+ Theories of Aging (Gems and Partridge) Flashcards
1
Q
Hyperfunction
Key pathologies, resultant theory of aging
A
- Purposeless continued activity of developmental programs in later life, leading most lethally to diseases of hypertrophy and hyperplasia
- ‘Aging is a sum of age-related pathologies; they are not distinct mechanisms’
- This idea is an alternative to the damage/maintenance paradigm
- Has led to the bloated soma theory of aging
2
Q
Bystander effects:
A
- Aspects of the aging process that are not contributing to loss of function
- e.g. greying hair
- Identifying bystander effects is a major challenge of biogerentology
3
Q
Lifespans of worms flies and mice:
A
- Worm: ~3 weeks
- Flies: ~3 months
- Mice: ~3 years
4
Q
Why have long-term randomised control trials of DR in humans struggled in comparison to short term?
A
- An extraordinary level of self control is required to sustain DR levels of food intake over long timespans
- Short term studies with volunteers have shown benefits consistent with the health benefits seen in rhesus monkeys
- e.g. Risk factors for atherosclerosis, delayed increased in heart-rate variability
5
Q
How were single-gene lifespan-extending mutations first identified in C.elegans?
A
- Systematic mutagenesis
- Initial candidates were part of IGF-1 signalling and IIS pathway
- Mutations in orthologous genes in flies and mice were also found to increase lifespan, as well as enacting a broad spectrum of health improvements
- -> evolutionarily conserved pathway
6
Q
Evidence for TOR signalling component as lifespan-extending in mice:
A
- S6K (Downstream effector of TOR) null mice -> long -lived with broad-spectrum health improvements
- TOR network is involved in sensing cellular nutritional conditions, particularly specific amino acids and energy status
- Multiple interactions and feedback loops between IIS and TOR
7
Q
Epistasis:
A
- Describes how gene interactions can affect phenotypes
- e.g. flower colour in peas
8
Q
Rapamycin:
A
- Macrolide drug approved for various conditions
- Inhibits activity of TOR kinase in a highly specific and potent manner
- Remarkably broad effects against aging and age-related diseases
- Shown to extend lifespan in both flies and mice
9
Q
TFs contributing to IIS effects on aging: (worm)
A
- HSF-1 heat shock TF
- Daf-12 nuclear receptor
- SKN-1 Nrf2 TF homolog -> DME expression
- SMK-1 and HCF-1 activators of FOXO
10
Q
Population genetic association studies in humans: FOXO
Name particular TFs in humans
A
- Studies have found enrichment in FOXO1a and FOXO3a in individuals who survive to late ages
11
Q
4E-BP role in TOR signalling:
A
- 4E binding protein
- Inhibitor of cap-dependent translation initiation
- Direct target of TOR, inhibited by TOR activity
12
Q
Argument against FRTA (concerning antioxidant enzymes)
A
- Enzymes such as SOD and catalase do not require energy input for their operation
- As such, the cell is well equipped to deal with these offenses and they should not pose a particular threat to the cell
13
Q
How does the body deal with potentially damaging species in environment (including food):
Link to DSTA
A
- Xenobiotic detoxification system
- Complex and costly processes
- Principally detoxification enzymes and cellular pumps to alter and excrete toxic chemical moieties
- Cytochrome P450 loosely involved alongside GSTs and UDP-glucosyltransferases which perform chemical alterations to reduce toxicity, increase solubility and aid excretion
- DME = Drug metabolising enzyme
- DME gene expression is highly regulated
- Altered DME gene expression implicated in long-lived animal models
- Link to DSTA = natural selection restricts xenobiotic metabolism because it is so costly in favour of upregulating reproductive programmes
14
Q
GH and cytokines: promoting different adipose tissue states
How does fat metabolism influence aging?
A
- GH appears to increase production by visceral fat of the pro-inflammatory cytokine IL-6
- Also decreases production of adiponectin -> anti-inflammatory, increases insulin sensitivity
- When considering role of fat metabolism in aging, it is the balance of types and not the overall volume of fat cells that is of import
- e.g. Snell mice are plump whereas S6K1 mutants are lean but both are long-lived
15
Q
Yolk synthesis and hypertrophy in worms:
A
- Worms: largely heamaphrodites that self-fertilise
- Yolk is made for oocytes production, which is synthesised in the intestine in large quantities then transported to gonad via body cavity
- After several days of reproduction, the store of self-sperm becomes depleted and reproduction ceases
- However, bulk yolk production persists, accumulating in body cavity
- This does not occur in daf-2 (IGF-1R) mutants
