Ageing (16-19)

Question 1

What is ageing?

Answer 1

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

Question 2

What are some physical signs of ageing?

Answer 2

→ 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

Question 3

If ageing is normal, why should be do anything about it?

Answer 3

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

Question 4

Why type of population dynamic does Japan show?

Answer 4

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

Question 5

What is life expectancy?

Answer 5

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

Question 6

How is life expectancy changing globally?

Answer 6

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

Question 7

What can cause reduced life expectancy?

Answer 7

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

Question 8

Do old people die preferentially to mortality shocks?

Answer 8

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

Question 9

What are some examples of mortality shock?

Answer 9

Natural disasters
Famine
Sporadic disease (e.g. Ebola)
Conflict - prolonged hard to recover from
→ wealth decreases mortality shock

Question 10

What are some ageing-associated diseases?

Answer 10

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

Question 11

What is Hutchinson-Gilford progeria syndrome?

Answer 11

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

Question 12

What genetic mutation was found to be responsible for Hutchinson-Gilford progeria syndrome?

Answer 12

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

Question 13

How did single-base substitutions to exon 11 (causing Hutchinson-Gilford progeria syndrome) have such as detrimental effect?

Answer 13

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

Question 14

What is lamin A?

Answer 14

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

Question 15

What effect do the nuclear changes of Hutchinson-Gilford progeria syndrome cause?

Answer 15

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

Question 16

What is Werner syndrome?

Answer 16

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)

Question 17

What is the mechanism of Werner syndrome?

Answer 17

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

Question 18

What are the causes of Down syndrome?

Answer 18

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

Question 19

Where is the protein Usp16 encoded?

Answer 19

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

Question 20

What does USP16 normally do?

Answer 20

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

Question 21

What is the age-1 gene?

Answer 21

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)

Question 22

What is daf-2 gene?

Answer 22

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

Question 23

What is the centenarian phenotype?

Answer 23

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

Question 24

What is a SNP?

Answer 24

Single nucleotide polymorphism
→ more frequent type of variation in human genome
→ inherited in a Mendelian manner

Question 25

What are proteasomes?

Answer 25

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

Question 26

What is the mechanism of action of proteosomes?

Answer 26

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

Question 27

How are reactive oxygen species formed?

Answer 27

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

Question 28

What are some sources of oxidative damage?

Answer 28

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

Question 29

What is autophagy?

Answer 29

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

Question 30

How does autophagy work?

Answer 30

1. an isolation membrane captures cytoplasmic contents
2. forms an autophagosome
3. which fuses with a lysosome
4. forming an auto lysosome that digests the cytoplasmic cargo

Question 31

How does LC3-II capture cargo receptors?

Answer 31

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

Question 32

How does autophagy interact with cancer?

Answer 32

Pro: suppresses tumours by removing damages organelles and growth factors
Con: can help cancer cells survive in low nutrient conditions

Question 33

How does autophagy interact with ageing?

Answer 33

Autophagy removes damaged organelles and can limit production of reactive oxidative species
→ induction of autophagy increases longevity
→ appears to be no cons

Question 34

What is the IIS pathway?

Answer 34

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

Question 35

How does the IIS pathway linked to autophagy?

Answer 35

Phosphorylated AKT
→ activates FOXO-3a transcription factor whose targets stimulate autophagy
→ inhibits mTORC1 (an autophage inhibitor) ao stimulates autophagy

Question 36

Does rapamycin up regulate autophagy - increase lifespan?

Answer 36

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

Question 37

Does resveratrol stimulate autophagy?

Answer 37

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

Question 38

Does caloric restriction increase lifespan?

Answer 38

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

Question 39

What are the primary hallmarks of ageing?

Answer 39

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)

Question 40

What is genomic instability?

Answer 40

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

Question 41

What are some DNA replication mechanisms?

Answer 41

→ those that repair damage inflicted to nuclear DNA
→ mechanisms for maintaining appropriate length and functionality of telomeres
→ integrity of mtDNA

Question 42

What can exogenous and endogenous damage lead to?

Answer 42

Base damage
Adduct formation
Interstrand crosslink
Double-strand break
Mismatch

Question 43

What is telomere attrition?

Answer 43

Normal ageing is accompanies by telomere attrition in mammals
→ pathological telomere dysfunction accelerates ageing

Question 44

What are telomeres?

Answer 44

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

Question 45

What are epigenetic alterations?

Answer 45

Heritable changes in gene expression that are not caused by changes in DNA sequence
→ DNA and histone methylation
→ acetylation of histones
→ chromatin remodelling

Question 46

How does methylation vs acetylation of DNA effect gene expression?

Answer 46

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

Question 47

How do epigenetic markers carry in to the next generations?

Answer 47

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

Question 48

How are epigenetic alterations associated with ageing?

Answer 48

Epigenetic markers cause:
→ changes in transcription and RNA processing
→ impaired DNA repair
→ chromosome instability

all push towards ageing phenotype

Question 49

What causes loss of proteostasis?

Answer 49

Heat shock, ER stress and oxidative stress cause protein unfolding
→ aggregation stimulates ageing phenotype

Question 50

What is the somatorophic axis?

Answer 50

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

Question 51

How is the signalling pathway of IGF-1 linked to ageing?

Answer 51

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

Question 52

How id the IIS pathway regulated with age?

Answer 52

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)

Question 53

What is mitochondrial dysfunction?

Answer 53

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

Question 54

What are the integrative hallmarks of ageing?

Answer 54

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

Question 55

What is cellular senescence?

Answer 55

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

Question 56

What happens to cellular senescence when you’re old?

Answer 56

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)

Question 57

What does altered intracellular communication lead to?

Answer 57

Neuroendocrine dysfunction
Inflammation
Immunosenescence
Bystander effects
→ ageing

Question 58

What is white adipose tissue?

Answer 58

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)

Question 59

How does obesity affect telomere length?

Answer 59

High levels of white adipose tissue are associated with accelerated leucocyte telomere attrition
→ implies weight-loss protects against telomere attrition

Question 60

What dietary interventions are associated with longevity and ageing well?

Answer 60

The Mediterranean diet
→ high: olive oil, fruits, legumes, vegetables
→ low: animal fat, meat, slaty foods