Age-related molecular disease Flashcards
What is incidence?
Number of new cases in a given time period.
What is the incidence rate?
Number of new cases/Number of persons at risk.
What is prevalence?
Total number of cases.
Prevalence rate?
Total number of cases/ Total population size.
What leads to a cancerous tumour?
An imbalance between apoptosis and and cell divsion.
How long does cancer take to develop?
Years to decades.
Where do cancers origanate from?
Single aberrant cell.
What is the affect of tumour supressing proteins on ageing?
Increases it.
What are 2 two types of cancer-critical genes?
Proto-oncogenes
Tumour suppressors
How do Proto-oncogenes cause cancer?
Mutated or overexpressed result in too much cell proliferation.
What was the first oncogene known?
Ras.
What are tumour suppressors?
Protects the cell from cancer.
What is gene X?
Tumour suppressor.
What happens when deletion or point mutation in coding sequences occurs?
Hyperactive protein is made in normal amounts.
What happens when a regulatory mutation?
Normal protein greatly overproduced.
What happens when gene amplification occurs?
Normal protein greatly overproduced.
What happens when chromosome rearrangement occurs?
Nearby regulatory DNA sequences cause normal proteins to be overproduced.
Fusion to actively transcribed genes produces hyperactive fusion protein.
How many mutations does it take for a somatic cell to become cancerous?
3.
What kinds of mutations lead to the overactivation of the cell cycle?
Ras or Myc.
What is the role of Rb?
Inhibits the cell cycle until cells are ready to divide.
How does the Rb control the cell cycle?
It is mutated which leads to the start of the cell cycle.
What happens when mitogenic signalling is excessive?
Inhibits the cell cycle.
Why is ageing a risk factor for cancer development?
- Time.
- Decline in quality control.
How can age-related decline in protein homeostasis contribute to cancer?
The gradual likelihood of mutations being accumulated as damaged protein isn’t being removed fast enough.
What is the function of p53?
Stops the cell cycle when cancer cells are formed.
What is diabetes?
A condition in which a person has high blood sugar.
What is type 1 diabetes?
The body does not produce enough insulin.
What is type 2 diabetes?
Cells do not respond to the insulin that is produced.
What are the risk factors for type 2 diabetes?
Genetic
Lifestyle
Age
What is insulin?
A hormone that is central to regulating energy and glucose metabolism in the body.
What is the function of insulin?
Causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle.
What are the stages of insulin signalling pathways?
- Receptor binding
- Translocation of Glut-4 to the plasma membrane
- Glucose uptake
- Glycogen synthesis
- Glycolysis
- Fatty acid synthesis
What causes diabetes?
Mutations in genes.
Decrease in receptor concentration.
Excessive phosphorylation of IRS1.
Increase in oxidative stress.
What is IRS1?
Insulin receptor substrate proteins.
What are AGEs?
Advanced Glycation End-products.
What kind of reaction is AGEs?
Glycation reaction (addition of a carbohydrate to a protein).
What kinds of proteins does AGEs affect?
Proteins with long half-life.
What is the function of AGEs?
Makes proteins resistant to degradation.
What are the steps in the formation of AGE products?
- Formation of a Schiff base
- Formation of an Amadori product
- Amadori product is oxidised to produce AGE
What is the function of RAGE receptors?
AGE binding to RAGE receptors leads to increased oxidative stress and inflammation.
What is the molecular pathway activated by AGE at its normal levels?
Binds to AGER1 and then is degraded.
What is the molecular pathway activated by AGE at its increased levels?
Binds to RAGE receptors.
Upregulates pro-inflammatory signalling.
Increase in RAGE receptors.
Increase in inflammation and oxidative stress.
What are cardiovascular diseases?
Involving the heart or blood vessels.
What is Atherosclerosis?
The artery wall thickens due to the build-up of fatty materials such as cholesterol.
What is ischemia?
Insufficient blood supply to the heart due to blocked arteries.
What occurs in the body due to ischemia?
Cellular ATP decrease.
ROS production increase.
Mitochondrial dysfunction.
Activation of autophagy.
What is reperfusion?
Blood supply returns after ischemia.
What occurs in the body during reperfusion?
Oxidative damage
Inflammation
Cell death
What causes cardiovascular diseases?
Multiple mutations usually.
Oxidative stress.
Formation of cross-linked proteins (AGEs).
What happens when the formation of cross-linked proteins occurs in arteries?
Stiffens the arteries which leads to higher pressure and results in the heart overcompensating.
What are cataracts?
Clouding of the lens leading to loss of vision.
Why do cataracts occur?
Lens proteins denature and degrade over time.
What molecular mechanism result in cataracts?
Oxidative stress.
Protein aggregation.
What is AMD?
Age-related macular degeneration.
What is AMD?
Gradual loss of central vision.
What are the types of AMD?
Dry and wet
What is dry AMD due to?
Build up of waste products called drusen.
What is wet AMD?
Abnormal blood vessels form under the macula and cause cellular damage.
What are the causes of AMD?
Oxidative damage
Advanced glycation end products.
Loss of proteins homeostasis.
What are Neurodegenerative diseases (proteinopathies)?
