Clearing aging cells keeps whole mouse from aging

Print 12 February 2016
Anette Breindl / BioWorld

Removing senescent cells from middle-aged mice by pushing them into apoptosis lengthened the life span of the animals by 25 to 35 percent, researchers from the Mayo Clinic have reported.

The findings confirm a broad role of senescent cells in promoting aging, and suggest that targeting such senescent cells could be beneficial in a number of age-related diseases. A spinout based on the results, Unity Biotechnology Inc., plans to put that idea to the test in the clinic.

Senescence is a broad concept – so broad, in fact, that "it's hard to say that there is really one uniform model of a senescent cell," Darren Baker told BioWorld Today. Baker is an assistant professor of biochemistry and molecular biology at the Mayo Clinic and co-corresponding author of the paper reporting the findings, which was published in the Feb. 4, 2016, issue of Nature.

In cell culture, senescent cells are those that no longer divide. But in a living organism, the situation is more complex.

Baker pointed out that "neurons would not be what we consider a senescent cell," despite the fact that the brain is notable for how few of its adult cells are still dividing.

In an organism, senescent cells are cells that, as a result of aging-related changes, "have now acquired a different phenotype" than they had in their youth. This is part of the reason they stop dividing – senescence is an important process to prevent cells that have accumulated genetic errors with age from turning into full-blown cancer cells.

The problem with such cells is not primarily that they are not dividing, but that as part of their aging, they start secreting factors that are actively bad for their surroundings. As such cells accumulate in the body – in humans that starts happening around age 30 – they appear to drive many age-related diseases.

Most senescent cells can be identified because they express the tumor suppressor p16ink4a. In the work now published in Nature, Baker, his co-corresponding author Jan van Deursen, and their colleagues used a transgenic mouse whose p16ink4a-expressing senescent cells can be prodded into apoptosis through drug treatment, preventing their accumulation.

Baker said he and van Deursen "fell into the aging field somewhat backwards." The transgenic mouse they used was originally "a very failed cancer model." But, it turned out, it was a good model of premature aging.

A few years ago, the team had demonstrated that clearing out senescent cells in their model could halt their premature aging and associated diseases.

In the current work, the team applied the same principle to normal rather than rapidly aging mice, clearing their senescent cells from age 12 to 18 months.

That treatment extended the animals' life span by 25 to 35 percent, regardless of gender, genetic background and diet.

Chronic treatment that promoted the death of senescent cells had no ill effects on the animals, and improved the overall health of the animals by slowing age-related deterioration of the heart, kidneys and fat.

Baker said that effect on health was critical. "Longer is always something that people talk about, but . . . we don't want to just be extending the span of a miserable life," he said.

The treatment did not appear to have any beneficial effects on muscle strength, metabolic profile or blood cells, though Baker noted that such effects might become apparent with longer treatment. Similarly, because the team started treating in early middle age, senescent cells never got a chance to accumulate. If animals were treated after such accumulation had occurred, the effects of treatment might be more apparent.

Van Deursen is co-founder of a start-up based on the work, San Francisco-based Unity, which launched with an undisclosed amount of funding "by founding investor Arch Venture Partners, with significant contributions from Venrock, Wuxi, Mayo Clinic, Unity's management team and others," according to a company press release.

Unity co-founder and CEO Nathaniel David told BioWorld Today that "we work on a deceptively simple problem, which is, 'How come when you get older, you get sicker?'"

The company currently has 21 employees and expects to expand to about 50 by the end of 2017.

EXTENDING HEALTHSPAN

The last anti-aging approach to catch the interest of scientists and investors alike was the sirtuins, whose spectacular rise culminated in the $720 million buyout of Sirtris Pharmaceuticals Inc. by Glaxosmithkline plc in 2008, and quieter fall ended in the shuttering of Sirtris' labs in 2014. (See BioWorld Today, April 24, 2008, and March 14, 2014.)

Several sirtuin-targeting drugs remain in clinical trials. Nashville, Tenn.-based Nusirt Biopharma Inc. is in phase II trials to treat nonalcoholic steatohepatitis and type 2 diabetes by activating the Sirt1/AMPK pathway with a combination of leucine and metformin. (See BioWorld Today, July 10, 2015.)

Torrent Pharmaceuticals Ltd. is also in phase II trials with sirtuin activator TRC-150094 in metabolic cardiovascular syndrome, and KT & G Life Sciences Corp. is testing sirtuin activator MB-12066 for nonalcoholic fatty liver disease.

Nevertheless, the hopes attached to sirtuin activators – especially resveratrol, which spurred its own cottage industry of supplements as well as dietary advice to drink red wine and eat dark chocolate – have not borne out.

David's assessment was "that biology is among the more widely discredited biological hypotheses in recent memory. The mechanism we are targeting is not conceptually related to the sirtuin story, so we don't feel there is any correlated risk."

Scientifically, Baker said, sirtuin-targeting approaches "attempted to modulate particular pathways in cells (most by boosting the activity)," but did not eliminate the whole aging cell.

Unity intends to initially focus on diseases where senescent cells accumulate at specific sites and lead to pathology such as osteoarthritis, which David characterized as "the main reason that aging hurts."

Those indications have clearly defined regulatory pathways, and comprise large markets in their own right. And although the scientific studies published to date have not shown any reversal of age-related decline, David said that clearing out senescent cells might make it possible to cure such diseases, which are currently chronic once they get started.

Ultimately, he said, the approach might lead to "acute treatments for chronic diseases," where an acute treatment to clear out senescent cells could be sufficient to turn back the clock on many age-related disorders.

"That's the big dream," David said. "Extending healthspan."

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