Cells and molecular aging Flashcards
Life span
- different from aging
- life expectancy increasing
- increased % elderly in the population
- Developed vs developing world
ageing
occurs in every multicellular animal
occurs only after sexual maturity
organ level changes with age
- increased mortality
- increased susceptibility to infection, malignancy and autoimmune disease
- decrease in physiological capacity eg max heart rate
- reduced ability to respond to environmental stimuli
theories of raging
galen
roger bacon
Darwin
Galen theroy
- changes in body humours beginning in early life
- slow increase in dryness and coldness of the body
roger bacon
- wear and tear theory
- result of abuses and insults to the body
- good hygiene may slow process
darwin
- loss of irritability in nervous and muscular tissue
programmed therories of ageing
- biological clocks (hormone regulated)
- purposeful programme driven by genes
- aging process is of evolutionary benefit
non programmed theories of raging
- progressive random accidental molecular damage (proteins, DNA)
- cross linking and free radicals (can damage biological molecules)
- functional decline in neuroendocrine and immune system
evolutionary theories
programmed ageing genes
- genome directs life until sexual maturity
- late onset diseases eg huntingtons disease not selected in a way that early ones are eg sickle cell anaemia
- some genes selected early in life may be deleterious later eg immune system
i. e. not beneficial later in life, but was beneficial in earlier life - longevity genetically controlled
- clear heritable component in human longevity (especially at extreme ages)
- large number of genes identified, modification of which affects longevity
cell and molecular hallmarks of ageing
geominc instability epigenetic changes loss of proteostasis mitochondrial dysfunciton deregulated nutrient sensing increased senescence telomere attrition stem cell exhaustion altered intercellular communication
genomic instability
- integrity challenged by external biological and chemical agents and internal replication errors
- includes mitochondrial DNA
- can happen by the reasons for the syndromes above eg unable to repair
epigenetic changes
- changes in phenotype not dependant on DNA sequence mutations
- DNA methylation, histone modification and chromatin remodelling
- family of genes may contribute to aging
loss of proteostasis
control of the structure and function of proteins
Changes in biochemical composition of tissues
- increased protein crosslinking, aberrant folding
- protein aggregates: amyloid
Failure of quality control with age
- autophagy/lysosome
- ubiquitin/proteasome (acts like a reverse chaperone, proteins that are tagged with ubiquitin are broken down)
mitochondrial dysfunction
Efficacy of respiratory chain decreases with age
- electron leakage
- Reduced ATP
Increased production of reactive oxygen (ROS, free radicals) due to the electrons leaking
- Oxidative damage to proteins and DAN
deregulated nutrient sensing
- insulin and insulin like growth factor pathway
- most conserved age controlling pathway
- Downstream (FOXO transcription factors, mTOR complex)
- Gene manipulation of these pathways can increase longevity
calorific restriction leads to
reduction in content leads to living longer
how does calorific restriction lead to living 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
cell ageing
Normal cells have limited ability to divide
- decline in proliferative capacity
- Senescence: cell division ceases cells can secrete
- Biological clock – in normal cells, cells told to stop growing
cancer cell agegin
no limit
telomeres
DNA sequence
protects ends of chromosomes from degredaton
progress shortening with each dividion
telomerase
reverse transcriptase
stabilises telomere length
telomeres and cancer
telomere activity present in many tumours
- cells don’t know there old as telomeres keep getting put back on
altered intercellular communication
accumulation of pro inflammatory tissue damage
failure of immune system to clear pathogens and cells
senescent cells secrete pro inflammatory cytokines
lifestyle and aging
skin wrinkles, pigmented lesions
sun exposure, air pollution
smoking increased metalloproteinase enzymes which breakdown collagen