Range of diseases which mainly affect neurons in the human brain.
What are the clinical features of Neurodegenerative diseases?
Movement disorder.
Dementia.
What are the main pathological features of neurodegenerative diseases?
Loss of brain cells (neurons)
Protein aggregation
What are the clinical features of Alzheimer’s?
Progressive dementia
What are the clinical features of Parkinson’s?
Movement disorder
What are the clinical features of Huntington’s disease?
Dementia
Motor and psychiatric problems.
What are the affected regions of the brain during Alzheimer’s?
Hippocampus and Cerebral cortex
What are the affected regions of the brain during Parkinson’s disease?
Substania nigra
Hypothalamus
What are the affected regions of the brain during Huntington’s disease?
Striatum
Cerebral cortex
What are the proteins involved in Alzheimer’s?
Amyloid-Beta
Tau
What are the proteins involved in Parkinson’s?
Alpha-synuclein
Parkin
UCH-L1
What are the proteins involved in Huntington’s disease?
Huntingtin
What happens to the brain in dementia?
Loss of neurons and tissue from the brain in dementia.
What happens to the brain during ageing?
It decreases in size.
What happens when there is too much apoptosis in the body?
Oxidative stress
Excessive calcium influx
Mitochondrial dysfunction
Toxic proteins
P53 upregulated.
What are the genetic factors that cause Alzheimer’s?
Small amounts due to inherited mutations most are sporadic.
What are the genetic factors which cause Parkinson’s?
Some forms due to mutations in family.
What are the genetic factors which cause Huntington’s disease?
An inherited mutation in Huntington’s disease.
What kind of structures appear in Alzieher’s disease?
- Extracellular amyloid plaques
- Intracellular tau tangles
- Neuritic plaques
What are neuritic plaques?
Aggregation of altered glial cells and swollen dendrites containing abnormal tau protein.
What is the effect of tau modification on aggregation?
Can now hyperphosphorylate and also be cleaved by caspases.
What is the amyloid hypothesis?
The initial event which triggers neuronal degradation in Alzheimer’s disease is enhanced amyloid-β generation and aggregation.
What are the aggregates in Parkinson’s disease called?
Lewy bodies
What are Lewy bodies made up of?
α-synuclein
Ubiquitin
UCH-L1
Parkin (an E3 ligase)
Synphilin-
Tau
What is α-synuclein encoded by?
SNCA gene
How big is α-synuclein?
Small (14KDa) soluble protein
What is α-synuclein?
Natively unfolded structure
What is the function of α-synuclein?
Binds to membranes in a α-helical structure.
Regulate dopamine release.
Where are α-synuclein?
Abundant in the brain – found at presynaptic terminals.
What is α-synuclein degraded by?
Degraded by CMA and ubiquitin - proteasome pathway.
What are the 2 types of arthritis?
Rheumatoid arthritis (RA)
Osteoarthritis (OA)
What is RA caused by?
Inflammation
When does RA occur?
Can occur at any age.
What is OA?
A degenerative disease
When does OA occur?
Incidence increases with age.
What occurs at joints during OA?
Cartilage thins and bone ends rub together.
What is the articular cartilage?
Mostly extracellular matrix.
What does the extracellular matrix within the articular cartilage contain?
Aggrecan (proteoglycan) and collagen.
What is cartilage homeostasis maintained by?
Growth factors and Cytokines
What kinds of growth factor are used in cartilage homeostasis?
TGF-Beta and BMPs
What kinds of cytokines are used in cartilage homeostasis?
IL-1, IL-6 and TNF-Alpha
What is MMP?
Matrix metalloproteinase
What is ADAMTS?
A disintegrin and metalloproteinase with thrombospondin motifs.
What are the main molecular mechanisms of OA?
- Overproduction of cytokines
- Lower growth factor activity
What is osteoporosis?
Normal gradual bone loss occurs at a faster pace.
When does gradual bone loss begin?
From the age of 35.
How much bone is replaced each year?
10% in adults.
How is bone removed?
By resorption by osteoclasts
What produces new bone?
Osteoblasts
What kinds of signalling pathways allow maintenance of bone density?
Parathyroid hormone (PTH)
Wnt signalling
Growth hormones
Cytokines
What is the function of PTH in bone remodelling?
Increases number and activity of osteoclasts.
What is the function of Wnt signalling in bone remodelling?
Stimulates osteoblast activity.
What is the function of bone hormones in bone remodelling?
Stimulates activity of osteoblasts and osteoclasts
What is the function of cytokines withing bine remodelling?
Regulate different stages
What is the function of cytokines withing bine remodelling?
regulate different stages
What genetic factors lead to osteoporosis?
Mutations in LRP5
Polymorphisms in genes in Wnt pathway
What is sarcopenia?
Sarcopenia results when there is an excessive loss of muscle mass.
When does muscle mass begin to decline?
From the age of 25.
At what rate does muscle mass decrease?
0.5-1% per year.
What are the causes of sarcopenia?
Genetics
Reduced physical activity
Lack of repose to nutrients
Dysfunctional autophagy
Can you think of the reasons for any of there co-morbidities?
