Senescent cells lurk in our tissues: these cells have exited the cell cycle and passed their sell-by date, but have not been destroyed as they should be, either by the internal processes of programmed cell death or by that portion of the immune system that watches for errant cells. Senescent cells behave badly, secreting chemicals that degrade surrounding tissue and harm nearby cells. In this way their presence contributes to degenerative aging.
As you become older the mechanisms keeping a lid on the number of senescent cells start to fail: there is more damage in cells and the immune system begins to run down, for example. The number of senescent cells grows inexorably, and the more of them there are, the more harm they cause. Thus any toolkit of therapies that aims to treat aging has to include some way of destroying senescent cells or reversing cell senescence.
Last year, researchers demonstrated that the onset of age-related degeneration in mice can be delayed by culling senescent cells. The method used was convoluted, however, and involved gene therapy - which makes it a poor candidate for anything other than demonstrating that removal of senescent cells is a good thing. There's no building a near-term therapy from that work.
The path to building a useful and straightforward therapy that kills senescent cells is pretty clear, however. There are any number of ways to kill a cell; the trick lies in picking out the cells you want to kill from the forest of their peers. Fortunately, the cancer research community has been very focused on this problem for many years now: how to deliver any of the proven cell-killing drugs to a specific set of cells that look slightly different from their neighbors without harming any of those neighbors. The past decade has seen great strides in the development of nanoparticles that can carry a payload, attached to some form of biological machinery capable of discriminating between cells based on one or more aspects of their surface chemistry. Flood the body with suitable nanoparticle delivery systems and they will find and kill only the cells you want to kill.
Cell surface chemistry is complex and far from black and white, of course. Nonetheless, work on targeting and delivery mechanisms is progressing rapidly in the laboratory. The results are very relevant to our desire to selectively and safely destroy senescent cells, and the real challenge here lies in the reliable identification of senescent cells. As noted last year, we need a robust way of identifying senescent cells; that is the one vital ingredient not yet in place that will allow all that cell-killing expertise present in the cancer research community to be turned to senescent cells.
It was only a matter of time, however, and here we have a first attempt at a targeting mechanism for senescent cells - which is exciting news if it pans out and the chemical signature of senescence that the researchers focused on here is a good distinguishing mark throughout the different tissue types in the body:
"The nanodevice that we have developed consists of mesoporous nanoparticles with a galactooligosaccharide outer surface that prevents the release of the load and that only selectively opens in degenerative phase cells or senescent cells. The proof of concept demonstrates for the first time that selected chemicals can be released in these cells and not in others," says Ramón Martínez Máñez, researcher at the IDN Centre - Universitat Politècnica de València and CIBER-BBN member.
José Ramón Murguía, a researcher at the Instituto de Biología Molecular y Celular de Plantas (UPV-CSIC) and also a CIBER-BBN member, explains that senescence is a physiological process of the body to eliminate aged cells or ones with alterations that may compromise their viability. "When we are young senescence mechanisms prevent, for example, the appearance of tumors, the problem is that with age senescent cells accumulate in organs and tissues, disrupting their proper functioning. The elimination of these cells would slow down the appearance of diseases associated with aging. Our work shows that we can develop a targeted therapy against these cells," says Murguía.
The researchers have evaluated the utility of the new nanodevices in primary cell cultures derived of patients with accelerated aging syndrome dyskeratosis congenita (DC). Such cultures show a high percentage of senescence characterized by elevated levels of beta-galactosidase activity, an enzyme characteristic of senescent state. "The aging cells overexpress this enzyme so we have designed nanoparticles that open when detected and release their contents in order to eliminate senescent cells, prevent deterioration or even reactivate for their rejuvenation"