Cell ageing and senescence

Cell ageing and senescence

1. Progerias

   • Werner's syndrome
   • Ataxia telangiectasia

2. What changes?

   • Expression of proteins and mRNA
   • Nuclear and mitochondrial genomes
     • MtDNA more exposed to damage: not complexed with histones, almost all is coding, repair not as efficient
       • cytochrome oxidase is critically important
   • Energy metabolism
     • enlarged mitochondria, decline in membrane potential, increase in production of ROS
   • Protein processing
     • Glycation - assoc with diabetes and alzeimers
       • Protein cross-linking and advanced glycosylation end products (AGES)
   • Accumulation of aggregated/damaged proteins and lipids
     • accumulation of misfolded proteins and peptides (amyloid fibrils/plaques) associated with disease
       • type II diabetes, alzheimers, parkinsons
   • Cessation of division of proliferative cells
   • Functional alterations

3. Network Theory, Free-Radical Theory, telomere theory

4. Free Radicals

   • Reactive Oxygen Species (ROS) Table 18.1 Page 102
     • Hydrogen peroxide
     • Lipid peroxide
     • Nitric oxide (also RNS)
     • Peroxynitrite (also RNS)
     • Main source: oxidative metabolism
       • Superoxide radicals Fig 18.1 Page 103
   • Metals (i.e. iron and copper)
   • ATOMS OR MOLECULES WITH UNPAIRED ELECTRONS
   • Exogenous agents: UV and ionizing radiation, some chemicals
   • Effects
     • DSBs and altered bases, i.e. 8-oxoguanosine
     • Lipid peroxidation
     • Proteins: formation of carbonyl groups, 3-nitrotyrosine, amino acid radicals
     • Oxidative Stress
   • Defenses
     • Molecules that scavenge ROS and RNS
     • Proteins that bind metal ions
     • Enzymes that convert FRs to less reactive or inactive forms
     • Table 18.2 Page 106
     • Enzymes that repair DNA damage
     • Protein degradation systems
     • Stress response proteins

5. Replicative Senescence

   • Cells cannot divide indefinitely
     • Proliferative reserve capacity
   • Senescent cells
     • Larger, with larger nuclei
     • Table 18.3 Page 112
   • Causes?
     • Shortening of telomeres, DNA damage, decondensation of chromatin, overactivation of mitotic stimuli and activation of some oncogenes
       • telomere shortening doesn't always occur
       • Telomere shortening detected by ATM results in withdrawal from the cell cycle and possibly apoptosis (p53)
         • Transfection with genes for telomerase can make a cell immortal
         • BUT: no correlation between telomere length and lifespan or replicative capacity in vitro. Telomere length is not consistent for all chromosomes in a cell
         • may be "sentinels that respond to cellular stress - particularly OXIDATIVE STRESS