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Enthusiasm for Senolytic Therapies

I think it is entirely appropriate to greet the advent of senolytics with enthusiasm. These treatments are the first legitimate rejuvenation therapies to successfully target one of the root causes of aging, the accumulation of lingering senescent cells in old tissues. The first human trial data is approaching publication, but even before it arrives, the evidence to date strongly suggests that meaningful levels of rejuvenation can be achieved in old people at a very low cost. The first senolytic drugs (such as dasatinib and navitoclax) and plant extracts (such as fisetin and piperlongumine) cost very little, and remove only some senescent cells, no more than half in some tissues, and far fewer than that in others. Nonetheless, in mouse studies they reliably reduce chronic inflammation, reverse the progression of numerous conditions ranging from arthritis to Alzheimer's disease, and extend healthy life span even when applied a limited number of times in very late life.

As we get older, more and more of our the cells in our bodies become dysfunctional and enter into a state known as senescence. These senescent cells no longer divide or support the tissues and organs of which they are part; instead, they secrete a range of harmful inflammatory chemical signals, which are known as the senescence-associated secretory phenotype (SASP). Dr. Judith Campisi from the Buck Institute for Research on Aging, along with her research team, identified that senescent cells secreted the various harmful chemicals that characterize the SASP in 2008, which was when interest in senescent cells really began.

The SASP is a real problem: it increases inflammation, harms tissue repair and function, causes the immune system to malfunction, and raises the risk of developing age-related diseases such as cancer. Even worse, the SASP also encourages nearby healthy cells to become senescent, so even a very small number of senescent cells can cause big problems. Normally, senescent cells destroy themselves by a self-destruct process known as apoptosis or are cleared away by the immune system. Unfortunately, as we age, the immune system becomes weaker, and the senescent cells start to build up in the body. The accumulation of senescent cells is considered to be one of the reasons why we age and develop age-related diseases.

With these experiments, the biotechnology industry had initial proof that targeting one of the aging processes directly could improve health by delaying aging in mice; this began the search to develop therapies that target and destroy these harmful cells. This was the birth of a new class of drugs and therapies that would become known as senolytics. So far, there have been a number of drugs and naturally occurring compounds with senolytic potential and multiple mouse experiments demonstrating that the clearance of these cells can delay the onset of diseases such as cancer, heart disease, osteoporosis, arthritis, and Alzheimer's.

Interest in senolytics has seen a meteoric rise in the last couple of years, with investment money pouring in as confidence in the approach has reached new heights. There are also a number of companies developing therapies to destroy senescent cells, and it is likely that more will join them in the coming years. Leading the charge is Unity Biotechnology, which was founded in 2011 and has raised over $385 million in funding since then. Other companies are hot on its heels developing ways to seek and destroy these harmful cells. Oisin Biotechnologies, based in Seattle, is one such company. Founded in 2016, it has raised around $4 million to date and is developing a unique lipid nanoparticle-based system to deliver senolytic and cancer therapies. Cleara Biotech, based in the Netherlands, and Spain-based Senolytic Therapeutics are also busy developing senolytic therapies.

Link: https://www.leafscience.org/senolytics-target-aging/

Comments

If, or rather when, senolitics work well in humans that will be huge. That would be the first treatment to have positive effects on all the tissues and extend the health span. It will also extend the life expectancy. We don't know for sure about the Max lifespan but having your LE jump from below 80(for men) to around 100 and with a better health will not only have a profound effect on the pension and retirement systems but will increase the credibility and funding for all other SENS-like studies. Senolitics alone, cold probably bring to the old an effect comparable to the sanitation for the young

Posted by: Cuberat at October 15th, 2018 8:15 AM

Btw, are there any recent updates on the OISIN mouse study? The last update was more than a month ago.

Posted by: Cuberat at October 15th, 2018 8:16 AM

Is there any data on the approximate amount of senescent cells by age? Do we have a guess as to the age that reducing senescent cells would have tangible near-term health/cosmetic benefits?

Posted by: Tim at October 15th, 2018 10:51 AM

@Tim
There are some measurements based on tissue samples and SASP factors. But f they aar from comprehensive or exact. You can use some estimation of the inflammation level as a proxy, but that one is hard to measure for the internal organs. As for at what age the senolitics become useful, I would guess , by pulling the number out of thin air, that before 30 they're is no much benefit, unless you were exposed to some oxidative stress or radiation. An autoimmune disease or high blood sugar also can be as bad.

