FightAging!
10-15-18

https://www.fightaging.org/archives/...d-development/

Research programs and investment in commercial development related to senolytic therapies are growing rapidly, particularly in the last couple of years. As today's article demonstrations, journalists in the popular press are improving when it comes to their ability to report sensibly on these developments. This has taken far too long to come to pass; it wasn't all that long ago that near every article in the media on the prospects for treating aging was some combination of nonsense, scorn, and fear-mongering.

Senolytic treatments are those that selectively destroy senescent cells in aged tissues. The accumulation of senescent cells is one of the root causes of aging; even in small numbers these errant cells cause chronic inflammation and degrade tissue function in numerous ways via the signal molecules they generate. Removing senescent cells is a form of rejuvenation, capable of reversing aspects of aging and age-related disease and extending healthy life span. The data in mice is robust, impressive, and expanding. The first human data will be published over the course of the year ahead.

Clearance of senescent cells as a way to intervene in the aging process has been recognized as a plausible goal for quite some time, and in fact was in the SENS rejuvenation research proposals from their inception around the turn of the century. Unfortunately, aging was not seen as a legitimate target for therapy at that time, and obtaining support for this line of work has required long years of advocacy and philanthropy. In a better world, in which the research community had not relinquished its duty in the matter of aging for the better part of a generation, this all could have happened two decades or more before it finally arrived.

These days there seems a certain eagerness to forget the years in which the SENS program was mocked, researchers dismissed the likely relevance of senescent cells to aging, and the talking heads of the media sneered at the idea of treating aging as a medical condition. It is now said that nothing could have happened any faster than it did, that in fact everyone was doing the right thing just as soon as they could. This is self-serving nonsense. Countless lives have been lost and continue to be lost because of entirely unnecessary delay in the matter of addressing aging and age-related disease as an urgent concern. Senolytics is just one branch of many needed approaches. Most of the others, biotechnologies that could be just as influential on the progression of aging, are still minority concerns, disregarded by the research community, the press, and the public at large. Much work remains to be accomplished.

Want to live for ever? Flush out your zombie cells

Two blown-up images of microscope 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. 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. 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; 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."

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. True longevity - the maximum time the animals remain alive for - remains relatively unchanged, though studies show a 36% extension of remaining lifespan in mice that were treated when they were very old.

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. 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 Gary 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.

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. 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.