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). SASPs were discovered in 2008, which was when interest in senescent cells really begans (Source) (1). In 2010, building on this initial research, Dr. Campisi went on to show the link between the SASP and cancer. (Source) (2). In clear, then, what was shown was that SASPs increase inflammation, harm 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. (Ibid).
Normally, meaning under natural and holistic conditions, senescent cells destroy themselves by a self-destruct process known as apoptosis before being cleared away by the immune system. (Ibid) However, as mammals age, the 500 millions years old 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 major hallmarks of aging.
A few years ago, researchers set out to see what would happen if these senescent cells were removed from the body. Jan van Deursen and his team at the Mayo Clinic demonstrated the potential of clearing senescent cells in 2011; this experiment kickstarted interest in clearance therapies . They created a special kind of mouse that destroyed senescent cells in the presence of a certain chemical. (Source)
In another experiment, one elder mouse was given senolytics, (senescent killing drugs) and the one on the left was left to age normally. The removal of senescent cells appeared to delay key aspects of the aging process in mice. After the results of these drug experiments were published in 2016, senolytic research exploded. (4).
A new class of drugs, Senolytics, that target this aging process
With these experiments as supporting evidence, the biotechnology industry had credible proof that targeting one of the aging processes directly could improve health by delaying aging in mice, thanks to which the search to develop therapies that target and destroy these “harmful cells” skyrocketed. This was the birth of a new class of drugs and therapies that would become known as senolytics.
One of the leading senolytic company is UNITY Biotechnology, which was founded in 2011 and has raised over $385 million in funding since then. This company has enjoyed backing from many investors, including big names such as Jeff Bezos and Peter Thiel. UNITY went public in May this year and is currently valued at over $700 million. Van Deursen, the pioneer of senescent cell clearance, is a scientific co-founder at UNITY.
The company’s first candidate drug, UBX0101, entered human trials back in June of this year with a focus on treating osteoarthritis, an age-related disease (ie, senescent cells can accumulated in arthritic joints) This company’s development pipeline has other diseases, such as idiopathic pulmonary fibrosis, COPD, kidney disease, and glaucoma, all earmarked for future trials. Senescent cells are found in all tissues and organ, so it makes to target senescent cells involved in other diseases. Given the huge profit perspectives, UNITY is not alone in its search for ways to remove senescent 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. Oisin is poised to begin human trials for cancer and then senolytics in 2019. Cleara Biotech, based in the Netherlands, is another company busy developing senolytic therapies, and it includes Dr. Peter de Keizer. He is one of the pioneers of senolytics for his work on the FOXO4-DRI peptide. Cleara is currently trying to optimize the FOXO4-DRI peptide to increase its potency and safety profile prior to entering human trials; the current version is good enough for proof-of-concept testing.
Spain-based Senolytic Therapeutics is another company developing senolytics and includes Dr. David Sinclair, who is famous for his work with NAD+ and its precursors and is an well known biochemist.
Lastly, the company CellAge, is taking a different approach from the traditional drugs of UNITY and the lipid nanoparticles of Oisin. CellAge is developing a synthetic biology approach to senolytics that can identify senescent cells and eliminate them through the creation of “genetic circuits”.
In this piece, i will examine seven new senolytic drugs that Research scientists claim to reverse aging by clearing out the body’s old and worn out zombie cells, called senescent cells. Several of these senolytics are slated for clinical trials.
Introduction: What Are Senolytics?
A senolytic is a compound that selectively destroys the senescent cells. In recent experiments, elderly mice treated with the compound appeared and acted more youthful. Their kidney function improved, their fur regrew, and they were able to run twice as far as untreated mice. Researchers hope that senolytics may do the same for us. In fact, scientists around the world are racing to develop even more senolytic drugs.
