Bone Aging, Cellular Senescence, and Osteoporosis

Abstract

Changes in aging bone that lead to osteoporosis are mediated at multiple levels, including hormonal alterations, skeletal unloading, and accumulation of senescent cells. This pathological interplay is superimposed upon medical conditions, potentially bone‐wasting medications, modifiable and unmodifiable personal risk factors, and genetic predisposition that accelerate bone loss with aging. In this study, the focus is on bone hemostasis and its dysregulation with aging. The major physiological changes with aging in bone and the role of cellular senescence in contributing to age‐related osteoporosis are summarized. The aspects of bone aging are reviewed including remodeling deficits, uncoupling phenomena, inducers of cellular senescence related to bone aging, roles of the senescence‐associated secretory phenotype, radiation‐induced bone loss as a model for bone aging, and the accumulation of senescent cells in the bone microenvironment as a predominant mechanism for age‐related osteoporosis. The study also addresses the rationale and potential for therapeutic interventions based on the clearance of senescent cells or suppression of the senescence‐associated secretory phenotype. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Impact of Donor Age on the Osteogenic Supportive Capacity of Mesenchymal Stromal Cell-Derived Extracellular Matrix

“…Aging is a complex process involving multiple mechanisms, orchestrated at different levels, that still remain to be elucidated ( Kirkwood, 2005 ). Clinical studies have shown that aging is associated with bone loss ( Zaim et al, 2012 ; Corrado et al, 2020 ) and loss of the osteogenic potential of MSC ( Sethe et al, 2006 ; Stolzing and Scutt, 2006 ; Baker et al, 2015 ; Pignolo et al, 2021 ). In this context, for instance, Mueller and Glowacki (2001) observed a decline in the osteogenic differentiation potential of MSC from donors above 60 years old.…”

Total body proton and heavy-ion irradiation causes cellular senescence and promotes pro-osteoclastogenic activity in mouse bone marrow

“…Moreover, radiation quality-dependent accelerated-senescence in BM cells, likely involve the acquisition of the senescence associated secretory phenotype (SASP) and pro-osteoclastogenic secretion from these cells plausibly results in persistent osteoclastogenesis ( Wang et al., 2021 ; Gorissen et al., 2018 ), as observed in aged mice ( Cao et al., 2003 , 2005 ; Shahnazari et al., 2012 ). The role of SASP-associated overexpression of RANKL in osteoclastogenesis is well established and emerging reports on IR-induced premature aging have also demonstrated the role of RANKL in osteoclastogenesis ( Pignolo et al., 2021 ). While SASP factors like RANKL, could originate from various tissue types after TBI, however, the RANKL expressed from BM cells after TBI might be the major contributor to the osteoclastogenesis.…”

Senescence and senolytics in cardiovascular disease: Promise and potential pitfalls

“…In this review, we highlight those studies that suggest potential clinical applications of senotherapies for the treatment of CVD. Furthermore, we will discuss the potential pitfalls that may hinder the translation of the preclinical studies - given the available literature regarding the undesirable on target and off-target side effects and toxicity profiles of senolytic compounds ( Blagosklonny, 2018 ; Malavolta et al, 2018 ; Medeiros et al, 2018 ; Pignolo et al, 2021 ), including those in the present issue of this journal, our review will focus specifically on the pitfalls relevant to the cardiovascular system as opposed to more generic challenges.…”