An Example to Illustrate Why Navitoclax is Not a Suitable Clinical Senolytic Drug

Senolytic therapies are those that selectively destroy senescent cells. Cells that become senescent grow in size, cease to replicate, and generate a potent mix of molecules known as the senescence-associated secretory phenotype (SASP). Senescence occurs at the Hayflick limit on cellular replication, or in response to cell damage and a toxic local environment. The SASP provokes the immune system into an inflammatory state, disrupts tissue structure and function, and encourages nearby cells to also become senescent. It is useful in the short term, in the context of wound healing and cancer suppression for example, but when present for the long-term, the SASP is an important cause of degenerative aging. A significant fraction of aging and age-related disease is driven by the accumulation of senescent cells throughout the body, and hence the research community is quite interested in finding ways to get rid of these errant cells.

The earliest discovered senolytic small molecule drugs are chemotherapeutics. It is fair to say that they are selective for senescent cells, but in some cases far from selective enough. They kill a lot of non-senescent cells and, further, cause all sorts of problematic and potentially serious side-effects. In addition, drugs such as the small molecules targeting Bcl-2 family proteins, particularly navitoclax, tend to require a few weeks of dosing at chemotherapeutic levels to generate senolytic effects. This is as opposed to the few doses or intermittent doses of the arguably more effective senolytic chemotherapeutic dasatinib. Less of a chemotherapeutic drug is almost always a good thing.

The open access paper I'll point out today provides an additional incentive to avoid navitoclax as a senolytic treatment. It does indeed kill senescent cells in aged tissues, but it is just too toxic, with too many harmful side-effects, for use in the clinic. This is the case, at least, without the use of one or more of the clever adaptations to limit its harms that have been proposed of late. Whether or not these approaches make it into clinical use is somewhat hit and miss, however, given that there are many other alternative senolytic therapies presently under development.

The Senolytic Drug Navitoclax (ABT-263) Causes Trabecular Bone Loss and Impaired Osteoprogenitor Function in Aged Mice

Senescence is a cellular defense mechanism that helps cells prevent acquired damage, but chronic senescence, as in aging, can contribute to the development of age-related tissue dysfunction and disease. Previous studies clearly show that removal of senescent cells can help prevent tissue dysfunction and extend healthspan during aging. Senescence increases with age in the skeletal system, and selective depletion of senescent cells or inhibition of their senescence-associated secretory phenotype (SASP) has been reported to maintain or improve bone mass in aged mice.

This suggests that promoting the selective removal of senescent cells, via the use of senolytic agents, can be beneficial in the treatment of aging-related bone loss and osteoporosis. Navitoclax (also known as ABT-263) is a chemotherapeutic drug reported to effectively clear senescent hematopoietic stem cells, muscle stem cells, and mesenchymal stromal cells in previous studies, but its in vivo effects on bone mass had not yet been reported. Therefore, the purpose of this study was to assess the effects of short-term navitoclax treatment on bone mass and osteoprogenitor function in old mice.

Aged (24 month old) male and female mice were treated with navitoclax (50 mg/kg body mass daily) for 2 weeks. Surprisingly, despite decreasing senescent cell burden, navitoclax treatment decreased trabecular bone volume fraction in aged female and male mice (-60.1% females, -45.6% males), and bone marrow stromal cells (BMSC) derived osteoblasts from the navitoclax treated mice were impaired in their ability to produce a mineralized matrix (-88% females, -83% males). Moreover, in vitro administration of navitoclax decreased BMSC colony formation and calcified matrix production by aged BMSC-derived osteoblasts, similar to effects seen with the primary BMSC from the animals treated in vivo. Navitoclax also significantly increased metrics of cytotoxicity in both male and female osteogenic cultures.

Taken together, these results suggest a potentially harmful effect of navitoclax on skeletal-lineage cells that should be explored further to definitively assess navitoclax's potential (or risk) as a therapeutic agent for combating age-related musculoskeletal dysfunction and bone loss.

Comments

Like most of these stories here, I'm not seeing anything of value just stupid experimental garbage. At this point It sounds like it would be better to explore risky enhancements that might end life prematurely but give a better quality of life https://www.fightaging.org/archives/2017/01/the-adventurous-are-undergoing-enhancement-gene-therapies/ and then sign up for cryonics though to be honest I'm pretty sceptical of that too, though it's better than nothing I suppose. I've been following this site since 2006 and the news is really beginning to look like the same year after year

Posted by: J at June 18th, 2020 5:10 AM

I seem to recall thar someone claiming inside information said that UBX0101 was navitoclax but a google search does not confirm that.

Posted by: JohnD at June 18th, 2020 11:34 AM

@JohnD

The paper in the link above clearly says so...

Posted by: Daniel Permisov at June 18th, 2020 12:55 PM

@J , if you don't like the progress in recent years -- which is exponential -- the right question is what do you do personally to speed up the progress?

