Can Aging be Slowed by Shutting Off the Inflammatory Signaling of Senescent Cells?

Today I'll point out an interesting paper in which researchers sabotage the ability of senescent cells to generate inflammation. Senescent cells are one of the root causes of aging. They are created constantly in all tissues, a normal part of the operation of cellular metabolism, but near all are destroyed shortly thereafter. Those that linger cause ever greater disruption and failure in tissues and organs because they secrete a variety of signals known as the senescence-associated secretory phenotype (SASP), useful in the short term and when localized, but outright destructive over the long term or in great volume. One of the characteristic outcomes of the presence of lingering senescent cells is a significant increase in chronic inflammation, and this in turn accelerates the progression of all of the common age-related conditions.

With regards to what to do about senescent cells, the research community seems fairly evenly split between groups working on ways to destroy them and groups working on ways to modulate their activities. I think the former approach will be far more beneficial in the near term: it bypasses the need to understand in detail all of the highly varied senescent cell signals and their effects, a task that will likely still be ongoing a decade from now. Further, modulating the signals of senescent cells without removing them will require continual medication, rather than the envisaged infrequent, once-every-few-years treatments that clear out senescent cells. I see this as one of many areas in which the rational incentives in academic research (find out more, map more of the system, better understand the whole picture) seem to lead inexorably towards the production of objectively worse solutions in medicine.

That to one side, and as today's research illustrates, researchers appear to be making some progress in linking existing knowledge on inflammatory signaling to the the quickly growing knowledge of the biochemistry of senescent cells in aging. I mentioned another paper on this same topic and mechanism a couple of months ago. Here, the authors have found a way to interfere in one of the primary pathways by which senescent cells communicate with the immune system, and demonstrated in mice that this can blunt some of the consequences of high levels of senescence that are artificially induced through techniques such as irradiation. Unfortunately this also prevents the beneficial short-term benefits arising from senescence-associated inflammation, such as in immune surveillance of cancer. It remains to be seen as to how much of an effect this sort of approach will have on the consequences of cellular senescence in normally aging mice. Not to mention humans: at this point we really have no idea what the impact of clearing senescent cells will turn out to be in our species, never mind any of the possible approaches to selectively reduce the impact of their signaling in very narrow ways.

Cell Stress Response Sheds Light on Treating Inflammation-related Cancer, Aging

Human cells have complicated ways to protect themselves from becoming cancerous. One way is to force "premature aging" via senescence, a process that induces cells to stop growing. Although senescence suppresses cancer, which is the good side of this physiological balance, there is also a dark side. Senescence is associated with normal aging, and senescent cells accumulate in aged tissues. This accumulation impairs healthy tissue by triggering hyper-inflammation. This overdrive eventually contributes to age-related diseases including cancer, heart disease, and neurodegeneration. The overall idea for future therapy is to make a small molecule that could stop the dark side of senescence to treat age-related diseases, especially those related to chronic inflammation.

"Chromatin - structures in the cell nucleus in which genes reside - is traditionally viewed as a cell component that stays put in the nucleus to regulate gene expression. We discovered misplaced chromatin fragments outside the nucleus that pinch off from the nuclei of senescent cells." This wayward chromatin activates a DNA-sensing pathway called cGAS-STING, a mechanism based outside the nucleus best known for restraining microbial infection, such as by bacteria or viruses. In the case of senescence and aging, the body's own chromatin leaking outside of the nucleus is read by cells as a "danger signal" akin to a microbial infection. The misplaced fragments and the cell's reaction to them eventually lead to inflammation. "While short-term inflammation can help stop cancer from starting, the problem is that long-term, chronic inflammation can lead to tissue destruction, aging, and even, paradoxically, can help cancer to grow and spread."

Mice without an active alarm pathway that have been exposed to a cancer-inducing stress do not call the immune-system for help. This causes problems because damaged cells give rise to tumors in the impaired mice. However, when normal mice are exposed to stressors that induce aging, the build-up of senescent cells stimulates a continual call for immune cells, leading to chronic inflammation, which ultimately causes tissue damage and premature aging. Months after receiving irradiation stress, normal mice with an active alarm system showed massive graying of their fur, a sign of aging in mammals, just like humans show grey hair in old age. By sharp contrast, mice without the alarm system still had their black fur after irradiation. The researchers believe that finding molecules to target the always-on inflammatory pathway may hold promise in treating chronic inflammation associated with numerous diseases, especially those of aging, such as arthritis, arteriosclerosis, neurodegeneration, obesity, and possibly even hair graying and loss.

Cytoplasmic chromatin triggers inflammation in senescence and cancer

Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing. However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from intact nuclei of primary cells during senescence, a form of terminal cell-cycle arrest associated with pro-inflammatory responses. The functional significance of chromatin in the cytoplasm is unclear.

Here we show that cytoplasmic chromatin activates the innate immunity cytosolic DNA-sensing cGAS-STING (cyclic GMP-AMP synthase linked to stimulator of interferon genes) pathway, leading both to short-term inflammation to restrain activated oncogenes and to chronic inflammation that associates with tissue destruction and cancer. The cytoplasmic chromatin-cGAS-STING pathway promotes the senescence-associated secretory phenotype in primary human cells and in mice.

Mice deficient in STING show impaired immuno-surveillance of oncogenic RAS and reduced tissue inflammation upon ionizing radiation. Furthermore, this pathway is activated in cancer cells, and correlates with pro-inflammatory gene expression in human cancers. Overall, our findings indicate that genomic DNA serves as a reservoir to initiate a pro-inflammatory pathway in the cytoplasm in senescence and cancer. Targeting the cytoplasmic chromatin-mediated pathway may hold promise in treating inflammation-related disorders.

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