In a lab just south of San Francisco I am looking at two blown-up images of microscope slides on a computer screen, side by side. The slides are the same cross-sections of mouse knees from a six-month-old and an 18-month-old animal. The older mouse’s image has a splattering of little yellow dots, the younger barely any. That staining indicates the presence of so-called senescent cells – “zombie cells” that are damaged and that, as a defence against cancer, have ceased to divide but are also resistant to dying. They are known to accumulate with age, as the immune system can no longer clear them, and as a result of exposure to cell-damaging agents such as radiation and chemotherapy. And they have been identified as a cause of ageing in mice, at least partially responsible for most age-related diseases. Seeing the slides, it makes me worried about my own knees. “Tell us about it,” says Pedro Beltran who heads the biology department at Unity Biotechnology, a 90 person-strong company trying to halt, slow or reverse age-associated diseases in humans by killing senescent cells. “We think about it all the time… Wait until you see your brain.”
Developing therapies to kill senescent cells is a burgeoning part of the wider quest to defeat ageing and keep people healthier longer. Unity, which was founded in 2011, has received more than $385m in funding to date including investment from big tech names such as Amazon’s Jeff Bezos and PayPal co-founder Peter Thiel. It went public this May and is valued at more than $700m. Its first drug entered early clinical trials in June, aimed at treating osteoarthritis.
Other startups with zombie cells in their sights include Seattle-based Oisín Biotechnologies which was founded in 2016 and has raised around $4m; Senolytic Therapeutics whose scientific development is based in Spain and which was established last September (it won’t disclose its financing other than to say it has a first round, which will allow it to reach clinical trials); and Cleara Biotech, formed this June backed by $3m in funding and based in the Netherlands. In addition, Scottish company CellAge, also founded in 2016, has raised about $100,000 to date, partly through a crowdfunding campaign.
“The concept is totally getting the imagination of investors [because] it isn’t about just slowing down the clock but actually turning it back and rejuvenating people,” says Aubrey de Grey, who for nearly a decade through his campaigning charity the Strategies for Engineered Negligible Senescence (Sens) Research Foundation has been urging scientists to work towards eliminating ageing and extending healthy lifespan indefinitely. “I’ve never seen a field grow so quickly,” says Laura Niedernhofer, a researcher who studies ageing at the University of Minnesota Medical School, adding that there isn’t even as yet any human data. “There is a recognition that there is potential here to go to a root cause [of ageing].”
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. Niedernhofer likens them to that bad strawberry in the punnet, rotting everything around it. Among the excretions are substances that produce inflammation, which if sustained is one of the major drivers of practically every important age-related disease. The effect explains the seeming paradox that even the diseased organs of very old people don’t contain high absolute numbers of senescent cells: it doesn’t take many.
That discovery and others made some people wonder what would happen if you cleared these cranky cells away. In 2011 Jan van Deursen and colleagues at the nonprofit medical organisation the Mayo Clinic showed that eliminating senescent cells in mice via a genetic trick delayed some of the ravages of age in prematurely aged mice. The paper sparked the formation of Unity (Van Deursen is a scientific co-founder). A follow-up study published in 2016 that repeated the experiment but this time in naturally aged animals, sealed the possibilities. “That [2016 paper] was literally the proof of concept for the entire industry,” says Gary Hudson, CEO and co-founder of Oisín Biotechnologies.
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 – though whether killing senescent cells extends life is complicated. 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 (being sick, after all, is risky). True longevity – the maximum time the animals remain alive for – remains relatively unchanged, though studies published in July and September 2018 show a 36% extension of remaining lifespan in mice that were treated when they were very old.
The race between Unity and its competitors is to excite interest in their different approaches to killing senescent cells and move them through the clinical trials needed to demonstrate that their therapies work safely in people.
Unity’s method is based on targeting the biological pathways senescent cells use to resist the normal death of ageing cells. Inhibit the right pathway and death can be “nudged” to occur. The company’s approach is to find small molecules (so called “senolytics”) that can do this. 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. “It is a walk-before-you-run strategy,” says Keith Leonard, Unity chairman and CEO. “A pill or an injection that would clean out senescent cells throughout your entire body would be a brilliant future but we have to be very careful.”
