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.

Keywords: Aging; DNA damage response; immune response; senescence; tumorigenesis.

Figure 1

Overview of cellular senescence characterized by permanent cell‐cycle arrest and the senescence‐associated secretory phenotype (SASP). A variety of stimuli can lead to cellular senescence by the activation of retinoblastoma protein (pRB) through the upregulation of cyclin‐dependent kinase inhibitors (CDKIs), followed by the inactivation of cyclin‐dependent kinases. Senescent cells are characterized by irreversible cell‐cycle arrest and paracrine activity of the SASP. DDR, DNA damage response; ROS, reactive oxygen species.

Figure 2

Dual roles of senescence‐associated secretory phenotype (SASP) in cellular senescence. SASP could have beneficial or detrimental outcomes in physiological and pathological processes during aging.

Figure 3

Multilevel control of senescence‐associated secretory phenotype (SASP) induction in cellular senescence. The expression of SASP factors is upregulated by multilevel control mechanisms, including transcriptional activation, stabilization of transcripts, and chromatin remodeling. Persistent DNA damage response (DDR) signaling could induce SASP without p53‐dependent signaling related to senescent growth arrest. ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia and Rad3‐related; BRD4, bromodomain‐containing protein 4; CEBPβ, CCAAT/enhancer binding protein‐β; GATA4, GATA binding protein 4; HMGB2, high mobility group box 2; IL, interleukin; MK2, MAPK‐activated protein kinase 2; MLL1, mixed lineage leukemia 1; mTOR, mammalian target of rapamycin; NF‐κB, nuclear factor‐κB; PcG, polycomb group protein.42

Figure 4

Strategies for the elimination of senescent cells. (a) Senolytic drugs ABT263/ABT737 induce apoptosis by inhibiting the B‐cell lymphoma 2 (Bcl‐2) family proteins, which confer resistance to apoptosis in senescent cells. Bclxl, B‐cell lymphoma–extra large; DDR, DNA damage response. (b) Immune system‐mediated clearance could be used to kill senescent cells. Antibodies against secretory factors could also block the “function” of senescence (see figure 5). CAR, chimeric antigen receptor; NK, natural killer; PD‐1, programmed cell death protein 1.

Figure 5

Strategies for senescence‐associated secretory phenotype (SASP) attenuation. SASP factors could be blocked by targeting its induction (e.g., nuclear factor‐κB [NF‐κB] inhibitor, mammalian target of rapamycin [mTOR] inhibitor, or bromo and extra terminal domain [BET] inhibitor) or its activity (e.g., interleukin [IL]‐1 receptor antagonist, anti‐IL‐6 receptor antibody, IL‐6 inhibitor, or tumor necrosis factor‐α inhibitor).