Emerging Therapeutic Approaches to Target the Dark Side of Senescent Cells: New Hopes to Treat Aging as a Disease and to Delay Age-Related Pathologies

Abstract

Life expectancy has drastically increased over the last few decades worldwide, with important social and medical burdens and costs. To stay healthy longer and to avoid chronic disease have become essential issues. Organismal aging is a complex process that involves progressive destruction of tissue functionality and loss of regenerative capacity. One of the most important aging hallmarks is cellular senescence, which is a stable state of cell cycle arrest that occurs in response to cumulated cell stresses and damages. Cellular senescence is a physiological mechanism that has both beneficial and detrimental consequences. Senescence limits tumorigenesis, lifelong tissue damage, and is involved in different biological processes, such as morphogenesis, regeneration, and wound healing. However, in the elderly, senescent cells increasingly accumulate in several organs and secrete a combination of senescence associated factors, contributing to the development of various age-related diseases, including cancer. Several studies have revealed major molecular pathways controlling the senescent phenotype, as well as the ones regulating its interactions with the immune system. Attenuating the senescence-associated secretory phenotype (SASP) or eliminating senescent cells have emerged as attractive strategies aiming to reverse or delay the onset of aging diseases. Here, we review current senotherapies designed to suppress the deleterious effect of SASP by senomorphics or to selectively kill senescent cells by “senolytics” or by immune system-based approaches. These recent investigations are promising as radical new controls of aging pathologies and associated multimorbidities.

From the Sun to the Cell: Examining Obesity through the Lens of Vitamin D and Inflammation

“…Several studies have shown that TLR signaling may have a direct impact on pathways related to cellular senescence [ 91 ], such as the activation of the NF-κB pathway [ 92 ]. Furthermore, SASP has the potential to induce further stimulation of TLRs, thereby establishing a feedback loop that amplifies both ageing-related changes and inflammation [ 93 ].…”

Targeting tumor suppressor p53 for organ fibrosis therapy

“…Several studies have pointed out that the senescent hepatocytes produce more SASP factors to promote HSC activation and hepatic fibrosis [ 83 ]. While the senescent activated HSCs remain metabolically active, exert an anti-fibrosis effect by reducing ECM components biosynthesis [ 84 ].…”

Translating the Biology of Aging into New Therapeutics for Alzheimer’s Disease: Senolytics

“…Senomorphics are currently under development to lower this inflammatory burden. Numerous signaling pathways, such as cyclooxygenase 2 (COX-2), mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK) signaling, phosphoinositide 3 kinase (PI3K), and the GATA4/p62-mediated autophagy pathways result in the stimulation of NF-κB and/or C/EBPβ pathways, which in turn regulate the SASP secretome ( 81 , 82 ). This convergence renders the NF-κB and C/EBPβ pathways promising drug targets for the modulation of the SASP.…”

“…The p38MAPK inhibitor SB203580, by decreasing the transcriptional activity of NF-κB, has been shown to reduce the levels of mRNA of genes of SASP factors in human senescent cells ( 81 ). Similarly, next-generation p38MAPK inhibitors UR-13756 and BIRB 796 inhibited IL-6 expression in human senescent fibroblasts, demonstrating their effectiveness in reducing SASP-related effects ( 93 ).…”