Objectives?
- understand the relationship between cell health and ageing and the factors and mechanisms which impact upon cells
- be able to relate the role of the IGF-1 pathway and autophagy in cellular senescence
What is ageing/senescence?
senescence: deterioration that is associated with ageing
maximum life span: the maximum number of years that a member of a species has been known to survive
drosophila: 3 months mouse = 3 years humans = 120 years some turtles and lake trout = 150 years some trees = >1000 yeras dahlia anemone - non ageing
What is stem cells and tissue homeostasis?
- balance between stem cells self renewing and replenishing baseline cell population
- differentiation.
- proliferation
- apoptosis
What are principle structural targets for cell damage?
- cell membranes → plasma and organelle membranes - DNA - proteins → structural → enzymes - mitochondria → oxidative phosphorylation
What is the general pathogenesis of cell injury?
- reduced ATP synthesis/mitochondrial damage
- loss of calcium homeostasis
- disrupted membrane permeability
- free radicals (as cell gets older gets less able to deal with free radicals)
What are general protective mechanisms?
heat shock response genes
- comprise a large group of genes
- expression is up-regulated in the face of cell stressors
- serve to protect proteins from stress-related damage
- “clean up” damaged proteins from the cell
many tissues and organs can survive significant injury if they are “pre-stressed” = adapt
- ways to exploit this phenomenon to improve organ transplantation and tissue repairs are being tested in clinical trials
What is the key factor that determines reversible and irreversible injury?
time
duration of injury → age
What are differences between reversible and irreversible injury?
reversible - loss of ATP → failure of Na/K pump - anaerobic metabolism → increased lactic acid and phosphate - reduced protein synthesis
irreversible
- massive intracytoplasmic calcium accumulation
- enzyme activation
irreversible arrest of cell proliferation (senescence)/tumour suppressor mechanism initiated by:
- DNA damage
- chromatin instability
- short/dysfunctional telomeres (replicative senescence)
- stress signals (oxidative damage, culture shock)
- oncogenes (oncogene-induced senescence)
What is autophagy?
- process in which a cell eats in own contents
- it is a survival mechanism in times of nutrient deprivation, which the starved cell lives by cannivalising itself and recycling the digested contents
- autophagy is important in maintaining cell health as it clears cellular ‘rubbish’
- when autophagy is inefficient, cellular rubbish accumulates and cells senesce faster
- important in ageing → becomes less efficient over time
What are factors that contribute to cellular ageing?
- telomere shortening
- environmental insults
- DNA repair defects
- calorie restriction
- abnormal growth factor signalling (e.g. insulin/IGF)
- genetic factors and environmental insults combine to produce the cellular abnormalities characterstic of ageing
What is the evolution of ageing?
- Huntington’s chorea: a genetic, neurodegenerative disease caused by a highly penetrant dominant mutation
- 1941 Haldane: why has natural selection not acted to remove the Huntington’s mutation from populations
- average age of onset of Huntington’s 35.5 years
- for much of the evolutionary history of mankind, most people did not live to be that old
→ the selective pressure to remove the Huntington’s mutation is therefore weak - therefore is ageing the result of late-acting (in oder people) deleterious mutations?
What is the mutation accumulation theory in ageing?
- even in a population free of ageing, death will none the less occur, from extrinsic hazards such as disease, predators and accidents
- mutation accumulation theory predicts that genetic diseases should increase in frequency with age and that there could be large heterogeneity in deleterious genes between different individuals throughout the entire genome – this is by and large accurate
What are causes of cell injury?
- hypoxia
- chemical
- physical
- infection
- immune
- nutritional deficiency or excess
How does protection from ROS change?
- superoxide dismutases, catalases, peroxidases, down regulate as time goes on
What is a feature of telomeres?
- cells with long replicative capacity have very long telomeres
What is Werner’s syndrome?
- characterised by premature senescence
- a rare inherited disease that results in premature ageing
- individuals are normal in childgood but stop growing in their teens
- patients are more susceptible to cancer, osteoporosis, diabetes and cataracts
- they usually die in their late 40s
- WRN: the gene responsible for Werner’s syndrome encodes a helicase, an enzyme that unwinds DNA for replications, DNA repair or transcription
- both copies of the gene must be mutated or lost
- one pssobile cause of Werner’s syndrome is improper DNA repair and rapid accumulation of mutations
- another possibility is improper transcription of genes that are needed to maintain vigor or normal function
- the ability of cells to grow to a confluent monolayer decreases with increasing population-doubling leveles: indicates change in telomerase and senescence
What is progeria?
- clues to specific genetic factors in ageing
- hutchinson gilford progeria syndrome: causes children to age rapidly, undergo senescent changes and to die as young as 12 years old
- it is an extremely rare disease, and there are only 100 known cases worldwide
- it appears to be caused by a dominant mutant gene, Lamin A, which appears to be involved in nuclear integrity
symptoms: are similar to ageing in older persons, these include loss of hair, thin transparent skin with age spots, osteoporosis and atherosclerosis
- the aetiology is unclear: infants with progeria have shorter telomeres than normal children, and this might be important in the pathogenesis of this syndrome
- other genes involved in preventing oxidative damage by free radicals may be involved
What is the role of macrophages in ageing?
- more men live past 100 on Sardinia, proportionally than anywhere else in the world
- the T and B cell immunity declines in these individuals, as in all older people
- however macrophages in these older men appear ‘younger’, more active
- however remember that chronic inflammation promotes injury, ‘disease’
What is the role of caloric restriction?
- one of the most reliable ways to proling life in laboratory animals is simply to restrict hteir calories
- when rats are maintained on a low calore diet throughout life, ther are 15% smaller but live 50% longer than letter mates that ate ad libitum
- if restriction of calories is started later in life, it still works, but lifespan is only extended 20%
- food restricted rats show less evidence of cancer, atherosclerosis and autoimmune disease
- why does caloric restriction delay senescence?
- caloric restriction induces levels of some antioxidant enzymes
- interacttion of metabolic pathways with the insulin and IGF-1 pathways?
What is insulin/IGF-1 signalling pathway?
- hypothalamus releases hormones
- pituitary gland is activated through receptor ligand interactions
- release of growth hormone
- liver
- liver releases IGF-1
- binds IGF-1R
- shortens lifespan
- extended longevity in mice lacking the insulin receptor in adipose tissue
- protected against age-related obesity
- 18% increase in mean lifespan in both sexes
mice heterozygous for a deletion of the IGF-1 receptor gene
- resistant to oxidative stress
- increased mean lifespan (33% females, males not long lived)
What is polypathology?
- age
- multiple diseases
- treating one disease won’t change a patient long term
- treat multiple diseases in a single patient
- stem cell function decreases throughout life
What is the nature of tissue-specific stem cells and ageing?
- the effect of age on (A) short-lived (frequently reneqable) and B) long-lived postmitotic cells
- stem cells acquire toxins
- become diluted
- accumulation of mutations
- quickly dividing cells
slowly dividing
- accumulation of toxins
- less mutation because less division
What is inflammageing?
antigenic load and environmental free radicals → immune activation and tissue damage → inflammation and repair (+ oxidative metabolism)
→ reactive oxygen species → further release of pro-inflammatory cytokines → immune activation and tissue damage
and
→ remodelling and inflammageing
What are contributing factors to inflammageing?
- obesity
- oxidative stress
- years of exposure to inflammatory proteins
- DNA damage
- immunosenescence
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