• Decreased cellular replication. Normal cells (other than stem cells) have a limited capacity for replication, and after a fixed number of divisions, they become arrested in a terminally nondividing state, known as replicative senescence. Aging is associated with progressive replicative senescence of cells. Cells from children have the capacity to undergo more rounds of replication than do cells from older people. In contrast, cells from patients with Werner syndrome, a rare disease characterized by premature aging, have a markedly reduced in vitro life span. Replicative senescence occurs in aging cells because of progressive shortening of telomeres, which ultimately results in cell cycle arrest. Telomeres are short repeated sequences of DNA present at the ends of chromosomes that are important for ensuring the complete replication of chromosome ends and for protecting the ends from fusion and degradation. Telomeric DNA also binds proteins that shield it, preventing activation of a DNA damage response. When somatic cells replicate, a small section of the telomere is not duplicated, and telomeres become progressively shortened. As they shorten, the ends of chromosomes cannot be protected and are sensed in cells as broken DNA, which signals cell cycle arrest. Telomere length is maintained by nucleotide addition mediated by an enzyme called telomerase. Telomerase is a specialized RNA-protein complex that uses its own RNA as a template for adding nucleotides to the ends of chromosomes. Telomerase is expressed in germ cells and is present at low levels in stem cells, but absent in most somatic cells (
Fig. 2.28 ). Therefore, as mature somatic cells age, their telomeres become shorter and they exit the cell cycle, resulting in an inability to generate new cells to replace damaged ones. Conversely, in immortalized cancer cells, telomerase is usually reactivated and telomere length is stabilized, allowing the cells to proliferate indefinitely. This is discussed more fully in Chapter 6. Telomere shortening also may decrease the regenerative capacity of stem cells, further contributing to cellular aging. Despite such alluring observations, however, the relationship of telomerase activity and telomere length to aging has yet to be fully established. Abnormalities in telomere maintenance have been implicated in many diseases, such as aplastic anemia and other cytopenias (thought to be caused by a failure of hematopoietic stem cells), premature greying of hair, skin pigment and nail abnormalities, pulmonary and liver fibrosis, and others.
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Accumulation of mutations in DNA Cellular replication DECREASED CELL FUNCTIONS, CELL LOSS CELL LOSS Altered transcription Proteins, damaged proteins Insulin/IGF signaling DNA repair Protein homeostasis TOR DECREASED CELL FUNCTIONS COUNTERACTS AGING ROS? Defective DNA repair CELLULAR AGING
Fig. 2.27 Mechanismsthatcauseandcounteractcellularaging.DNAdamage,replicativesenescence,anddecreasedandmisfoldedproteinsareamongthebest-describedmechanismsofcellularaging.Someenvironmentalinfluences,suchascalorierestriction,counteractagingbyactivatingvarioussignalingpathwaysandtranscriptionfactors.IGF, Insulin-likegrowthfactor;ROS, reactiveoxygenspecies;TOR, targetofrapamycin.
These disorders are sometimes considered the prototypic “telomeropathies.” • Defective protein homeostasis. With the passage of time, cells are unable to maintain normal protein homeostasis, because of increased turnover and decreased synthesis caused by reduced translation of proteins and defective activity of chaperones (which promote normal protein folding) and proteasomes (which destroy misfolded proteins). The resultant decrease in intracellular proteins can have many deleterious effects on cell survival, replication, and functions. The concomitant accumulation of misfolded proteins exacerbates the loss of functional proteins and can trigger apoptosis.
• There has been great interest in defining biochemical signaling pathways that counteract the aging process, not only because of their obvious therapeutic potential