Genomic Instabilities, Cellular Senescence, and Aging: In Vitro, In Vivo and Aging-Like Human Syndromes

Abstract

As average life span and elderly people prevalence in the western world population is gradually increasing, the incidence of age-related diseases such as cancer, heart diseases, diabetes, and dementia is increasing, bearing social and economic consequences worldwide. Understanding the molecular basis of aging-related processes can help extend the organism’s health span, i.e., the life period in which the organism is free of chronic diseases or decrease in basic body functions. During the last few decades, immense progress was made in the understanding of major components of aging and healthy aging biology, including genomic instability, telomere attrition, epigenetic changes, proteostasis, nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and intracellular communications. This progress has been made by three spear-headed strategies: in vitro (cell and tissue culture from various sources), in vivo (includes diverse model and non-model organisms), both can be manipulated and translated to human biology, and the study of aging-like human syndromes and human populations. Herein, we will focus on current repository of genomic “senescence” stage of aging, which includes health decline, structural changes of the genome, faulty DNA damage response and DNA damage, telomere shortening, and epigenetic alterations. Although aging is a complex process, many of the “hallmarks” of aging are directly related to DNA structure and function. This review will illustrate the variety of these studies, done in in vitro, in vivo and human levels, and highlight the unique potential and contribution of each research level and eventually the link between them.

Role of p53 in the Regulation of Cellular Senescence

“…Upon physiological conditions, proliferating cells commit to a regular cell cycle [15,16]. On the other hand, both physiological aging, characterized by telomere shortening, and long-term chronic stress, which impairs genomic integrity and stability, could lead to the activation of the senescence pathway [17]. In this sense, the senescence can be viewed as an adaptative response of cells and organisms when exposed to certain unfavorable environmental conditions.…”

“…Upon physiological conditions, proliferating cells commit to a regular cell cycle [15,16]. On the other hand, both physiological aging, characterized by telomere shortening, and long-term chronic stress, which impairs genomic integrity and stability, could lead to the activation of the senescence pathway [17]. In this sense, the senescence can be viewed as an adaptative response of cells and organisms when exposed to certain unfavorable environmental conditions.Stressors include both intrinsic factors, such as oxidative damage, telomere attrition, hyperproliferation, oncogene activation, and environmental sources, including UV-light, γ-irradiation, and chemotherapeutic drugs [18,19].…”

Introductory Chapter: Gene Expression Controlling System and Its Application to Medical Sciences

“…Aging is thought to be accelerated by the accumulation of damage on chromosomal DNAs. This hypothesis is supported by the identification of responsive genes for premature aging, for example, LMNA, WRN, ATM, and SRPTN [61,62]. Therefore, the aberrances in the nuclear architecture and DNA repair systems may cause premature aging.…”

Mesenchymal Stem Cell Derived Extracellular Vesicles in Aging

“…Aging is a complex process resulting from the accumulation of unpredictable molecular and cellular alterations in a time-dependent manner. Aging is characterized by nine hallmarks: genomic instability, telomere attrition, epigenetic alteration, loss of proteostasis, metabolic dysfunction, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communications (for review see Lopez-Otin et al, 2013;Lidzbarsky et al, 2018). Subsequently, aging is a cell-autonomous accumulation of damages to organelles and macromolecules in cells and organs.…”