A Conservative View of the Present State of Senolytic Development for Rejuvenation

Here, one of the leading researchers working on the biochemistry of senescent cells - and their relevance to aging - considers the state of development of senolytic therapies. These are treatments, largely small molecule drugs at this stage, but also including suicide gene therapies, immunotherapies, and more, that are capable of selectively destroying some fraction of the senescent cells present in old tissues. There is tremendous enthusiasm in the scientific and development communities for the potential to create significant degrees of rejuvenation via this approach. The results in mice are far and away more impressive and reliable than anything else that has yet been tried in the matter of aging and age-related disease. Simple one time treatments with senolytics lead to significant extension of life span and reversal of aspects of age-related disease. Leading researchers, of course, have to be far more muted when writing for scientific journals, so the tone here is more cautious than enthused.

Healthy aging is limited by a lack of natural selection, which favors genetic programs that confer fitness early in life to maximize reproductive output. There is no selection for whether these alterations have detrimental effects later in life. One such program is cellular senescence, whereby cells become unable to divide. Cellular senescence enhances reproductive success by blocking cancer cell proliferation, but it decreases the health of the old by littering tissues with dysfunctional senescent cells (SNCs). In mice, the selective elimination of SNCs (senolysis) extends median life span and prevents or attenuates age-associated diseases. This has inspired the development of targeted senolytic drugs to eliminate the SNCs that drive age-associated disease in humans.

SNCs produce a bioactive "secretome," referred to as the senescence-associated secretory phenotype (SASP). This can disrupt normal tissue architecture and function through diverse mechanisms, including recruitment of inflammatory immune cells, remodeling of the extracellular matrix, induction of fibrosis, and inhibition of stem cell function. Paradoxically, although cellular senescence has evolved as a tumor protective program, the SASP can include factors that stimulate neoplastic cell growth, tumor angiogenesis, and metastasis, thereby promoting the development of late-life cancers. Indeed, elimination of SNCs with aging attenuates tumor formation in mice, raising the possibility that senolysis might be an effective strategy to treat cancer.

Given that our knowledge of SNCs in vivo is limited, how should researchers identify senolytic drug targets? One strategy is to identify vulnerabilities shared by cancer cells and SNCs and then use tailored variants of anticancer agents to target such vulnerabilities to selectively eliminate SNCs. Although cancer therapeutics that interfere with cell division are unsuitable as senolytic drugs, agents that block the pathways that cancer cells rely on for survival might be worth pursuing as senolytics. For example, resistance to apoptosis (a form of programmed cell death) is a feature shared by cancer cells and SNCs. Proof-of-principle evidence for the effectiveness of this strategy comes from targeting the BCL-2 protein family members: BCL-2, BCL-XL, and BCL-W. These antiapoptotic proteins are frequently overexpressed in both cancer cells and SNCs. Two targeted cancer therapeutic agents, ABT-263 and ABT-737, have been shown to selectively eliminate SNCs in mice by blocking the interactions of BCL-2, BCL-XL, and BCL-W.

Senolytic drugs that inhibit targets originally discovered in oncology could yield promising first-generation drugs to treat humans. However, this strategy may not accomplish the long-term goal of developing ideal senolytics that selectively, safely, and effectively eliminate SNCs upon systemic administration. Efforts to identify such "next-generation" senolytics could nonetheless benefit from general principles that have been used in anticancer drug discovery. For instance, it will be important to focus drug development on age-associated degenerative diseases in which SNCs are clear drivers of pathophysiology and in which senolysis could be disease modifying (e.g., osteoarthritis and atherosclerosis).

As knowledge of the fundamental biology and vulnerabilities of SNCs expands, the rational design of targeted senolytics is expected to yield therapies to eliminate SNCs that drive degeneration and disease. This positive outlook is based on successes in oncology and because the main limitation of cancer therapies - the clonal expansion of drug-resistant cells - does not apply to SNCs. Additional confidence comes from the recent progress in bringing senolytic agents into clinical trials. The first clinical trial is testing UBX0101 for the treatment of osteoarthritis of the knee. Success in these first clinical studies is the next critical milestone on the road to the development of treatments that can extend healthy longevity in people.

Link: https://doi.org/10.1126/science.aaw1299

Comments

I try to avoid going to the doctor, and don't have a personal physician (which they keep asking me for when I do go). But here is what I would like to see on "Shark Tank" this year:

What if a national chain of doctors started offering senolytic and other extreme longevity treatments? I suspect that millions of healthy people would start going to these doctors.

