Fight Aging!

Many of the approaches to selective cell destruction pioneered in the cancer research community distinguish target cells from bystander cells via cell surface markers. Do senescent cells have a sufficiently distinct set of surface markers to safely employ this strategy to reduce the burden of cellular senescence in old tissue, and thereby produce rejuvenation of tissue function? Almost certainly yes, as the immune system uses exactly this approach to identify and kill senescent cells. Identifying the surface markers involved is a plausible goal, presently underway. Several biotech companies work on forms of senolytic immunotherapy, based on the present state of knowledge regarding senescent cell surface features. The open access paper noted here discusses this topic in more depth.

Cellular senescence is a phenotype associated with limited replicative capacity and irreversible growth arrest of primary cells first described in the early 1960s. Senescent cells are characterized by specific phenotypical features including enlarged and flattened cell morphology, enhanced lysosomal beta-galactosidase activity, increased expression of cell cycle inhibitors (p21Cip1/Waf1, p16Ink4A, p15Ink4B, and p53), and high metabolic activity including GSK3, AMPK, and mTOR pathways. In this regard, senescent cells differ from quiescent cells, which instead display a reversible cell cycle arrest and are characterized by a low metabolic status, a decrease in glucose uptake, and a reduction in mRNA translation.

Senescent cells arise in culture and in tissues following a variety of damaging insults such as DNA damage, oxidative stress, telomere shortening, mitochondrial dysfunction, and aberrant activation of oncoproteins. Besides the role of damaging agents, cellular senescence may also be induced by physiological stimuli including developmental and repair signals. Therefore, transiently-induced senescence plays a beneficial role in physiological events such as organogenesis, tissue homeostasis, and wound repair. Furthermore, the upregulation of cell cycle inhibitors in senescent cells plays a crucial role in their ability to suppress the development of cancer, thus senescence is considered as a tumor-suppressor phenotype.

Alongside the beneficial roles associated with transiently-induced senescence, the accumulation of senescent cells exerts detrimental effects on the functionality of tissues and organs. Indeed, the active metabolism of senescent cells drives the production of several members of cytokines, chemokines, growth factors, and proteases collectively known as senescence-associated-secretory-phenotype (SASP). Members of SASP include pro-inflammatory cytokines and chemokines such as IL-6, IL-8, and matrix degrading enzymes like MMP-1, MMP-3, and MMP-10. The release of such molecules in the cellular microenvironment induces a pro-inflammatory milieu, therefore leading to immune cell recruitment with the reinforcement of inflammation, paracrine senescence, tissue remodeling, and tissue degeneration.

Cellular senescence is one of the processes contributing to aging. With aging, senescent cells accumulate in the body tissues and associate with age-related pathologies, which include, among others, neurodegenerative diseases (Alzheimer's disease, Parkinson's disease), atherosclerosis, type 2 diabetes, tissue fibrosis, and cancer. Given the role of senescence in aging and age-associated diseases, there is a growing interest in developing approaches in order to target senescent cells. Much of this effort is focused on the development of strategies aimed at the clearance of senescent cells in vivo to reduce their accumulation and the subsequent alterations in tissue functionality. Here, we review the main approaches used to identify senescent cells in vitro and in vivo, with a focus on novel biomarkers of cellular senescence localized on the cell surface. We discuss the roles of surface proteins in SASP production and in the regulation of immune surveillance. Finally, we highlight the main therapeutic approaches that can be adopted to eliminate senescent cells in vivo by pharmacological and genetic approaches, with a focus on targeting the senescent surfaceome.

Link: https://doi.org/10.3390/cells10071740