Impact of senescence‐associated secretory phenotype and its potential as a therapeutic target for senescence‐associated diseases

Abstract

“Cellular senescence” is a state in which cells undergo irreversible cell cycle arrest in response to a variety of cellular stresses. Once cells senesce, they are strongly resistant to any mitogens, including oncogenic stimuli. Therefore, cellular senescence has been assumed to be a potent anticancer mechanism. Although irreversible cell‐cycle arrest is traditionally considered the major characteristic of senescent cells, recent studies have revealed some additional functions. Most noteworthy is the increased secretion of various secretory proteins, such as inflammatory cytokines, chemokines, growth factors, and MMPs, into the surrounding extracellular fluid. These newly recognized senescent phenotypes, termed senescence‐associated secretory phenotypes (SASPs), reportedly contribute to tumor suppression, wound healing, embryonic development, and even tumorigenesis promotion. Thus, SASPs appear to be beneficial or deleterious, depending on the biological context. As senescent cells are known to accumulate during the aging process in vivo, it is quite possible that their accumulation in aged tissues promotes age‐associated functional decline and various diseases, including cancers, at least to some extent. Here, we focus on and discuss the functional and regulatory network of SASPs toward opening up new possibilities for controlling aging and aging‐associated diseases.

Elimination of p19ARF‐expressing cells protects against pulmonary emphysema in mice

“…Senescent cells secrete a series of chemokines and cytokines, thereby promoting the infiltration of macrophages and other immune cells for their clearance; however, this action may also result in adverse effects by inducing local inflammation (Coppé, Desprez, Krtolica, & Campisi, 2010). SASP appears to elicit deleterious effects in several disease models (He & Sharpless, 2017; Watanabe et al, 2017), and its inhibition was shown to be sufficient for preventing senescence‐induced bone loss (Farr et al, 2017). Thus, SASP appears to accelerate alveolar macrophage accumulation upon PPE challenge and the release of tissue‐destructive enzymes, including MMP‐12, which ultimately leads to alveolar collapse.…”

“…Senescent cells accumulate in several tissues during aging in humans and mice (Dimri et al, 1995; Krishnamurthy et al, 2004) and are considered to contribute to tissue aging and aging‐associated disorders through their cell nonautonomous functions (Freund, Orjalo, Desprez, & Campisi, 2010; Watanabe, Kawamoto, Ohtani, & Hara, 2017). Recent studies using transgenic mice designed to eliminate senescent cells from tissues by sensitizing them to specific drugs have more clearly elucidated the roles of senescent cells in tissue aging and disease.…”

Hepatocyte expression and prognostic importance of senescence marker p21 in liver histopathology samples from dogs with chronic hepatitis

“…In addition to the well‐known effects on cell cycle regulation, accumulating evidence suggests that senescent cells also secrete an array of pro‐inflammatory cytokines, chemokines and proteases, including TNF‐α, IL‐6, and metalloproteinases 31, 32, 33, 34. This senescence‐associated secretory phenotype (SASP) is thought to result in various autocrine and paracrine effects which have the potential to significantly alter cellular function 11.…”

“…This senescence‐associated secretory phenotype (SASP) is thought to result in various autocrine and paracrine effects which have the potential to significantly alter cellular function 11. Furthermore, additional deleterious roles of the SASP in modulation of the extracellular matrix, causation of inflammatory diseases, and promotion of oncogenic transformation in neighboring cells have been suggested 10, 33, 34, 35, 36. These findings consequently raise questions regarding the cause and effect relationship between cellular senescence and inflammatory diseases, such as CH.…”

Beneficial and Detrimental Effects of Antiretroviral Therapy on HIV-Associated Immunosenescence

“…Cellular senescence can be triggered by numerous mechanisms, including critical telomere shortening due to repeated cell divisions, stressors such as hypoxia, accumulation of reactive oxygen species (ROS), oncogenic stimuli [12] and altered p53/p21 or p16 INK4a /retinoblastoma (Rb) tumour suppressor pathways [13]. Senescence also induces the onset of a senescence-associated secretory phenotype [10, 13] that is related to increased production of inflammatory cytokines, including interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), chemokines, extracellular matrix remodelling agents, and growth factors [14]. …”