In 2011 a research group published the results from an animal study that demonstrated, in a way that couldn't be ignored, that the accumulation of senescent cells is a significant cause of aging and age-related disease. In fact, the evidence for this to be the case had been compelling for a very long time - this demonstration came nearly a decade after Aubrey de Grey, on the basis of the existing evidence at the time, included cellular senescence as one of the causes of aging in the first published version of his SENS research proposals. Yet nothing had been done to move ahead and achieve something with this knowledge. That did not change until researchers obtained sufficient philanthropic funding to run the 2011 animal study, using a sophisticated genetic mechanism that eliminated senescent cells as they formed.
From that point on, a slow-moving avalanche of interest and funding fell into this part of the field of aging research. All of the groups with an existing interest in cellular senescence, and that had previously struggled to raise sufficient resources to make progress, could now move rapidly. With the aim of selectively destroying senescent cells to reverse aspects of aging, small molecule senolytic pharmaceuticals and then other methods such as gene therapies and immunotherapies were discovered or constructed. Today there are at least a dozen such small molecule drugs, published and in the works, and a handful of increasingly well-funded startup biotech companies bringing these therapies to human trials and the clinic.
That is the practical side that will lead to rejuvenation treatments in the near future. But the pure scientific impulse isn't to build new technology, it is to learn how our biochemistry works. Much of the funding for further work on cellular senescence goes towards mapping and understanding its details. Now that it is inarguable that this phenomenon is important in the progression of degenerative aging, scores of research groups are picking apart the biochemistry of senescent cells. They are categorizing, trying to understand whether all senescence is essentially the same, or whether there are significant differences in different cell types. They are attempting to better grasp all of the relevant mechanisms that operate inside cells as senescence occurs, and how the triggering change works - or, indeed, whether or not it is a single trigger. They are exploring the details of the senescence-associated secretory phenotype (SASP), the means by which these cells cause harm to tissues.
The four open access papers noted here are recent examples of this sort of thing. There is a great deal to learn, and while the work is largely irrelevant to the senolytic therapies currently in development, there will no doubt be discoveries that steer and inform development of the second generation of more subtle and sophisticated therapies. Those will likely commence development five to ten years from now, and be mature and in widespread use by the early 2030s.
Cellular senescence is a cell fate program that entails essentially irreversible proliferative arrest in response to damage signals. Tumor necrosis factor-alpha (TNFα), an important pro-inflammatory cytokine secreted by some types of senescent cells, can induce senescence in mouse and human cells. However, downstream signaling pathways linking TNFα-related inflammation to senescence are not fully characterized. Using human umbilical vein endothelial cells (HUVECs) as a model, we show that TNFα induces permanent growth arrest and increases p21CIP1, p16INK4A, and SA-β-gal, accompanied by persistent DNA damage and ROS production. By gene expression profiling, we identified the crucial involvement of inflammatory and JAK/STAT pathways in TNFα-mediated senescence. We found that TNFα activates a STAT-dependent autocrine loop that sustains cytokine secretion and an interferon signature to lock cells into senescence.
Cellular senescence has been viewed as a tumor suppression mechanism and also as a contributor to individual aging. Widespread shortening of 3′ untranslated regions (3′ UTRs) in messenger RNAs (mRNAs) by alternative polyadenylation (APA) has recently been discovered in cancer cells. However, the role of APA in the process of cellular senescence remains elusive. Here, we found that hundreds of genes in senescent cells tended to use distal poly(A) (pA) sites, leading to a global lengthening of 3′ UTRs and reduced gene expression. Genes that harbor longer 3′ UTRs in senescent cells were enriched in senescence-related pathways. Rras2, a member of the Ras superfamily that participates in multiple signal transduction pathways, preferred longer 3′ UTR usage and exhibited decreased expression in senescent cells. Depletion of Rras2 promoted senescence, while rescue of Rras2 reversed senescence-associated phenotypes.
Oncogenic signals lead to premature senescence in normal human cells causing a proliferation arrest and the elimination of these defective cells by immune cells. Oncogene-induced senescence (OIS) prevents aberrant cell division and tumor initiation. In order to identify new regulators of OIS, we performed a loss-of-function genetic screen and identified that the loss of SCN9A allowed cells to escape from OIS. The expression of this sodium channel increased in senescent cells during OIS. This upregulation was mediated by NF-κB transcription factors, which are well-known regulators of senescence. Importantly, the induction of SCN9A by an oncogenic signal or by p53 activation led to plasma membrane depolarization, which in turn, was able to induce premature senescence. Computational and experimental analyses revealed that SCN9A and plasma membrane depolarization mediated the repression of mitotic genes through a calcium/Rb/E2F pathway to promote senescence.
A relevant feature of aging is chronic low-grade inflammation, termed inflammaging, a key process promoting the development of all major age-related diseases. Senescent cells can acquire the senescence-associated (SA) secretory phenotype (SASP), characterized by the secretion of proinflammatory factors fuelling inflammaging. Cellular senescence is also accompanied by a deep reshaping of microRNA expression and by the modulation of mitochondrial activity, both master regulators of the SASP. Here, we synthesize novel findings regarding the role of mitochondria in the SASP and in the inflammaging process and propose a network linking nuclear-encoded SA-miRNAs to mitochondrial gene regulation and function in aging cells. In this conceptual structure, SA-miRNAs can translocate to mitochondria (SA-mitomiRs) and may affect the energetic, oxidative, and inflammatory status of senescent cells.