Epigenetics recording varied environment and complex cell events represents the origin of cellular aging

Abstract

Although a relationship between epigenetics and aging phenotypic changes has been established, a theoretical explanation of the intrinsic connection between the epigenetics and aging is lacking. In this essay, we propose that epigenetic recording of varied cell environment and complex history could be an origin of cellular aging. Through epigenetic modifications, the environment and historical events can induce the chromatin template into an activated or repressive accessible structure, thereby shaping the DNA template into a spectrum of chromatin states. The inner nature of diversity and conflicts born by the cell environment and its historical events are hence recorded into the chromatin template. This could result in a dissipated spectrum of the chromatin state and chaos in overall gene expression. An unavoidable degradation of epigenome entropy, similar to Shannon entropy, would be consequently induced. The resultant disorder in epigenome, characterized by corrosion of epigenome entropy as reflected in chromatin template, can be stably memorized and propagated through cell division. Furthermore, the hysteretic nature of epigenetics responding to the emerging environment could exacerbate the degradation of epigenome entropy. As well as stochastic errors, we propose that outside entropy (or chaos) derived from the varied environment and complex cell history, gradually input and imprinted into the chromatin via epigenetic modifications, would lead inevitably to cellular aging, the extent of which could be aggravated by hysteresis of epigenetics without error erasing and correction.

Keywords: Epigenetics; Environment; Cell event; Cellular aging; Epigenome entropy; DNA methylation.

Fig. 1

Cells live in an unpredictable environment comprising many diversified environmental factors (a) and undergo a wide variety of cellular historical events (b)

Fig. 2

Varied environmental factors producing irreconcilable conflict between the ideal genetic regulation and the suboptimal epigenetic state (a) A specific collection of gene variations, up-regulated (↑) or down-regulated (↓), is involved to answer a specific environmental factor (EF I); (b) Actually, cells are exposed to and inevitably have managed to answer some other different environmental factors (i.e. EF II, EF III, EF IV, and EF V); (c) Both the synergistic (↑ or ↓ (red), vertical arrows) and antagonistic (↔, horizontal arrow) effects can be generated in the assembly pattern of gene expression in answer to all of these varied environmental factors; (d) Imprinted by these varied environmental factors, a spectrum of epigenetic states could be generated in the related regions of chromatin (A: activated epigenetic state; HA: highly activated epigenetic state; R: repressive epigenetic state; HR: highly repressive epigenetic state; M: medium epigenetic state). Consequently, the irreconcilable conflict between the ideal genetic regulation (a) and the suboptimal epigenetic state (d) would be conveyed in answering each environmental factor. (e) A perfect match between the ideal genetic regulations and actual epigenetic states in answering each specific environmental factor (here refers to EF I) actually does not exist (Note: for interpretation of the references to color in this figure legend, the reader is referred to the web version of this article)

Fig. 3

Irreversibility and hysteresis of epigenetic modifications in response to new environment and emerging events, which would inevitably lead to a dissipated spectrum of chromatin state with increasing loss of epigenome entropy (a) Cells make compromised epigenetic modifications between the epigenetic records and stresses derived from environment. (b) Epigenetic hysteresis may produce a range of epigenetic states (from E ₁ to E ₂) when confronted with a specific genetic stress (G ₁). A, B, C, D, and E refer to the possible states when a cell responds to the varied environment. (c) Hysteresis thereby results in epigenetic drift, where the epigenetic states (Eps₁, Eps₂, Eps₃, …, Eps_X) of different cells at each gene location (Gn₁, Gn₂, Gn₃, …, Gn_X) vary greatly in a specific environment; (d) The epigenetic state at each gene location (symbol of five-point stars) is first at their beginning position. After a series of round-trip changes (R ₁, R ₂, R ₃, …, R_X) in specific cellular events or environmental parameters, dissipated patterns of epigenetic states are generated due to the different degrees of hysteresis for different gene locations

Fig. 4

Outside entropy (or chaos) derived from the varied environment and complex cell history, gradually input and imprinted into the chromatin via epigenetic modifications, would lead inevitably to cellular aging, the extent of which could be aggravated by hysteresis of epigenetics without error erasing and correction