Free radical pathology in ageing Flashcards
Effects/Targets of ROS
Membranes (unsaturated fatty acids-lipid peroxidation) Lead to changes in:
- membrane ………………….
- fl………… and c…………….
- membrane-bound …………… ………………
Proteins (via SH, Tryptophan and Tyrosine oxidation, etc)
- Cross linking; frag………………..; alterations in enzymes
and cell receptor ………………..
DNA damage
- Base ……………, strand be………….., mut………., imp……….protein/gene expression
A number of systems that generate oxygen free radicals catalyze the oxi……….. mod………. of proteins. Protein oxidation contributes to the pool of damaged enzymes, which increases in size during a………. and in various pat……………. states. The age-rel……. increase in amounts of oxidized protein may reflect the age-dependent acc…………… of unrepaired DNA damage that, in a random manner, affects the concentrations or activities of numerous factors that govern the rates of protein oxidation and the degradation of the oxidized protein. E Stadtman,
Effects/Targets of ROS
Membranes (unsaturated fatty acids-lipid peroxidation) Lead to changes in:
- membrane permeability
- fluidity and channels
- membrane-bound signaling proteins
Proteins (via SH, Tryptophan and Tyrosine oxidation, etc)
- Cross linking; fragmentation; alterations in enzymes
and cell receptor function.
DNA damage
- Base oxidation, strand breakage, mutations, impaired protein/gene expression
A number of systems that generate oxygen free radicals catalyze the oxidative modification of proteins. Protein oxidation contributes to the pool of damaged enzymes, which increases in size during aging and in various pathological states. The age-related increase in amounts of oxidized protein may reflect the age-dependent accumulation of unrepaired DNA damage that, in a random manner, affects the concentrations or activities of numerous factors that govern the rates of protein oxidation and the degradation of oxidized protein. E Stadtman,
Aging is a process characterized by the progressive loss of ………….. and organ f………….. The oxidative stress theory of aging is based on the hypothesis that age-associated functional losses are due to the accumulation of RONS-in…………… damages.
Aging is a process characterized by the progressive loss of tissue and organ function. The oxidative stress theory of aging is based on the hypothesis that age-associated functional losses are due to the accumulation of RONS-induced damages.
Oxidative stress and ageing
Excessive production of free radicals and failure of enzymatic and non-enzymatic regulation leads to ROS and Reactive nitrogen species (RNS).
This leads too:
- Impairment of ……………………. signalling
- M………………. dy………………..
- Promotes cellular a……….. and a……………….
- Disruption of membrane ……………….
- Damages to l………… , p……….. and nu……… acid
Oxidative stress and ageing
Excessive production of free radicals and failure of enzymatic and non-enzymatic regulation leads to ROS and Reactive nitrogen species (RNS).
This leads too:
- Impairment of intracellular signalling
- Mitochondrial dysfunction
- Promotes cellular aging and apoptosis
- Disruption of membrane integrity
- Damages to lipid , protein and
The free radical theory of Ageing
Key points (Harman, 1956) : Relationship between lif,,,,,,,,, and m,,,,,,,,,,,,, rate. Universality of ageing suggest a similar mechanism in different organisms.
In some organisms (flies, worms), extension of life span shown with raised antioxidant en,,,,,,,, activities. Similar experiments with rodents were not ,,,,,,,,,,,,,,,,,
The free radical theory of Ageing
Key points (Harman, 1956) : Relationship between lifespan and metabolic rate. Universality of ageing suggest a similar mechanism in different organisms.
In some organisms (flies, worms), extension of life span shown with raised antioxidant enzyme activities. Similar experiments with rodents were not successful.
Ageing process is linked to Oxidative Stress
Theory of ag…………
Rate of Living theory!
Immune theory!
Telomere theory!
Cross linking and Membrane hypothesis!
Lipofuscin accumulation!
Mitochondrial hypothesis!
Oxidative stress is linked to various proposed theories of ageing I.e. raised me………. damage, mitochondrial leaking of ele……… with ageing, altered immune function
Ageing process is linked to Oxidative Stress
Theory of ageing
Rate of Living theory!
Immune theory!
Telomere theory!
Cross linking and Membrane hypothesis!
Lipofuscin accumulation!
Mitochondrial hypothesis!
Oxidative stress is linked to various proposed theories of ageing I.e. raised membrane damage, mitochondrial leaking of electrons with ageing, altered immune function
Membrane Hypothesis of ageing
Cross lin………. within the membrane changes str………….. and compromises the fu………. of cells.
Free r,,,,,,,,,,, find,,,,,,,, damage and cross linking of proteins and lipids > changes in transm…………….. poteinetal > Accu……………. of w…….. products > loss of intracellular water > Reduction in En………. activities and RN…. and port……. synthesis.
