cell and molecular ageing Flashcards
What is ageing?
Complex biological process in which changes at the molecular cellular and organ levels results in a progressive, inevitable and inescapable decrease in the body’s ability to respond appropriately to internal/external stressors
What is lifespan?
Life expectancy increasing Increased % of elderly 2050- 85yrs Developed/developing (40yrs?) Increase in age related disease
Ageing vs disease?
Ageing not a disease Occurs in every multicellular animal Occurs only after sexual maturity Occurs in animals removed from wild Has universal molecular etiology
What are organ level changes with age?
Increased mortality
Increased susceptibility to infection, malignancy and autoimmune disease
Eg. >65years, 92x likely to get heart disease
Decrease in physiological capacity
Eg. Reduced glomerular filtration rate, max heart rate
Reduced ability to respond to environmental stimuli
What are theories of ageing?
Galen- changes in body humours (fluids) beginning in early life, slow increase in dryness and coldness of body
Roger bacon- wear and tear theory, good hygiene may slow process
Darwin- loss of irritability in nervous and muscular tissue
MAIN THEORIES
Programmed theories- biological clocks (hormones), driven by genes
Non programmed theories- error, stochastic- progressive random, accidental molecular damage (proteins DNA), cross linking and free radicals, functional decline in neuroendocrine and immune system
How do genes age?
Genome directs life until sexual maturity
No selective pressure after this
Late onset diseases eg. Huntington’s disease (30-40yrs) not selected in way early ones are
Some genes selected early in life may be deleterious later eg. Immune system
Clear heritable component in human longevity
Large no of genes identified- modifying affects longevity
BUT phenotypic differences in ageing between monozygotic twin (20-30%)
What is Hutchinson-Guilford Progeria?
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
Accelerating ageing + age related diseases eg. Atherosclerosis
Usually die by 13
What is Werner syndrome?
Mutation in WRN, DNA helipads family DNA repair and transcription Accelerated features of ageing eg. Balding, cataracts, arthritis, cancers Die by 50 Central control of ageing
What are cell and molecular hallmarks of ageing?
- Genomic instability- integrity challenged by bio/chem agents and internal replication errors, includes mitochondrial DNA
- Epigenetic changes- changes in phenotype not dependent on DNA sequence mutations (DNA methylation, histone modification and chromatin remodelling)
Eg. Loss of SIRT6 gene in mice leads to ageing - Loss of proteostasis- changes in biochem composition of tissues (increased protein cross linking, aberrant folding, protein aggregates-amyloid), failure of quality control w age (autophagy/lysosome and ubiquitin/proteasome)
- Mitochondrial dysfunction- efficacy of resp chain decreases w age (electron leakage, reduced ATP), increased production of ROS (oxidative damage to proteins and DNA)
- Deregulated nutrient sensing- insulin and insulin-like GF pathway, downstream (FOXI transcription factors, mTOR complex), gene manipulation may increase longevity
- Increased senescence w age
- Normal ageing in mammals is accompanied by telomere shortening
- Stem cell exhaustion eg. Haematopoiesis have less adaptive immune cells
- Altered intercellular communication- accumulation of pro-inflam tissue damage, failure of immune system to clear pathogens and cells, senescent cells secrete proinflam cytokines
Why might calorific restriction allow people to live longer?
Reduced oxidant production by mitochondria- less ROS damage
Induction of SIRT1- key regulator of cell defence
Increased protein turnover- lack of accumulation of damaged protein
Low evidence- Okinawa, Japan- 40% fewer calories, longest lifespan and highest % of centenarians
What is cells senescence?
Limited ability to divide so 50x
Cancer cells have no limit- immortal
What are telomeres?
DNA sequences
Protect ends of chromosomes
Progressive shortening w each cell division
Biological clock
Active individuals have longer telomeres?
What is telomerase?
Reverse transcriptase
Stabilises telomere length
~how cancers are immortal (present in 90% tumours)
~therapeutic target in cancer
What are lifestyle and ageing links?
Skin wrinkles, pigmented lesions etc
Sun exposure, air pollution, alcohol, poor nutrition
Smoking- increase in metalloproteinase enzymes which break down collagen
