Hallmarks of senescence and aging

Abstract

The complex process of biological aging, as an intrinsic feature of living beings, is the result of genetic and, to a greater extent, environmental factors and time. For many of the changes taking place in the body during aging, three factors are important: inflammation, immune aging and senescence (cellular aging, biological aging). Senescence is an irreversible form of long-term cell-cycle arrest, caused by excessive intracellular or extracellular stress or damage. The purpose of this cell-cycles arrest is to limit the proliferation of damaged cells, to eliminate accumulated harmful factors and to disable potential malignant cell transformation. As the biological age does not have to be in accordance with the chronological age, it is important to find specific hallmarks and biomarkers that could objectively determine the rate of age of a person. These biomarkers might be a valuable measure of physiological, i.e. biological age. Biomarkers should meet several criteria. For example, they have to predict the rate of aging, monitor a basic process that underlies the aging process, be able to be tested repeatedly without harming the person. In addition, biomarkers have to be indicators of biological processes, pathogenic processes or pharmacological responses to therapeutic intervention. It is considered that the telomere length is the weak biomarker (with poor predictive accuracy), and there is currently no reliable biomarker that meets all the necessary criteria.

Keywords: aging; biomarkers; hallmarks; senescence.

Figure 1

Overview of the process of senescence and its contribution to aging of entire organism (adapted according to references , and 11). Based on kinetics of cell senescent processes there are two main categories of senescence – acute (programmed, transient) and chronic (not programmed, persistent) senescence. While acute senescence leads to embryonic development, wound healing and tissue repair of specific populations of cells and tissues, chronic senescence that is not directed towards specific cells leads into a stable cell-cycle arrest, a state that limits the proliferation of damaged cells. The main mediator of acute senescence is SASP. It seems that, because of age-related immunodeficiency or less production of proinflammatory SASP factors, immune cells becomes inefficiently in the elimination of senescent cells. p53, p16 and other tumour suppressor pathways mediators leads to senescence. Cancer development will occur if pre-senescent cells (stressed cells) would not been removed by specific mechanisms. However, it is not known which mechanisms are responsible for direction to senescence, apoptosis or to autophagy. Production of SASP factors may be inhibited by the use of: nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), interleukine 1α blockers, rapamycin, metformin; senescent cell killing may be induced by natural killer cells, T cell targeting, antibodies or antibody-mediated drug delivery. Early in life, senescent cells are transiently present and have a beneficial effect on development, homeostasis, and regeneration. However, at a later age, senescent cells accumulate and produce detrimental effects. ROS – reactive oxygen species. SASP – senescence-associated secretory phenotype. p53 – cellular tumour antigen p53. p21 – cyclin-dependent kinase inhibitor 1, cell-cycle inhibitor. p16 – cyclin-dependent kinase inhibitor 2A, multiple tumour suppressor 1.