The mechanism of membrane hypothesis of ageing is linked to oxidative theory due to susceptibility of protein and lipid components of membranes to oxidant damage. When such damage occurs it leads to alterations in transmembrane potential, accumulation of waste products and changes in intracellular pot…………. and eventual reduction of enzyme activities and RNA and protein synthesis.
Membrane Hypothesis of ageing
Cross linking within the membrane changes structure and compromises the function of cells.
Free radical induced damage and cross linking of proteins and lipids > changes in transmembrane poteinetal > Accumulation of waste products > loss of intracellular water > Reduction in Enzyme activities and RNA and protein synthesis.
The mechanism of membrane hypothesis of ageing is linked to oxidative theory due to susceptibility of protein and lipid components of membranes to oxidant damage. When such damage occurs it leads to alterations in transmembrane potential, accumulation of waste products and changes in intracellular potassium and eventual reduction of enzyme activities and RNA and protein synthesis.
Lipofuscin accumulation ‘
Also known as ageing pi………… - a cross linked lipoprotein mass of ly………….. digestion.
In animals, protease inhibitors raise its accu………….
O……….. derived free radicals promote lipofuscin formation.
Calorie restricted diet and antioxidants such as vitamin E and glutathione are reported to in………. the lipofuscin accu………… in the cells.
Lipfuscin accumulation ‘
Also known as ageing pigment - a cross linked lipoprotein mass of lysosomal digestion.
In animals, protease inhibitors raise its accumulation.
Oxygen derived free radicals promote lipofuscin formation.
Calorie restricted diet and antioxidants such as vitamin E and glutathione are reported to inhibit the lipofuscin accumulation in the cells.
Mitochondrial Hypothesis of Ageing
As we age the mitoch………… is able to generate less energy.
Cells are dependent on mol……… oxygen and oxidative phos………… to provide ATP needed for biological functions.
The mitochondria – site of ATP production.
The mitochondrial genome - a dou,,,,-stranded circular DNA molecule that encodes 13 components of the electron transport system (ETS). Oxidative damage to these will affect mit,,,,,,,,,,,,,, function.
Mitochondrial Hypothesis of Ageing
As we age the mitochondria is able to generate less energy.
Cells are dependent on molecular oxygen and oxidative phosphorylation to provide ATP needed for biological functions.
The mitochondria – site of ATP production.
The mitochondrial genome - a double-stranded circular DNA molecule that encodes 13 components of the electron transport system (ETS). Oxidative damage to these will affect mitochondrial function.
Figure.A Schematic Model of ROS Generation in the Mitochondria
The major production sites of superoxide anions at sites I and III are identified along with the major ROS s…………….. pathways. Antioxidant enzymes include various iso………. of per…………….. (Prx), superoxide dis…………. (SOD), and glutat…………… peroxidase (GP). The scavenging reaction of the peroxiredoxin family requires other cellular d……… proteins such as thior…………… (TrxS2). Similarly, the enzymatic action of GP requires re………….. glutathione (GSH). Specific family members of SOD, GP, and Prx are found inside the mitochondria, while other family members loc…..to the c……….. or extract……….. space.
The two major sites for RO…….. generation are believed to be at sites I and III where large changes in the pot………. energy of the electrons, relative to the reduction of oxygen, occur. Experimental manipu………… that increase the redox potential of these sites (Kushnareva et al., 2002)
Figure.A Schematic Model of ROS Generation in the Mitochondria
The major production sites of superoxide anions at sites I and III are identified along with the major ROS scavenging pathways. Antioxidant enzymes include various isoforms of peroxiredoxin (Prx), superoxide dismutase (SOD), and glutathione peroxidase (GP). The scavenging reaction of the peroxiredoxin family requires other cellular dithiol proteins such as thioredoxin (TrxS2). Similarly, the enzymatic action of GP requires reduced glutathione (GSH). Specific family members of SOD, GP, and Prx are found inside the mitochondria, while other family members localize to the cytosol or extracellular space.
The two major sites for ROS generation are believed to be at sites I and III where large changes in the potential energy of the electrons, relative to the reduction of oxygen, occur. Experimental manipulations that increase the redox potential of these sites (Kushnareva et al., 2002)
Mitochondrial theory of ageing
Mirochodnria produce ROS
ROS damage n………… DNA…. affects p………….. synthesis
Mitochondria / nucleus com………… break down
cell me……… effected
Mitochondria produce ROS
ROS damage enz……… of ETC, lower membrane po………..; cause mtDNA damage
Less ……….. produced
Cell metabolism affected
Mitochondrial theory of ageing
Mirochodnria produce ROS
ROS damage nuclear DNA…. affects protein synthesis
Mitochondria / nucleus communication break down
cell metabolism effected
Mitochondria produce ROS
ROS damage enzymes of ETC, lower membrane potential; cause mtDNA damage > Less ATP produced. Cell metabolism affected
Less ATP produced
Cell metabolism affected
Activation of ROS
Smo…….., ob………, ……………. radiation and ……….. abuse
Inhibition of ROS
Oxygen exercise, C……… restriction, a b………..diet and smoking cess……….
