Ageing and senescence Flashcards
what is senescence?
Senescence is the age-dependent decline in vital physiological functions
what 2 factors cause senescence?
- wear and tear
- e.g. decline in C. elegans muscle function, teeth worn off in elephants - genetics
- e.g. salmon die as soon as they lay eggs
- e.g. species difference in ageing such as elephant and mouse: gestation of elephant has finished at 21 months, which is halfway through a mouse’s life
what is the 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
- As soon as an individual cannot increase number, or the chance of survival of its offspring any further, there is no natural selection against decline/ageing in that individual
- If genes/mechanisms exist that increase the reproductive success in early life stages but are deleterious once progeny is independent, they will be selected for
- Genetic programs drive ageing
what are the 3 senescence factors?
- metabolism
- reactive oxygen species (ROS)
- DNA damage
what 3 factors increase the lifespan of an organism?
- dietary restriction
- environmental stresses
- signals from the somatic gonad
what is the rate of living theory?
if an organism has a high metabolism, it has a short lifespan
- e.g. mice have fast metabolism and short life, elephants have slow metabolism and long life
- link between rate of metabolism and age - this is especially clear in cold-blooded animals like drosophila where low temperatures slow metabolism and increase life span
what evidence is there for the rate of living theory?
Cold-blooded animals like Drosophila can live longer at low temperatures as it slows their metabolism
- If you compare lifespan in drosophila at 29 and 18C, they live at least 3 times as long at low temperature, where metabolism is slowed
what is the ROS theory of ageing?
high metabolism produces ROS and oxidative damage:
- The superoxide radical is central in the ROS theory of ageing
- Superoxide 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.
how is the ROS theory of ageing limited?
It seems radicals may even be anti-aging
- In C. elegans, treatment of worm with compound that leads to the production of oxygen radicals like paraquat or juglone (known ROS generators), causes increased life span, the opposite of what would be expected.
- Importantly by using antioxidants in addition to the ROS producers it could be shown that the effect is really due to ROS rather than some unknown effect of these compounds
- Similarly it has been shown that glucose restriction in C. elegans can extend life span by inducing mitochondrial respiration and increasing oxidative stress.
what evidence suggests that the ROS theory of ageing is true?
longevity genes (long life promoting genes) are inducing genes that increase resistance to ROS
how does dose have an impact on the ROS theory of ageing?
very high doses of ROS forming chemicals will be ageing promoters, but low levels may be harmless and even beneficial
how has DNA damage been implicated in ageing?
many genetic disorders which have accelerated ageing express mutations in DNA repair mechanisms:
- Werner syndrome: RecQ DNA helicase DNA repair/ replication/ chromosome segregation causes premature ageing
- Cockayne syndrome: group 8 excision-repair cross-complementing protein=> DNA repair
- Hutchinson Guilford: LAMINA mutations=> nuclear architecture and mitosis altered
what is the DNA damage theory of ageing?
Ageing may be caused by defects in genome maintenance and DNA repair
- In non-replicating cells unrepaired DNA damage may accumulate and cause aging (in dividing cells it will lead to mutations)
how is it certain that mutation doesn’t cause ageing, and instead it is defect DNA repair?
Mice with a high mutation rate do not age quicker
- Perhaps NAD depletion? via excessive PARP activation?
- Therefore damage, not mutation, must be the cause
what is Poly (ADP-ribose) polymerase (PARP)?
Poly (ADP-ribose) polymerase (PARP) is an enzyme that responds to damaged DNA, and uses NAD as a cofactor to do this
- PARP creates senescent cells
how are senescent cells induced?
Unrepaired DNA in a non-dividing cell can cause a cell to become senescent
how may senescent cells drive ageing?
- Senescent cells may get “in the way” of normal stem cell-based repair
- senescent cells may promote an ageing phenotype by secreting proinflammatory mediators called SASPs (senescence-associated secretory phenotype)
- they therefore cause inflammation and block normal cell replacement, leading to ageing
what evidence is there that senescent cells drive ageing?
- A mouse was genetically engineered where senescent cells could be killed/removed specifically.
- The wildtype mouse is clearly aged, whereas the engineered mouse that had its senescent cells removed looks much better
how is dietary restriction thought to increase lifespan?
- The life extending effects of caloric restriction were already discovered in the 1930s.
- This has now been confirmed in all model organisms, it was also shown that it is not simply due to a reduced metabolism as a result of the reduce intake
- as calorie intake increases, lifespan decreases
how are environmental stresses such as ROS thought to increase lifespan?
Normal ROS levels not an issue, as ROS alerts a cell to a problem->allows activation of counter-measures: “Fire-alarm”
- High level of antioxidants causes ROS to be suppressed: “Fire-alarm OFF”
A certain amount of ROS is optimal to promote protection
- ROS may not be dangerous unless they go over a certain level
- Hormesis: low level insults may activate protective mechanisms
how have forward genetics been used in model organisms to understand ageing?
Found mutants that affect aging, clone the gene, see what is does:
- Screen for short lived mutants - tricky….is it aging?
- Screen for long lived mutants
- Developmental models C. elegans, Drosophila have led the way - short life span/isogenic strains/cheap/genomics
- Found mutants that live longer than usual
- Genetic analysis has identified mutations that affect life span and this has provided a molecular handle on the crucial genes
what 3 genetic pathways were identified to be implicated in ageing?
