Wednesday, April 2, 2025
4/2/2025
Chronic sleep deficiency as a cause of bone loss in aging - More than 35% of adults in the U.S. undergo chronic sleep restriction (SR) which is associated with multiple, incompletely understood adverse health outcomes. Chronic SR is increasingly recognized as a risk factor for bone loss, bone fractures, and osteoporosis. Night shift work and chronic SR in middle-age to older adults imparts a similar risk of fracture as corticosteroid therapy. Our preliminary data in skeletally immature male rats show that chronic SR results in marked osteopenia, decreased cancellous bone mass, and lower bone mineral density—effects that are not fully reversible despite discontinuation of sleep restriction. The effects of SR on bone health during adulthood are unknown and the implications for diseases of aging may be different than for immature bone. The objective of the proposed research is to determine the mechanisms by which chronic sleep deficiency impairs bone quality and integrity in aging. Our rat model uniquely enables us to produce long-term SR under controlled conditions to allow age-related changes in bone to become manifest in vivo. In Aim 1, we will test the hypothesis, supported by preliminary data, that chronic SR exposure after attainment of skeletal maturity impairs bone remodeling, resulting in decreased bone quality and increased fragility. Male and female rats will be studied under chronic SR or control conditions for 10 wk (approximately equivalent to 7 human yr) until 13.5 mo of age. We predict that this chronic SR exposure predisposes to accelerated bone loss both then and later in aging. Therefore, a second cohort will be aged with sleep ad libitum for 12 wk after chronic SR (approximately equivalent to 8 human yr) until 17.5 mo of age to compare their bone quality and integrity to age-matched controls. In Aim 2, we will test the hypothesis that sympathetic nervous system (SNS) activation, which is a hallmark of chronic SR in adults, mediates abnormal bone remodeling. We will evaluate the role of SNS activation by 1) directly removing neural innervation by surgical unilateral hindlimb sympathectomy, with the contralateral hindlimb serving as a paired control, and 2) systemically blocking β-adrenergic receptors (β-AR) that, in other experimental conditions, decreases bone formation and increases bone resorption by actions on bone cells, osteoclastogenic factors, and metabolism. Biomechanical testing of bone will provide functional assessments and will be complemented by structural and cellular determinants of bone quality. Static and dynamic histomorphometry will determine the extent to which bone formation, turnover, and resorption explain SR-induced abnormalities in remodeling. We will elucidate cellular, hormonal, and molecular-mediated mechanisms in chronic SR effects on bone quality and integrity. The studies are innovative because they are firsts in the fields of sleep science and bone metabolism and employ novel interventions. These studies will define a biological role for chronic sleep restriction in bone loss and fracture risk with aging and define the role of SNS activation in its pathogenesis. These studies are important to public health because both SR and fracture are common and amenable to intervention.
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