lectures 16-19 Flashcards
define what is meant by ageing
a set of gradual and spontaneous changes that occur in maturation from infant to adult
what are the main physical signs of ageing?
- wrinkles on the face and body
- sight, hearing, taste, and smell become less acute
- hair begins to thin and turn grey
- reduced bone density
- slower reflexes and altered gait
- less acute mental agility and declining memory
what % of the population is above 65 in the UK
18.5%
define what is meant by lifespan
the period of time in which the events of a species typically occur
what is meant by the maximum life span?
- the maximum period of time members of any given species can live
human’s is currently 122 years and 164 days
define what is meant by life expectancy
a measure of the average time we can expect to live based on the year of birth, current age, and sex
what causes a reduced life expectancy in Haiti?
- it is the poorest population in the Western Hemisphere
- few natural resources due to deforestation
- corruption
- low levels of education for much of the population
- natural disasters cause mortality shocks but life expectancy often recovers quickley
does conflict cause mortality shock?
yes
do old or young people tend to be more affected by mortality shock?
young people
what 3 diseases show accelerated ageing?
- Hutchinson-Gilford syndrome
- Werner syndrome
- Down’s syndrome
what is the incidence of Hutchinson Gilford progeria syndrome?
1 in 4 million to 1 in 8 million
what are the main features of HGP
- slow growth + dwarfism
- early loss of hair
- disproportionately large head
- stiff joints
- coronary artery disease
what is the average life expectancy of those with HGP?
14 years
what is the genetic cause of HGP?
- can be mapped to chromosome 1q
- most cases are a single de novo base substitution resulting in a silent change in the LMNA gene
- this mutation in exon II activates a cryptic splice resulting in production of a defective lamin A protein (progerin)
what does the LMNA gene code for?
the nuclear lamin A protein
what is the normal function of lamin A?
- it forms intermediate filaments to be part of the cytoskeleton
- forms a network with other lamins inside the nuclear envelope
- in late passage, normal cells lamin A and lamin B mostly co-localise at the nuclear lamina
- lamin A promotes genetic stability by maintaining levels of proteins that have key roles in repair of DNA double strand breaks
how does the production of progerin cause problems?
- in HGPs there is an instability to rapidly repair DNA damages, causing aspects of premature ageing
why is HGPs not a perfect model for ageing?
- males do not develop prostate issues
- there is no increased risk of cancers
- high blood pressure is rare
- diabetes is rare
- no Alzheimers
what are the physical characteristics and effects of Werner syndrome?
- individuals typically grow and develop normally until they reach puberty
- accelerated ageing in their 20s causes:
greying and hair loss
a hoarse voice
thin skin
abnormal fat deposition
what is the global incidence of Werner syndrome?
1 in 1 million
what pattern of inheritance does Werner syndrome follow?
autosomal recessive
what are the cellular features and causes of Werner syndrome?
- there is limited cellular division capacity
- caused by a mutation in the WRN gene (a DNA helicase)
- mutations are typically loss of function
how does faulty telomere production cause Werner syndrome?
- the telomeres that are normally replicated by lagging strand synthesis are not replicated efficiently
- causes premature ageing of cells
overexpression of which enzyme in vitro counteracts WRN mutations?
telomerase
why is it suggested that the nuclear lamina may also regulate DNA replication?
wild type WRn interacts with the nuclear lamin
why is Werner syndrome not an effective model for ageing?
- no prostate issues
- generally no high blood pressure
- no strokes
- no Alzheimers
what is the incidence of Down’s syndrome?
1 in 700 births
what is the life expectancy of someone with Down’s?
60 years
what suggests that Down’s is a good model for ageing?
- premature greying/ hair loss
- early vascular disease
- early onset Alzheimers
what suggests that Down’s is not a good model for ageing?
- no prostate cancer
- no cataracts
- not associated with high blood pressure
what are the genetic causes of Down’s syndrome?
- trisomy 21 - 95% of cases
- translocation Down’s - 4% cases
- mosaic downs - 1% cases
what is the Down’s critical region?
- an area of about 30 genes in which Usp16 protein is over-expressed
what is the Down’s critical region?
- an area of about 30 genes in which Usp16 protein is over-expressed
what is Usp16?