Posted by: Ariel at June 18th, 2020 3:43 PM

Just one more example that senolytics can even reduce the functionality of tissues and require simultaneous adjustment using methods to activate the proliferation of young progenitor cells.
I don't think that Navitoclax is a bad senolytic - you just need to use it wisely, given the fact that for some part of a Senescent Cell Population Elimination Might be Problematic. See:
https://www.fightaging.org/archives/2020/06/evidence-of-a-senescent-cell-population-for-which-elimination-might-be-problematic/#comments
It is obvious that cleansing the body of aged cells with the help of senolytics should be accompanied by methods of replenishment them with young functional cells. One such method. http://doi.org/10.26347/1607-2499202001-02059-064
See also: Can a combination of senolytics with ROCK inhibitors and 5-LOX inhibitors contribute to tissue rejuvenation?
https://docs.google.com/document/d/10onyRyohpZPwRnPUyMpBSfuGWOlqS489Xe5WEZNrVDQ/edit?usp=sharing

Posted by: Dmitry Dzhagarov at June 18th, 2020 10:01 PM

@Daniel Permisov: Other papers including the PROTAC paper consider UBX0101 a separate chemical entityh from Navitoclax.

Whatever the case may be, both UBX0101 and Navitoclax are bcl-2/bcl-xL inhibitors mechanistically speaking, so it's quite probable whatever UBX0101 is it's derived from Navitoclax, but that's not necessarily indicative of its off target effects, many molecules are modified to "tune" undesirable toxicity or off-target effects.

Posted by: Dylan Mah at June 18th, 2020 10:09 PM

@Ariel what can you I do beyond giving some meagre funds, I'm not a billionaire. It honestly doesn't seem exponential to me.

Posted by: J at June 21st, 2020 4:39 AM

Surely Dmitry Dzhagarov is on to something... read his paper " Can a combination of senolytics with ROCK inhibitors and 5-LOX inhibitors contribute to tissue rejuvenation?"
... here are some highlights:

Balkalein can inhibit 5-LOX lipoxygenase and one of the cell aging pathways induced by it [50, 51]. Baicalein, a flavonoid derived from the roots of Scutellariae baicalensis Georgi, has shown health benefits for an array of human diseases..., baicalein possesses potent ROCK inhibitory activity,
. Another 5-LOX inhibitor Zileuton (zileuton, commercial name Zyflo) convincingly proved its therapeutic properties in asthma and a number of other diseases [61, 62, 63].

. ... treatment with ROCK inhibitors approved for clinical use (fasudil or ripasudil) together with 5-LOX inhibitors (baicalein, berberine or zileuton). ... curcumin also reduces the expression of 5-LOX gene [68] and, to a certain extent, at the posttranslational level the catalytic activities of 5-LOX [69].

The correct choice of Senolytic can significantly increase the effectiveness of such treatment. For example, the use of quercetin, which also can significantly decrease the activities of inflammatory enzymes such as 5-LOX lipoxygenase [88] likely to demonstrate synergistic effect with other components of the proposed combination of drugs.

It is logical to assume from Shekhar et al. results that 5-LOX inhibitors will be able to replace Δ133p53 as an activator of CRC cell formation in a mixture with a ROCK inhibitor (or even without it). The use of 5-LOX inhibitors instead of Δ133p53 or irradiated feeder cells in long-term cell culture technology will simplify CRC method and standardize cultivation conditions by switching to chemical culture media.

Posted by: Quartz at November 13th, 2020 1:34 PM

@Quartz Dzhagarov is definitely on something. Objectively fisetin is twice as strong as quercetin as a senolytic in vitro. But when I take fisetin with scutellaria baicalensis root decoction (baicalin and wogonin mainly) fisetin seems subjectively to be about 10-20 times stronger than quercetin, not twice. And before I added fisetin, this decoction was strong enough to turn some grey hair back into their natural structure and color.

Posted by: SilverSeeker at November 14th, 2020 11:31 AM

I have got the impression that quercétine alone is not that strong a Senolytic and it boosts dasatinib. On the other hand it seems fisetin night be even stronger than d+,q combo

Posted by: Cuberat at November 14th, 2020 11:48 AM

@Cuberat on the cell types that both work, the original study that identified fisetin as a senolytic, quercetin is only about 2 weaker than fisetin. But definitely the range of cell type with senolytic effect most probably differs (more broad for fisetin). Wogonin is a sure bet here because there are a number of pulmonary cancer prospective screens many years ago where it was identified as most potent anticancer for some type of pulmonary cancer when used in combination fisetin+wogonin. What we need here is more research and more hard data, more prospective studies on different combinations. But here comes the funding problem. Everybody is looking for something that could be patented, and supplement combinations that won't make you billionaire are outside of this interest.

Posted by: SilverSeeker at November 16th, 2020 10:37 AM

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