Downregulation of the inflammatory network in senescent fibroblasts and aging tissues of the long‐lived and cancer‐resistant subterranean wild rodent, Spalax

Abstract

The blind mole rat (Spalax) is a wild, long-lived rodent that has evolved mechanisms to tolerate hypoxia and resist cancer. Previously, we demonstrated high DNA repair capacity and low DNA damage in Spalax fibroblasts following genotoxic stress compared with rats. Since the acquisition of senescence-associated secretory phenotype (SASP) is a consequence of persistent DNA damage, we investigated whether cellular senescence in Spalax is accompanied by an inflammatory response. Spalax fibroblasts undergo replicative senescence (RS) and etoposide-induced senescence (EIS), evidenced by an increased activity of senescence-associated beta-galactosidase (SA-β-Gal), growth arrest, and overexpression of p21, p16, and p53 mRNAs.Yet, unlike mouse and human fibroblasts, RS and EIS Spalax cells showed undetectable or decreased expression of the well-known SASP factors: interleukin-6 (IL6), IL8, IL1α, growth-related oncogene alpha (GROα), SerpinB2, and intercellular adhesion molecule (ICAM-1). Apparently, due to the efficient DNA repair in Spalax, senescent cells did not accumulate the DNA damage necessary for SASP activation. Conversely, Spalax can maintain DNA integrity during replicative or moderate genotoxic stress and limit pro-inflammatory secretion. However, exposure to the conditioned medium of breast cancer cells MDA-MB-231 resulted in an increase in DNA damage, activation of the nuclear factor κB (NF-κB) through nuclear translocation, and expression of inflammatory mediators in RS Spalax cells. Evaluation of SASP in aging Spalax brain and intestine confirmed downregulation of inflammatory-related genes. These findings suggest a natural mechanism for alleviating the inflammatory response during cellular senescence and aging in Spalax, which can prevent age-related chronic inflammation supporting healthy aging and longevity. K E Y W O R D S cellular senescence, DNA damage, DNA repair, interleukin-1 alpha (IL1α), nuclear factor κB (NF-κB), senescence-associated secretory phenotype (SASP), Spalax S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Odeh A, Dronina M, Domankevich V, Shams I, Manov I. Downregulation of the inflammatory network in senescent fibroblasts and aging tissues of the longlived and cancer-resistant subterranean wild rodent, Spalax.

Translation of Cellular Senescence to Novel Therapeutics: Insights From Alternative Tools and Models

“…Moreover, a recent study showed that replicative senescence in BMR fibroblasts was manifested by the increased activity of SA-β-gal and overexpression of p16, p21, and p53 mRNA expressions ( Odeh et al, 2020 ). Suprisingly, in senescent BMR fibroblasts, SASP, as one of the important features of CS, was found to be undetectable or decreased unlike senescent human and mouse fibroblasts ( Odeh et al, 2020 ).…”

Targeting Senescent Cells for a Healthier Aging: Challenges and Opportunities

“…[22,83] A natural but distinct mechanism responsible for dampened inflammatory response during cellular senescence (particularly replicative senescence and therapy-induced senescence) and aging in Spalax was recently discovered, providing a rationale for developing senolytic agents that act through the immune system. [84] Although senescent cells can chemo-attract various immune cell types, a process promoting senescent cell clearance by the immune components, many studies have suggested that senescent cells can also circumvent innate and adaptive immune responses. Therapeutics enhancing immune-potentiated clearance of senescent cells include but are not limited to vaccines and small molecule immune modulators.…”

Nontraditional systems in aging research: an update

“…Because the occurrence of necrosis was abolished by targeting p53 and pRb by simian SV40 large T antigen, these two tumor suppressors emerged as critical for growth cessation of BMR fibroblasts [ 172 ]. Replicative senescence in BMR-derived fibroblasts was manifested by the cytosolic activity of SA-β-Gal and the overexpressed mRNA for p16, p21, and p53 [ 174 ]. Importantly, the termination of the replicative capabilities of these cells was not associated with any loss of telomeric DNA, plausibly due to the high activity of telomerase.…”

“…Very recent studies provided another explanation for BMR cancer resistance based on a unique feature of their cells. Namely, senescent fibroblasts appeared to be negative for one of the most procancerous traits seen in human somatic cells, which is the senescence-associated secretory phenotype (SASP) [ 174 ]. SASP refers to the ability of senescent cells to overproduce multiple cytokines (e.g., IL-1, IL-6), chemokines (e.g., IL-8, MCP-1, GRO-1, SDF-1), growth factors (e.g., TGF-β, VEGF, heregulin), and extracellular matrix (ECM) resysteming agents (e.g., PAI-1, -2, tPA, uPA) that promote various steps in tumor progression, including adhesion, proliferation, migration, invasion, epithelial–mesenchymal transition (EMT), and angiogenesis [ 176 ].…”

“…SASP refers to the ability of senescent cells to overproduce multiple cytokines (e.g., IL-1, IL-6), chemokines (e.g., IL-8, MCP-1, GRO-1, SDF-1), growth factors (e.g., TGF-β, VEGF, heregulin), and extracellular matrix (ECM) resysteming agents (e.g., PAI-1, -2, tPA, uPA) that promote various steps in tumor progression, including adhesion, proliferation, migration, invasion, epithelial–mesenchymal transition (EMT), and angiogenesis [ 176 ]. Senescent BMR cells possess undetectable or decreased expression of several SASP proteins, such as IL-6, IL-8, GRO-1, and ICAM-1, which indicates that in contrast to senescent human somatic cells [ 177 ], they are unable to support tumor growth [ 174 ].…”