks of aging)

Question 9

What are the cellular and molecular hallmarks in aged tissues?

Answer 9

1. genome instability
2. telomere attrition (shortening)
3. epigenetic alterations (methylation, post-translational modifications)
4. proteostatic stress (protein misfolding/aggregation)
5. deregulated nutrient sensing (reduced insulin)
6. mitochondrial dysfunction (increased ROS, mt DNA mutations, bioenergetic defects)
7. cellular senescence
8. stem cell exhaustion
9. altered intercellular communication

Question 10

What is the free radical theory of aging?

Answer 10

toxic byproducts of metabolism (hydroxyl radical esp) damage cellular components leading to aging - progressive damage of mitochondria by free radicals results in increased production of ROS

Question 11

What is the mitochondrial theory of aging?

Answer 11

mutations or deletions in mitochondrial DNA, oxidation of mitochondrial proteins, structural destabilization of respiration complexes, changes in membrane lipid composition, and alterations for mitochondrial dynamics and quality control

Question 12

How does dysfunctional mitochondria contribute to aging?

Answer 12

1. reduced energy production
2. increased apoptotic or necrotic cell death
3. defective iron-sulfur biosynthesis (affects nuclear genome stability)
4. altered redox balance and ROS signaling
5. affecting global protein homeostasis

Question 13

What is the cell senescence theory of aging?

Answer 13

permanent arrest of cell division due to DNA damage and telomere erosion (which are synthesized by telomerase not expressed in most somatic cells)
-cells remain metabolically active but have altered morphology, cell function, and proliferative capacity

Question 14

What is the cost/benefit of cell senescence?

Answer 14

benefit early in life by suppressing cancer

cost - becomes detrimental later on by causing frailty in somatic tissues

Question 15

What is the somatic mutation theory of aging?

Answer 15

DNA damage is the primary cause of aging and age-related accumulations of mutations

Question 16

What is Hutchinson Gilford Progeria Syndrome?

Answer 16

has mutations that accelerate the emergence of features of aging - specifically LMNA gene encoding lamin A (provides structural support to nucleus) - mutant form called progerin and causes nuclear defects

Question 17

What is the proteostatic stress theory of aging?

Answer 17

protein homeostasis critical for cell function
stress that induces loss of protein homeostasis leads to protein dysfunction, disruption of cell membranes, the formation of toxic protein aggregates, and apoptotic or non apoptotic cell death

Question 18

Which theory is most strongly supported?

Answer 18

proteostatic based on protein misfolding and aggregation increased in aged cells and degenerative diseases (alzheimer’s and parkinson’s)

Question 19

Why do dwarf mice stay healthy and look young?

Answer 19

mutations that reduce the growth hormone and secondarily IGF-1 signaling which shares same signaling pathway with insulin

Question 20

What is the IIS pathway?

Answer 20

insulin and IGF1 signaling pathway
-downstream effectors = FOXO family of transcriptional factors - increased FOXO and reduced mTOR signaling promotes longevity

Question 21

What do the FOXO proteins do?

Answer 21

active - promote transcription of genes involved in glucocneogenesis, autophage, cell cycle arrest, apoptosis, DNA repair and resistance to oxidative stress
-protect undamaged cells in energy-utilizing tissues in response to stress stimuli by entering self-preservation state

Question 22

What does mTOR do?

Answer 22

• Target of Rapamycin - family of kinases that are responsive to stress, nutrients and growth factors
• play a critical roll in promoting cell growth by stimulating protein synthesis, energy metabolism, lipogenesis, inhibit autophay

Question 23

What is Laron Syndrome?

Answer 23

human dwarfism - defective in growth hormone

-free on cancer, less DNA damage, lower blood insulin, no type II diabetes

Question 24

What genes are associated with longevity? What do they specifically do?

Answer 24

1. FOXO3A: component of signaling pathways that control growth, metabolism, and stress resistance
2. CETP: facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins
3. APOC3: component of VLDL - inhibits lipoprotein lipase and hepatic uptake of triglyceride-rich particles
4. TOMM40: encodes protein translocase on the mitochondrial outer membrane

Question 25

What are the downstream effectors of caloric restriction?

Answer 25

1. activation of FOXO transcriptional factor (increases antioxidant enzyme activity and autophagy)
2. Reduced mTOR signaling - decreases protein translation - improves protein homeostasis
3. activation of AMPK - stimulates beta oxidation of FA (improves energy homeostasis and reduces ROS production)
4. increased autophagy ^ those three stimulate autophage

Question 26

What are the anti-aging effects of physical activity?

Answer 26

1. increased bioenergetic reserve
2. increased metabolic capacity
3. increased resistance to oxidative stress
4. removing excess fat

Question 27

What is rapamycin? What are side effects?

Answer 27

inhibitor of mTOR (inhibition increases protein translation and improves protein homeostasis)
side effects: immunosuppression, impaired wound healing, insulin resistance, cataracts, testicular degeneration

Question 28

What is resveratrol?

Answer 28

anti aging compound found in red grape skins and red wines - increases motor coordination and other anti-aging effects