In March of this year, the magazine Chemical & Engineering News (CE&N) interviewed several longevity researchers. Among those interviewed was longevity researcher Judith Campisi, who claim a redefinition of moder medicine: “If chemists can come up with drugs that can kill senescent cells in humans, we think this is going to revolutionize modern medicine” (Source) The longevity researcher pointed out that senolytics would have multiple health benefits when she added:
“No longer would you have a pill for your blood pressure and a pill for your glaucoma and a pill to stabilize your heart and a pill to improve your kidney function. You’d have a pill that would hit multiple problems that affect the elderly,” Campisi concluded with “It is very unlikely that these are drugs that you would have to take every day. Just when enough senescent cells had accumulated again.”
Our bodies are continually producing senescent cells, even in our youth. Cells divide about 50 times before becoming senescent and stop dividing. Senescent cells normally self-destruct in a program called apoptosis. Some refuse to commit suicide. The immune system clears out many of these holdouts, immune function weakens with age, and increasing numbers of zombie cells build up.
As we get older, senescent cells build up in our tissues, where they contribute to conditions such as arthritis, type 2 diabetes, and heart disease. Senescent cells are zombie-like damaged cells that stop working. They don’t just sit around idly. Instead, they wreak havoc throughout our bodies, causing dysfunction and inflammation. Lifespan extension proponents such as the outspoken Aubrey de Grey of the SENS Research Foundation and other anti-aging enthusiasts have been long advocating for ways to remove these troublemakers from our bodies. By the time individuals reach old age, significant numbers of senescent cells have accumulated in the body. Senescent cells remain metabolically active and cause inflammation and damage to surrounding cells and tissue. They may have been a healthy liver or pancreas cell, but once they senesce, they change their role and churn out buckets of inflammation-causing molecules. Senescent cells and the inflammation they produce cause a vast array of problems throughout the body and accelerate the process of aging.
Seven Senolytics and Human Clinical Trials
Senolytics destroy these zombie cells and reduce inflammation and improve tissue function. Removing senescent cells not only delays aging, but it also reverses parts of the aging process. Researchers have used senolytics to clean out the senescent cells in mice, allowing them to live longer and reducing plaque buildup in their arteries, a natural process of aging due to cholesterol in the blood. Many research teams are working to develop therapeutic senolytics. In total, researchers have found at least seven compounds which kill senescent cells.
Hoping that senolytics will help people, researchers are currently conducting a clinical trial to test two of the compounds in patients with brain tumors. Other trials are in the works. Many of the senolytic compounds are cancer drugs and come with downsides. They also kill some healthy cells or trigger side effects such as reducing the number of platelets that help our blood clot.
1. FOXO4-DRI Senolytic
Peter De Keizer is a researcher with the Erasmus University Medical Center in Rotterdam knows a thing or two about senescent cells. The 36-year-old scientist has spent much of his career studying them. One day he and his colleagues uncovered a different strategy for attacking them.
Most senescent cells self-destruct in a process called apoptosis. It’s the best thing that can happen to senescent cells. Normally senescent cells have a type of DNA damage that spurs a protective protein, called p53 to eliminate the cell. Instead, the researchers found that a different protein, called FOXO4 binds to p53 and prevents it from doing its duty.
FOXO4 is a protein that controls gene expression, a master transcription factor associated with aging and development. When FOXO4 is activated in a cell, it can block apoptosis. P53 is the most common trigger of apoptosis and has multiple functions in the cell nucleus. FOXO4 latches onto p53 and blocks apoptosis.
To counteract this effect, De Keizer’s team designed a molecule, known as a peptide. This custom-designed peptide prevents the FOXO4 and p53 from linking up, prompting the senescent cells to commit suicide. Most notably, the peptide spared healthy cells.
The peptide is an artificially modified FOXO4, a dummy that binds to p53 in place of regular FOXO4. It works just like a senolytic. De Keizer calls it FOXO4-DRI, and it works by crowding out the native FOXO4.
To test the FOXO4-DRI senolytic, De Keizer injected it into normal, elderly mice. In addition to improving their kidneys and fur, the peptide also increased their energy levels. While the senolytic compound did not reduce the number of platelets, it could still have potentially lethal side effects.
