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.

Keywords: aging; cellular senescence; evolutionary biology; molecular biology of aging; molecular damage; theories of aging; wound healing.

FIGURE 1

The concept of cellular aging. (A) The lifespan curve of primary cells in culture. After the culture establishment, cells enter into a phase characterized by exponential growth, which is followed by induction of senescence and a decline in growth rate. The final stage is a post‐senescence continuation of cellular aging and degradation of cell population. The graph simplifies cellular aging and does not show the transition gradient. (B) Cellular aging is a gradual process, which reduces cell functionality and increases risk of cell death over time. (*) The changes in the risk of death are unlikely to be linear, for example, cells shortly after senescence induction might be less prone to death than younger cells

FIGURE 2

Phenotypical changes observed within aging cells. With progression of cellular aging, cells experience a gradual transition from the balanced state of coordinated growth and proliferation, to the state where soma growth dominates over proliferation. That occurs in parallel to metabolic shifts, reduction in NAD⁺, intracellular damage accumulation, and telomere shortening

FIGURE 3

The concept of cellular aging in vivo. Cells found in tissues of aging animals are at different stages of cellular aging, thus showing markers associated with cellular senescence before the establishment of the cell cycle arrest. In addition, senescent cells in vivo might show different levels of senescence markers as cellular aging progresses even after senescence induction and cells continue changing over time until death