Basic biology of skeletal aging: role of stress response pathways

Abstract

Although a decline in bone formation and loss of bone mass are common features of human aging, the molecular mechanisms mediating these effects have remained unclear. Evidence from pharmacological and genetic studies in mice has provided support for a deleterious effect of oxidative stress in bone and has strengthened the idea that an increase in reactive oxygen species (ROS) with advancing age represents a pathophysiological mechanism underlying age-related bone loss. Mesenchymal stem cells and osteocytes are long-lived cells and, therefore, are more susceptible than other types of bone cells to the molecular changes caused by aging, including increased levels of ROS and decreased autophagy. However, short-lived cells like osteoblast progenitors and mature osteoblasts and osteoclasts are also affected by the altered aged environment characterized by lower levels of sex steroids, increased endogenous glucocorticoids, and higher oxidized lipids. This article reviews current knowledge on the effects of the aging process on bone, with particular emphasis on the role of ROS and autophagy in cells of the osteoblast lineage in mice.

Keywords: Autophagy; Bone; Mesenchymal stem cells; Osteocytes; Oxidative stress..

Figure 1.

Mechanisms of age-related changes in bone. Both cell intrinsic and cell extrinsic mechanisms contribute to the reduced osteoblast generation and increased osteoblast and osteocytes apoptosis that lead to the loss of bone mass with aging. For example, an increase in ROS and endogenous hyperglucocorticoidism with age, as well as sex steroid deficiency, promote osteoblast and osteocyte apoptosis. Osteocyte apoptosis leads to a reduction in osteocytes density.

Figure 2.

Autophagy degrades and recycles cellular components. Autophagy is an intracellular recycling pathway in which cellular components, including protein aggregates and organelles such as mitochondria, are targeted to the lysosome for degradation. Cellular components targeted for degradation are engulfed by a double-membrane structure known an autophagosome. Autophagosome formation depends on series of ubiquitin-like conjugation reactions. In this process, Atg7, which is an E1-like enzyme, activates a ubiquitin-like protein known as LC3. LC3 then becomes conjugated to phosphatidyl ethanolamine (PE) and thereby promotes autophagosome production. Importantly, Atg7 is essential for autophagy and conditional deletion of this gene can be used to examine the importance of autophagy in specific cell types.