- IGF (insulin-like growth factor) pathway – negative regulators of age
- Block to prevent ageing - TOR pathway – negative regulators of age
- Block to prevent ageing - Sirtuins – positive regulators of age
- Activate to prevent ageing
what is IGF (insulin-like growth factor) signalling?
- IGF signalling via DAF2 (IGF receptor) inhibits DAF16 (FOXO)
how was IGF signalling discovered?
IGF signalling discovered C. elegans:
- C. elegans can dauer state to survive adverse conditions such as low food
- Normal life: 25 days, dauer can last 60 days, under insulin/IGF1 control
- A particular combination of age1 alleles can extend lifespan by 10-fold
- If IGF signalling is lost, they enter dauer state and live longer
what is FOXO?
FOXO (DAF16) is a transcription factor which regulates genes that increase resistance to stressors and promote longevity
how is IGF signalling implicated in ageing?
- 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
If IGF is mutated, FOXO is no longer inhibited, resulting in anti-ageing
what is the result of IGF signalling vs IGF mutation?
IGF signalling shortens life span, as it inhibits FOXO
- IGF signalling promotes ageing
mutations in IGF promote anti-ageing factors, as FOXO is no longer inhibited
what human data supports that FOXO is anti-ageing and IGF signalling is ageing?
- GWAS data identified FOXO1 and FOXO3A, AKT and IGF1 receptor variants that have been linked in Human longevity in multiple cohort studies
- Lifespan extension by dietary restriction is mostly (mice) or partly mediated by blocking IGF signalling (Worms Fly)
- In mice, growth hormone receptor mutant mice (downregulating IGF), dietary restriction does not extend life
what is downstream of FOXO/DAF16?
- FOXO downregulates Insulin-like genes=> nonautonomous effects
- FOXO is an anti-ageing transcription factor - Antioxidant genes such as superoxide dismutase, metallothionine, catalase, glutathione S-transferase => ROS theory FOXO leads to increased resistance 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
- Autophagy extends lifespan
what is TOR kinase?
The TOR kinase is a major amino-acid and nutrient sensor that stimulates growth and blocks salvage pathways such as autophagy when food is plentiful
what is the TOR signalling loop?
salvage:
- Stress activates TSC, TSC blocks TOR
- This then blocks S6K1 and activates 4E-BP => “salvage” pathway active to inhibit protein synthesis and cell growth, inhibit ageing
Wasteful:
- Growth Factors and amino acids block TSCs which normally block TOR
- TOR kinase now active, 4E-BP inactive, S6K active=> “wasteful” pathways active to promote cell growth, protein synthesis but also promoting aging
how do IGF and TOR interact? how does this affect ageing?
- Insulin is a growth factor that “talks” to TOR via PI3K & Akt, thereby inactivating TSC1/TSC2 and activating TOR
- So blocking insulin signalling could inactivate TOR and cause “longevity pathways” to be activated
- blocking IGF and TOR is therefore anti-ageing
what is rapamcyin?
blocker of TOR which extends lifespan
- upregulates FoxA and 4E-BP to increase longevity pathway
- downregulates S6K to decrease ageing pathway
rapamycin given to an ageing mouse provides longevity and reduces its rate of ageing
what are sirtuins?
Sirtuins are NAD+-dependent protein deacetylases
overexpression of Sirtuins extends lifespan in yeast, worms and flies
how are sirtuins implicated in ageing?
overexpression of Sirtuins extends lifespan in yeast, worms and flies:
- In C. elegans, Sir-2.1 activates FOXO/Daf16, and mitochondrial unfolded protein response (UPR-mt)
- UPR degrades unfolded proteins to reduce accumulation of damage in the cell - Sirtuins upregulate this so are anti-ageing
- Sir proteins act as Insulin-independent activators of Daf16/FOXO
- Sir has direct interaction with FOXO - anti-ageing
- In mammals: many isoforms, SIRT6 has been linked to longevity in male mice, as it acts to downregulate IGF
Sir promotes FOXO and inhibits IGF, so Sir is anti-ageing
adam
* Downregulates IGF
*Upregulates FOXO
*Upregulates UPR
what is resveratol?
Resveratrol, the proposed anti-ageing compound in red wine (and even more in Japanese knotweed) activates Sir proteins
- promotes Sirtuins to increase longevity
how are mitochondrial mutations thought to increase lifespan?
- Sirtuins (which require NAD) lead to activation FOXO and in addition to a protective mitochondrial response called the mitochondrial unfolded protein (UPR) response
- This fits with the fact that certain mitochondrial mutations have also been found to extend lifespan
- similar to activation of SIRT- mitochondrial mutations will lead to the mitochondrial unfolded protein response (UPR-mt) which by an unknown mechanism protects against ageing and increases lifespan
what is the NAD-depletion theory of ageing?
- NAD is an essential cofactor for Sirtuins
- NAD levels decline with age
- Unrepaired DNA damage might lead to NAD depletion via poly ADP ribose polymerase (PARP) activation
- DNA damage results in NAD being mopped up for repair
how do signals from the somatic gonad increase lifespan?
- In C. elegans, removal of entire reproductive system does not extend lifespan, but when only germ cells are removed animals live 60% longer
- Somatic gonads extend lifespan, their effects counteracted by germline cells
- It can extend the lifespan of IGFR/DAF2 mutants even further
- Steroidal hormones (dafachronic acid) and DAF12 Nuclear hormone receptor are involved in this, they appear to act on DAF16/FOXO but in a different manner than insulin
