Neuron Death in Aging and Pathology

1. Neuron Death in Aging and Pathology

8. Pathways to Senescence

9. Aging = an exponential increase in the likelihood of mortality with time (Gompertz, 1825). • Cellular and Physiological aging – see next slide.

10. Chronological Aging Stress Decline in functioning neurons, mass, and capacity to withstand stress Oxidant stress Ischemia/reperfusion Haemodynamic stress Disease stress Physiological senescence Cellular senescence Apoptosis Pro inflammatory cytokine expression Telomere erosion DNA breaks Mitochondrial damage ROS oxidative damage Stress response Cell cycle control Lipofuscin accumulation, Plasma membrane e- transport Necrosis Physiological senescence ROS extracellular macromolecular damage Decr ability to withstand insult Predisposition to disease

11. Damage, repair, and disposal • Metabolism (ETS)  ROS • Defense mechanisms against FRs and ROSs. What saves proteins? What saves DNA? Aging and the MTR Trinity • Mitochontria • Telomere-nucleo-protein clusters • rDNA-Sirtuins

12. Mitochondria • Oxidative damage is a strong correlate of aging. • Oxidative damage also a strong correlate of metabolism (mitochondria DNA). • Aging and mito diseases (e.g., mitochondrial myopathy). • Even low (< 1%) loss-of-function mutations in mito genomes  use plasma membrane ET as a compensatory mechanism  ROS outside the cell and amplifies oxidative stress.

13. Telomeres as Molecular Triggers for Stress Response • Telomere length of human chromosomes in dividing somatic cells erodes with increasing chronological age. • [due to incomplete replication of chrom ends and nuclease actions]. • Beneficial – telomere erosion is considered to be an anti-neoplastic mechanism that functions as a mitotic clock. • Telomere shortening implicated in many human diseases and aging. • Telomeric proteins form part of a damage-sensing and signalling system. • Such proteins (e.g., Ku70-Ku80, Mre11-Rad50-Nbs1) highly conserved and detect ds breaks  inhibit mitosis  facilitate DNA repair or apoptosis. • Telomere-nucleoprotein complexes work in tandem with the above proteins to repair DNA. • Such complexes are signaled to the mito. • Inability to respond to or to repair damage  accelerated aging.

14. rDNA, Aging, and Sirtuins • ExtrachromosomalrDNA circles (yeast) (ERCs) – compete with telomere-binding proteins (rDNA has the same sequence as telomeres), telomeres are not protected  cell death. • Sirtuins (SIRTs) regulate aging and enhanced life span due to caloric restriction (CR). • Carry an extra copy of the Sir2 gene incr ML. • Sir2 correlated with NAD+-dependency of cell. • Yeast: CR incr ML through incr C metabolism towards mito TCA (incrresp) decrglycolytic rate and incr ETC rate (and NADH  NAD+) in mito and activation of Sir2. • Interfere with mito ETC  prevents the CR-assoc longetivity. • This undermines the current thinking that incr metabolism jeopardizes ML (brain critically needs higher metabolism). • CR does not appear to increase the resistance to oxidative stress during the replicative lifespan (yeast). • ROS do affect survival of post-mitotic and stationary-phase cells. • Increases in anti-oxidant levels associated with CR may no longer per se be viewed as a direct cause of longevity. • Rather, but of CR driving C into the TCA, thus increasing respiration.

15. DNA Damage Response Pathways SIRT 1 XRCC5/G22P1 POT1 Telomerase ALT Telomere erosion DNA breaks p16ink4 p19ARF MDM2 ATM CKD 4/6 Cyclin D P21 waf SIRT 1 p53 G1 arrest Senescence pRb Apoptosis E2F S phase

16. Apoptotic Pathways in Mammals Cell Stress Genotoxic insult Cell death Death ligand/ receptor interaction PKC MAPK BID DNA fragmentation Initiator caspases AIF ROS Bcl Mitochondria PIGS Bax DNA damage Effector caspases p53 activation Cytochrome c Apaf-1 Smac/Diable Initiator caspases Cell death

17. Mechanisms of Neuronal Necrosis Lytic system activated cellular degeneration Ca2+ Ca2+ influx Disruption of ET in mito NOS activation NO ROS Macromolecular damage ONOO Membrane lysis Neurotransmiter release Excitotoxic injury