Clearance of Senescent Cells as a Treatment for Osteoporosis

Senescent cells accumulate with age throughout the body. While only present in comparatively small numbers, even in very late life, their potent inflammatory signaling actively maintains a damaged, dysfunctional state in tissues and the body as a whole. Removing them dampens chronic inflammation and restores regenerative capacity. In animal studies senolytic therapies capable of removing 25-50% of senescent cells in at least some tissues are proving to be a more effective therapy than any presently available option for a wide range of age-related conditions. One example, noted here, is the characteristic loss of bone density with age known as osteoporosis. This is partially a consequence of inflammation, as inflammation disrupts the balance between osteoblasts that create bone and osteoclasts that break down bone. Both types of cell are constantly active in bone tissue, but the balance tips too far towards osteoclasts in the damaged tissue environment of later life.

Cellular senescence refers to a process induced by various types of stress that causes irreversible cell cycle arrest and distinct cellular alterations, including profound changes in gene expression, metabolism, and chromatin organization as well as activation/reinforcement of anti-apoptotic pathways and development of a pro-inflammatory secretome or senescence-associated secretory phenotype (SASP). However, because of challenges and technical limitations in identifying and characterizing senescent cells in living organisms, only recently have some of the diverse in vivo roles of these unique cells been discovered.

New findings indicate that senescent cells and their SASP can have acute beneficial functions, such as in tissue regeneration and wound healing. However, in contrast, when senescent cells accumulate in excess chronically at sites of pathology or in old tissues they drive multiple age-associated chronic diseases. Senotherapeutics that selectively eliminate senescent cells ("senolytics") or inhibit their detrimental SASP ("senomorphics") have been developed and tested in aged preclinical models. These studies have established that targeting senescence is a powerful anti-aging strategy to improve "healthspan" - i.e., the healthy period of life free of chronic disease.

The roles of senescence in mediating age-related bone loss have been a recent focus of rigorous investigation. Studies in mice and humans demonstrate that with aging, at least a subset of most cell types in the bone microenvironment become senescent and develop a heterogeneous SASP. Furthermore, age-related bone loss can be alleviated in old mice, with apparent advantages over anti-resorptive therapy, by reducing the senescent cell burden genetically or pharmacologically with the first class of senolytics or a senomorphic. Collectively, these findings point to targeting senescence as a transformational strategy to extend healthspan, therefore providing strong rationale for identifying and optimizing senotherapeutics to alleviate multiple chronic diseases of aging, including osteoporosis, and set the stage for translating senotherapeutics to humans, with clinical trials currently ongoing.

Link: https://doi.org/10.1016/j.bone.2019.01.015

Comments

Osteoarthritis is so painful and common that one can easily find human volunteers who would agree on high risk therapies as long as it is less risky than the joint replacement operation.

In fact, an injection of gel that slowly releases a bioavailabile mix of Dasatinib, qercetin and fisetin sounds like low tech enough to be used in also any clinic...

The biggest difficulty is to make a targeted delivery.

Now I have the following question or rather concern. Did anybody on regular Dasatinib treatment experience a marked improvement for a knee hot pain?

Posted by: Cuberat at January 23rd, 2019 9:04 AM

"One example, noted here, is the characteristic loss of bone density with age known as osteoporosis. This is partially a consequence of inflammation, as inflammation disrupts the balance between osteoblasts that create bone and osteoclasts that break down bone. Both types of cell are constantly active in bone tissue, but the balance tips too far towards osteoclasts in the damaged tissue environment of later life."

So...you try to use supplements/foods that enhance bone health and some that reduce inflammation.

Men that fall and break a hip are more likely to NOT get out of a nursing home...than women.

Those waiting for some big pharma breakthrough are also waiting for Godot?

Posted by: bob at January 30th, 2019 6:27 AM

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.