Lecture 8 - Ageing and Senescence Flashcards
What is Senescence ?
Senescence is the age dependent decline in vital physiological functions. A typical example of this decline in function can be seen in the survival of drosophila. Initially survival is almost 100% but as the flies age the rate of death rapidly increases.
An age related decline in function
What is Disposable soma theory ?
Natural selection tunes life history of the organism so that sufficient resources are invested in maintaining the repair mechanisms that prevent ageing, at least until that organism has reproduced and cared for its young.
AKA as soon as the individual cannot increase number or the chance of survival of its offspring any further, there is no natural selection against decline/ageing
What are the 3 Senescence factors ?
Metabolism
Reactive oxygen species
DNA damage
What 3 factors increase life span?
Dietary restriction
Environmental stresses
Signals from the somatic gonad
What is the rate of living theory ?
High metabolism and short lifespan - large animals live longer, cold blooded animals live longer at low temperature.
What does a high metabolism lead to ?
Reactive oxygen species (ROS) and Oxidative damage.
this is an oxygen molecule that contains an extra unpaired electron and makes the oxygen highly reactive and can therefore oxidise cellular components and leads to oxidative damage. This is a theory of aging.
What do genetic diseases that lead to premature aging tell us about the critical factors of Senescence ?
aging may have to do with defects in genome maintenance and DNA repair
Name some Progeria Syndromes
Hutchinson Guilford - LAMINA mutations=> nuclear architecture DNA repair?
Nestor Guillermo - BANF1 mutations=> LAMINA/mitosis
Ehlers Danos - xylosylprotein 4-beta-galactosyltransferase
Cockayne - group 8 excision-repair cross-complementing protein=> DNA repair
Werner - RecQ DNA helicase DNA repair/replication/chromosome segregation
What is the DNA damage theory of ageing?
Accumulated damage to the DNA molecule over time causes aging process.
Suggests that it is unrepaired damage in nonreplicating cells that causes aging.
Lose NAD = Lose PARP
PARP is an enzyme that is essential for certain DNA repair processes and it uses up NAD
How could senescent cells drive ageing?
These cells can cause inflammation and block normal cell replacement.
Senescent cells are cells that have entered a state of irreversible cell cycle arrest, typically in response to DNA damage, telomere shortening, or other cellular stressors. While cellular senescence is a protective mechanism that prevents damaged cells from becoming cancerous, the accumulation of senescent cells in tissues over time can contribute to the aging process
How does SASP drive ageing ?
Senescent cells exhibit a specific secretory phenotype called SASP, where they release a variety of pro-inflammatory cytokines, growth factors, and proteases. SASP components can disrupt tissue homeostasis, promote chronic inflammation, and contribute to the development of age-related diseases. Persistent inflammation can impair tissue function, compromise the regenerative capacity of stem cells, and contribute to tissue degeneration.
How does SASP drive ageing ?
Senescent cells exhibit a specific secretory phenotype called SASP, where they release a variety of pro-inflammatory cytokines, growth factors, and proteases. SASP components can disrupt tissue homeostasis, promote chronic inflammation, and contribute to the development of age-related diseases. Persistent inflammation can impair tissue function, compromise the regenerative capacity of stem cells, and contribute to tissue degeneration.
How does dietary restriction increase lifespan ?
Dietary restriction, all model organisms
not simply due to lower nutrient metabolism that causes damage and reduces calorie intake.
How do environmental factors increase life span?
Other environmental stresses, e.g. heat, ROS generators
Hormesis:low level insults may activate protective mechanisms.
One explanation for this has been that a small ROS insult can unleash a disproportionate protective response, a process called Hormesis, reducing overall ROS impact.
Can we use forward genetics in model organisms?
Model organisms, such as fruit flies (Drosophila melanogaster), and nematodes (Caenorhabditis elegans).
Find mutants that affect ageing, clone the gene, see what it does
Short-lived mutants - tricky
Long-lived mutants - developmental models C.Elegans have led the way. Short life span, isogenic strains, cheap, genomic
What is Forward genetics ?
Forward genetics is an approach used to identify and study the function of genes by observing the phenotype (observable characteristics) resulting from mutations or genetic variations.
What is the IGF/Insulin signalling pathway?
Mutations in Insulin/IGF1 pathway double lifespan (flies are in reproductive diapause) linked to resistance to oxidative stress
Female mice with a mutation in IGF1R (IGF1&2 receptor) live 33% longer
IGF signaling INHIBITS the transcription factor DAF16 aka FOXO. The FOXO/DAF16 transcription factor regulates many genes that increase resistance to various stressors.
Loss IGF signaling has been linked to increased resistance to oxidative stress.
It overall shortens life span so FOXO steps in to extend it
What is the human data on IGF signalling ?
FOXO1 and FOXO3A, AKT and IGF1 receptor variants have been linked in Human longevity in multiple cohort studies
Lifespan extension by dietary restriction is mostly (mice) or partly mediated by IGF signalling (Worms Fly),
In mice, GH receptor mutants (downregulating IGF) dietary restriction does not extend life.
What is downstream of DAF16/FOXO ?
FoxO downregulates Insulin-like genes=> nonautonomous effects
Antioxidant genes
such as superoxide dismutase, metallothionine, catalase, glutathionine S-transferase => ROS theory FoxO leads to increased resisitance against ROS
Metabolic genes
apolipoprotein genes (downregulated), glyoxylate-cycle genes, and genes involved in amino acid turnover
Chaperones
particularly small heat-shock protein genes
Antibacterial genes
Blockage of autophagy limits lifespan of long-lived DAF2/IGFR mutants
What does the TOR pathway stimulate and block?
TOR kinase stimulates growth and blocks salvage pathways such as autophagy.
So TOR promotes aging
How does TSC extend lifespan?
Stress activates TSC
TSC blocks TOR
TOR stimulates growth by activating 4E-BP1 and blocks S6
This activates Salvage pathway
Lifespan extension
How does TOR PROMOTE AGEING?
GFs and aa block TSC
TOR is activated
4E-BP1 IS INACTIVE and S6 IS ACTIVE
wasteful pathways are inactive
Promotes aging (cell growth)
How does IGF interacting with TOR cause longevity pathways to activate?
IGF interacts with TOR via PI3K and Akt
This activates TOR and inactivates TSC
Blocking insulin signalling could inactivate TOR and cause longevity pathways to activate
What is Rapamycin?
Can block TOR, extends lifespan
It blocks S6 and over expresses 4E-BP
What are Sirtuins?
Overexpression increase lifespan
Activates FOXO
They are insulin-independent activators of FOXO
Requires NAD
Mitochondrial mutations expand lifespan
NAD levels decline with age
Unrepaired DNA damage might lead to NAD depletion via PARP activation
What are the 3 signalsl from the somatic gonads?
- Remove germline Cells live longer
- Somatic gonads extend the lifespan
