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.

Purpose. The purpose of this in vivo study was to evaluate the proliferative response of immunologic cells during the acute phase after optic nerve (ON) lesion in the neural retina and the ciliary body (CB) in the adult mouse. Methods. The number of cells obtained 5 to 10 days after ON crush was compared with that counted after intraorbital ON transection. In addition, after ON crush, the time course of in situ proliferating Ki67⁺ microglia and macrophages was analyzed from 6 hours up to 10 days. Results. The number of BrdU⁺F4/80⁺ retinal microglia and ciliary macrophages increased over time, reaching the peak number 10 days after ON lesion. In the retina, both ON lesion types resulted in a similar number of BrdU⁺F4/80⁺ microglia. Approximately 85% of all BrdU⁺ cells were identified as F4/80⁺ microglia. However, this cell population represented only 30% of all F4/80⁺ microglia. The peak of microglial in situ proliferation was found 2 days after ON crush. In the CB, both ON lesion types induced a significant increase in the number of BrdU⁺F4/80⁺ macrophages. Of interest, the number of cells after ON transection further increased over time, whereas those after ON crush did not. Conclusions. ON lesion significantly increased proliferation of F4/80⁺ immunologic cells in both the retina and CB. Although no significant differences in cellular response were observed in the retina between both lesion types, ON transection had a more pronounced effect on ciliary macrophages than did ON crush. Therefore, both regions seem not to act in concert during the acute phase after ON lesion.

Still unresolved is the question of how a lifetime accumulation of somatic gene copy number alterations impact organ functionality and aging and age-related pathologies. Such an issue appears particularly relevant in the broadly post-mitotic central nervous system (CNS), where non-replicative neurons are restricted in DNA-repair choices and are prone to accumulate DNA damage, as they remain unreplaced over a lifetime. Both DNA injuries and consecutive DNA-repair strategies are processes that can evoke extrachromosomal circular DNA species, apparently from either part of the genome. Due to their capacity to amplify gene copies and related transcripts, the individual cellular load of extrachromosomal circular DNAs will contribute to a dynamic pool of additional coding and regulatory chromatin elements. Analogous to tumor tissues, where the mosaicism of circular DNAs plays a well-characterized role in oncogene plasticity and drug resistance, we suggest involvement of the “circulome” also in the CNS. Accordingly, we summarize current knowledge on the molecular biogenesis, homeostasis and gene regulatory impacts of circular extrachromosomal DNA and propose, in light of recent discoveries, a critical role in CNS aging and neurodegeneration. Future studies will elucidate the influence of individual extrachromosomal DNA species according to their sequence complexity and regional distribution or cell-type-specific abundance.