Ageing (16-19) Flashcards
What is ageing?
A set of normal gradual and spontaneous changes that occur in maturation from infant to adult
→ characterised by: loss oh physiological integrity, impaired function and increased possibility of death
What are some physical signs of ageing?
→ wrinkles on the face and body
→ sight, hearing, taste, smell become dull
→ hear turns thin and grey
→ weight gain (waist and hips)
→ osteoporosis
→ slower reflexes
→ less acute mental agility, declining memory
If ageing is normal, why should be do anything about it?
currently 18.5% of our population is 65+
→ 1 in 5 65+ get inappropriate medicines prescribed
→ increased physician time, hospital stays
→ will get worse - ~20mil > 65yrs
Why type of population dynamic does Japan show?
Ageing population (declining birth rate)
→ 29% > 65yrs in Japan / 18.5% in UK
Two age peaks:
→ ~75yrs, baby boomers born after WWII
→ ~50yrs, in 1970s Japan doing well economically
What is life expectancy?
Statistical summary of mortality at all ages
→ measure of the average time we can expect to live based on year of brith, current age, sex
→ measures the overall quality of life in a country
How is life expectancy changing globally?
Life expectancy at birth is generally increasing globally
→ however e.g. in US its plateauing
→ there are inequalities e.g. in 2020 newborn European expected to live 15.2 years longer than a newborn African
What can cause reduced life expectancy?
Poverty reduces life expectancy
→ natural disaster cause mortality shocks, poorer countries suffer most
e.g. earthquake in Haiti (poorer) vs Dominican Republic (richer) - Haiti saw significant drop in life expectancy + it recovered to lower level due to cholera outbreak while DR was unaffected
Do old people die preferentially to mortality shocks?
Prediction: old people die more easily than young → ‘death curve’ become steeper than the pre-shock curve
evidence from history suggests otherwise (e.g. Finnish famine records)
→ old people seem relatively resilient to mortality shocks
What are some examples of mortality shock?
Natural disasters
Famine
Sporadic disease (e.g. Ebola)
Conflict - prolonged hard to recover from
→ wealth decreases mortality shock
What are some ageing-associated diseases?
Atherosclerosis → thickening or artery walls, result of invasion/accumulation of WBC and proliferation of intimal-smooth-muscle cell creating fatty plaque
Cardiovascular disease → agina, myocardial infarction, stroke, heart failure…
Cancer
Arthritis
Cataracts
Osteoporosis
Diabetes
Alzheimer’s
Parkinson’s
→ ageing in a health and economic burden
What is Hutchinson-Gilford progeria syndrome?
Genetic disorder: symptoms resembling aspects of ageing at a very early age
→ 1 in 4,000,000-8,000,000
→ rarely inherited as people with HGPS do not live to reproduce
→ features: dwarfism, fragile bodies, senile appearance, early loss of hear, disproportionally large head, small face…
→ life span: 7-30yrs
What genetic mutation was found to be responsible for Hutchinson-Gilford progeria syndrome?
HGPS phenotype can be mapped to chromosome 1q
→ upon comparison to the human genome project mutations were found in the LMNA gene that encodes lamin A protein
How did single-base substitutions to exon 11 (causing Hutchinson-Gilford progeria syndrome) have such as detrimental effect?
Mutations to exon 11 activate a cryptic splice site resulting in production of lamin A protein much smaller (deletes 50aa near C terminus)
→ defective lamin A - progerin
What is lamin A?
Lamin A forms intermediate filaments
→ part of the cytoskeleton (structural integrity)
→ forms a network (nuclear lamina) with other lamins inside the nuclear envelope
→ involved in other things too like gene regulation, cell differentiation, DNA damage repair, and telomere protection
What effect do the nuclear changes of Hutchinson-Gilford progeria syndrome cause?
Inability to adequately repair DNA damages, due to defective lamin A
→ may cause aspects of premature ageing
→ partial model for ageing, not perfect as not all signs of ageing seen like high BP, alzheimer’s or diabetes
What is Werner syndrome?
Adult onset progeria
→ typically grow and develop normally until they reach puberty
→ in 20s beings accelerated ageing: greying + loss of hair, hoarse voice, thin hardened skin
→ thin arms and legs - abnormal fat deposition
→ 1 in 1,000,000
→ autosomal recessive
→ leads to: cataracts, skin ulcers, type 2 diabetes, infertility, atherosclerosis, osteoporosis, rare cancers (not perfect model for ageing but phenotype overlaps)
What is the mechanism of Werner syndrome?
Faulty DNA replication - at the telomeres
→ telomeres that are normally replicated by lagging strand synthesis are not replicated efficiently in Werner cells
→ telomere dysfunction and consequent genomic instability
→ also interacts with nuclear lamina - nuclear lamina also regulated DNA replication
What are the causes of Down syndrome?
Trisomy 21 → 95% cases, extra chromosome 21
Translocation Down’s → ~4% cases, extra chromosome 21 attached to another chromosome
Mosaic Down’s → ~1% cases, some cels are triatomic some are not
230 protein-coding genes in chromosome 21
300 non-coding RNA genes
→ many potential targets for progeria
Where is the protein Usp16 encoded?
