The accumulation of senescent cells over time is one of the causes of aging. It is one of the limited number of root cause mechanisms that collectively distinguish old tissue from young tissue. Cells become senescent constantly, most because they have reached the Hayflick limit on replication, but senescence also occurs in response to cell damage, tissue injury, or a harmful tissue environment. Near all of these cells are destroyed shortly after becoming senescent, either through the programmed cell death process of apoptosis, or by the immune system. A tiny fraction linger, however. These cells generate a mix of signals and other proteins that promote inflammation, destructively remodel the nearby extracellular matrix, and change the behavior of normal cells for the worse, among other things. This all makes sense in the context of their presence in embryonic development, wound healing, and cancer suppression - and when there are comparatively few such senescent cells. When there are many senescent cells, however, and when they are not destroyed as they should be, this behavior adds up to cause significant harm. Destructive processes such as fibrosis, arterial calcification, development of atherosclerotic plaques in blood vessels, loss of tissue elasticity, chronic inflammation in joints, and many more can all be directly tied to the presence of senescent cells, and can be improved by removing those cells.
Targeted removal of senescent cells to at least some degree is in fact now fairly easy to accomplish in a laboratory setting through the methodology of targeting known suppressors of apoptosis. As a consequence a whole range of drug candidates of varying quality are emerging. The senescent cells that linger in old tissue are remain primed for the fate of apoptosis, but are held back by a few mechanisms that are increasingly well characterized. Near any established medical research group with experience in cellular biochemistry can jump in and try their hand. Clearly a growing number of researchers are doing just this, managing to raise funding and join the field. There is plenty of room for them. Clearance of senescent cells - as a rejuvenation therapy capable of turning back some of the consequences of aging - has a target market of every human much over the age of 40, for treatments undertaken once every few years. This is such an enormous potential industry that no one company or methodology will win it all. In the next few years, we'll probably see sizable and successful companies emerge in many different countries, all of which have different regulatory regimes, and thus there will be comparatively little direct competition between these ventures.
The publicity materials below are really just banging the drum for work published last year, in which researchers used ABT-737 to inhibit BCL-W and BCL-XL. These two members of the Bcl-2 family suppress the process of apoptosis. Targeting them thus selectively destroys senescent cells by removing one of the blocks to undergoing apoptosis - a manipulation that should have comparatively little effect in normal cells. Many of the apoptosis inducing drug candidates at this time have significant side-effects, however, and so it is likely that those succeed will be the ones that lack that problem. At this point, the researchers here are somewhere in the early stages of commercializing their approach, and hence the emergence of extra publicity from their supporting institution. There will be a lot more of this sort of thing going on in the next few years.
Understanding why cells refuse to die may lead to treatments for age-related disease
One of the things that happens to our bodies as we age is that certain cells start to accumulate. So-called senescent cells - cells that "retire" and stop dividing but refuse to undergo cellular death - are always present, and they even serve some important functions, in wound repair, for example. But in aging organs, these cells don't get cleared away as they should, and they can clutter up the place. Researchers are revealing just how these cells are tied to disorders of aging and why they refuse to go away. The work is not only opening new windows onto the aging process, but is pointing to new directions in treatments for many of these disorders and diseases.
Research into cellular senescence has taken off in recent years, due to findings that clearing these cells from various parts of the body can reverse certain aspects of aging and disease processes. Pharmaceutical industries have taken note, as well, of research that could lead to the development of drugs that might target senescent cells in specific organs or tissues. In basic research conducted on human cell culture and on mice, researchers have asked exactly what ties senescent cells to aging. Are they, for example, a primary cause of age-related disease, or a side effect? And why don't these cells die, despite being damaged, so that the "clean-up crews" of the immune system have to clear them away?
The researchers hypothesized that the answer to the second question might lie in a family of cellular proteins that regulate a type of cell suicide known as apoptosis. They identified two proteins in this family that prevent apoptosis and which were overproduced in the senescent cells, BCL-W and BCL-XL. When they injected mice that had an extra supply of senescent cells with ABT-737 molecules that inhibit these two proteins, the cells underwent apoptosis and were then eliminated, and there were signs of improvement in the tissue. "In small amounts, these cells can prevent tumors from growing, help wounds clot and start the healing process. But as they amass, they trigger inflammation and even cancer."
Certain common age-related diseases have been shown to be associated with this build-up of senescent cells, for example, chronic obstructive pulmonary disease (COPD), and researchers hope to apply these findings to research into treatments for such diseases. The trick will be to target the offensive cells without causing undue side effects. Researchers have been developing mouse models of COPD and asking whether clearing senescent cells just from the lungs can prevent or ease the disease. They are now working to patent and license these discoveries.
View the full article at FightAging
