Is "cellular senescence" a misnomer?

Abstract

One of the most striking findings in biogerontology in the 2010s was the demonstration that elimination of senescent cells delays many late-life diseases and extends lifespan in mice. This implied that accumulation of senescent cells promotes late-life diseases, particularly through action of senescent cell secretions (the senescence-associated secretory phenotype, or SASP). But what exactly is a senescent cell? Subsequent to the initial characterization of cellular senescence, it became clear that, prior to aging, this phenomenon is in fact adaptive. It supports tissue remodeling functions in a variety of contexts, including embryogenesis, parturition, and acute inflammatory processes that restore normal tissue architecture and function, such as wound healing, tissue repair after infection, and amphibian limb regeneration. In these contexts, such cells are normal and healthy and not in any way senescent in the true sense of the word, as originally meant by Hayflick. Thus, it is misleading to refer to them as "senescent." Similarly, the common assertion that senescent cells accumulate with age due to stress and DNA damage is no longer safe, particularly given their role in inflammation-a process that becomes persistent in later life. We therefore suggest that it would be useful to update some terminology, to bring it into line with contemporary understanding, and to avoid future confusion. To open a discussion of this issue, we propose replacing the term cellular senescence with remodeling activation, and SASP with RASP (remodeling-associated secretory phenotype).

Keywords: Aging; Cellular senescence; Fibroblast; Osteoarthritis; Remodeling activation; Remodeling-associated secretory phenotype (RASP).

Fig. 1

Rethinking cellular senescence. A Traditional conception of cellular senescence. Damage to cells causes exit from the cell cycle and abnormal behavior (hypertrophy, hypersecretion) that contributes to aging pathology, particularly through action of the SASP (senescence-associated secretory phenotype). B Revised view. Remodeling activation (an alternative descriptor for cellular senescence) supports multiple tissue remodeling functions, including embryogenesis, acute inflammation (including wound healing) and tissue homeostasis, particularly through action of the RASP (repair-associated secretory phenotype). Such cells are healthy and useful, and not senescent in any true sense of the word. In later life, futile remodeling quasi-programs, including chronic sterile inflammation, contribute to aging pathology [9]. Here, RASP becomes pathogenic, e.g., due to chronic secretion. Developmental cues include those directing restoration of tissue architecture after injury [33]