Here I'll point out a paper in which researchers link the suddenly popular JAK-STAT signaling pathway with the harmful activities of senescent cells in old tissues and the rising level of chronic inflammation that contributes to the progression of most age-related diseases. The varied roles of the genes and proteins involved in the JAK-STAT signaling pathway have been studied by a number of research groups of late. There are four Janus kinases (JAK) and at least seven Signal Transducer and Activator of Transcription (STAT) proteins involved in this very small slice of cellular metabolism, and of course their activities influence and are influenced by scores of other mechanisms. Nothing ever happens in isolation inside a cell. The JAK-STAT pathway is of interest because inhibition of some of its components and activities appears to somewhat restore the activity of old stem cell populations, and has also been shown to reduce the growth in chronic inflammation that accompanies aging.
In the open access paper linked below, the authors propose that reductions in inflammation resulting from JAK inhibition occur because the intervention damps down the harmful output of senescent cells. Cellular senescence is a mechanism that removes cells from the cycle of replication in response to damage or stress. It may be an evolved adaptation of a tool of embryonic development that serves to suppress cancer risk, but it unfortunately also produces damage as these cells grow in number - and aging is nothing more than an accumulation of damage and reactions to that damage. Senescent cells generate a disruptive mix of signal molecules known as the senescence-associated secretory phenotype; this alters the behavior of surrounding cells, damages nearby tissue structures, and to the point of this paper, creates inflammation. When few senescent cells are present, as is the case in younger life, there is little harm done. Most are destroyed by the immune system or by their own programmed cell death processes, but over time an ever-increasing number of senescent cells evade these fates to linger indefinitely. In old age a substantial proportion of some tissues are made up of these dysfunctional cells, and tissue function declines as a direct result. Even the cancer suppression falters in the end, with the inflammatory and other effects of SASP promoting cancerous growth more effectively than the removal of cellular replication suppresses it.
The direct approach to cellular senescence is to periodically destroy senescent cells to keep their numbers low. It doesn't matter how exactly they are causing havoc if they can be safely removed. This is the best and fastest path to therapies, but is nonetheless very much a minority concern in the research community. Shortcuts carried out in advance of understanding, even when they work as this destructive approach does, go against the grain of scientific culture. The usual preferred approach is to gather full understanding of what is going on under the hood and then alter the operation of cellular metabolism in targeted ways to reduce undesirable outcomes. Never mind that this is far harder, slower, more expensive, and - for the foreseeable future - less effective. What is important to the research community is that it aligns with the goal of mapping cellular metabolism. Along these lines, it is interesting to note that the paper below, essentially advocating modulation of SASP via JAK inhibition as a desirable approach to therapies, is written by the very same researchers who recently demonstrated improved healthspan via partial elimination of senescent cells.
This is why we need philanthropy and advocacy and organizations like the SENS Research Foundation to get out there and push forward down the fast and effective path. No distractions, no mapping, just straight to the first generation therapies capable of meaningfully treating the causes of aging. It is far from an academic question as to how rapidly effective treatments can be created to address the effects of cellular senescence in aging. Countless lives depend upon this and the other necessary components of a toolkit of rejuvenation therapies. So I'd say that the point to take away from this particular research paper is that it provides one more set of evidence to confirm that, yes, destroying senescent cells to remove SASP as soon as possible is a great idea. In that I'm not in agreement with the authors' summary on possible ways forward:
A hallmark of aging is chronic, low-grade, "sterile" inflammation. Elevated proinflammatory cytokines and chemokines are closely associated with mortality and with a variety of age-related diseases, including atherosclerosis, depression, cancers, diabetes, and neurodegenerative diseases. Inflammation also is associated with frailty, a geriatric syndrome characterized by decreased strength and incapacity to respond to stress.
The underlying mechanisms of age-related chronic inflammation, tissue dysfunction, and frailty remain elusive. Cellular senescence, stable arrest of cell growth in replication-competent cells, is a plausible contributor. Senescence can be induced by a number of stimuli and stresses. Senescent cells accumulate with aging in the skin, liver, kidney, the cardiovascular system, and other tissues in various species. The senescence-associated secretory phenotype (SASP), largely comprised of proinflammatory cytokines and chemokines, links senescent cells to age-related inflammation and diseases. We found that elimination of senescent cells delayed the onset of age-related phenotypes and enhanced healthspan. Therefore, senescent cells and the SASP could play a role in age-related pathologies, particularly those that involve systemic inflammation.
The JAK/STAT pathway plays an important role in regulating cytokine production. We hypothesized that it may directly affect the SASP. We demonstrate here that senescent preadipocytes, fat cell progenitors, accumulate in adipose tissue with aging and can contribute to adipose tissue inflammation. We found that JAK inhibitors decrease the SASP in preadipocytes and human umbilical vein endothelial cells (HUVECs). They also decrease age-related adipose tissue and systemic inflammation as well as frailty. Our findings provide insights into the possible contribution of senescent cells to age-related inflammation and, in turn, to age-related pathologies, as well as potential therapeutic targets to alleviate age-related dysfunction.
There are three potential approaches for targeting senescent cells. One is to prevent them from arising by disabling p16- or p53-related processes or other upstream mechanisms that drive the generation of cellular senescence. This approach, however, is likely to induce cancer. The second is to eliminate senescent cells that already have formed. The third is to blunt the proinflammatory nature of the SASP. Mounting evidence suggests that senescent cells can have both harmful and beneficial effects. Therefore, partial suppression of the SASP seems to be a reasonable option, particularly when short-term alleviation of age-related dysfunction might be indicated.