1.8 - Cellular Aging

Cells age because damage gradually accumulates, while repair and regenerative capacity become progressively less effective.

cellular aging

accumulation of damage over time

• causes —

  • progressive decline in functional capacity and lifespan of cells

  • effects of continuous exposure to factors causing an accumulation of damage

• mechanisms —

  • DNA damage

  • decreased cellular replication

  • reduced regenerative capacity of stem cells

  • defective protein homeostasis

DNA damage

repeated insults cause accumulated DNA damage

• repair enzymes correct damage, but do not repair all damage

• threshold of DNA damage may commit cell to apoptosis

replicative senescence

permanent loss of cell’s ability to continue dividing after a finite number of divisions

• telomeres are repetitive DNA sequences at the ends of linear chromosomes to protect chromosome ends

  • prevent chromosome ends from fusing

  • protect chromosome DNA from degradation

• telomeres shorten during each somatic cell division

  • when critically short, chromosome ends become vulnerable and triggers DNA damage response to cause cell-cycle arrest

• telomerases are RNA-protein complexes that maintain or restore telomere length in germ and stem cells

  • uses its own RNA as a template to add nucleotides to chromosome ends

  • activated in some immortal cancer cells for continued replication

defective protein homeostasis

protein homeostasis requires chaperones and proteasomes

• chaperone defects → proteins unable to fold properly

• proteasome defects → inability to destroy proteins that are damaged or no longer needed

• accumulation of misfolded proteins can trigger apoptosis

sirtuins

deacetylase proteins that may activate DNA repair mechanisms

• example — Sir2

  • calorie restriction may activate Sir2, improving DNA repair and cellular longevity

• sirtuins may connect metabolic state with repair and aging