Apoptosis is an important cell function throughout the lifespan of an organism. A cell needs to have good judgment about when to self-destruct; apoptosis can go haywire in either direction. In the elderly, apoptosis fails to eliminate senescent cells, but sometimes healthy cells undergoing apoptosis prematurely, and we lose vital organ tissue as a result. FOXO4 has many roles, including DNA repair.
Researchers measure the value of a senolytic by its ability to kill senescent cells without harming healthy cells. Compared to earlier senolytics, the FOXO4-DRI senolytic is more selective. When researchers give an optimal dose of the peptide to mice, more than 80% of their senescent cells succumb to apoptosis, while destroying an undetectable number of healthy cells.
Clinical Trials of the FOXO4-DRI Senolytic
De Keizer’s findings raise the possibility of a future senolytic treatment that protects people against the ravages of old age.
However, many more tests are needed. There are limitations to using senolytics. After repeatedly removing all the senescent cells, eventually, there will be no healthy cells left. To counter this problem, science needs to find a way to replenish healthy cells. But, that’s an issue for the distant future. For now, getting rid of the zombie cells provides tremendous health benefits.
De Keizer and colleagues plan to move cautiously with the FOXO4-DRI senolytic. They want to determine whether their peptide kills cancer cells, which share some similarities with senescent cells. They will test the compound in people with a form of brain cancer called glioblastoma. If the FOXO4-DRI senolytic proves safe, they will begin testing the peptide against age-related diseases and even aging itself.
Senolytics Hold Great Promise
The tactic of removing senescent cells has a great deal appeal. A lot of animal experiments support the effectiveness of senolytics as an anti-aging treatment. Furthermore, the concept of senescence pulls together several ideas about the origin of aging.
As we grow older, aging accelerates exponentially, as though it were driven by a positive feedback loop. Senescent cells secrete inflammatory molecules called cytokines. In turn, these cytokines make even more senescent cells, in a feedback loop. Senolytics stop this feedback loop.
2. Parabiosis Linked To Cellular Senescence
The bizarre practice of parabiosis is a procedure in which two mice are joined surgically and share a common circulatory system. Scientists use the technique to study how the blood of young mice affects the older one.
Senescent cells churn out oodles of chemical messengers, depositing them directly into the bloodstream. Parabiosis experiments have shown that circulating chemical signals form the basis of an epigenetic clock. Using senolytics to remove the senescent cells turns off the supply of the chemical messengers and stops the epigenetic clock.
Doctors believe this can be turned into a therapy and use senolytics to clear out the senescent cells, which in turn shuts off off the supply of the chemical messengers and stops the epigenetic clock.
Senescent cells aren’t entirely bad. In some aspects, they have a beneficial role. Senescent cells evolved to benefit young reproductive animals, but they are problematic for the elderly.
When we are young, senescent cells are programmed to stop dividing if they think are in danger of becoming cancerous. Additionally, senescent cells secrete a host of inflammatory molecules that stimulate regeneration and repair in young people.
However, over time, as more and more cells become senescent, and the levels of inflammatory molecules increase and stop having positive effects. Instead, they cause inflammation. Clusters of senescent cells produce such high levels of inflammatory molecules that they persuade healthy cells to turn senescent. This inflammatory loop causes a variety of chronic diseases of aging, including type 2 diabetes, heart disease and certain types of cancer.
The problem is that senescent cells help protect us from cancer, and we certainly don’t want to obliterate them entirely. Nor do we want to let them accumulate in old age.
The Race To Develop Senolytics
As there are many ways to skin a cat, there are other ways to eliminate senescent cells. Researchers have investigated small interfering RNA, and dietary flavonols, as well as many other promising techniques.
Regarding pure senolytics, researchers have discovered two classes so far: Quercetin and Dasatinib and the pan-BCL inhibitors ABT-263 and ABT-737 are both shown to kill senescent cells.
Two years ago, scientists were excited about the powers of the Quercetin and Dasanatib combination. Most notably, the medications are already known, and FDA approved. The combination of drugs proved to be an effective senolytic that eliminated senescent cells. Unfortunately, the twin-drug cocktail also killed a lot of healthy cells. The Quercetin and Dasanatib combination was a bust so far as a potential therapeutic agent, but it did prove the principle that senolytics can be used to kill senescent cells.
