General Aspects of Cellular Senescence

As for all mammalian cells, be they of fibroblastic or epithelial origin, the cells that form the soft tissues of the musculoskeletal system will also undergo senescence. This process starts after an extended period of

Handbook of Models for Human Aging

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proliferation or in response to inadequate growth conditions or physiologic stress. Senescent cells cease to respond to mitogenic stimuli; they undergo changes in the chromatin structure and gene expression and become enlarged and flattened (Serrano et al., 2001; Shelton et al., 1999). Characteristically, such cells show increased adhesion to the extracellular matrix, while losing cell-cell contact. Regarding these alterations, cellular senescence can be seen as a program activated to prevent cell proliferation in various situations of physiologic stress (Ben Porath et al., 2004).

In classical experiments in the 1960s it has been shown that normal human fibroblasts cease to divide following a period of propagation in culture (Hayflick et al., 1961), which was later called Hayflick-limit.

There exist various triggers of senescence of which telomere uncapping has garnered much attention in senescence research. Telomeres are the terminal DNAproteins of chromosomes. Analysis of telomere length as a function of age, either in cells of people of different age or as a function of cell division number in cultures of human fibroblast, show that mean telomere length gradually decreases with increased age or cell division number (Cooke et al., 1986; Harley et al., 1990). The shortening of the telomeres leads to telomere ''uncapping,'' which causes disruption of the structure of the protective cap at the end of the telomere (Blackburn, 2001). The uncapped telomere is thought to be recognized as a DNA-break, which activates the DNA damage machinery.

Besides telomere dysfunction, senescence of normal cells can be induced by direct DNA damage, oxidative stress, and oncogene expression.

Oxidative stress plays an important role in the induction of senescence by causing DNA damage and accelerating telomere loss (Forsyth et al., 2003; Parrinello et al., 2003). It has been demonstrated that human fibroblasts undergo premature senescence in high ambient oxygen conditions (Chen et al., 1995). In the condition of internal accumulation of reactive oxygen species, cellular components can be damaged through the oxidation of DNA, proteins, and lipids (Chen et al., 1998).

Reactive oxygene species can be induced by overexpression of the RAS oncogene, promoting cellular senescence (Lee et al., 1999). This response to the RAS activity has been suggested to represent a tumor-suppressor mechanism, by which cells prevent uncontrolled proliferation in response to the aberrant activation of proliferation-driving oncogenes. However, the role of reactive oxygene species in RAS-induced senescence is not fully understood.

Direct DNA damage can be caused by irradiation of cells or by treatment with DNA-damaging agents and may induce cells to undergo senescence. In many cases, the cellular response to such damage is cell death, but also irreversible cell-cycle arrest, depending on the type of agent and/or dosage administered (Wahl et al., 2001).

All these inductors of senescence share a central activating pathway of senescence. P53 and Rb, two tumor suppressor proteins, have been shown to play a critical role in senescence induction, since both are activated upon the entry into senescence. The specific targets of these proteins constitute the majority of the effectors that are necessary for cell-cycle progression.

As a result of aging and cellular senescence, the biological and mechanical behaviors of all musculoskele-tal tissues, including skeletal muscle, tendons, ligaments, cartilage, synovial membrane, joint capsule, and bone, undergo specific alterations. These changes follow similar patterns that comprise alterations in the number and function of cells, in their proliferative and synthetic capacity, as well as in the composition of the extracellular matrix. However, since the tissues differ in their composition, structure, and function, age-related changes must be considered individually.

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