LAUSR

Senescence is a fundamental cellular mechanism that has received increasing attention in recent years as a potentially important contributor to developmental, physiological and pathological processes including aging [1]. The term was initially proposed by Hayflick andMoorhead in 1961 to describe the limited proliferative capacity of cultured normal human fibroblasts [2]. After completing a finite number of divisions, these cells entered a state of permanent growth arrest without dying, termed replicative senescence (RS) [1]. It is nowadays well-established that RS relies on telomere shortening following several cell replication events; however, various other stimuli can induce senescence. Stress-induced premature senescence (SISP) is induced independently of telomere length and occurs in response to a variety of stress signals, such as oncogene activation (oncogene-induced senescence, OIS), oxidative stress (oxidative stress-induced senescence), DNA damage, and others [1, 3]. Irrespective of the type of stimulus, senescence is characterized by programmed cell cycle arrest, resistance to apoptosis, metabolic activity, and modified cellular function [1, 3]. Senescent cells exhibit a set of core morphological and biochemical features that distinguish them from other non-dividing cells. However, none of these features is specific or universal. Senescent cells are characterized by large size, activation of cell cycle inhibitors (CDKN2A locus and p21) and often DNA damage markers, nuclear heterochromatin foci (SAHFs), increased lysosomal senescence-associated β-galactosidase (SA-β-Gal) activity at pH 6, and acquisition of a pro-inflammatory, proteolytic secretome, known as senescent-associated secretory phenotype (SASP) or senescence-messaging secretome [1, 3]. SASP consists of a complex mixture of secreted cytokines, chemokines, growth factors, and proteases. Additional features, such as discontinuous nuclear lamina due to loss of lamin B1, telomere-associated foci, and senescenceassociated heterochromatin foci, have recently been proposed [4, 5]. The accumulation of lipofuscin was initially observed in aged post-mitotic cells, implying a direct link with accumulating stress or damage that occurs with age and has been experimentally proven as a hallmark of senescence [4]. It is an intralysosomal, polymeric substance composed of crosslinked oxidized proteins/lipoproteins, oxidized lipids, sugars, and metals. Lipofuscin is undegradable and cannot be removed via exocytosis; therefore, it accumulates in cells that undergo cell cycle arrest, whereas proliferating ones dilute it out while dividing [4, 5]. Cellular senescence may have both beneficial and deleterious implications. During development and normal adult life, senescence is temporarily activated (acute senescence) in order to preserve cell/tissue homeostasis, similarly to apoptosis. In this context, elimination of senescent cells by the immune system ensures normal embryonic morphogenesis and proper tissue remodeling in adults, the latter by withdrawal of injured cells [1, 3]. In contrast, accumulation of senescent cells in tissues with age (chronic senescence), due to persistent injury and/or reduction in damaged cell removal (immune aging), may have detrimental effects. Indeed, various reports denote the role of chronic senescence in the development and progression of age-related diseases and aging [1, 3]. In early stages of carcinogenesis, cellular senescence as a stress-responsive cell cycle arrest program acts as a tumor barrier terminating the expansion of malignant cells [6]. In advanced stages, the SASP can stimulate in a paracrine * Dina Tiniakos [email protected]; [email protected]