This early discovery set off a worldwide effort to find more selective senolytics. As the FOXO4-DRI discovery shows, scientists have made rapid progress toward finding more efficient senolytic treatments.
Start-up companies have gotten in on the act. For example, Unity Biotechnology aims to clear senescent cells from the joints, arteries, eyes, and kidneys using the senolytic compound ABT-263. Scientists at the Weizmann Institute of Science are on a similar track, using a sister senolytic called ABT-737. In 2016, these researchers reported that ABT-737 could clear senescent skin cells from the bodies of mice, increasing the number of hair-follicle stem cells. The potential for regrowing hair will be lucrative if it passes muster in humans.
FOXO4-DRI Compared With Other Senolytics
How does FOXO4-DRI stack up against other senolytics?
The senolytics ABT-263 and ABT-737 are promising, but they also have issues. It seems they kill healthy control cells. ABT-263 is a more selective senolytic than ABT-737, but neither is as particular as FOXO4-DRI.
So far, FOXO4-DRI is the most selective senolytic in that it kills senescent cells, yet is relatively safe for healthy cells.
Reprogramming Senescent Cells
CE&N also reported that others researchers are considering a different strategy for eliminating senescent cells. Instead of trying to kill and remove senescent cells, some scientists want to reprogram them to a more youthful state. The key principle is to erase the cellular markers of aging in senescent cells. Juan Carlos Izpisua Belmonte from the Salk Institute for Biological Studies is leading the reprogramming approach. The beauty of pluripotent stem cells is that they possess the potential to become any cell type in the body. Belmonte is borrowing from strategies used by other researchers and is reprogramming mature cells such to become pluripotent stem cells.
In a recent paper published in the journal Cell, Belmonte and colleagues announced that they successfully reprogrammed senescent cells in mice. They accomplished this feat by temporarily activating four genes known to make stem cells pluripotent. Belmonte said that the four genes remodel a cell’s epigenetic markings and remove markers of aging at the cellular level. Remarkably, the treatment made the mice more youthful, rejuvenating their muscle, spleen, and pancreas. The mice had more youthful skin and lived longer as well. As reported in CE&N, Belmonte remarked that
“We are now trying to develop novel ways to achieve cellular rejuvenation using combinations of chemicals” adding, “We think these chemical approaches might be in human clinical trials in the next ten years.”
3. Intermittent Rapamycin Zaps Zombie Cells
While waiting for senolytics to arrive, there may be an alternate solution to the problem of inflammation-causing zombie cells.
Two years back, scientists showed that rapamycin acts as a circuit breaker to shut off the harmful effects of senescent cells. Because rapamycin shuts down the system for maybe a week or longer, it only has to be taken every once in a while, potentially bypassing side-effects. As the linked article shows, intermittent rapamycin dosing may be one stop-gap solution to the problem of cellular senescence.
5. Life extension: combo quercetin and ..
As it turned out, no such effort on my part was actually needed, as the formal conference materials contained a fairly comprehensive section covering senolytics, featuring the dasatinib and quercetin combination front and center. The position put forward by Bill Faloon of the Life Extension Foundation at the conference is that older people should absolutely be taking advantage of NAD+ boosting therapies such as nicotinamide riboside, then senolytics, then mesenchymal stem cell therapies, in that order, envisaged as an ascending stairway of benefits. There is good evidence to suggest that positive results for older individuals will result from all of these, though senolytics are by far the most impressive in animal studies. I’m omitting the presence of basic good health practices and supplements in this stairway picture, but they are still there and being emphasized. That said, I have to think that they will drift away from being as central to the anti-aging message as they have been in the past, as the biotechnologies improve.
A new class of drug called senolytics has joined the ranks of leading lifespan-extending therapies, such as the drug metformin, currently in clinical trials and other anti-aging interventions such as telomere therapy, the Fasting Mimicking Diet, and a drug called rapamycin, also in clinical trials.