Encoded in the human Down’s critical region
→ normally 2 copies
→ in Down’s there’s 3 - over-expressed
→ over expressing USP16 reduces the growth rate of two different human fibroblast cell lines
What does USP16 normally do?
USP: Ubiquitin specific protease
→ USP16 removes ubiquitin from histones - therefore a critical regulator of the DNA damage response
→ histones can be ubiquitylated by covalent attachment of ubiquitin
→ occurs at DNA double strand breaks and act as a focus for recruitment of DNA repair mechanisms
What is the age-1 gene?
Found in Caenorhabditis elegans - mutation found to increase lifespan
→ age-1 encodes the catalytic subunit P13K (involved in glucose regulation)
→ mutant age-1 worms have dysregulated glucose metabolism - a link of ageing with diet and caloric restriction (occurs only in the absence of glucose as high glucose levels toxic)
What is daf-2 gene?
Encoded a receptor tyrosine kinase
→ involved in same pathway as age-1 gene, as worm insulin receptor
→ daf-2 mutants can form dauer above 25C but bypass the dauer state below 20C with a doubling lifespan
What is the centenarian phenotype?
Compared with younger adults centenarians have a:
→ lower BMI
→ lower body fat
→ lower plasma triglycerides
→ lower oxidative stress levels
→ higher insulin sensitivity
→ higher plasma levels of active IGF -1 (insulin-like growth factor 1)
→ slower age-related decline
→ marked delay in onset of chronic diseases of ageing
What is a SNP?
Single nucleotide polymorphism
→ more frequent type of variation in human genome
→ inherited in a Mendelian manner
What are proteasomes?
Degrade unneeded or damages cells by proteolysis
→ found in the cytosol and around the nuclear pore complexes
→ multi-subunit particles with a barrel-shaped catalytic core capped with regulatory particles
→ caps select proteins hat are directed through the barrel
What is the mechanism of action of proteosomes?
Proteins destined for destruction are:
→ unfolded by the regulatory particles
→ degraded in the core particle
→ expelled as peptides
(ATP drives it though the barrel)
Peptides can be displayed at the cell surface or further degraded by cellular proteases into aa
How are reactive oxygen species formed?
Oxygen acts as a terminal electron acceptor in ATP-producing oxidative phosphorylation
→ leaked e- not captures by ox. phos. can react directly with oxygen to form superoxide anion radicals
→ these can modify proteins (usually unfolding them) and damage metal prothetic groups of enzymes
→ the modified proteins age the cell
→ the 20S core proteasome can degrade oxidised and unfolded proteins
What are some sources of oxidative damage?
UV light/O2
High energy radiation
Singlet oxygen
Metal ion/H2O2
Azo compounds/O2
Heme proteins/H2O2
Heme peroxidases/H2o@ with O2
Auto-oxidation of sugars
Activates leucocytes
What is autophagy?
Reusing old and damaged cell parts
→ removal of aggregates, damaged organelles and invading microbes
→ provides amino acids, nucleotides, lipids and sugars under low nutrient conditions
→ its highly specific, size of membrane depends on the size of target
How does autophagy work?
- an isolation membrane captures cytoplasmic contents
- forms an autophagosome
- which fuses with a lysosome
- forming an auto lysosome that digests the cytoplasmic cargo
How does LC3-II capture cargo receptors?
LC3-II protein is recruited to the isolation membrane during autophagy
→ it captures cargo receptors that contain LC3-interacting region motif
→ cargo receptor recruits cargo by covalent ubiquitation
How does autophagy interact with cancer?
Pro: suppresses tumours by removing damages organelles and growth factors
Con: can help cancer cells survive in low nutrient conditions
How does autophagy interact with ageing?
Autophagy removes damaged organelles and can limit production of reactive oxidative species
→ induction of autophagy increases longevity
→ appears to be no cons
What is the IIS pathway?
The insulin/insulin-like growth factor signalling pathway
→ hormonally regulated cell-signaling pathway that includes insulin and insulin-like peptides
→ linked to MAPK pathway - changes gene expression
→ found to be linked to regulation of autophagy: ageing
How does the IIS pathway linked to autophagy?
Phosphorylated AKT
→ activates FOXO-3a transcription factor whose targets stimulate autophagy
→ inhibits mTORC1 (an autophage inhibitor) ao stimulates autophagy
Does rapamycin up regulate autophagy - increase lifespan?
Rapamycin has been found to extend mouse lifespan and incidence of cancers
→ in people its an immunosuppressant - inhibits activation of T cells and B cells by making them less sensitive to interleukin-2
→ used primarily to prevent organ transplant rejection and inhibit mTORC1-stimulated inflammation in lupus
Does resveratrol stimulate autophagy?
Resveratrol, found in skin of grapes, has been found to stimulate autophagy in cells with wt mTOR
→ also found to reduce weight gain of mice on high caloric diet and improve motor skills and co-ordination
→ very little evidence that resveratrol increases human lifespan
Does caloric restriction increase lifespan?
