In Rats, Navitoclax Removes Senescent Chondrocytes that Contribute to Osteoarthritis

Senescent cells are created constantly throughout life, largely as a result of somatic cells reaching the Hayflick limit on replication, but the pace at which they are cleared by programmed cell death or the immune system slows with age. Senescent cells thus accumulate in old tissues, and this accumulation directly contributes to the progression of age-related disease and dysfunction. Senescence cells secrete a mix of molecules that cause chronic inflammation, disrupt tissue structure, and alter surrounding cell behavior. The more senescent cells there are in an organ, the worse the outcome.

Fortunately, this contributing cause of aging now has potential solutions. Senolytic treatments are those that selectively destroy some fraction of senescent cells, as much as half in some tissues for first generation senolytic drugs. Given that senescent cells work to actively maintain an aged, damaged state of tissue, removing them is a form of rejuvenation. This rejuvenating effect been demonstrated in numerous animal studies, showing that senolytics can reverse many specific age-related diseases, as well as extend healthy life span.

Today's open access paper reports on a representative example of such animal studies of senolytic drugs. The authors used perhaps the worst of the early senolytics, navitoclax, a drug that certainly kills senescent cells, but also kills or disrupts the function of enough normal cells to have significant side-effects that prevent easy clinical use in humans. Nonetheless, one can use this proven senolytic in animal studies to demonstrate the quite rapid reversal of age-related disease produced by the destruction of senescent cells - as is the case here.

Navitoclax (ABT263) reduces inflammation and promotes chondrogenic phenotype by clearing senescent osteoarthritic chondrocytes in osteoarthritis

Cell senescence is characterized by arrest of cell cycle, changes in metabolism, and loss of proliferative ability. Various markers have been used to identify senescent cells (SnCs), including gene expression of p21, p16, and p53, elevated levels of reactive oxygen species (ROS), and activation of senescence-associated β-galactosidase (SA-β-Gal). In aging articular cartilage, the senescent-related alterations in chondrocytes and mesenchymal stem cells (MSCs) during osteoarthritis, such as hypertrophy and loss of cell proliferative and differentiation capacity, may affect chondrogenic differentiation of MSCs and bring obstruction to cartilage regeneration.

In this regard, the term "chondrosenescence" was proposed to describe the age-dependent destruction of chondrocytes and highlight its hallmarks, and explain how they affect the phenotype of these cells and their specialized functions. Furthermore, SnCs have been shown accumulation in OA cartilage tissues with aging. These SnCs exhibit positive staining of SA-β-Gal, increased level of the senescence-related gene p16INK4a, senescence-associated secretory phenotype (SASP), increased production of pro-inflammatory mediators, and increased secretion of cytokines and chemokines.

Selective removal of these SnCs through a senolytic molecule (UBX0101) from osteoarthritic chondrocytes has been shown to reduce the expression of inflammation- and age-related molecules, and simultaneously delay the progression of post-traumatic osteoarthritis in p16-3MR mice. This finding supports a promising therapeutic strategy by targeting SnCs for osteoarthritis treatment. Another senolytic pharmacological agent navitoclax (also named ABT263), a specific inhibitor of the BCL-2 and BCL-xL proteins, has been reported to selectively clear SnCs in the hematopoietic system from premature aging mice after total-body irradiation by inducing cell apoptosis, and thus, rejuvenating aged tissue stem cells in normally aged mice.

In this study, we examined the ability of the senolytic drug ABT263 to clear SnCs and further evaluated the therapeutic effect of ABT263 on post-traumatic osteoarthritis. A destabilization of the medial meniscus (DMM) rat model was established for in vivo experiments. We found that ABT263 reduced the expression of inflammatory cytokines and promoted cartilage matrix aggregation by inducing SnC apoptosis. Moreover, osteoarthritis pathological changes in the cartilage and subchondral bone in post-traumatic osteoarthritis rat were alleviated by ABT263 intra-articular injection. These results demonstrated that ABT263 not only improves inflammatory microenvironment but also promotes cartilage phenotype maintenance]. Furthermore, ABT263 might play a protective role against post-traumatic osteoarthritis development. Therefore, strategies targeting SnC elimination might be promising for the clinical therapy of osteoarthritis.


It is interesting that in the last couple of years we don't witness new Senolytic compounds. Is that a selection bias ?

Posted by: Cuberat at July 15th, 2020 9:21 PM

Still waiting for significant progress on Senolytic treatments. I thought it would be nearly here in clinics. If only regenerative medicine would arrive as quickly as virus vaccine is expected to be here, we'd save a ton of people.

Posted by: Robert at July 15th, 2020 10:08 PM

@Robert: I'm not sure where you got that idea from. Senolytics for the indication of osteoarthritis are current in phase II clinical trials. That makes it another 3-5 years minimum before the compound in question receives approval, and there's a very good chance it flunks in phase II or III, drug development is not easy.

As far as senolytics as a prophylactic against ARDs, that's going to happen at the very soonest maybe 5-10 years after a senolytic drug is approved for an indication like AD or OA; the best surrogate of biological aging we currently have (and are likely to have) is multi-morbidity, and that needs to be studied over a period of several years with an already approved drug.

Don't expect senolytics to be used for another 5-10 years if there's any indication they work for, and don't expect them to be used for aging if that pans out for another 10-15 years after that.

Posted by: Dylan Mah at July 20th, 2020 4:58 PM

@Dylan Mah
I think the adoption speed will depend also in how during and profound the effects are.

If it reduces all types of morbidity be 1% and gives a few months of life expectancy if started at 40 something, then there not much to be excited about. That's basically what metformin can do. Probably rapamycin had even stronger effects but I don't see bootlegger beauty parlours pushing it.

On the other hand, if the effect from a couple of treatments is visually apparent, there would be an industry using those FDA and safety be damned. There are many people that would choose to look and feel younger now, even if it brings risks a couple of decades later.

Posted by: Cuberat at July 21st, 2020 11:19 PM
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