FOXO-DRI is the most promising senolytic we have today. It is more selective because it kills senescent cells while avoiding collateral damage to healthy cells. Peter De Keizer and colleagues, the inventors of the peptide, are taking a slow approach to testing the senolytic in humans. They will try out the compound on brain cancer first. If that proves successful, they will try the FOXO4-DRI senolytic on age-related diseases. Other researchers are seeking to reprogram cells, turning them into pluripotent stem cells, which rejuvenate the body. While waiting for senolytics to be approved, intermittent rapamycin dosing may be one way of reducing the inflammation and dysfunction caused by senescent cells.
Related Article: Mayo Clinic scientists use senolytic compounds to reverse symptoms of respiratory disease in mice and hope to translate their findings to humans.
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To date about a dozen drugs have been reported that can mop up zombie cells. Clearance of the cells in mice has been shown to delay or alleviate everything from frailty to cardiovascular dysfunction to osteoporosis to, most recently, neurological disorders. However, no credible evidence as of yet has been shown that Senolytics can significantly extend human lifespans. Most of the benefit seen in mice seems to be in extending healthspan, the time free of frailty or disease, and as a result median lifespan. the published studies in Nature (Source) and in another journal have shown an extension of lifespan benefit for mice that were treated when they were quite old. (Source)
Furthermore, the current methods that researchers use to identify and clear senescent cells have additional limitations, including being too large to place inside current gene therapies, not being selective enough when targeting cells, and not removing enough senescent cells. CellAge is creating synthetic promoters, which are special DNA sequences that can regulate the activity and expression of genes to overcome these limitations.
CellAge is currently working with Circularis to screen for new senescent cell promoters using a unique technological platform that has never been used before with human senescent cells. If this is successful, the company will then move onto screening from a library of over 100,000 novel synthetic promoters. After identifying suitable promoters, CellAge intends to develop accurate methods of senescent cell detection that surpass the current state of the art.
However, one of the key hurdle is that it is not wise to remove all of senescent cells, as these can be beneficial to Life, from wound healing to cancer avoidance. In this realm, one of the keys is to find senolytic compounds that increased both healthspan and lifespan. (5) Couple drugs have shown some promise. (5 bis).
Because of the body’s need of senescence and given the potential sides effects of senolytic drugs and the need to increase both health and lifespans, it may be reasonble to first explore the naturally occurring compounds with senolytic potential. In effect, multiple mouse experiments demonstrated that the clearance of these cells with natural compounds can delay the onset of diseases such as cancer, heart disease, osteoporosis, arthritis, and Alzheimer’s. In this perspective, the natural compound called fisetin, (Source) improved healthspan and lifespan in mice via the targeting of senescent cells. (6). More human clinical trials are of course needed.
Previous mouse studies have shown that even removing as few as 30% of senescent cells is enough to significantly benefit health. This also suggests that drug treatment could be infrequent. However, other studies have shown complications. (7) While still others have shown promising perspectives. (8)
Although killing zombie (senescent) cells seems like a good idea, which method, if any, will be successful in humans is an open question. The History of medical research shows that in the beginning, everything looks nice, especially with mice, but when these animal studies are applied to humans, up to 90 percent of them don’t work.
Pending more evidence, by using natural senolytic compounds, we can mimimize the senescence damage while activating other longevity pathways. Furthermore, meditation, fasting, exercise, reducing stress and a healthy diet stave off multiple age-related pathways diseases. And for those who do not want to take the holistic route, these above-mentioned companies are intensely working on finding efficient drugs.
 Coppé, J. P., Patil, C. K., Rodier, F., Sun, Y., Muñoz, D. P., Goldstein, J., … & Campisi, J. (2008). Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS biology, 6(12), e301. https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.0060301
 Senescent cells were first described in the late 1950s but remained largely a curiosity until 2008 when their dark nature was revealed by Judith Campisi, a researcher based at the Buck Institute for Research on Aging in California, and others. She found that the cells secrete a cocktail of foul factors, which poison the surrounding tissue, like a rotten fruit corrupting its milieu Coppé, J. P., Desprez, P. Y., Krtolica, A., & Campisi, J. (2010). The senescence-associated secretory phenotype: the dark side of tumor suppression. Annual Review of Pathological Mechanical Disease, 5, 99-118.
 Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., … & Van Deursen, J. M. (2011). Clearance of p16 Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232.
 The previous experiment had used a specially engineered mouse, whose senescent cells were not strictly the same as those accumulated naturally during aging. This follow-up used a drug in normally aging mice to demonstrate that the removal of senescent cells is beneficial. As before, the researchers found that treatment improved mouse health and appeared to delay the aging of various organs and tissues.Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., … & Khazaie, K. (2016). Naturally occurring p16 Ink4a-positive cells shorten healthy lifespan. Nature, 530(7589), 184
 Xu, M., Pirtskhalava, T., Farr, J. N., Weigand, B. M., Palmer, A. K., Weivoda, M. M., … & Onken, J. L. (2018). Senolytics improve physical function and increase lifespan in old age. Nature medicine, 24(8), 1246.
(5 bis). Metformin is a well-established, cheap diabetes drug seems to have some bonus age-defying side-effects in the form of an extended lifespan and fewer age-related diseases for those taking it. A clinical trial in elderly people is pending. One way metformin works is to inhibit senescent cells’ deleterious secretions. The FDA can’t approve anti aging drugs, but it can consider drugs that impact aging diseases. Another clinical trial drug, rapamycin is also in the works. Normally, this drug is used to suppress the immune system of organ transplant patients but it is also thought to mimic the body’s starvation response. In mice, it extends lifespan by 25% and it has been shown, counterintuitively, to boost the immunity of older people. The startup resTORbio is currently trialling a derivative of the compound to cut respiratory tract infections. Boosting immunity is important because immune cells help to remove senescent cells. Boosting the chemical NAD+ in the body activates a particular protein that removes that also helps with down regulating aging pathways. A small clinical trial of the NAD+ booster is under way as well as other in other age related fields and templates including DNA repair mechanisms..
 Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., … & McGuckian, C. (2018). Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine.
(7). Unity’s approach is to find small molecules (so called “senolytics”) that can get deep into the tissues and kill senescent cells. But because small molecules, by their nature, can get everywhere in the body, the approach is prone to unwanted side-effects.The company’s way round the problem is to start with localised treatment, which is possible in a few organs such as the knee, eye and lung that essentially “trap” the drugs so they can’t leak elsewhere in the body where they can cause toxicity to other cells. Following fair success in mice, in June Unity began an early stage clinical trial of its first drug in the knees of patients with moderate to severe osteoarthritis, an age-associated chronic disease that causes joint pain. The trial, involving 40 patients injected locally in the space around the knee, is expected to run for about nine months. The drug itself was selected because it appears to kill the two types of senescent cell that accumulate in the knee. Another complication with senescent cells is that because they all spring from different normal cell types they retain their own individuality; a drug might kill senescent skin cells, fat cells or blood vessel cells but is unlikely to kill all three.
(8). Unity has recently shown some success in demonstrating in human beings that the elimination of senescent cells takes a feature of ageing that was untreatable and uncurable, and can make it a treatable medical condition. But more data is still needed before senolytics get marketed. Oisín is trying to do something more ambitious: killing all a person’s zombie cells in one go. The idea is to load the body with nanoparticles that insert a “suicide gene” into every cell. It only triggers if a cell has a lot of a particular protein called P16 that acts as a marker of zombie cells. Oisín is planning to run what co-founder Hudson calls a “stealth ageing trial” in people with a variety of late-stage cancers next year (ie, cancers for which no treatment is available allows low regulatory bar standards. However, not every cell that expresses high p16 is senescent; and not every senescent cell has high p16. Cleara’s approach, meanwhile, which uses an engineered peptide molecule, targets a particular subtype of senescent cell, which, says scientific co-founder Peter de Keizer, will make it safer.