Aging = an exponential increase in the likelihood of mortality with time (Gompertz, 1825). Cellular and Physiological aging – see next slide.
Oxidant stress Ischemia/reperfusion Haemodynamic stress Disease stress Stress Decline in functioning neurons, mass, and capacity to withstand stress Chronological Aging Cellular senescence Apoptosis Physiological senescence ROS oxidative damage Telomere erosion DNA breaks Mitochondrial damage Stress responseCell cycle control Lipofuscin accumulation, Plasma membrane e - transport Pro inflammatory cytokine expression ROS extracellular macromolecular damage Physiological senescence Decr ability to withstand insult Predisposition to disease Necrosis
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
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.
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.
rDNA, Aging, and Sirtuins Extrachromosomal rDNA 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 (incr resp) decr glycolytic 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.
Apoptotic Pathways in Mammals Cell Stress Genotoxic insult PKC MAPK BID Mitochondria Bcl Bax Cell death DNA fragmentation Death ligand/ receptor interaction Initiator caspases Effector caspases Cell death Initiator caspases Cytochrome c Apaf-1 Smac/Diable ROS DNA damage PIGS p53 activation AIF
Disruption of ET in mito Ca 2+ Lytic system activated cellular degeneration Ca 2+ influx NOS activation NO ROS ONOO Macromolecular damage Membrane lysis Neurotransmiter release Excitotoxic injury Mechanisms of Neuronal Necrosis