What is Known of the Contribution of Cellular Senescence to Osteoporosis

The vast majority of senescent cells are produced when somatic cells reach the Hayflick limit to cell division, their telomeres shortened to a point at which they either self-destruct or enter the senescent state. Damage due to mutation or cytotoxic compounds can also induce senescence, as can the regenerative processes following injury. Senescent cells cease replication, become larger, and change their behavior in many other ways. Senescent cells secrete a pro-growth, pro-inflammatory mix of signals, the senescence-associated secretory phenotype (SASP), that attracts the attention of immune cells capable of destroying senescent cells, but also encourages nearby cells to become senescent.

Throughout much of life, senescence serves as a way to remove damaged cells and suppress the risk of cancer, but this is only the case because these cells are promptly cleared as they arise. Unfortunately, the immune system becomes ever less capable with advancing age, and senescent cells accumulate as the pace of create outstrips the pace of destruction. When senescent cells are constantly present, the SASP turns from helpful to harmful. It induces chronic inflammation, disrupts tissue structure and function, and contributes meaningfully to the onset and progression of all of the common age-related conditions. One of those conditions is osteoporosis, the age-related loss of bone density and the subject of today's open access paper.

Recent advances in senescence-associated secretory phenotype and osteoporosis

Although aging is an uncontrollable process, it is possible to mitigate age-related disorders by modifying the fundamental aging mechanisms. Cellular senescence is one of the mechanisms that can manifest in various biological processes via senescence-associated secretory phenotypes, SASPs. SASPs contribute to releasing cytokines and chemokines that promote local and systemic inflammatory responses, immune system activation, tissue damage, fibrosis, apoptosis, and malfunction. In addition, SASP can cause amplification of localized and systemic senescence via paracrine or endocrine pathways.

Osteoporosis (OP) has emerged as a significant health risk for individuals aged 50 and beyond. As the population ages, there are more instances of osteoporosis and fragility fractures, which puts an increasing strain on the health system. Osteoporosis formation and occurrence in aging are associated with deficient hormone levels, imbalanced bone remodeling, and a restricted number of osteoblasts, osteocytes, and their progenitor cells. Connecting the dots directly to osteoporosis, it is clear that the build-up of senescent cells (SCs) and the overexpression of SASPs in the bone microenvironment are closely linked to the etiology of this illness. In addition, senescent cells have also been shown to be present in the setting of radiotherapy-induced bone loss, and bone biopsy samples from elderly postmenopausal women. Current studies have found that targeting senescent bone cells in the bone and modulating SASP activity can promote bone remodeling and alleviate the symptoms of OP.

Many studies indicate that anti-senescence therapy drugs may have a role in treating osteoporosis associated with aging, radiation, diabetes, estrogen shortage. Nowadays, essential senescence treatment drugs can be categorized into two groups. One is the senolytic approach, which eliminates senescent cells by targeting the apoptotic pathway of senescent cells. The other one is senomorphic technique that targets SASP without influencing cell death. Senolytic medicines such as Dasatinib (D), quercetin (Q), D + Q, Navitoclax (ABT263), BCL-XL inhibitor, HSP90 inhibitor, and ABT-737 are utilized in animal studies to decrease the number of senescent bone marrow stromal cells and preosteoblasts and to increase the osteogenic capacity. Neutralizing antibodies can also inhibit senescence by targeting specific SASP components, such as TNF-α, TGF-β, IL-1β, IL-6, and IL-8. These drugs effectively ameliorate bone loss in inflammation-related diseases. Unfortunately, the efficiency of these anti-SASP agents in clinical OP is obscure.


OT: In a recent interview, Aubrey gave examples of some new treatment types for the old 7 categories of damage, some of them I never heard about, like "IF1 inhibition" against mitochondrial mutations and "extraction" against intracellular junk. Can someone point me to some links for extra information?


Posted by: Antonio at March 1st, 2024 3:40 PM

IL 17 of great significance in RA and OA too :

Samarpita, S. & M, R. (2021). Cyanidin attenuates IL-17A cytokine signaling mediated monocyte migration and differentiation into mature osteoclasts in rheumatoid arthritis. Cytokine, 142. doi: 10.1016/j.cyto.2021.155502

If you block it with high dose polyphenols then the blast/clast balance reverses in favour of osteoblasts.
Probably improves the rest of the SASP components too.

Posted by: JLH at March 1st, 2024 5:06 PM
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