Fibrates as a Potential Class of Senolytic Therapy to Clear Senescent Cells

Accumulation of senescent cells with age is one of the causes of aging. In recent years, the broader scientific community has become convinced of this point, and thus funding is now directed towards many varied investigations of cellular senescence and what to do about it. A young industry has emerged, made up of biotech companies focused on the selective destruction of senescent cells, mostly using small molecule drugs. Since these drugs operate through different mechanisms, tend to be tissue specific, only clear a fraction of senescent cells that varies by tissue, and will thus probably be more effective when combined together, research continues to find ever more senolytic compounds.

Senescent cells are created constantly, either in response to damage or a toxic local environment, or more commonly as the result of a somatic cell reaching the Hayflick limit on cell replication. Senescence is an irreversible state in which cell replication shuts down, and a potent mix of inflammatory signals is secreted. This can be useful in the short term, such as during wound healing, or to put a halt to potentially cancerous cells. Near all senescent cells either self-destruct or are destroyed by the immune system quite quickly. It is the tiny minority to linger that contribute to the aging process, such as by generating an environment of chronic inflammation.

The open access paper here is representative of numerous projects presently underway in the research and development communities, performing screening of small molecules from established databases in search of new senolytics. Some of these searches are more informed by prior investigation of plausible mechanisms than others, but at the end of the day the output is compounds that are then evaluated in detail for their ability to selectively destroy senescent cells. The best of the compounds noted here, fenofibrate, is on a par with navitoclax for selectivity, which is about at the lower level of what might be tolerable as a human therapy. The more off-target cells that are destroyed, the worse the side-effects. This is a starting point, however: other compounds in this category will no doubt be better, or might be engineered to be better.

Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy

Increasing evidence about the molecular mechanisms of ageing suggests that many chronic diseases such as osteoarthritis (OA) are associated with the hallmarks of ageing, including cellular senescence and defective autophagy. Accumulation of senescent cells in tissues contributes to age-related diseases. Articular cartilage of patients with OA shows features of senescence. Senescence-associated secretory phenotype (SASP) factors released from chondrocytes, such as pro-inflammatory cytokines and extracellular matrix degrading enzymes, have been identified as major mediators contributing to the development and progression of OA. Similarly, intra-articular injection of senescent cells in mice results in OA-like pathology.

Cartilage ageing can be modified by selective elimination of senescent chondrocytes to prevent the detrimental microenvironment changes occurring in joint dysfunction. A major step into the translation of senolytic treatments for OA was demonstrated by the beneficial effects of selective clearance of senescence chondrocytes using the Bcl-2 family inhibitor Navitoclax in animal models. The broad impact of senolytic treatment is also highlighted by the efficacy of dasatinib and quercetin combination in several models of age-related disease, which results in an extension of healthspan and lifespan in mice.

Cellular senescence and autophagy are not only essential for homeostasis but are potential therapeutic targets for age-related diseases. We aim to test this therapeutic hypothesis in preclinical models of OA, where senescence and autophagy play a relevant role. A novel cell-based dual imaging screening assay was developed to identify both senotherapeutics, able to either suppress markers of senescence (senomorphics) or to induce apoptosis of senescent cells (senolytics), and autophagy modulators.

Senotherapeutic molecules with pro-autophagic activity were identified. Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via apoptosis, increased autophagic flux, and protected against cartilage degradation. FN reduced both senescence and inflammation and increased autophagy in both ageing human and OA chondrocytes whereas PPARα knockdown conferred the opposite effect. Moreover, PPARα expression was reduced through both ageing and OA in mice and also in blood and cartilage from knees of OA patients.

Remarkably, in a retrospective study, fibrate treatment improved OA clinical conditions in human patients from the Osteoarthritis Initiative (OAI) Cohort. Blood from the PROspective Osteoarthritis Cohort of A Coruña (PROCOAC) and human cartilage from non-OA and knee OA patients were employed. Levels of PPARα were lower in OA patients compared to non-OA controls. The potential efficacy of PPARα agonists was also evaluated using the Osteoarthritis Initiative (OAI) Cohort. In this cohort, there were 35 fibrate users and 3322 participants not taking fibrates in the selected sample. Using a genetic matching, 35 fibrate users were matched to 35 participants in the control group. Interestingly, the results indicate that fibrate use by time interaction was associated with a statistically significant improvement of self-reported Western Ontario McMaster Osteoarthritis Index (WOMAC) function and WOMAC total scores. There was also a trend towards a decrease in WOMAC pain score. The results suggest that the fibrate use, when compared with non-use, was associated with a yearly decrease in WOMAC.

Comments

The fibrate drug class have been in clinical use for almost 90 years

Is there any retrospective analysis that can be done in millions of people who took them about systemic senolytic benefits?

They did have a range of side effects that led to statins taking over the space

Posted by: David Permisov at July 19th, 2019 5:20 AM

@David Permisov
I have similar doubts. However, fibrate might be a good addition to the senolitics cocktail and could enhance the action of the other senolitics. They're should be a point of diminishing returns where either the senolytics are too harmful to the health y cells or they're not many SC left. We are not the yet, though

Posted by: Cuberat at July 19th, 2019 6:06 AM

I still think Oisin's genetically targeted technology will beat small molecule drugs due to a lack of off target side effects and therefore a better ability to remove a higher percentage of senescent cells in a higher number of different tissues by allowing higher dosages.

Posted by: jimofoz at July 19th, 2019 6:47 AM

@jimofoz
They are my favorite bet. But you never know. They have low off-site damage but the delivery method had its own limitations. And there were platform is in its infancy. It is sure than in 40 years or will be programmable, very specific , personalizable and inexpensive. I can imagine issuing it, for example, to do plastic surgery by delivering apoptosis to one area and growth factors to another. Probably will solve 99 % of cancer too. Senecent cells too. But we need it now not on 40 years. I can probably, with a good chance (0.6-0.8) survive 40 more years all else being equal. My parents don't have much left, though.

In short term, though, some sleep molecules might prove to be more efficient.

Posted by: Cuberat at July 19th, 2019 8:34 AM

Fenofibrate: patented in 1969 and came into medical use in 1975. Available as a generic medication.
A month supply in the United Kingdom costs the NHS about £3.67 per month as of 2019.
In the United States the wholesale cost of this amount is about US$8.40. In 2016 it was the 67th most prescribed medication in the United States with more than 11 million prescriptions.

Minor side effects. Lower side effect profile and much lower cost than navitoclax.

Retrospective studies needed !

Posted by: JLH at July 19th, 2019 2:12 PM

OR: getting rid of senescent cells doesn't extend lifespan much. Something nobody wants to hear but a real possibility given that people have been unknowingly taking this and other senolytic supplements for years. It may very well turn out that the benefits of clearing senescent cells in humans are minimal, whatever the degree of clearance and hence protocol.

Posted by: Barbara T. at July 24th, 2019 3:25 PM

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