L3, Damage Theories I Flashcards
1
Q
Molecular mechanistic theory of aging:
A
- Insults and metabolism cause molecular damage to accumulate
- Cellular damage and dysfunction accrue over time, leading to cell death and cancer
- Tissue and organ tissue follow, resulting in organ failure and eventual system failure -> DEATH
2
Q
Leslie Orgel’s error catastrophe: Outline and issues
A
- 1960s theory; mistranslation of mRNA produces faulty proteins, propagating further mistranslation
- Easily disproved; no increase in altered/abnormal protein observed with age
- Producing non-functional proteins does not shorten lifespan
- DNA polymerase error rate does not change with age in mice
3
Q
Accumulation of somatic DNA damage (early theory of aging)
A
- Linked to MATA
- DNA damage leads to imperfect repair and thus mutations -> incorrect mRNA produces faulty proteins
4
Q
Rate of living theory:
A
- 1930s; Pearl described a coefficient relating rate of metabolism and lifespan (temperature thus important)
- Lifetime inversely correlated with rate of energy spending
- High mass-specific metabolic rate -> shorter lifespan
5
Q
Rubner’s constant:
A
- 1910s
- Experiments on various mammals, measuring resources used using isolated chambers for each individual
- Mammals tend to use about 200kcal/g body weight over their lifetime
- Effect of cold temperature slows metabolic rate -> increased lifespan
6
Q
Evidence for rate of living theory:
A
- Relationship between basal metabolic rate (BMR) and maximum lifespan potential (MLSP) of birds and mammals showed that BMR was inversely proportional to lifespan in both cases
- Statistically significant correlation (at least in homeotherms)
7
Q
Describe the Lifetime Energy Potential (LEP):
A
- Concept by Pearl, there is a finite amount of metabolic work an organism can complete before failure -> in theory, consistent across organisms
- LEP: Total lifetime metabolic work (per Kg tissue)
- In mammals this amounts to about 60k litres oxygen / kg tissue / lifetime
- LEP differs across phyla; compared to mammals, birds had 4x bigger LEP whereas reptiles had 5x smaller LEP
8
Q
LEP exceptions:
A
- Little brown bat: Half size of mouse and high BMR as expected but can live to 30 years in wild
- Storm petrel (seabird): Smaller seabird living over 37 years
- Intraspecies variation: Insect colony queens can live to 28 years old
- Variation in primates (humans vs apes)
9
Q
Free radical theory of aging:
A
- 1950s, Harman
- Irradiation induces free radical formation and shortens lifespan
- ROS = natural byproduct of aerobic metabolism
- Faster BMR -> more ROS -> more damage -> shorter life
- Suggests aging is due to accumulation of oxidative damage on biomacromolecules, cells, tissues, organs (presumably modifiable by environmental and genetic factors)
10
Q
ROS formation and reduction:
A
- Formed during electron transport in mitochondrial oxidative phosphorylation
- Hydroxyl radical created in fenton reaction from superoxides by oxidation of Fe(II)
- Lots of enzymes exist to detoxify these materials (e.g. SOD converts superoxides into hydrogen peroxides)
- Catalase produces water and oxygen from hydrogen peroxide
- Draw out mechanisms…
11
Q
Supporting evidence for FRTA (cell biology):
A
- Existence of extensive enzymes and mechanisms for detoxification of ROS
- SOD, catalase, GSH system, reductase, peroxidases, S-transferases etc
- Hydrophilic and lipophilic scavengers
12
Q
Supporting evidence for FRTA (experimental):
A
- Houseflies with clipped wings and thus less activity lived longer than flies that could fly despite same LEP, less ROS damage
- MRSA overexpression in neurons (reduces oxidised ET) -> increased lifespan in flies, also resistant to paraquat (a superoxide generator)
- Mammalian tissues: Susceptibility to x-ray damage correlates to max lifespan
- However, there is a lot of counterevidence
13
Q
What types of biomolecules are affected by oxidants? (x4):
A
- DNA
- Lipids
- Proteins
- Sugars
14
Q
Commonly observed DNA oxidation product:
A
- 8-oxoG is a modified base commonly observed -> mutagenic if not repaired by BER
- In women, 8-oxoG excretion correlated with oxygen consumption
15
Q
Lipid peroxidation:
Mechanism, further products
A
- Lipid peroxidation occurs a lot to membrane lipids (with a bis-allylic hydrogen) -> lipids radicals -> chain reaction propagates throughout membrane eventually producing more stable lipid peroxides
- MDA and HNE are most commonly measured (short lasting)
- Adducts of lysine and other amino acid adducts are more stable
16
Q
Overall peroxidation index:
A
- Determined by amount of bis-allylic hydrogens in the lipids making up the membrane
- Strong relationship shown between peroxidation index and maximum lifespan
17
Q
Membrane pacemaker theory
A
- Hulbert, 2010
- Low membrane poly-unsaturation -> low mass-specific metabolic rate ->…-> low ROS, low oxidative stress
- Vice versa
- Predicts that long-lived species will have more peroxidation-resistant membrane lipids than shorter living species
18
Q
Protein oxidation:
A
- e.g. Carbonylation
- Free or incompletely ligand-bound Fe ions or bound to proteins as iron-sulfur clusters
- Used as oxidative stress marker and biomarker of aging
19
Q
What are AGEs?
A
- Advanced Glycation End-products
- Produced in Maillard reactions (non-enzymatic reaction between reducing sugars and amine residues)
- Mostly glycoxidation products
- Probably part of a wider group of age-relate protein modifications
- e.g. HbA1c (glycated form of haemoglobin)
20
Q
+ 3 mammalian species that have exceptionally long-lifespans and peroxidation-resistant membranes:
A
- Human
- Echidna
- Naked mole rat
- The membrane of most crucial importance appears to be mitochondrial (human studies) -> follows since mitochondria are the site of respiration and free radical production