Posted by: Tom Schaefer at May 22nd, 2019 8:46 AM

"The SASP is considered the driver of tissue deterioration and disease, but several fundamental questions regarding the bioactive secretome of SNCs in vivo remain unanswered. For instance, it is unclear to what extent SASP factors systemically drive age-associated pathologies by entering the circulation. If this is substantial, local clearance of SNCs at specific disease sites may not provide therapeutic benefit, and systemic senolysis may be required."

It's rather surprising that Unity let him say this, since it undermines the UBX0101 local treatment of OA story.

Posted by: Gary at May 22nd, 2019 9:53 AM

@Tom Schaefer
There are enough sick people to flock to such doctors if senolitics ameliorate their chronic conditions. In fact, it seems SC make everything worse, except some short term wound and gets signalling.... So the question is how bad are the side effects of the senolytics compared to the HARM from SASP. if you are young and healthy taking Dasatinib doesn't look like a good decision. Fisetin seems safer ( probably because it has poor bioavailability)...

@Gary

Interesting indeed. Either they have something else in the pipeline, or that's fine kind of damage mitigation. Or simply shows he is a scientist of integrity...

But I would be surprised if they find no benefits. The joints have local inflammation, which is exacerbated by local (again) population of Sc. So applying senolytics locally should ameliorate the inflammation... And when releasing senolitics locally, the concentration cold be much higher then the gruel good steam. But on the other hand the biological pathways are misterious and messy

Posted by: Cuberat at May 22nd, 2019 12:16 PM

@Gary

Could you give us an estimate on when Oisin will start human trials?

Posted by: dayvan_cowboy at May 22nd, 2019 3:43 PM

I did one dose of D&Q 24 days ago and I can say without a doubt it works to remove SASP. Make a long story short it's most dramatic effect is a marked reduction in post workout fatigue. Even during aerobic workouts just a short period of recovery can recharge the body for more hard efforts. I seem to have a much clearer mind too but that is more amenable to a placebo effect. I've taken everything since the Durk and Sandy Pearson days and nothing is like this. Truely amazing stuff.

Posted by: RTE at May 22nd, 2019 4:18 PM

@RTE

Did you try fisetin? How does it compare to Dasatinib+qercetin? What about a cocktail off Al there of them?

Posted by: Cuberat at May 22nd, 2019 6:45 PM

At RTE, how old are you? I suspect DQ is your first senolytic. And that if you had tried Fisetin or Piperlongumine first your response to DQ would have been far less noticeable. I remember Pearson and Shaw, even bought one of their books, I think they are still alive, so props there, but they look their age, antioxidant fail.

It only undermines UBX101 if you ignore the potential off label use.

Posted by: JohnD at May 22nd, 2019 8:15 PM

I read the Mayo Clinic study on fisetin when it came out and jumped right in. I don't remember the specific dose but it was a large dose. I was expecting something but felt no effect at all. I measure my power very closely and saw no change at all and no reduction in post workout fatigue.
Late 50s and have been on rapamycin and metformin for over two years. Could that have something to do with my strong reaction? I just don't know. Never tried fisetin with D&Q. The effects are so broad and profound that I think Unity Bio has got it wrong. I understand why they are targeting one spot but I think you can do SASP removal in a whole body fashion. I have a small holding in UBX.

Posted by: RTE at May 22nd, 2019 9:47 PM

I tried senolytic Activator. It had an anti-inflammatory effect that had disappeared. What remained was barely perceptible. Meanwhile, I have discovered products that cause much more pronounced rejuvenation. In addition to antiglucocorticoids, I started taking Fo-Ti in combination with Berberin 14 days ago, both twice a day. I did a great deal. I began to drop 0.25 kg per day.

Posted by: Omasta at May 26th, 2019 7:00 PM

When the fisetin study was releases, I too, jumped in. I took 1200mg for 2 days in a row, then again, one month later. It has reduced my osteoarthritis pain (inflammation?) to the point that I have stopped taking Etodolac (anti-inflammatory), which I was on for 6 years. I have also cut my pain med (Tramadol) dose by a third - planning to do more soon. I have more stamina, to the point that I have started riding a 3-wheel recumbent bike 4 days/week. I've started taking quercetin daily, along with NAD, TMG, B12 and some other supplements. I am 66 years old, in general good health except for arthritis (both hips replaced, one knee replaced, fused spine). I am trying to determine when I should go through another dosage of fisetin. Any thoughts?

Posted by: Ron Pagano JD at May 28th, 2019 10:46 AM

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