Today's papers are representative of present investigations that aim primarily to expand our knowledge of the details of cellular senescence. This is as opposed to efforts to immediately produce treatments that can address the impact of senescent cells on health. Senescent cells accumulate with age, and their presence is one of the root causes of degenerative aging. The most important work on cellular senescence at the moment is that aimed at selective destruction of these cells. The vast majority of cells that become senescent in our bodies, countless numbers day in and day out, are in fact already efficiently destroyed, either through programmed cell death or via the actions of the immune system. We'd all be much better off if the lingering remainder, the tiny fraction that evade this fate, were also removed.
That said, a sizable fraction of today's research into cellular senescence aims to better understand the processes involved, or to intervene so as to reduce the harms caused by these cells, or reduce the number of cells that become senescent, or even attempt to reverse senescence, rather than destroy these cells after the fact. I have to think that this isn't anywhere near as cost-effective a path forward when it comes to the development of practical therapies, in particular because destroying senescent cells effectively deals with the harms we don't understand in addition to those we do - and mapping cellular biochemistry is a slow and expensive process. There are long years ahead for those who want to fully understand how senescent cells cause harm at the detail level, and destruction solves the problem now. It is nonetheless the case that more information is better than less information in the long term, and expanded knowledge may well lead to new targets for the development of selective cell destruction therapies - a point illustrated in the first of the two papers below.
How is it that a comparatively small number of senescent cells are so harmful? In old age, senescent cells are perhaps a few percent by number of the cells present in any given tissue, yet their presence strongly shapes the functional decline of that tissue. The answer is that they produce a potent mix of signal molecules that cause chronic inflammation, degrade the normal regenerative and tissue maintenance activities of stem cells and immune cells, induce fibrosis and other disruptions of the extracellular matrix structure important for normal tissue function, and reduce tissue elasticity, among other issues. There is evidence for many other contributions to disease progression, from calcification of arteries to buildup of fatty deposits in blood vessels to failing lung function. Ridding our bodies of these cells would produce rapid benefits in later life, a point already well illustrated in a number of animal studies.
Senescent cells present elevated activity of senescence-associated beta-galactosidase (SA-β-gal) and a persistent DNA damage response that distinguish them from other non-proliferating cell populations. In addition, senescent cells produce a variety of characteristic secreted factors, collectively termed the senescence-associated secretory phenotype (SASP), which reinforces senescence arrest in an autocrine manner and mediates immune surveillance of the senescent cells. With aging, however, senescent cells accumulate in the organism promoting local inflammation that drives tissue aging, tissue destruction, and potentially also tumorigenesis and metastasis in a cell non-autonomous manner. Recent studies have shown that elimination of senescent cells promotes stem cell proliferation and prolongs lifespan. Therefore, mechanisms that regulate the viability of senescent cells in tissues evidently play an important role in tissue homeostasis.
The senescence program is driven by a complex interplay of signaling pathways. To promote and support cell cycle arrest, p16INK4A (CDKN2A), accompanied by the p53 (TP53) target p21 (CDKN1A), inhibits cyclin-dependent kinases (CDKs), thereby preventing phosphorylation of the retinoblastoma protein (pRb) and thus in turn suppressing the expression of proliferation-associated genes. In addition, the nuclear factor kappa B protein complex (NF-κB) acts as a master regulator of SASP and therefore affects both the microenvironment of senescent cells and their immune surveillance.
Whereas mechanisms driving senescence have been extensively studied, the mechanisms allowing their prolonged retention in tissues are much less well characterized. Recently, the anti-apoptotic BCL-2 family members BCL-W, BCL-XL, and BCL-2 were shown to facilitate the resistance of senescent cells to apoptosis. However, the contribution of pathways that regulate the formation of senescent cells to the resistance of these cells to cell death has yet to be determined. On one hand, senescent cells cannot accumulate p53 protein to the levels required for apoptosis. On the other hand, the p53 target p21, via its ability to promote cell cycle inhibition, can protect some cells from apoptosis.
This effect might be governed by both p53-dependent and -independent upregulation of the pro-apoptotic protein BAX, or by activation of members of the tumor necrosis factor (TNF)-α family of death receptors, or by effects on DNA repair. We therefore set out to determine how p21 regulates the viability of senescent cells after DNA damage. We found that following p21 knockdown, senescent cells sustain multiple DNA lesions, leading to further activation of DNA damage response and NF-κB pathways. This activation was regulated by both TNF-α secretion and JNK activation, and it mediated senescent cell death in a caspase-dependent and JNK-dependent manner. Moreover, p21 knockout in mice led to the elimination of senescent cells from fibrotic scars in the liver and alleviated liver fibrosis. These results uncovered new mechanisms that control the fate of senescent cells.
In the past years, microRNAs (miRNAs) turned out to be important players in controlling aging and cellular senescence by regulating gene expression. Of note, a global decrease in miRNAs abundance was found in aging of different model organisms, suggesting aging-associated alteration of miRNAs biogenesis. In fact, aging-induced dysregulation of miRNAs biogenesis proteins is reported to promote aging and aging-associated pathologies. Among them, ribonuclease Dicer is most studied and a reduced level was reported in tissues of aged mice and rats, as well as in senescent cells.
Although the mechanisms of miRNA biogenesis have been intensively investigated in recent years, processes regulating miRNA stability remain to be explored. miRNAs have been generally considered as stable molecules with half-life of days long, while some miRNAs are actually short lived with half-life of no more than few hours. It is now clear that the absolute levels of mature miRNAs are also controlled by factors that directly affect stability. Whether miRNA stability changes during cellular senescence is so far, to our knowledge, not known. Further researches on miRNA stability and degradation mechanisms in cellular senescence and aging are needed to identify its impact on age-associated process and may provide potential new targets to interfere the process.
A number of miRNAs have been found to be differentially expressed in senescent cells or aged tissues and play a role in cellular senescence. Recently, miRNAs have been found extracellularly and function in intercellular communication upon taken up by recipient cells. The fact that circulating miRNAs are packed in the form of microvesicles protects them from degradation. The stability of miRNAs in the circulation and in body fluids, their tissue and disease specificity, and the easy and reliable quantification methods make them feasible as potential biomarkers. Several miRNAs detected in blood samples have been found in several studies to be associated with human aging. Further efforts are needed to identify consensus miRNA biomarkers not only as indicators of aging process and aging-associated disease but also as longevity predictors and eventually therapeutic approaches to modulate the aging process.
Although a relatively new field of research, miRNAs add substantial complexity to the regulation of aging processes and cellular senescence. On one side, a single miRNA can regulate the expression of hundreds of genes from different signaling pathways, which means the whole signaling network could be reset by modulating the expression of one single miRNA. In contrast, miRNAs as players of adaptive stress response could act both as promoters and inhibitors of senescence, depending on the type of stress, the cell or tissue where they are located, and the molecular context in which they play a role. Further efforts are needed to explore the modulatory role of miRNAs in cellular senescence.