Peroxisome dysfunction
1) Mitoc……… oxid……….. phos…………….. Impaired
2) The number of abnormal mitochondrial structures I………….
3) The activity and expression of the respi……….. chain complex altered
1) Membrane phospholipids perox…………
2) Mito………. protein quality control process dysfu……….. Protein mismatch Increased mito……….. autophagy.
3) DNA mu……….. > mitoch……… funct…… decreased
the effect of oxidative stress on seen……. is related to the function and structure of per……… and mito………., oxidative stress may cause senescence finally through mitochondrial dys……….
Activation of ROS
Smoking, obesity, ultraviolet radiation and Drug abuse
Inhibition of ROS
Oxygen exercise, Calorie restriction, a balanced diet and smoking cessation
Peroxisome dysfunction
1) Mitochondrial oxidative phosphorylation Impaired
2) The number of abnormal mitochondrial structures increased
3) The activity and expression of the respiratory chain complex altered
1) Membrane phospholipids peroxidation
2) Mitochondrial protein quality control process dysfunction Protein mismatch Increased mitochondrial autophagy.
3) DNA mutation > mitochondrial function decreased
the effect of oxidative stress on senescence is related to the function and structure of peroxisomes and mitochondria, oxidative stress may cause senescence finally through mitochondrial dysfu
More the …………. demand of tissue/organ: higher the mito…………….
Tissues with high energy demand (heart,brain, eyes, liver etc) – High mitochondria/cell.
More a…………by a de………. in mitochondria function
More the energy demand of tissue/organ: higher the mitochondria.
Tissues with high energy demand (heart,brain, eyes, liver etc) – High mitochondria/cell.
More affected by a decline in mitochondria function
Calorie Restriction and Ageing
In laboratory animals, an extension of lifespan, as well as suppression of age-related diseases, has been demonstrated with calorie restriction.
Mechanisms underlying the effects of calorie restriction on ageing and age-related diseases include:
- Reduction in …………… stress
- Epigenetic modification of his……. and chro……….
- Reduction in inflammatory cyt………..
- Effects on IG….. signalling pat……….
Calorie Restriction epigenetic modifier
Decrease oxidative stress > MA…/IK..
NF-kb decr………. > Infla………..
Increase in SiR…., decrease in m…… > aut……
Above links too aging age-related diseases
Calorie Restriction and Ageing
In laboratory animals, an extension of lifespan, as well as suppression of age-related diseases, has been demonstrated with calorie restriction.
Mechanisms underlying the effects of calorie restriction on ageing and age-related diseases include:
- Reduction in oxidative stress
- Epigenetic modification of histones and chromatins
- Reduction in inflammatory cytokines
- Effects on IGF signalling pathways
Calorie Restriction epigenetic modifier
Decrease oxidative stress > MAPK/IKK
NF-kb decreased > Inflammation
Increase in SiRT1, decrease in mTOR > autophagy
Above links too aging age-related diseases
Type of Calorie Restriction diets
Reduction of calorie intake by …..% (maintaining adequate nutrient intake).
Calorie restriction plus ex………….
Intermittent fasting:
- 5:2 diet – Calorie restriction to 2….% on two non-consecutive days of the week.
- Alternate day fasting – Two interchange days with normal food intake on one day and calorie intake reduced by 25% on second day and so on…..
- Time restricted fasting: 12:12, 16:8 and 18:6 fasting:feeding
Type of Calorie Restriction diets
Reduction of calorie intake by 40% (maintaining adequate nutrient intake).
Calorie restriction plus exercise.
Intermittent fasting:
- 5:2 diet – Calorie restriction to 25% on two non-consecutive days of the week.
- Alternate day fasting – Two interchange days with normal food intake on one day and calorie intake reduced by 25% on second day and so on…..
- Time restricted fasting: 12:12, 16:8 and 18:6 fasting:feeding
Calorie restriction in aging
Experiments done in flies, worms, dogs , yeast, mice: 10-40% CR > Increase Lifespan
>49% CR > Increase Mortality
Extension of life increases with an increase in CR until it reaches malnutrition
CR reduces:
- O………… stress,
- Infl……………..,
- Improves glucose met…………, improves insu……… sensitivity of cells
CR Enhances:
Autophagy
Healthy population of mito………
BUT No effect on age related loss of bo….. and mu……… mass
Calorie restriction in aging
Experiments done in flies, worms, dogs , yeast, mice: 10-40% CR > Increase Lifespan
>49% CR > Increase Mortality
Extension of life increases with an increase in CR until it reaches malnutrition
CR reduces:
- Oxidative stress,
- Inflammation,
- Improves glucose metabolism, improves insulin sensitivity of cells
CR Enhances:
Autophagy
Healthy population of mitochondria
BUT No effect on age related loss of bone and muscle mass
