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The future of anti-aging therapies that target senescent cells.

ROTTERDAM, The Netherlands, December 29, 2016 -- Removing senescent cells (i.e., cells with a persistent damage response) that naturally accumulate with age allows older rodents to regrow hair, run faster, and improve organ function, new research here shows.

Though the strategy may bring us one step close to the "fountain of youth," said Peter de Keizer of the Erasmus University Medical Center, there are milestones the field still needs to reach before translation in humans is ready for discussion.

The removal of senescent cells, first discovered in the 1960s, received renewed interest in the 2010s as a therapeutic option to combat some aspects of aging.

Researchers noticed that these permanently arrested cells accumulate in mature tissue and that some of them secrete factors that are harmful to tissue function and impair their neighboring cells.

To explain what causes this noise in the system, de Keizer proposed a "senescence-stem lock model" in which the chronic secretion of pro-inflammatory factors by these senescent cells keeps neighboring cells in a permanent stem-like state and thereby prevents proper tissue renewal.

A perfect anti-senescence therapy would not only clear away senescent cells, but also kickstart tissue rejuvenation by stimulating differentiation of nearby stem cells.

This may be complementary with, for instance, the findings in the field of transient expression of stem cell factors.

Basic research needs to be done before humans visit their local rejuvenation clinic for their annual shot of anti-aging serum.

Identifying potential safety issues or off-target effects, which is understudied in rodents, is a major part of the process. (Senescent cells do have a temporary role in wound healing, so you don't want to eliminate them when you are injured or at the wrong point in time.)

De Keizer pointed to three milestones for realistic translation of an anti-senescence approach:

* Proof of Concept. Several studies have already addressed whether senescence is a cause of aging and whether its elimination stalls this process. By taking out senescent cells, naturally aging mice lived 25 percent longer, which is evidence that it could be possible.

* Safe Therapeutics. Anti-senescent drugs are already being tested, but none of them have been deemed safe because they also target pathways expressed by nonsenescent cells. It is likely that this marker will be passed in the near future.

* Reversal of Aging. Lastly, researchers will need to identify whether clearance of senescence can also be applied retrospectively to counteract features of natural aging that have already manifested. Although aging does seem like it can be stalled through therapeutic compounds, it remains unclear whether age-related diseases can be completely deterred.

"What if we have a brilliant anti-senescence treatment, then what?" de Keizer said. "How can we hit two birds with one stone: anti-senescence and tissue rejuvenation?"

He advised caution for claiming too much, too soon about the benefits of the fast-growing list of therapeutic compounds that are being discovered.

But de Keizer also said "these are clearly very exciting times" he is certain applicable anti-senescence treatments will be found that can counteract age-related pathologies.

Researchers will also need to think about when such treatments should be administered--before or after the onset of certain conditions?--and who would benefit the most.

The potentially high cost of an anti-aging therapy, as well as off-target toxicity, could also be limiting factors for widespread market use as it is translated.

De Keizer plans to co-found a company based on the discovery of anti-senescence compounds from his lab, and hopes that cell-penetrating peptides that can block specific activities of these retired cells could be the path forward over broad-range inhibitors.

Citation: Peter L. J. de Keizer, "The Fountain of Youth by Targeting Senescent Cells?" Trends in Molecular Medicine, 2016; DOI: 10.1016/j.molmed.2016.11.006


Contact: Peter L. J. de Keizer,
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Title Annotation:Preclinical Research
Publication:Stem Cell Research News
Date:Jan 16, 2017
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