Aging mechanisms in bone

Abstract

Advancing age and loss of bone mass and strength are closely linked. Elevated osteoblast and osteocyte apoptosis and decreased osteoblast number characterize the age-related skeletal changes in humans and rodents. Similar to other tissues, oxidative stress increases in bone with age. This article reviews current knowledge on the effects of the aging process on bone and its cellular constituents, with particular emphasis on the role of reactive oxygen species (ROS). FoxOs, sirtuins and the p53/p66^shc signaling cascade alter osteoblast number and bone formation via ROS-dependent and -independent mechanisms. Specifically, activation of the p53/p66^shc signaling increases osteoblast/osteocyte apoptosis in the aged skeleton and decreases bone mass. FoxO activation in osteoblasts prevents oxidative stress to preserve skeletal homeostasis. However, while defending against stress FoxOs bind to β-catenin and attenuate Wnt/T-cell cell factor transcriptional activity and osteoblast generation. Thus, pathways that impact longevity and several diseases of ageing might also contribute to age-related osteoporosis.

Figure 1. The role of ROS in age-related skeletal involution.

(Left panel) In young normal mice, ROS produced in the mitochondria or in the cytoplasm are scavenged by several cellular antioxidants, resulting in redox homeostasis. This leads to balanced remodeling of the skeleton, low osteoblast (Ob) and osteocyte (Ot) apoptosis and normal bone mass. (Right panel) Antioxidant deficiency, as a result of superoxide dismutase (SOD)1 or FoxO1, 3, 4 deletion, leads to elevated levels of ROS and oxidative stress that, in turn, promote altered signal transduction and cell damage. Thus, SOD1 or FoxO1, 3, 4 KO mice exhibit premature skeletal aging characterized by low bone formation, high osteoblast and osteocyte apoptosis and low bone mass.