If you spend much time scanning through papers of interest to the field of aging research, one of the things that may strike you about the past few years of work on senescent cells is the way in which it dovetails so well with past research of all sorts. A great deal of life science work in many parts of the broader field makes a whole lot more sense given the context of senescent cell accumulation as both (a) an important contributing cause of aging, and (b) an important source of chronic inflammation.
Yet this context wasn't missing a decade go or more - there was more than enough evidence to place senescent cell clearance into the first SENS rejuvenation research proposals, for example. It was there for anyone to recognize. But it wasn't given the weight it deserved, and too many researchers let the biochemistry of cellular senescence fade into the background, failing to consider it as a matter of importance for the mechanisms they happened to be focused upon. This is a problem, because, put simply, any condition or change in aging with a strong inflammatory component is fundamentally linked to cellular senescence. It cannot be ignored.
The paper noted here is a good example of this snug fit between older research and modern, more widespread realizations of the importance of cellular senescence. Researchers have long investigated links between cancer cells, inflammation, and platelet regulation. Platelets are a form of small cell-like structure that are primarily responsible for clotting as a way to control bleeding. They are manufactured by a fascinating process of shedding from cells known as megakaryocytes. But in this context, you might think of platelets as an abstract bundle of mechanisms by which cells can amplify inflammatory signaling to generate much larger effects on surrounding tissues and bodily systems, though that is perhaps an oversimplification.
Like all systems in cellular metabolism, the behavior of platelets runs awry in older people. Blood clotting can run amok or proceed incorrectly and fail to resolve. It turns out that the inflammatory signals from tumor cells and their relationship with platelets, categorized by interested cancer researchers over the years without giving all that much thought to cellular senescence, are probably very relevant to the activities of senescent cells as well. Senescent cells are the missing third leg for the stool portrayed in this picture, and platelets may be an important part of the bigger picture for cellular senescence and cancer risk in aging.
The functional connection between cancer and platelets has been recognized since the late nineteenth century, when an association between the occurrence of certain solid tumors and the development of venous thrombosis and blood hypercoagulability was first described. Accordingly, defects in platelet function or reduced platelet counts have both been associated with a reduced ability of tumors to metastasize. We now know that platelets may contribute to the establishment of various hallmarks of cancer, including the ability of cancer cells to sustain proliferation, to resist apoptosis and to promote angiogenesis and metastasis. It is presently unclear, however, to what extent these contributions are the result of a direct action of platelets on tumor cells or, alternatively, may be part of an underlying inflammatory process inherent to many tumors. Inflammatory cells and soluble mediators of inflammation are important constituents of the tumor microenvironment.
Typical hallmarks of physiological aging include impaired tissue regeneration and repair, a functional impairment of progenitor cellsalterations of the immune system. While the specific cellular changes associated with each one of these hallmarks will vary depending on the tissue analyzed, cellular senescence is rapidly emerging as an underlying process that may help explain some of these changes. In keeping with this idea, senescent cells accumulate in several tissues derived from aged animals. In addition to cell cycle arrest, the establishment of a mature senescent phenotype involves extensive metabolic reprograming, as well as the implementation of complex traits such as the senescence-associated secretory phenotype (SASP). The SASP refers to the almost universal capacity of senescent cells to produce and secrete a variety of soluble and insoluble factors, including extracellular proteases, cytokines, chemokines, and growth factors.
A common feature of aging and age-related diseases is chronic inflammation. The term "inflammaging" has been coined to describe a low-grade, chronic, and systemic inflammation associated with aging and aging phenotypes in the absence of evidence of infection. In line with this concept, many of the factors secreted by senescent cells are also well-known pro-inflammatory molecules with the potential to induce chronic inflammation in certain biological contexts. More recently, a unique type of inflammation triggered by senescent cells, the senescence-inflammatory response, has been identified.
Based on the emerging physiological and pathological processes in which the SASP might be involved, it is conceivable that senescent cells may also affect hemostasis through mechanisms that include, but are not limited to, changes in the production and functional status of platelets. As mentioned elsewhere in this review, IL-6 is one of the most prominent pro-inflammatory cytokines present in the SASP. Moreover, IL-6 upregulates the synthesis of hemostatic factors, such as fibrinogen, and may also directly activate platelets.
Thus, it is tempting to speculate that the high levels of IL-6 (and other pro-inflammatory factors, such as IL-1β and TNF-α) detected in aged individuals could reflect, at least in part, an increased rate of secretion of this cytokine by senescent cells - or by other cells responding to senescent cells - in the context of a senescence-induced chronic inflammation. An age-dependent increase of pro-inflammatory factors would, in turn, contribute to platelet activation and a higher proclivity to thrombus formation. Therefore, we postulate that cellular senescence (as a result of physiological aging or secondary to therapeutic stress) might play an important role in the regulation of platelet function. By regulating the activation of platelets, senescent cells could provide yet another mechanism contributing to the higher prevalence of chronic inflammation (and cancer) in aged individuals.
The functional interaction between cancer cells and platelets has been well established. Most of the efforts aimed to clarify these interactions have been focused on the ability of tumor cells (or tumor-associated stromal cells) to produce and secrete pro-inflammatory factors that can result in the activation of platelets. Active platelets - acting synergistically with other components of the tumor stroma - can then promote or enhance tumor progression and metastasis. Paradoxically, many of the factors secreted by tumor cells or tumor-associated inflammatory cells with a known effect on platelet activity are also produced and secreted by cells undergoing senescence, a process originally regarded as tumor suppressive. Indeed, the evidence indicates that cellular senescence may also play an active role in driving, rather than suppressing, tumor formation, a non-cell autonomous role that seems to be largely dependent on the SASP. Accordingly, factors released by senescent cells may help create a pro-tumorigenic microenvironment that enhances proliferation and migration of neighbor cells. Although still controversial, this model would be in line with the observation that the prevalence of most cancers increases with age.
Alterations in hemostasis involving platelet dysfunction or alterations in the process of fibrinolysis are at the core of thrombogenesis. As with cancer, thrombogenesis is most commonly observed in older individuals, who presumably harbor a higher proportion of senescent cells in their tissues. We, therefore, postulate that cellular senescence, either as a result of normal aging or secondary to stress, could play an important role in the regulation of platelet function. According to this model, senescent cells have the ability to modify the microenvironment in ways that may enhance tumorigenesis. Similarly, senescent cells might also regulate the activity of platelets, the process of fibrinolysis, or both. By regulating the activation of platelets, senescent cells may provide yet another mechanism to enhance tumorigenesis. Whether or not these circuits are relevant to tumorigenesis and/or thrombogenesis remains to be fully elucidated.