Cellular aging beyond cellular senescence: Markers of senescence prior to cell cycle arrest in vitro and in vivo

Abstract

The field of research on cellular senescence experienced a rapid expansion from being primarily focused on in vitro aspects of aging to the vast territories of animal and clinical research. Cellular senescence is defined by a set of markers, many of which are present and accumulate in a gradual manner prior to senescence induction or are found outside of the context of cellular senescence. These markers are now used to measure the impact of cellular senescence on aging and disease as well as outcomes of anti‐senescence interventions, many of which are at the stage of clinical trials. It is thus of primary importance to discuss their specificity as well as their role in the establishment of senescence. Here, the presence and role of senescence markers are described in cells prior to cell cycle arrest, especially in the context of replicative aging and in vivo conditions. Specifically, this review article seeks to describe the process of “cellular aging”: the progression of internal changes occurring in primary cells leading to the induction of cellular senescence and culminating in cell death. Phenotypic changes associated with aging prior to senescence induction will be characterized, as well as their effect on the induction of cell senescence and the final fate of cells reviewed. Using published datasets on assessments of senescence markers in vivo, it will be described how disparities between quantifications can be explained by the concept of cellular aging. Finally, throughout the article the applicational value of broadening cellular senescence paradigm will be discussed.

Regulation of Cellular Senescence Is Independent from Profibrotic Fibroblast-Deposited ECM

“…This could implicate, in the context of senescence, that fibroblasts need prolonged exposure to an altered ECM before they make this adaptation. There is evidence suggesting that the upregulation of proinflammatory cytokines may precede the induction of cell-cycle inhibitors p21 Waf1/Cip1 and p16 Ink4a in senescence, as reflected in this study [ 40 ]. Moreover, as IPF is a multifactor disease, a secondary stimulant such as reactive oxygen species (ROS) leading to DNA damage, pathological stiffness might be needed to create an environment that favours cellular senescence.…”

Chromosome Instability, Aging and Brain Diseases

“…Focusing on cellular senescence has revealed the tight connection to cell cycle regulation, neuronal cell death and genome stability maintenance in the aged brain [61,62]. Furthermore, aging-related mechanisms for neurodegeneration have the potential to lead both to CIN and cellular senescence [63,64]. As systematically shown, cell senescence is linked to genome instability/CIN and neuronal cell death [31,65,66].…”

“…It is more likely that genetic-environmental interactions may help to inhibit CIN or eliminate affected cells at early stages of aging and/or disease [71,73]. A candidate process for these interactions would be mitotic/cell cycle regulation, programmed cell death and cellular senescence [49,53,59,60,64]. For instance, the analysis of DNA damage response in neurons shows the possibility of switching between programmed cell death (apoptosis) and a pseudo-stationary cellular state (senescence-like state) [31].…”

Role of Melatonin in Angiotensin and Aging

“…There is significant evidence which suggests that telomeres are the most common targets for cell senescence and chronic DNA damage response in aging, while failure to maintain a minimum telomere length triggers cell replicative senescence [ 18 , 19 ]. Differences in telomere length have been linked to different diseases such as dyskeratosis congenita and liver cirrhosis.…”