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