Other Free Encyclopedias » Medicine Encyclopedia » Aging Healthy - Part 1 » Cellular Aging: Basic Phenomena - Changes In Cell Morphology And Contact, Senescence And Cell-cycle Progression, Growth Signals And Senescence

Cellular Aging: Basic Phenomena - Growth Signals And Senescence

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If the cellular machinery that replicates DNA is intact in senescent cells, then it is possible that the proteins that carry some of the signals that stimulate DNA replication are diminished in senescent cells. Human diploid cells, near the beginning of their in vitro replicative life span, vigorously respond to stimulation with serum or a combination of certain growth factors by initiating DNA synthesis and mitosis. As these cells approach the end of their proliferative potential in culture, they become increasingly resistant to mitogenic signals. The basis for this loss of responsiveness cannot be attributed to any dramatic reductions in the number of cell-surface growth-factor receptors, nor to changes in the binding affinities with which these receptors bind their ligands (the generic name given to substances that bind to receptors). Instead, the intracellular proteins that convey signals from receptors to the nucleus decrease in number or become inactive.

Cells respond to mitogens through the intracellular actions of secondary events, including phospholipid turner, protein kinase C activation, and calcium mobilization. Alterations in post-receptor transduction pathways have been documented for each of these pathways. Repression of c-fos transcription in senescent cells is evidence for an early block in one or more pathways potentially required for DNA synthesis. However, this alone does not account for the cessation of growth in senescent cells, since overexpression of c-fos fails to prevent senescence. Interestingly, in skin fibroblast cultures derived from individuals with Werner syndrome (a disease of precocious aging), c-fos expression in response to serum is equal in both young and senescent cultures. The expression of some late-acting cell-cycleregulated genes, is also lower in senescent cells. Thus, it is the attrition of multiple signaling pathways associated with cell growth, rather than a decrease in any one pathway, that appears to govern the appearance of a senescent phenotype.

It is also known that the expression of certain genes that suppress growth, such as p53, p21, and p16, increases in senescent cells. These changes in expression may exert profound effects on the proliferative life of cultures. Treatment of normal cells with antisense p53 and retinoblastoma protein (pRB) extends the life span of senescent cells in a cooperative manner. Disruption of tumor/growth suppressor genes such as p21, a gene controlled by p53, can extend proliferative life span. Additionally, transfection of human tumor cells that lack p53 with the wildtype gene can induce a senescent phenotype; yet elimination of p53, and hence p21, fails to prevent senescence in human cells. Loss of p16, an inhibitor of cell cycle regulatory proteins, has also been reported to extend proliferative life span. Constitutive activation of the cellular-signaling protein MEK (a component of the MAP Kinase cascade) induces both p53 and p16 and results in permanent growth arrest in primary mouse fibroblasts. In contrast, overexpression of constitutively active MEK causes uncontrolled mitogenesis and transformation in cells lacking either p53 or p16. Although these changes might at first appear to suggest that signaling proteins decline while growth-inhibitory proteins increase—as part of a coordinated mechanism— this may not be the case. At least one of the growth inhibitory genes (p16) appears to increase, because the family of proteins (Id proteins) that block its transcription in young cells decline in senescent cells. Thus, the senescence-associated increase in p16 results partially from loss of an inhibitor, rather than from direct stimulation of transcription.

Cellular Aging: Basic Phenomena - The Genetics Of Cellular Senescence [next] [back] Cellular Aging: Basic Phenomena - Senescence And Cell-cycle Progression

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