L7, Dietary restriction Flashcards
1
Q
How does dietary restriction affect organisms lifespan and fecundity?
A
- Reduced food intake without starvation or malnutrition results in extended lifespan and late life health
- Reproduction, however, gets worse as relative caloric intake reduces (reduced fecundity)
2
Q
How are the effects of DR measured?
A
- Survival analysis to measure the lifespan of a population of animals -> often median lifespan used
- Analysis of health and function throughout life -> fecundity/reproduction, immune function, locomotor function, incidence of age related disease (obesity, cancer, CHD etc)
3
Q
Results of DR studies in flies:
A
- Lower fecundity in DR flies (measured by rate of egg laying)
- Increased lifespans in both females and males (bigger effect in females than males) -> sexual dimorphism
- Dietary restriction with supplementation of essential amino acids restored normal lifespan (both median lifespan and survival analysis); also restored fecundity
4
Q
DR in rodents: 3 methods
A
- Control animals given unrestricted diet (‘ad libitum’) and DR animals are given a percentage of the AL diet
- Control animals are fed an average daily amount of food and the DR animals are fed a percentage of this amount
- Intermittent fasting at every other day (OED) feeding
- Important to remember that specific AAs are modulating the DR lifespan effect
- Aiming the control to be a true representation of healthy mice; ad libitum is ill-advised as obese mice have their own mortality risks associated and DR would relieve this
5
Q
DR in Rhesus monkeys:
A
- Improved survival
- Reduced incidence of cancer, CD, diabetes, obesity prevention
6
Q
DR in human volunteers:
Benefits
A
- Beneficial effects against obesity, diabetes, insulin resistance, inflammation and oxidative stress
- -> Reduced risk factors for CD and cancer
7
Q
+ Hallmarks of DR:
Impact on major causes of death?
A
- CD disease (lower, with better post-ischemic recovery)
- Excess adiposity and diabetes (lowered, with better insulin sensitivity and glucose tolerance)
- Kidney disease (lower, with better glomerular filtration)
- Autoimmune disease and inflammation (lowered, with better SC self-renewal)
- ND disease (lower amyloid deposition, atrophy and inflammation in brain)
- Cancer (lower with later onset, better genetic stability)
8
Q
Side effects of DR in humans:
A
- Can lead to infertility, sarcopenia, osteoporosis, immune deficiencies
- Long term effects on resistance to infection, wound healing and cognitive function not known
9
Q
Evidence for the IIS/TOR signalling network mediating the lifespan effects of DR:
A
- Overall: response of lifespan to DR is altered or removed in animals mutant for IIS/TOR signalling
- The lifespan of TOR mutants in flies and worms cannot be extended further by DR
- Deletion of DILPs or ablation of IPCs (i.e. reduced IIS) in flies protects them from the effects of high yeast intake
- Overexpression of FOXO in flies produced an altered response to DR
- The median lifespan of GHR KO mice is not extended further by DR
10
Q
Describe the AMPK protein and its involvement in IIS/TOR signalling pathway:
A
- AMPK is considered a key checkpoint to ensure energy balance in both cells and organisms (‘nexus’)
- Negatively regulated by pAKT, S6K
- Active AMPK activates ULK1 -> autophagy
- Active AMPK activates FOXO
- Heterotrimer controlled by allosteric regulation by AMP, ADP and ATP, and phosphorylation
- Acts as a protective response to energy stress, and is a key player in diabetes and related metabolic diseases and cancer, as well as aging
11
Q
Evidence in flies and worms for role of AMPK in lifespan extension:
A
- Activating AMPK is sufficient to extend lifespan in model organisms
- e.g. Increasing expression of aak-2 in C.elegans increases lifespan by 13% and mimics DR in well-fed animals
- Overexpression of the single Drosophila AMPK-alpha subunit in either muscle or the fat body extends lifespan in the fruit fly
12
Q
Early findings on role of sirtuins in aging:
A
- Respond to NAD/NADH ratio
- Activate FOXO (removing inhibitory modification)
- First elucidated in budding yeast -> overexpression of SIR2 increased replicative lifespan
- Later shown that increased levels of sirtuins in worms and flies also extends lifespan -> evolutionarily conserved role?
13
Q
Early findings on resveratrol:
A
- Purported to be a pharmacological activator of sirtuins; promoted as a therapeutic agent in humans to mimic DR and slow aging
- -> recent studies raise questions about the evolutionary conservation of the role of sirtuins in lifespan
14
Q
Outline sirtuins in yeasts vs mammals:
A
- First described as NAD-dependent type II histone deacetylases (Sir2)
-> silences specific loci in DNA via deacetylation of H3 and H4 - Mammalian sirtuins (1-7) deacetylase histones and other proteins in other cellular compartments
- -> also function as ADP-ribosyltransferases
15
Q
Evidence for role of sirtuins in lifespan:
A
- Increased expression of sir-2 gene in worms extended lifespan
- Increased dsir2 in flies extended lifespan, decreased expression blocked effect of DR
- Sirt1-/- mice do not show lifespan extension under DR conditions
