Cell and molecular ageing

Question 1

Ageing (biological) - logical definition

Answer 1

Complex biological process in which changes at the molecular, cellular and organ levels results in progressive inevitable and inescapable decrease in body’s ability to respond appropriately to internal and/ or external stressors

Question 2

Lifespan

Answer 2

Different from ageing
Life expentancy increasing
Increased % elderly in population
Increase in age related diseases

Question 3

Big differences in lifespan

Answer 3

Developed vs developing world (some under 40 years)

Question 4

Ageing vs (age related) disease

Answer 4

Ageing not a disease
Occurs in every multi-cellular animal
All species
Occurs only after sexual maturity
Occurs in animals removed from wild
Has universal molecular etiology

Question 5

Characteristics of ageing

Answer 5

> mortality
susceptibility & vulnerability to disease (>65, 92x more likely to get heart disease)
Changes in biochemical composition of tissues (> protein crosslinking, abberant folding, lipofuscin accumulation)
< in physiological capacity (

Question 6

Theories of ageing: Galen

Answer 6

Changes in body humours beginning in early life

Slow increase in dryness and coldness of body

Question 7

Theories of ageing: Roger Bacon

Answer 7

Wear and tear theory
Result of abuses and insults to body
Good hygiene may slow proess

Question 8

Theories of ageing: Charles Darwin

Answer 8

Loss of irritability in nervous & muscular tissue

Question 9

Ageing theories: programmed theories

Answer 9

Biological clocks

Purposeful programme driven by genes

Question 10

Theories of ageing: Non programmed (error, stochastic) theories

Answer 10

Progressive random, accidental damage

Loss of molecular fidelity

Question 11

Evolutionary ageing theory

Answer 11

Programmed: Ageing genes

• Genome directs life until sexual maturity
• No selective pressure after this
• Late onset diseases e.g. Huntington’s (30-40y) not selected in way that early ones are e.g. sickle cell anaemia
• Some genes selected early in life may be deleterious later (e.g. immune system, androgens)

Question 12

Molecular/ cellular ageing theory

Answer 12

Non-programmed: Free radical damage to molecules
> frequency to senescence
Intrinsic thermodynamic instability of biomolecules
3D structure cannot be maintained
Conformational change, aggregation, precipitation, amyloid formation
Ageing: catabolic chance driven?

Question 13

System ageing theory

Answer 13

Non-programmed
Neuroendocrine alterations results in age related physiological changes
Immunological function declines - < reisitance to infection, cancer & > recognition of self

Question 14

Ageing genes: extreme longevity genetically controlled?

Answer 14

Higher chance of siblings of centurions surviving more than 100 years

Question 15

Ageing genes: gene manipulation can > longevity

Answer 15

Yeast, nematodes, mice
Conserved pathways regulating growth, energy metabolism, nutrition sensing & reproduction
-e.g. insulin/ insulin like GF-1, FOXO transcription actors, sirtuin proteins

Question 16

Genetic test predicting chances of living to 100

Answer 16

• 77% accuracy
• Might be genetic background to exceptional longevity
• 150 DNA variants more common in old-age group

Question 17

Ageing genes: syndromes

Answer 17

Hutchinson-Guilford Progeria

Werner Syndrome

Question 18

Hutchinson-Guilford Progeria

Answer 18

Rare genetic disorder
Mutation in LMNA encoding nuclear envelope protein: lamin A
Affects RNA transcription and chromatin organisation
Lack of DNA strand rejoining after irradiation
Accelerated ageing (atherosclerosis)
Usually die by 13

Question 19

Werner Syndrome

Answer 19

Mutation in WRN, DNA helicase family
-‘caretaker of genome’: DNA repair & transcription
Baldness, hair & skin ageing, calcification of vessels, cancers, cateracts, arthritis, diabetes
Die by age 50
Central control of ageing?

Question 20

Cellular ageing

Answer 20

Normal cells: limited ability to divide (approx 50x)
Decline in proliferative capacity
Senescence
Cancer cells have no limit (immortal)

Question 21

Telomeres

Answer 21

Cellular ageing
DNA sequences
Protect ends of chromosomes
Progressive shortening with age

Question 22

Telomerase

Answer 22

Stops cellular ageing
Reverse transcriptase
Stabilise telomere length
Temolerase activity in 90% tumours so telomerase inhibition is target for cancer therapy

Question 23

Ageing (lifestyle)

Answer 23

Leading a sedentary lifestyle may make us genetically old before our time
Twins who were physically active during their leisure time appeared biologically younger than their sedentary peers
Telomeres shortened more quickly in inactive people
Could signify faster cellular ageing

Question 24

Molecular ageing: free radicals?

Answer 24

Accumulation of oxidative damage in proteins and DNA
Damage to mitochondrial DNA: e- leak from e- transport, form free radicals leading to more DNA damage
Flies expressing superoxide dismutase (free-radical scavenger) live longer
Antioxidants to counter ageing (Vit C, E, beta-carotene, 2-dexyglucose)

Question 25

Molecular-ageing-lifestyle: skin ageing

Answer 25

Intrinsic
Extrinsic
-wrinkles, pigmented lesions etc.
-sun exposure, air pollution, alcohol, poor nnutrition
-smoking: > in metalloproteinase enzymes which break down collagen

Question 26

Calorific restriction

Answer 26

Those mice with calorific restrictions lived up to 1/3 longer

• < oxidant production by mito (less ROS damage)
• induction of SIRT1 (key regulator of cell defence)
• > protein turnover (lack of accumuation of damaged protein)
• inhibitants of Okinawa, Japan: 40% fewer calories, longest lifespan and highest % of centenarians

Question 27

Hayflick limit

Answer 27

Number of times a normal human cell population will divide until cell division stops

Question 28

ROS

Answer 28

Reactive oxygen species