ROS II (ageing and disease)

definition of ageing

progressive decline in physiological function characterised by increasd susceptibility to diseas and eventually death

ageing is a … of changes that are …, …, universal and thus far …

deleterious, progressive, universal and irreversible

the two most common theories of ageing?

genetic and damage accumulation theories

ageing damage occurs to …, … and …

molecules, cells and organs

what are the 4 most important theories of ageing

1. rate of living theory

2. membrane theory

3. oxidative stress theory

4. mitochondrial dysfunction theory

rate of living theory

… is inversely related to … … and organisms with a faster … burn through a fixed … … faster and age/die sooner

lifespan, metabolic rate, metabolism, energy quota

rate of living theory

lifespan is inversely related to metabolic rate and organisms with a faster metabolism burn through a fixed energy quota faster and age/die sooner

membrane theory

ageing results from cumulative … … to cell … (lipid …)

oxidation damage, membranes, peroxidation

membrane theory

ageing results from cumulative oxidative damage to cell membranes (lipid peroxidation)

oxidative stress theory

ageing is driven by cumulative … … damage to …, outpacing the cell’s … …

ROS induced, macromolecules, antioxidant defences

oxidative stress theory

ageing is driven by cumulative ROS induced damage to macromolecules, outpacing the cell’s antioxidant defences

mitochondrial dysfunction theory

… accumulates … … mutations, impairing … …, which generates more … and this is a … … cycle driving cellular …

mtDNA, ROS induces, oxidative phosphorylation, ROS, self amplifying, ageing

mitochondrial dysfunction theory

mtDNA accumulates ROS induced mutations, impairingoxidative phosphorylation, which generates more ROS and this is a self amplifying cycle driving cellular ageing

the rate of living theory states that the lifetime expenditure of … per … of … is approximately …

energy per gram of tissue, constant

mitochondrial rate of … … production is more important than metabolic rate in terms of …

free radicals, longevity

… … decreases ROS production and increases lifespan

caloric restriction

free radical theory of ageing evidence from drosophila melanogaster

1. overexpression of … and … slow down …

2. some strains are resistant to … … and live 35% longer

1. SOD and catalase, ageing

2. oxidative stress

free radical theory of ageing evidence from mice

1. mice with defects in … signalling are …, have lower body … and have enhanced … defences and live …

2. loss of … receptor increases resistance to … … and increases …

3. SOD +/- mice have more … damage and reduced …

1. IGF, smaller, temp, antioxidant, longer

2. IGF, oxidative stress, longevity

3. oxidative, lifespan

ROS damage the mitochondrial …-generating apparatus, leading to deficiencies in … generation and decline of … … (aging). Proteins are released from the mitochondria, activating the … pathway, leading to cell … and ...

energy generating, ATP, physiologcial function, caspase, death and ageing

Artificial introduction of excessive … in the mtDNA can impair mitochondrial … resulting in many manifestations of … without causing a further increase in … production

mutations, function, ageing, ROS

Generation of … as a by-product of mitochondrial oxidative phosphorylation, results in damage to mitochondrial … including the … which leads to deleterious …

ROS, macromolecules, mtDNA, mutations

mitochondrial dysfunction theory

… damage → decreased … production → …

mtDNA, energy, ageing

in post mortem analysis it has been found that there are elevated levels of … … in … tissue of aged AD patients and more … … in the … of Parkinson’s patients

mtDNA deletions, cortical, mtDNA deletions, striatum

linking oxidative damage and memory decline

increase in ROS → decrease in … → decrease of … → impaired …

PUFAs, AA, LTP

lipid peroxidation is commonly found in … … in AD patients

senile plaques

increased levels of … … and … are indicators of protein oxidation

carbonyl groups and 3 nitrotyrosine

increased levels of carbonyl groups happen during protein oxidation due to direct … … … or ROS mediated … … where large inactive … proteins are cleaved into shorter active …

amino acid oxidation, peptidergic cleavage, precursor, peptides

there are increased levels of 3NT during protein oxidation because … ions (…) add a … group to tyrosine

peroxynitrite, ONOO-, nitro

a 1989 study on Rhesus Macaques tested two groups of monkeys - one … … and the other … (between 7 and 14 yrs)

they found that at the 20 year point … of thr CR monkeys were alive and only … of the other group

caloric restriction, control

80%, 50%

caloric restriction during early growth is the only … experimental manipulation that increases …

reproducible, lifespan

it has been proposed that caloric restriction acts to reduce … … as mitochondria produce less … at the same … consumption

oxidative stress, ROS, oxygen

heat shock proteins (HSP) are molecular … induced by cellular … that help … … proteins or target them for …

chaperones, stress, refold damaged, degradation

CR appears to selectively … the most protective HSP (…) while calming the broader and less useful elevation in … HSP expression

boost, HSP70, basal

basline HSP levels tend to … with age as a chronic and low grade … response

this baseline increase is … since chronically elevated … signalling can itself contribute to cellular …

… lowers age related rise in basal HSP expression

rise, stress

maladaptive, stress, dysfunction

CR