neuron death in aging and pathology. pathways to senescence
TRANSCRIPT
Neuron Death in Aging and Pathology
Pathways to Senescence
• Aging = an exponential increase in the likelihood of mortality with time (Gompertz, 1825).
• Cellular and Physiological aging – see next slide.
Oxidant stressIschemia/reperfusionHaemodynamic 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 erosionDNA breaks
Mitochondrialdamage
Stress response Cell cycle control
Lipofuscin accumulation,Plasma membrane e- transport
Pro inflammatorycytokine expression
ROS extracellularmacromolecular damage
Physiological senescenceDecr 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.
DNA Damage Response Pathways
POT1
SIRT 1 XRCC5/G22P1
Telomerase ALT
Telomere erosion DNA breaks
p19ARF MDM2 ATM p16ink4
p53 Cyclin DCKD 4/6P21 waf
pRb
E2F
SIRT 1
Apoptosis
G1 arrestSenescence
S phase
Apoptotic Pathways in Mammals
Cell StressGenotoxic insult
PKC
MAPK
BID
MitochondriaBcl
Bax
Cell death
DNA fragmentation
Death ligand/receptor interaction
Initiatorcaspases
Effectorcaspases
Cell deathInitiatorcaspases
Cytochrome cApaf-1
Smac/Diable
ROS
DNA damage
PIGS
p53 activation
AIF
Disruption of ET in mito
Ca2+Lytic system activatedcellular degeneration
Ca2+ influx
NOS activation NO ROS
ONOOMacromolecular
damage
Membrane lysisNeurotransmiter releaseExcitotoxic injury
Mechanisms of Neuronal Necrosis