Cellular senescence is a cause of aging. Enormous numbers of cells become senescent day in and day out, entering a state in which they secrete damaging signals that disrupt surrounding tissue. Near all self-destruct or are quickly destroyed by the immune system. It is the very few that linger and build up in tissues over the years that act to produce chronic inflammation, fibrosis, and ultimately age-related disease. Current approaches to the problem aim at killing these errant cells, finishing the job that was left uncompleted by natural processes, and turning back this aspect of aging.
As this research makes apparent, it may be possible in the near term to take the alternative approach of completely preventing senescence from occurring in the first place. Is this a good idea, however? My first reaction would be to say "no, absolutely not"; senescent cells play a role in in wound healing, as well as in cancer suppression, at least in small numbers. Also, and perhaps more importantly, what happens to the enormous number of somatic cells that reach the end of their replicative life span if they don't then become senescent and self-destruct? How would this disrupt the normal balance of tissue regeneration and maintenance? But the researchers here are maintaining a genetically altered lineage of mice in which cGAS, a controlling gene for senescence, is deleted. So far the mice appear largely normal, though deficient in the innate immune response to cancer due to loss of other functions of cGAS. So perhaps this does bear further investigation from a therapeutic point of view despite all the obvious objections that might be mounted.
Since its formal description more than 50 years ago, cellular senescence has been extensively studied and found to play a critical role in cancer, aging, and age-related diseases. Cellular senescence can be induced by DNA damage, telomere shortening, oxidative stress, and oncogenes. Interestingly, all of these senescence-inducing conditions impinge on DNA directly or indirectly. The DNA damage response is a key event leading to senescence, which is characterized by the senescence-associated secretory phenotype (SASP) that includes expression of inflammatory cytokines. Here we show that cGMP-AMP (cGAMP) synthase (cGAS), a cytosolic DNA sensor that activates innate immunity, is essential for senescence. We found that damaged DNA is associated with cGAS in the cytoplasm and that deletion of cGAS abrogated SASP gene expression and other markers of cellular senescence. These results reveal cGAS as an important molecular link between DNA damage, SASP gene expression, and senescence.
Whereas cGAS clearly plays an important role in cellular senescence, it should be noted that cGas-deficient mice appear to be healthy. We have not observed a significant increase in spontaneous tumors in our cGas-/- mice even though some of these mice are more than 20 months old. Because there are multiple barriers for a cell to become a malignant cancer cell, removal of cGAS alone may not be sufficient to cause spontaneous tumors. However, it will be very interesting to test whether cGAS deletion promotes tumor development driven by oncogenes such as Ras, which is known to induce senescence. In this context, we recently reported that cGas-deficient mice are refractory to the antitumor effect of immune checkpoint blockade, indicating that cGAS is required for generating intrinsic antitumor immunity. It remains to be determined whether cGAS has a cell-autonomous function in impeding the transformation of a normal cell into a cancer cell.
Recent studies have provided strong evidence that senescence has a causal role in aging and age-related diseases and that genetic deletion of senescent cells increases the lifespan and ameliorates age-related pathologies in mice. It would be very interesting to determine whether cGAS plays a role in normal aging as well as age-related diseases in animal models. If so, cGAS inhibitors may be used for treating not only autoimmune diseases but also a variety of age-related diseases.
Link: https://dx.doi.org/1...pnas.1705499114
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