Lecture 4: Senescence Flashcards
What is cellular ageing?
Cellular ageing is the result of a progressive dec.ine in the life span and functional activity of cells.
- Reflects the progressive accumulation of sublethal cellular and molecular damages
- Due to genetic and exogenous mechanisms
- Lead to cell death and diminished capacity to respond to injury -> ageing of entire organism
Describe senescence.
In tissues, senescence is characterised by accumulated damage to macromolecules, cells, tissues, and organs with the passage of time.
At a cellular level, senescent cells have stopped dividing by mitosis because of shortening of telomeres or excessive DNA damage.
Describe the occurrence of ageing in cells, tissues, and organs.
Recall the mechanisms of cellular ageing.
Describe progeria.
Hutchinson Gilford progeria syndrome:
- children age rapidly, senescent changes
- patients die as young as 12 years old
- extremely rare
- Dominant mutant gene, lamin A - has a role in nuclear integrity
- Symptoms:
- Hair loss
- thin, transparent skin with age spots
- osteoporosis
- atherosclerosis
Mention the possible aetiology of progeria.
- Infants with progeria have shorter telomeres
- Other genes involved in preventing oxidative damage by free radicals may be involved
Describe the characteristics of Werner’s Syndrome.
- recessive rare inherited disease that results in premature ageing
- Individuals normal in childhood, but stop growing in their teens
- Patients are more susceptible to cancer, osteoporosis, diabetes, and cataracts
- Point mutation in the WRN gene, that encodes a helicase, an enzyme that unwinds DNA for replication, DNA repair, or transcription
- One possible cause is improper DNA repair and rapid accumulation of mutations
- Another is improper transcription of genes - required for normal function
Senescence causes a loss of _____________ because cell cycle arrest in progenitor cells.
tissue-repair capacity
Senescent cells produce ____________ and _______________ (known as _______)
pro-inflammatory and matrix-degrading molecules
Senescence-associated Secretory Phenotype
Mention the relevance of telomeres in replicative senescence.
- Progressive telomere shortening activates p53 and Rb
- This leads to cell cycle arrest at the G1/S and G2/M checkpoints
- Replicative senescence triggers cell death
What is SASP?
Senescence-associated secretory phenotype (SASP) is a phenotype associated with senescent cells wherein those cells secrete high levels of inflammatory cytokines, immune modulators, growth factors, and proteases.
Describe the relevance of cytokines in replicative senescence effects on healthy cells.
IL-6 and IL-8 both contribute to the maintenance of the secretion-associated senescent phenotype (SASP), also known as cytokine-induced bystander senescence.
Transcriptional regulation that the cytokines trigger inhibit cellular proliferation and promote senescence in surrounding healthy cells.
Why does calorie restriction of calories delay senescence?
Caloric restriction induces levels of some antioxidant enzymes, helping neutralise the damaging effects of oxygen radicals.
Calorie restriction also reduces signalling in the Insulin and IGF-1 pro-aging pathways, increases the production of FOXO1 (leading to increased expression of longevity genes). It also increases SIRT1 (involved in glucose control), which also increase FOXO1 production.
Describe the process of autophagy.
Autophagy can be a survival mechanism in times of nutrient deprivation when starved cell lives by cannibalizing itself and recycling the digested contents. It is also important in maintaining cell health as it clears cellular waste.
When autophagy is inefficient, cellular waste accumulates and cells enter in senescence.
Recall the correlation between macrophages and ageing.
Macrophages play an important role in inflammation and cell repair when activated. While both T and B cell immunity declines as one age, in some cases there is evidence in long-lived individuals where their macrophages appear “younger”, and more active. This would assist in cell repair and halt the process of senescence.
Recall the diagram of inflammageing.
Inflamm-aging (also known as inflammaging or inflamm-ageing) is a chronic low-grade inflammation that develops with advanced age. It is believed to accelerate the process of biological aging and to worsen many age-related diseases.
What is the NFKB?
NF-kappa-B is a complex of proteins that is a central transcriptional regulator of stress/inflammatory response. This pathway can both promote/repress inflammation/immune response depending on the balance of ReIA vs p50.
Recall the Insulin and IGF-1 pro-ageing pathway.