Another interesting question is at what age taking something toxic like dasatinib is more benefitial than harmful. I will guess ( again I am using gut feel and not founded numbers) that before 40-45 dasatinib would be doing more harm than good. If you have something extremely targeted that would be changing the balance towards a younger age. Ideally, the senolitic did kill only senecent cells work close to 100 efficiency. If you had such a medicine, than probably , even late 20s could benefit from some senolitic without side effects

Posted by: Cuberat at October 15th, 2018 12:25 PM

As soon as my Fisetin arrives, which is supposed to be this week, my self-experimentation with senolytics will begin. I will try all of them over the next few months with the exception of the Dasatinib, as I consider this latter one to be somewhat risky. It is not very specific and will kill founctional cells along with senescent ones.

Posted by: Abelard Lindsey at October 15th, 2018 12:44 PM

It is a bit surprising that clearance of senescent cells in the skin is not a major goal, given that the FDA hurdles would be easier to surmount and that the cosmetic market would likely be huge.

Several online papers indicate that senescent fibroblasts damage the extracellular matrix and cosmetic appearance. Also, interesting is that restoring the state of the ECM may reverse some effects of senescents cells according to the following --
"Restoration of senescent human diploid fibroblasts by modulation of the extracellular matrix"
https://www.ncbi.nlm.nih.gov/pubmed/21108727

Posted by: L Pagnucco at October 15th, 2018 2:16 PM

@L Pagnucco
I doubt that 60% of SC is viable. It would mean that almost every cell has SAPS... Even 20% would be too much. Probably they are not at the same inflammation level.

As for senolitics, killing even 10% of your cells , even without the lisys shock, would probably kill you

Posted by: cuberat at October 15th, 2018 3:56 PM

While I have no evidence one way or another for skin, I expect that typical skin treatments will have limited utility if the systemic SASP is not cleared first. Otherwise the systemic SASP will take the place of the paracrine SASP being secreted by dermal fibroblasts and continue to suppress local repair and regeneration. (I specifically said "for skin" above, since we do have evidence for the systemic SASP preventing regeneration in cartilage in aged knees, even when SCs are cleared.)

@Cuberat: our next update on the aged mouse study will come after all the controls have died, which should be around the end of the year.

Posted by: Gary at October 15th, 2018 4:50 PM

@Gary
Thanks for the feedback. Do you have a hypothesis on what caused the systematic SASP inflammation?

Posted by: Cuberat at October 15th, 2018 6:39 PM

@Cuberat: the systemic SASP is generated by the SCs present throughout the body. Local killing of SCs (for example, in the knee compartment, the eye, or the skin) won't clear other SCs in viscera, muscle, etc. - those SCs will continue to generate SASP that reaches the whole organism via the circulation.

Posted by: Gary at October 15th, 2018 8:26 PM

@Gary

Wouldn't chemical/peptide ablation of SC inevitably spill to some degree trough the whole body. Or is it rather, a different set of SC which don't respond well to the localized medicine?

Posted by: Cuberat at October 16th, 2018 1:37 AM

@Cuberat: perhaps a little, but the stated clinical plan for (as one example) Unity Bio is to only treat local SC compartments, specifically joints and eyes, to specifically avoid systemic effects. No doubt there will be some leakage but not enough to be effective therapeutically against the systemic SASP.

Note that when Unity tried the OA knee experiment in young and old mice, they killed SCs in both age groups, but only saw regeneration in the young group, not in the old animals. This failure in old animals is likely due to the systemic SASP in aged mice. (Ref. Nature, mid 2016, I don't have the citation to hand.)

Posted by: Gary at October 16th, 2018 10:19 AM

@L Pagnucco
Thanks for the article links. Goldenrod (Solidago) extract is often used for relief from urinary tract infections, ostensibly because of its antibacterial effects. However, people often report almost immediate relief, indicating powerful anti-inflammatory properties. The same is true for d-mannose.

Posted by: CD at October 16th, 2018 10:44 AM

@Gary
Since the effect is very surprising ( the line cap is kinda isolated, and having major secretion percolate in from somewhere else on high concentration looks less likely).

This effects Beth's for a follow-up study to try a whole body SC ablation in old mice.

The inflammation child as well be caused by other local cells, for example...

Posted by: Cuberat at October 16th, 2018 12:15 PM

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