The Existence of Senolytics May Trigger the Shift Towards Targeting Root Causes of Disease

It is sadly true that little medical research and development involves targeting the root causes of the treated condition. This is exactly why therapies largely fail in trials, and are largely only marginally effective when approved. In the case of age-related disease, efforts to target root causes are a tiny faction of the field. This is slowly changing for the better, but the state of affairs today versus a decade ago is still only a matter of making that tiny fraction a little bit larger.

Senolytic therapies that selectively destroy senescent cells are the first rejuvenation therapies, treatments that target something close to a root cause of aging and age-related disease. The accumulation of senescent cells with age is highly detrimental to tissue function, even though they are only a tiny fraction of all cells even in late life. Removing senescent cells produces impressive benefits for dozens of age-related conditions in animal models. Going by the present data, senolytics are far and away more effective and useful than any other approach so far undertaken to intervene in the aging process.

Effective outcomes have a way of dragging the field along with them. It is hard to argue against large effect sizes and robust, replicated evidence of efficacy. For the period in which the majority of this data remains associated with animal models, it is only the research community engaged in revising its ideas on how to approach aging. As human data accumulates, we can hope that the broader medical and funding communities will follow, and then the public at large.

Insights from In Vivo Studies of Cellular Senescence

Recent observations using genetically-modified animal models indicate that the elimination of senescent cells attenuates aging and age-related diseases. These findings have opened new avenues to explore pharmacological approaches to induce apoptosis in senescent cells termed senolytics. With the absence of a unique marker for senescence, interventions have been developed to take advantage of some vulnerabilities that senescent cells have.

Senescent cells, like cancer cells, are resistant to apoptosis through the upregulation of BCL-2 anti-apoptotic proteins. Efforts in cancer research have found ABT263 (navitoclax), a potent inhibitor of BCL-2 and BCL-xL anti-apoptotic proteins, can be used to treat lymphomas and other types of cancer. Interestingly, due to the overexpression of BCL-2 in senescent cells, ABT263 exhibits senolytic activity and prolongs healthy lifespan in normally-aged mice. Importantly, using mouse models of age-related chronic diseases, including atherosclerosis and neurodegeneration, in which the accumulation of senescent cells is detrimental, treatment with ABT263 attenuated disease pathology.

Additional pharmacological interventions have been shown to target senescent cells in mice. These include a peptide that disrupts the interaction of FOXO4 and p53 leading to apoptosis, as well as nanoparticles that target senescence-associated β-gal positive cells. Interestingly, using a mouse model for osteoarthritis (OA), it was shown that senescent cells accumulate in articular cartilage and synovium promoting the development of OA. Consistent with the concept that senescent cells drive pathology, local administration of a new molecule named UBX0101, was used to disrupt the interaction of MDM2 and p53 to trigger apoptosis in senescent cells, yielding positive results in attenuating OA, plus validating UBX0101 as a senolytic. Consequently, UBX0101 was initiated in a clinical trial with adult patients diagnosed with femorotibial osteoarthritis to evaluate the safety, tolerability, and pharmacokinetics of the drug. It is currently being evaluated in phase 2 clinical trials for the effectiveness in treating musculoskeletal diseases with an emphasis on patients with OA.

Natural compounds, such as quercetin and fisetin, have also been used in combination with anti-cancer drugs, particularly the pan-tyrosine kinase inhibitor dasatinib to treat naturally aged mice and senescence-related diseases. The combination of dasatinib and quercetin (D + Q) target particular sensitivities of pro-survival pathways found in senescent cells, known as senescent cell anti-apoptotic pathways (SCAPs). These drugs could theoretically influence a broad spectrum of pathways in all cells, which may make it difficult to assess if senescence ablation occurs or there has been some amelioration of key features of senescent cells, such as the SASP. Nevertheless, these findings set a foundation to start clinical trials in adult patients with idiopathic pulmonary fibrosis and diabetic kidney disease. These studies have provided evidence that intermittent doses of senolytics can be systematically used in humans and tolerated.

The current philosophy of the healthcare system is to systematically treat chronic diseases with medications that, for the most part, address the consequence rather than the cause of the malady. Our desire to improve human care has motivated us to investigate how and why senescent cells accumulate with age and whether they may play therapeutically-relevant casual roles in age-related diseases. The objective is to start treating chronic diseases from the root and not the symptoms of the disease. As we are starting to enroll patients in "senolytics-clinical trials," it will be imperative to assess if senolysis efficiently targets the primary cause of disease or if it works best in combination with other drugs. Additional basic science research is required to address the fundamental role of senescent cells, especially in the established contexts of disease.

Comments

I wish testing of dasatinib + quercetin against a host of aging related diseases had got that 40 million anonymous donation instead of metformin.

I wish Unity had gone for whole body treatment with their senolytic instead of just injections into the knee.

The best hope I think is for Oisin to get a good result in their cancer soon off then plough some of that cash back into senolytic trials.

Posted by: jimofoz at April 29th, 2020 5:27 PM

It's unfortunate that because aging isn't classified as a disease, those bio pharma companies can't get senolytic treatments approved for aging. To satisfy the FDA they must seek approval for something a lot more specific, like knee arthritis or pinky finger cancer. They are forced to play the game not to mention spending tens of millions of dollars and year's gathering data rather than be allowed to innovate in a way enjoyed by say, cell phone designers...

Currently, Covid has busted down the stone walls of FDA regulations. Clinical trials are being approved in days instead of months. A drug is being approved after testing for weeks rather than years. Alternative none-patenable treatments are even being taken seriously ( plasma, intravenous C, off patent drugs). Do you all think this will be a temporary blip, or are we entering a new future where Health science will finally be free to grow at a much faster rate?

Posted by: August33 at April 29th, 2020 9:08 PM

@August33

I think the FDA will return in its previous state : long & costly clinical trials. The only thing that can and will make them change is AI companies like Insillico who are basically trying to simulate clinical trials. Kurzweil and Diamandis said that in the 2030s, AI clinical trials could be a matter of weeks rather than years, and at a ridiculous price. Companies won't design new drugs every 10 years but every year, so the rate will be much faster. Fortunately for us, a few senolytics are accessible to us already, some are very cheap, with few to no side-effects.

Posted by: Jonathan Weaver at April 30th, 2020 7:23 AM

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