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. (One 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.)
Beyond that, it has another drug in the pipeline with which it hopes to target eye disease and beyond that, more drugs in a competitive bake-off for lung disease.
“We are now in the midst of chapter one,” says Unity co-founder and president Nathaniel David. “And chapter one concludes with the successful demonstration in human beings that the elimination of senescent cells takes a feature of ageing that was untreatable and uncurable, and makes it a treatable medical condition.”
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 (p16) that acts as a marker of zombie cells, albeit imperfectly.
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 (there are lots of cancers for which no treatment is available so the regulatory bar to the clinic is lower). That will test a version of its anti-ageing therapeutic modified to target cancer, but it may also be possible to see – by virtue of observable age characteristics – whether the drug has had any effect on senescent cells. Not everyone is convinced Oisín’s method can work. “Not every cell that expresses high p16 is senescent; and not every senescent cell has high p16,” notes James Kirkland, a researcher who studies ageing at the Mayo Clinic.
Other approaches from Senolytic Therapeutics and CellAge could respectively make Unity and Oisín’s methods more precise. 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.
Although killing zombie cells seems like a good idea, which method, if any, will be successful in humans is an open question. “I have been around long enough that everything looks good in mice and when you get to people that is where things go wrong,” says Kirkland, who is also running a handful of clinical trials at Mayo for repurposed cancer drugs and natural products that have been shown to kill senescent cells in mice.
If eliminating senescent cells does improve specific age-related diseases in humans, the next step will be to go broader. That’s tough because regulators don’t recognise ageing as a treatable condition (which is why the companies’ clinical trials don’t focus on ageing per se but instead on specific age-related diseases). There is hope on the horizon, however, with the recent approval by the FDA of a novel clinical trial to assess the power of the drug metformin [see below] against what is ageing in all but name. “There now exists a template,” says De Grey.
On the positive side, if there is an eventual treatment it wouldn’t have to be taken every day. Imagine an annual or biennial therapy, starting from middle age, that sweeps away any senescent cells building up. And because you wouldn’t chronically be on the drug, the risk of side-effects would be minimised.
The drugs also wouldn’t have to be super-efficient at killing senescent cells, says Niedernhofer: mouse studies suggest just getting rid of 30% of them is enough to have an impact. It isn’t like cancer where to cure it, you have to kill every cancer cell.
Even with the uncertain road ahead, the prospect is tantalising: everybody wants to keep going as far as possible in healthy circumstances. I leave Unity’s labs not full of fear for my knees but full of hope. Sign me up for my annual dose of zombie-killing, age-defying treatment.
Five more ways to cheat death
This 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, set to start next year if funding comes through, aims to get to the bottom of whether it really is an anti-ageing drug. One way metformin works is to inhibit senescent cells’ nasty secretions.
Strictly limiting calories is known to extend the lifespan of animals. Could the drug rapamycin be caloric restriction in a pill? The drug is used to suppress the immune system of organ transplant patients but 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.
Unresolved DNA damage in our cells is one of the main drivers of ageing. Boosting the chemical NAD+ in the body activates a particular protein that removes that damage. Mice treated with a drug to boost NAD+ got fitter with increased muscle tone and blood flow. A small clinical trial of the NAD+ booster, which is actually a dietary supplement, is currently under way.
What if you could temporarily convert regular cells into stem cells again so they automatically repair themselves? This has been done in mice with a genetic trick, extending the lifespan of those with a premature ageing disease by 30% and helping normal old animals to better repair their muscles and pancreas after injury. More research is currently being done in the lab to translate the approach to the clinic. It focuses on achieving similar effects in old tissues and organs, but using drugs instead.
Fix your lifestyle
Exercise, reducing stress and a healthy diet stave off multiple age-related diseases, in essence slowing ageing. Studies also indicate that so called intermittent fasting, which restricts when you eat rather than how much you eat, promotes a longer lifespan in both animals and people.
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