Lecture 6 Flashcards
Why do we need stem cells?
Because cells age and need to be replaced or added for growth. Failure of endogenous stem cells causes aging
What is senescence? Give an example.
An age related decline in physiological functions. Drosophila survival rate rapidly decreases as they age
What are the causes of death?
1) wear and tear e.g. decline in muscle in C. elegans and elephants die due to their teeth falling out and not being able to chew their food
2) genetics= salmon almost always die after they lay their eggs
3) different species have different life spans e.g. elephants have 21 months of gestation where as a mouse’s lifespan in 42 months
What is the disposable soma theory?
Once an organism has reproduced and cared for its young, there is no longer natural selection against it and will be selected for (killed)
What is the rate of living theory?
Higher metabolism= shorter lifespan
larger animals live longer and cold animals live longer at lower temperatures. Place fly in 18 degrees instead of 25= live up to 130 days (significant increase)
What is the ROS theory of aging?
That high metabolism generates ROS= have free electrons which are highly unstable and oxidise structures in cell. However it is not always true- give a fish juglone (increases ROS)= lives longer. Glucose restriction increases the resistance against oxidative stress and extends lifespan
What is the primary cause of aging?
DNA damage- not mutation rate but due to unrepaired DNA
What are the 5 diseases associated with premature aging?
1) Ehlers Danos= mutation in 4-Beta-galactotransferase
2) Werner syndrome= RECQ gene mutation for DNA helicase
3) Hutchinson-Guilford progeria= Mutations in laminin which effects the DNA architecture
4) cockayne= group 8 excision repair proteins
5) Nester Guillermo = BANf1 mutations which effect mitosis and lamina
What is the DNA damage theory of aging?
That DNA damage in non-dividing cells causes aging (in dividing cells it causes mutations). Mice with mutations doesn’t effect their aging. When DNA damage occurs it is detected by the PARP enzyme which attempts to repair the DNA and depletes the NAD stores, causing cellular senescence
How do senescent cells cause aging?
They don’t die- just sit there and secrete SASPs which recruits the immune system (CD4+ and Tcells). They accumulate and block the system e.g. paracrine and autocrine senescence and tissue remodelling especially if they block a niche. When senescent cells are ablated in a mouse, they appear healthier
What are 2 factors that effect life span?
1) environmental stress e.g. heat- increases cellular ROS as an alarm bell
2) dietary restrictions= restrict caloric intake and rats live up to 40% longer
How can forward genetics be used to understand genetic aspects of aging and what are the limitations?
Can clone gene and see what it does but many gene mutations can kill an animal but not effect aging- very difficult. Can be carried out on short lived mutant drosophila and C. elegans due to short lifespan (easier to deal with than mammals). Can be used to understand IGF and TOR pathway.
Why do C. elegans have interesting life spans?
They have a normal lifespan of 25 days but can enter a dauer stage when a L4 larva which can last up to 60 days- found that it is due to block in insulin signalling
How does blocking the insulin pathway prevent aging in C elegans and drosophila?
signalling through DAF2 (IGFR) inhibits DAF16 (FOXO), HSF1, and SKN1. DAF16 (FOXO) transcription regulates genes that increase resistance to various stresses. In drosophila it doubles the lifespan however they are unable to reproduce (in survival mode)
What is the human data on insulin signalling and how does it effect mice?
FOXO1, FOXO3A, AKT and IGF1 receptor variants have been linked to human longevity. Dietary restrictions in mice extends life span due to IGF signalling- if mutant for GH (downregulating IGF signalling) dietry restrictions will have no effect
