Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Apr 1;103(4):1282-1290.
doi: 10.1210/jc.2017-02694.

Inhibiting Cellular Senescence: A New Therapeutic Paradigm for Age-Related Osteoporosis

Sundeep Khosla  1 , Joshua N Farr  1 , James L Kirkland  1
Affiliations
Review

Inhibiting Cellular Senescence: A New Therapeutic Paradigm for Age-Related Osteoporosis

Sundeep Khosla et al. J Clin Endocrinol Metab. .

Abstract

Context: With the aging of the population and projected increase in osteoporotic fractures coupled with the declining use of osteoporosis medications, there is a compelling need for new approaches to treat osteoporosis. Given that age-related osteoporosis generally coexists with multiple other comorbidities (e.g., atherosclerosis, diabetes, frailty) that share aging as the leading risk factor, there is growing interest in the "Geroscience Hypothesis," which posits that manipulation of fundamental aging mechanisms will delay the appearance or severity of multiple chronic diseases because these diseases share aging as the underlying risk factor. In this context, one fundamental aging mechanism that has received considerable attention recently as contributing to multiple age-related morbidities is cellular senescence. This mini-review provides an overview on cellular senescence with a focus on its role in mediating age-related bone loss.

Methods: This summary is based on the authors' knowledge of the field supplemented by a PubMed search using the terms "senescence," "aging," and "bone."

Results: There is compelling evidence from preclinical models and supportive human data demonstrating an increase in senescent cells in the bone microenvironment with aging. These cells produce a proinflammatory secretome that leads to increased bone resorption and decreased bone formation, and approaches that either eliminate senescent cells or impair the production of their proinflammatory secretome have been shown to prevent age-related bone loss in mice.

Conclusions: Targeting cellular senescence represents a novel therapeutic strategy to prevent not only bone loss but potentially multiple age-related diseases simultaneously.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
The central role of aging in most serious chronic diseases. Adapted from Tchkonia et al. (14).
Figure 2.
Figure 2.
Molecular mechanisms determining lifespan and healthspan that have been identified across species. Reproduced from Tian et al. (15).
Figure 3.
Figure 3.
Overview of pathways and molecular mechanisms inducing cellular senescence and the SASP. C/EBP-β, CCAAT/enhancer binding protein-β; IL-1β, interleukin 1β; IL-6, interleukin 6; NF-κB, nuclear factor κB; ROS, reactive oxygen species; TGF-β, transforming growth factor β; Adapted from Tchkonia et al. (14).
Figure 4.
Figure 4.
Comparison of the effects of antiresorptive vs senolytic therapies on bone metabolism. (a) (1) Senescent cells (SCs) increase in the bone microenvironment with aging, where they (2) increase bone resorption by osteoclasts (OCs) and (3) reduce bone formation by osteoblasts (OBs). (4) Antiresorptive drugs inhibit or eliminate OCs and decrease bone resorption; (5) because of coupling between OCs and OBs, bone resorption is also reduced. (b) (1) Senolytic therapy reduces the burden of (2) SCs, which leads to (3) a reduction in bone resorption with (4) either an increase (cortical bone) or maintained (trabecular bone) bone formation, resulting in (5) a beneficial “uncoupling” between bone resorption and bone formation. Adapted from Farr et al. (29).
Figure 5.
Figure 5.
The accumulation of senescent cells with aging in multiple tissues leads to a number of age-related diseases. Targeting these cells holds the prospect of simultaneously preventing or ameliorating these age-associated morbidities. Adapted from Tchkonia et al. (14).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int. 2006;17(12):1726–1733. - PubMed
    1. Gullberg B, Johnell O, Kanis JA. World-wide projections for hip fracture. Osteoporos Int. 1997;7(5):407–413. - PubMed
    1. Cauley JA, Wampler NS, Barnhart JM, Wu L, Allison M, Chen Z, Hendrix S, Robbins J, Jackson RD; Women’s Health Initiative Observational Study . Incidence of fractures compared to cardiovascular disease and breast cancer: the Women’s Health Initiative Observational Study. Osteoporos Int. 2008;19(12):1717–1723. - PMC - PubMed
    1. Rossouw JE, Prentice RL, Manson JE, Wu L, Barad D, Barnabei VM, Ko M, LaCroix AZ, Margolis KL, Stefanick ML. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297(13):1465–1477. - PubMed
    1. Riggs BL, Hartmann LC. Selective estrogen-receptor modulators: mechanisms of action and application to clinical practice. N Engl J Med. 2003;348(7):618–629. - PubMed

Publication types