Dietary/caloric restriction (reduced intake of food without malnutrition) increases the lifespan of many organisms from yeast to mammals
→ CR can have negative effects in humans lie decreased strength, stamina, heart rate, fatigue…
→ ongoing scientific study, well know in like 60 years
What are the primary hallmarks of ageing?
The causes of cellular damage associated with ageing: specific alterations to DNA and proteins in the cell accumulated over time
→ genomic instability
→ loss of telomeres
→ epigenetic alterations
→ loss of proteostasis
(there are links between these)
What is genomic instability?
DNA damage
→ caused by exogenous threats (chemical and biological agents) and by endogenous threats (DNA rep errors, spontaneous hydrolytic reactions, reactive O2 species)
→ point mutations, translocations, chromosomal gains and losses, telomere shortening, gene disruption - integration of viruses or transposons
What are some DNA replication mechanisms?
→ those that repair damage inflicted to nuclear DNA
→ mechanisms for maintaining appropriate length and functionality of telomeres
→ integrity of mtDNA
What can exogenous and endogenous damage lead to?
Base damage
Adduct formation
Interstrand crosslink
Double-strand break
Mismatch
What is telomere attrition?
Normal ageing is accompanies by telomere attrition in mammals
→ pathological telomere dysfunction accelerates ageing
What are telomeres?
Repetitive DNA sequences at the ends of metazoan chromosomes
→ about 10-15kb in length, repeat sequence: TTAGGG
→ without telomeres ends of chromosomes would deteriorate - chromosomes fusion and abnormal function
→ regulate how many times a cell can divide, shorten each time a cell replicates
What are epigenetic alterations?
Heritable changes in gene expression that are not caused by changes in DNA sequence
→ DNA and histone methylation
→ acetylation of histones
→ chromatin remodelling
How does methylation vs acetylation of DNA effect gene expression?
Methylation of DNA/histones → causes nucleosomes to pack together hindering access of transcription factors - genes are not expressed
Acetylation of histones → loose packing of nucleosomes, transcription factors have easy access and genes are expressed
→ methylation state can be inherited
How do epigenetic markers carry in to the next generations?
Mother → female epigenetic markers are passed to the ova: part of the environmental history of the mother is inherited by offspring
Father → protamines associated with sperm DNA are (mostly) replaced with acetylated histones from the ovum’s cytoplasms and male DNA is then systematically demethylated - but some markers remain
How are epigenetic alterations associated with ageing?
Epigenetic markers cause:
→ changes in transcription and RNA processing
→ impaired DNA repair
→ chromosome instability
all push towards ageing phenotype
What causes loss of proteostasis?
Heat shock, ER stress and oxidative stress cause protein unfolding
→ aggregation stimulates ageing phenotype
What is the somatorophic axis?
Key role in control of of regulation of metabolism are key physiological processes and consists of:
→ growth hormone - produces by the anterior pituitary
→ insulin-like growth factor - produced in response to GH by many cell types
How is the signalling pathway of IGF-1 linked to ageing?
Signalling pathway of IGF-1 informs cells of the presence of glucose (nutrient sensing)
→ insulin and IGF-1 signalising: highly conserved ageing-controlling pathway in evolution
→ multiple targets including, FOXO family of transcription factors and mTOR complexes - involved in ageing
How id the IIS pathway regulated with age?
ISS down regulated as a defensive response to ageing to minimise cell growth and metabolisms - limits damage
→ not a cause of ageing
(dietary/caloric restriction extends longevity)
What is mitochondrial dysfunction?
As cells and organisms age, the efficacy of the respiratory chain tends to diminish
→ increasing electron leakage and reducing ATP generation
→ increased ROS triggers survival in stress conditions - activated compensatory homeostatic responses
What are the integrative hallmarks of ageing?
The end results of the primary and antagonistic hallmarks are ultimately responsible for the functional decline associated with ageing
→ cellular senescence
→ stem cell exhaustion
→ altered intracellular communication
What is cellular senescence?
The process by which the capacity for cell division, growth and function is lost over time
when you’re younger
sporadic damage → cellular senescence → reduced proliferation of damaged cells → anti-cancer + tissue homeostasis + anti-ageing
What happens to cellular senescence when you’re old?
Accumulate damage and lose repair mechanisms:
more damage, less repair clearance cell renewal → cellular senescence leads to:
→ reduces proliferation of damages cells (anti-cancer)
→ reduced tissue functions, increased inflammation, effects on neighbouring cells, stem cell exhaustion (pro-ageing)
What does altered intracellular communication lead to?
Neuroendocrine dysfunction
Inflammation
Immunosenescence
Bystander effects
→ ageing
What is white adipose tissue?
Predominant type of fat in the human body
→ stores energy
→ increased WAT - higher chance of famine survival
→ WAT regulates: immune responses, mechanical protection, endocrine functions, regulates thermoregulation
→ high0fat diet induces obesity (bad)
How does obesity affect telomere length?
High levels of white adipose tissue are associated with accelerated leucocyte telomere attrition
→ implies weight-loss protects against telomere attrition
What dietary interventions are associated with longevity and ageing well?
The Mediterranean diet
→ high: olive oil, fruits, legumes, vegetables
→ low: animal fat, meat, slaty foods
