The authors of today's open access research offer an interesting viewpoint on cellular senescence in the context of cancer, presenting it as an aspect of the innate immune response to the signs of cancer-inducing mutational damage, or to the signs of cancer suppression programs operating in cells. The objective of the body's numerous, layered defenses against cancer is to destroy all cells that show the signs of becoming cancerous. The first line of defense is the state of cellular senescence, in which cells shut down their ability to replicate, prime themselves to self-destruct via the programmed cell death path of apoptosis, and alert the immune system via a mix of inflammatory secretions known as the senescence-associated secretory phenotype (SASP). These secretions also raise the odds of other surrounding cells becoming senescent, which in theory helps to stay ahead of the replication of an early cancer.
Cellular senescence in this context of cancer is likely an adaptation of an existing tool. Transient cellular senescence occurs during embryonic growth and wound healing, a way to help guide structure and regeneration. That it can also help to shut down early stage cancer has the look of a later development. Unfortunately cellular senescence is an imperfect tool: senescent cells are not reliably removed by the immune system, and they do not reliably self-destruct. Some tiny fraction linger, and their continued inflammatory secretions are an important contributing cause of aging and age-related disease.
In recent years, the research community has found ways to selectively destroy a fraction of the senescent cells present in old tissues. This approach to the treatment of aging reliably extends life span and reverses numerous age-related diseases in mice. Numerous companies are working on ways to destroy senescent cells, and the first therapies are entering human trials. Meanwhile, ever more funding is flowing towards fundamental research into the biochemistry of senescence, as there are likely many more potential approaches to the destruction or management of senescent cells yet to be discovered. This point is illustrated well in the open access paper here, as the authors propose a new point of intervention based on their research.
The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype
We describe here an essential innate immune signaling pathway in oncogene-induced senescence (OIS) established between TLR2 and acute-phase serum amyloid A1 and serum amyloid A2 (A-SAAs) that initiates the senescence-associated secretory phenotype (SASP) and reinforce cellular senescence in vitro and in vivo. We also identify new important SASP components, A-SAAs, which are the senescence-associated damage-associated molecular patterns (DAMPs) sensed by TLR2 after oncogenic stress. Therefore, we are reporting that innate immune sensing is critical in senescence. We propose that cellular senescence shares mechanistic features with the activation of innate immune cells and could be considered a program of the innate immune response by which somatic cells switch their regular role to acquire an immune function under certain conditions of stress and danger, for instance, upon oncogene activation.
Besides revealing a role for TLR2 in SASP induction and cell cycle regulation, we identified the DAMP that activates TLR2 in OIS. Acute-phase proteins SAA1 and SAA2 act to prime the TLR2-mediated inflammasome, and in turn, their full induction depends on TLR2 function. Hence, they establish a foundational feedback loop that controls the SASP. A-SAAs are systemically produced in the liver and released into the bloodstream during an acute inflammatory response. Our identification of these molecules as mediators of senescence suggests that systemic elevation of A-SAAs might have an impact on the accumulation of senescent cells and the activation of their proinflammatory program at the organismal level.
We found activation of TLR2 expression in parallel to A-SAAs in models of OIS in mice, in inflammation-induced senescence, in aging, and in different in vitro systems of senescence. Also, we have shown that TLR2 controls the activation of the SASP and OIS in vivo. Moreover, we have observed a dose-dependent effect for TLR2 in A-SAA sensing and a role for TLR2 in SASP activation during paracrine senescence. Together, these data suggest that systemic A-SAA elevation during acute inflammation could affect cells expressing TLR2, thereby promoting aging and other pathological roles of senescence. Further investigation may reveal additional physiological circumstances under which senescence is induced or reinforced by the interaction of TLR2 with A-SAAs or indeed with other endogenous DAMPs or exogenous pathogen-associated molecular patterns (PAMPs) from the microbiome. These circumstances could have implications for organismal well-being, in particular, the development of aging and cancer.
In recent years, several strategies have been implemented to eliminate senescent cells or to modulate the activation of the SASP in anti-aging and cancer therapies (senotherapies). For example, genetic targeting for the elimination of senescent cells can delay organismal aging and aging-associated disorders. Furthermore, the pharmacological suppression of the SASP has been shown to improve homeostasis in tissue damage and aging. However, most of these manipulations are directed to essential homeostatic regulators such as mTOR or crucial proinflammatory mediators such as IL-1 signaling. Here, we propose the alternative of manipulating A-SAA-TLR2 as a new rationale for senotherapies aiming to manipulate nonessential and senescence-specific signaling pathways.
View the full article at FightAging
