June 18th, 2016
New drugs can delay aging and rejuvenate tissues.
As our bodies age, all tissues become less efficient in performing their functions because they accumulate old cells, termed senescent cells. Senescent cells, though still alive, have lost their normal functional properties and produce a series of molecules, called senescent-associated secretory phenotype (SASP), that act on their neighbor, normal cells decreasing their performance. In this way, tissues progressively lose their competences, including the ability to repair damages and to renew.
Besides aging, another factor that can turn healthy cells into senescent cells is tissue damage. An example is the effects on healthy tissues of radiation or chemotherapy that increase tissue senescence, therefore contributing to the toxic side effects associated with most cancer therapies.
In front of this scenario, the idea comes immediately to mind: what if we get rid of senescent cells within a tissue? Could this maintain the tissue young, delay aging, and improve recovery from injuries? Some studies have already shown that this could be the case: killing senescent cells in animal models through genetic techniques actually retards the appearance of diseases associated with aging.
With the goal of targeting senescent cells in mind, Chang and colleagues from the University of Arkansas started their search for “senolytic” drugs, anti-aging molecules that ideally target only senescent cells in any aging or damaged tissues and eliminate them. After screening a collection of candidate drugs in a culture plate, the scientists identified a molecule called ABT263 that showed the desired properties. When testing this molecule in vivo, the researchers studied its effects in two different experimental settings: aging mice and mice that had been irradiated. In both cases, the animals had accumulated senescent cells especially in their bone marrow, lungs, and muscles.
ABT263 was able to eliminate senescent cells irrespectively of their origin (aging or irradiation) in the three tissue types and, as a consequence, to improve tissue function. In particular, researchers observed that in irradiated mice the drug significantly rescued normal hematopoietic stem cells from the effects of SASP produced by the senescent cells nearby, and in this way protected the bone marrow from the deleterious effects of radiation.
Well, not exactly: ABT263 has in fact some important toxic side effects and has to be further studied before it can be administered to people. It seems clear though that similar drugs with limited toxicity can be of great benefit in the clinic:
With these new discoveries, the search for the youth pill has definitely started moving on solid ground.
Chang, J., Wang, Y., Shao, L., Laberge, R., Demaria, M., Campisi, J., Janakiraman, K., Sharpless, N., Ding, S., Feng, W., Luo, Y., Wang, X., Aykin-Burns, N., Krager, K., Ponnappan, U., Hauer-Jensen, M., Meng, A., & Zhou, D. (2015). Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice Nature Medicine, 22 (1), 78-83 DOI: 10.1038/nm.4010
Baker, D., Wijshake, T., Tchkonia, T., LeBrasseur, N., Childs, B., van de Sluis, B., Kirkland, J., & van Deursen, J. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders Nature, 479 (7372), 232-236 DOI: 10.1038/nature10600
van Deursen, J. (2014). The role of senescent cells in ageing Nature, 509 (7501), 439-446 DOI: 10.1038/nature13193ABT263, anti-aging, SASP, senescent cells, youth pill,