Cell Death Flashcards
Biological Programmed Theories of Aging
- Programmed Senescence Theory
- Endocrine senescence theory
- Immune Senescence theory
Accumulation of Errors or Damage Theories of Aging
- Wear and Tear
- Rate-of-living
- Environmental Exposures Theory
- Failure to repair and neurogenesis
- Free Radical
Programmed Genetic Senescence Theory
- Genes regulate a “program” of bodily aging
- after spawning - massive corticosteroid release leading to death of salmon
- “hayflick’s limits”
- Telomerase Theory of Aging
Endocrine homeostasis theory
- Decreased hypothalamic/pit/ovarian function leading to sexual senscence
- Decrease in additional hormones (GH, melatonin)
- Difficult to maintain homeostasis as we age
1) decline in production of hormones
2) Target organs respond less
Immune Homeostasis Theory
Changes in the immune system lead to increased infections and disease vulnerability.
- Decrease in T helper cells
- Increase in autoimmune diseases
- Involution of Thymus
Accumulation of Damage and Errors
Cellular function –> Oxygen/glucose use –> accumulating cell debris
- Live fast die young
- Failure of one system causes failure of all
Rate of Living Theory
- All cells have a metabolic “bank account”
- Once consumed allotment of calories, systems fail
- Greater oxygen basal metabolism, shorter lifespan
- Caloric restriction studies
Failure of neurogenesis theory
Neurogenesis occurs throughout life in the:
1) Hippocampus
2) Olfactory bulb
-Crucial for synaptic plasticity and learning
Failure of endogenous repair mechanisms
- Exogenous exposure to toxins
- Failure of neurotrophic signalling to be turned back on –> failure to repair
Oxidative stress/Free Radical theory
- Free radicals causing damage
- Slow accumulation o fdamage
- Mitochondria acting as death switch for neurons
Appropriate Cell Death
-Apoptosis
-Part of normal brain development
Induced by neurotrophic factor withdrawal
-Multiple genes coordinate
Inappropriate Cell Death
-Apoptotic (active)
-Necrotic (passive)
-
Apoptosis following mild cellular stressor
-Necrotic cells placed in toxic environments and passively die (low O2, high temp, trauma, toxicants, disease)
Apoptosis: Intrinsic vs. Extrinsic
- Intrinsic: mitochondrial impairment: BAX/bad insertion and release of procaspase 9
- Extrinsic: Death signal binding: Procaspase 8
Apoptosis Process
- Nuclear Compaction
- Chromatin condensation
- DNA cleavage
- Blebbing
- Formation of apoptotic bodies
- Microglia scavenge what is left
How is it that cellular constituents do not cause inflammatory response after apoptosis
Plasma membrane stays intact, not released into the local environment
Necrosis Process
- Cellular swelling is followed by rupture of all cell membranes
- All constituents are dumped into local area causing secondary damage
- Associated with robust inflammation and microglial inflammation
ROS and CNS DAmage
Metabolism of oxygen and Ca++ overload can lead to damage in neurons
What are endogenous and exogenous causes for Ox Stress
- Endogenous: Mitochondria, Peroxisomes, Inflammatory cell
- Exogenous: Radiation, Ozone, Xenobiotics
Defense System for ROS
Enzymatic and non enzymatic
Enzymatic: Superoxide dismutase, Glutathione peroxidase, Catalase
Non-enzymatic: Vitemin E, C, Glutathione, Polyphenols
Why are Neurons particularily vulnerable to ROS?
1) High metabolic demand
2) little capacity to make or store energy
3) metabolic demands increase with age
Why do ROS beget ROS
If Glucose/ox availibility is reduced, cannot make ATP and calcium buffering /glutamate reuptake are reduced
Specific effects of ROS
- DNA strand breaks
- Protein Nitration
- Lipid peroxidation
- Iron catalyst increases speed
What is the most studied excitotoxicity?
Why
Calcium Overload
Huge neuron death on the order of a few minutes
Ischemiia or trauma
Three Proteins involved in calcium buffering
1) ATP-dependent CA pump: mitochondria and ER
2) Cytosolic Ca sensor: Calmodulin
3) Cytosolic Ca binding proteins: Calbindin`
How does ischemic stroke cause excito toxicity
Lack of oxygen and Glc No ATP Ca++ and GLU buffering fails Calcium overload Uncontrolled neurotransmitter release Ca Dependent lipases, DNAases, proteases
