Aging and senescence Flashcards
What is senescence?
Age dependent decline in vital physiological function
Example of wear and tear’
C.elegans muscles get used and over time they decline in function- there is degeneration of the muscles required for feeding due to their overuse
Elephants can die in old age because their teeth become worn
Why is wear and tear thought to not be the only reason for death?
Salmon die soon after they have laid eggs
Different animals have different aging times
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 aging, at least until the animal has reproduced and cared for its young
i.e. as soon as an individual cannot increase in number, or better the chance of its offspring any further, there is no natural selection against aging in that individual
If genes exist which increase the reproductive success in early life stages but are deleterious once progeny is independent- they will be selected for
What are some senescence factors?
Metabolism- high metabolism short lifespan
Reactive oxygen species- produced during metabolism
DNA Damage
What are some factors increasing life span?
Dietary restriction
Environmental stresses
Signals from the somatic gonad
What is the DNA damage theory?
In non-replicating cells, unrepairable damage may accumulate and cause aging
Mice with a high mutation rate will not age any quicker than usual- so aging is due to damage not mutations
Might be due to NAD depletion by DNA induced PARP activation
PARP is an enzyme which is essential for certain DNA processes
ROS?
People thought that these would cause aging but there is evidence to suggest the opposite e.g. exposing e.elegans to them actually increases their life span
progeria?
Basically premature aging caused by mutations in DNA repair mechanisms
What is a senescent cell?
Cell which may get in the way of normal cell based repair= cause aging.
People think that this is because they secrete factors which attract immune cells and activate inflammation
They may be ‘hogging’ stem cell niches.
Removing senescent cells from the niche showed to increase life span
What are the two theories as to how ROS works
Hormesis- low level insults may activate protective mechanism which is larger than in insult itself
Protective superoxide induced pathway- the superoxides are not actually damaging they are a warning sign which activates a protective pathway
How to find genes associated with aging?
Forwards genetics- find mutants which reduce life span (can be somewhat unsuccessful because a lot of non-aging genes can reduce lifespan)
Find long-life mutants
What is the dauer state?
In C.elegans- they survive in adverse conditions. Can last up to 60 days and then fo on to having a normal lifespan after exiting this stage
Insulin Signalling Role
One of the pathways identified in extended life mutants- of you k/o the IGF pathway animals live longer
IGF pathway
IGF- DAF2 receptor, age1 (PI3 kinase) which inhibits DAF16 which is a FOXO type genes
Human data for insulin signalling
FOXO1 and 3A, AKT and OGF1 receptor variants have all been linked in human longevity studies.
Lifespan extension by dietary restriction is mostly mediated by IGF signalling
GH receptor mutants which downregulate IGF- dietary restriction does not extend life
Downstream genes of DAF16 and FOXO
Antioxidant genes (supporting that ROS cause aging)
Metabolic genes
Chaperones
Antibacterial genes
What is the TOR pathway?
TOR kinase is a major amino acid and nutrient sensor- stimulates growth and blocks pathways such as autophagy when food is plentiful
Link between IGF and TOR
They talk to one another via PI3K and Akt this blocks TSC1 and 2
This activates the TOR pathway and protein synthesis is activated
If you block IGF- block TSCs which means that TOR will not be activated- slow protein synthesis
What is rapamycin?
Blocker of TOR-extends lifespan.
What are Siturins?
NAD dependent protein deacetylases
Over expression causes longer lifespan
What does Sir2.1 do>
Activates FOXO/DAF16 (insulin independent)
SIRT6
Downregulates IGF1 levels and thus longevity
What is the effect of sirtuins?
Require NAD and lead to activation of DAF16 in addition to a protective mitochondrial response called mitochondrial unfolded protein response
What is the effect of mitochondrial mutations?
Extend lifespan- theory that this is similar to sirtuins in that it will lead to UPR-mt which by an unknown mechanism leads to protections against aging
What is the implication of mitochondrial diseases on ROS
Mitochondria are the source of ROS- inhibiting these ROS by antioxidants will cancel out their life extending effects in mitochondrial mutants
What is the effect of PARP (DNA damage) on NAD
Reduces it which is thought to be a factor in aging
What is the effect of the germ line on aging
In C.elegans- there is no effect removing the entire reproductive system on aging, but when the germ cells were removed animals lived 60% longer.
Appears that germ cells inhibit a longevity signal that is produced in the soma. DAF12 and ligand are involved in this
