2 Aging and Bone

In clinical medicine, aging may be best defi ned by the words Supreme Court Justice Potter Stewart used to describe pornography: “I know it when I see it” (JACOBELLIS v. OHIO, 378 U.S. 184 (1964)). Every physician has witnessed the effects of aging, both in individual patients followed over a period of time and in their collective patient population base. Nevertheless, a number of defi nitions of aging have been offered, and these have been elegantly summarized in Carrington’s review entitled: “Aging bone and cartilage: cross-cutting issues” (1). In the clinical care setting, aging is generally associated with the loss of a wide range of physiological processes (1) (Table 2.1). These include decreased fertility (2), decreased resilience in response to environmental stressors such as infections, surgery, or physical attack (3), and decreased physical strength. Inevitably, aging is also associated with end of life and death (2,4). At the cellular level, several fundamental and interconnected processes accompany aging in vitro and in vivo (1) (Table 2.1). Hayfl ick fi rst defi ned the process of cellular senescence, demonstrating that “normal” diploid cells can undergo a limited number of cell doublings in vitro (5). These pioneering observations set the framework within which much of our understanding of aging is now predicated. Consequently, the Hayfl ick model for replicative senescence has been employed in biogerontology research to unravel mechanisms of age-related cellular defects (6). Using this model, several investigators have reported an inverse relationship between the donor age and maximal proliferative potential of the cells in vitro (7). The Kassem laboratory has characterised a Hayfl ick model for replicative senescence of human osteoblasts (8,9). During continuous culture in vitro, human osteoblasts exhibited typical senescence-related phenotype including senescent-associated decrease in osteoblast marker production (alkaline phosphatase [AP], osteocalcin, collagen type I), decrease in mean telomere fragment length, and increase in the number of senescence-associated β-galactosidase (SA β-gal) positive cells (10,11). With each progressive mitotic cycle, each telomere, located at the ends of individual chromosomes, decreases in length; and this has been associated with senescence (12). It has been postulated that the telomere length acts as a “mitotic clock,” and it is known that the overexpression of telomerase, the enzyme responsible for maintaining telomere length, leads to cell immortalization (13). The Kassem laboratory has further examined the effect of donor age on the maximal proliferative potential of bone marrow stem cells (BMSC). An age-related decline in the maximal life span from