Dissecting Aging and Senescence—Current Concepts and Open Lessons

Abstract

In contrast to the programmed nature of development, it is still a matter of debate whether aging is an adaptive and regulated process, or merely a consequence arising from a stochastic accumulation of harmful events that culminate in a global state of reduced fitness, risk for disease acquisition, and death. Similarly unanswered are the questions of whether aging is reversible and can be turned into rejuvenation as well as how aging is distinguishable from and influenced by cellular senescence. With the discovery of beneficial aspects of cellular senescence and evidence of senescence being not limited to replicative cellular states, a redefinition of our comprehension of aging and senescence appears scientifically overdue. Here, we provide a factor-based comparison of current knowledge on aging and senescence, which we converge on four suggested concepts, thereby implementing the newly emerging cellular and molecular aspects of geroconversion and amitosenescence, and the signatures of a genetic state termed genosenium. We also address the possibility of an aging-associated secretory phenotype in analogy to the well-characterized senescence-associated secretory phenotype and delineate the impact of epigenetic regulation in aging and senescence. Future advances will elucidate the biological and molecular fingerprints intrinsic to either process.

Role of p53 in the Regulation of Cellular Senescence

“…The classical depiction of senescence as a static, uniform, and irreversible cellular state has been progressively reconsidered, and senescence is now envisioned as a dynamic and multistep process [60]. During the initiation of the senescence, which is also called as "primary senescence", the stressed cells may be still able to repair and/or eliminate the cause of the damage and then can escape from cell cycle arrest.…”

Development of an in vitro senescent hepatic cell model for metabolic studies in aging

“…Such a tool would not only enable better understanding of the molecular and metabolic defects associated with aging, but also could potentially help identify druggable targets to treat age-associated chronic hepatic diseases such as fatty liver, steatohepatitis, Type 2 diabetes, hepatic fibrosis in a time-and cost-efficient manner [3, 5-7, 16, 23]. Cellular senescence and the number of senescent cells significantly increases in most tissues during aging [9,12,24]. Previous in vitro senescence models have utilized primary fibroblasts or hepatic carcinoma cells that were subjected to oxidative stress conditions or irradiation [17][18][19][20][21][22][23].…”

“…It is characterized by permanent cell cycle arrest, resistance to apoptosis, and a senescence-associated secretory phenotype [5]. Under pathological stress conditions, excessive accumulation of senescence cells in affected tissues adversely affects the tissue's regenerative ability and creates a proinflammatory environment that can resemble various age-related disorders such as Alzheimer's disease, cancer, arthritis, cataracts, osteoporosis, atherosclerosis, hypertension, cardiovascular disease, Type 2 diabetes, and chronic liver disorders [3,5,7,[9][10][11][12]. Targeting senescent cells has the potential to delay age-associated disorders and/or reverse pathological metabolic phenotypes [3,[13][14][15][16].…”

Immunosenescence is both functional/adaptive and dysfunctional/maladaptive

“…This consideration generated many studies to evaluate whether senescence of the immune cells could be considered detrimental or beneficial. Certainly, the accumulation of senescent cells has numerous maladaptive aspects [146,147]; but, as many recent studies have shown, it also has adaptive aspects [148]. Finally, the exact percentage of the senescent/exhausted T cells at different ages and what role they may play physiologically is not clearly settled in this context.…”