- ubiquitin specific protease
- histones can be ubiquitylated by covalent attachment of ubiquitin
- histones become ubiquitylated at DNA double strand breaks and acts as a focus for recruitment of DNA repair enzymes
what mutation do nematodes possess to increase lifespan
- age-1 gene mutation
what is the dauer stage in nematodes?
feeding stops and movement is reduce in which no ageing occurs
- it reduces activity of the glucose pathway so no PI-3K is produced
what is the general phenotype of centenarians
- low bmi
- low plasma triglycerides
- low oxidative stress levels
- high insulin sensitivity
- higher plasma levels of active IGF-1
what mutation is thought to increase risk of Alzheimer’s?
- mutation of the APoE-4 gene
- APoE regulates lipid homeostasis, so APoE-4 mutation can lead to plagues of amyloid beta in the brain
what are proteasomes?
- multi subunit particles with a barrel shaped catalytic core capped with regulatory particles
- found in the cytosol and around nuclear pore complexes
- proteins to be destructed are degraded there
- the 20S core proteasome can degrade oxidised proteins (these damage regular proteins)
what are the general roles of autophagy?
- removal of aggregates, damaged organelles, and invading microbes
- providing amino acids, nucleotides, lipids, and sugars under low nutrient conditions
what is the mechanism of action of autophagy?
1 - an isolation membrane captures cytoplasmic contents
2 - an autophagosome is formed
3 - the auto-phagosome fuses with a lysosome
4 - this forms an autolysosome that digests the cytoplasmic cargo
what is the main source of the isolation membrane?
- primary source is the omegasome on the ER
- multiple other sources are used
how does an LC3-II protein capture cargo?
1 - LC3-II protein captures a cargo receptor that contains an LC3-interacting region motif that captures cargo
2 - autophagosome fuses with lysosome
how is autophagy stimulated?
- phosphorylated AKT activates FOXO-3a transcription factors whose targets stimulate autophagy
- the mTOR complex 1 inhibits autophagy but AKT phosphorylation inhibits mTORC1
what other molecule can inhibit mTORC1
Rapamycin
how does caloric restriction upregulate autophagy?
- it inhibits mTOR
- it also upregulates FOXO-3a by producing SIRT-1
list the primary hallmarks of ageing
- genomic instability
- loss of telomeres
- epigenetic alterations
- loss of proteostasis
what is genomic instability caused by?
- it is DNA damage caused by exogenous and endogenous threats
- includes point mutations, translocations, chromosomes gains and loss, telomere shortening, and gene disruption caused by the integration of viruses or transposons
how do telomeres show ageing?
- telomeres regulate how many times a cell can divide - they shorten with each division
- once telomeres shrink to a certain level, cells can no longer divide
how are epigenetic alterations passed between generations?
- the epigenetic marks of the female re passed to the ovum
- protamines associated with sperm DNA are mostly replaced with acetylated histones from the ovum’s cytoplasm
what are the antagonistic hallmarks of ageing?
(things that happen in response to ageing)
- deregulated nutrient sensing
- mitochondrial dysfunction
what occurs in deregulated nutrient sensing?
- the signalling pathway IGF-1 is the same as insulin, informing cells of glucose presence
- its targets are FOXO and mTORC, so when IGF-1 levels decline with age, nutrient sensing decreases
what occurs to induce mitochondrial dysfunction?
- as ageing occurs, electron leakage increases, reducing ATP generation which should activate ROS and stimulate ageing
- however ROS could trigger survival in stress conditions instead of ageing
list the integrative hallmarks of ageing
- cellular senescence
- stem cell exhaustion
- altered intracellular communication
what is cellular senescence?
it is the processes by which the capacity for cell division, growth, and function is lost over time
accumulation of senescent cells increases inflammation and decreases tissue function
what are the causes of stem cell exhaustion?
- anaemia
- osteoporosis
- poor fracture repair
- reduced intestinal function
- poor muscle fibre repair
how can stem cell exhaustion be prevented?
induced pluripotent stem cells can be artificially produced
what are the effects of altered intracellular communication?
- neuroendocrine dysfunction
- inflammation
- immunosenescnece
how is obesity an ageing accelerator?
- obesity causes SIRT1 inhibition and MTORC1 activation
- high levels of white adipose tissues are associated with accelerated leucocyte telomere attrition
