<aside> 🟥 The theoretical foundation, the conceptual core of my work, is what I’ve named the delocalized entropy aging theorem (because I have yet to prove it). I’m in the process of connecting the dots to present the theorem to the public as convincingly as possible, but the first glimpse of what I’m to offer can be had below.
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Age-related alteration of intracellular processes has been recognized as tipping of homeostatic balance towards increased entropy, reflected in, for instance, such hallmarks of aging as the loss of epigenetic information and disruption of proteostasis. Although the hallmarks of aging paradigm is useful in directing research in the field of geroscience, it does not explain what causes the hallmarks to emerge in the first place. I propose that the cell and its surroundings can be regarded as a single thermodynamic unit. I start with a supposition that at an early stage the sum of entropies inside and outside the cell is some constant value. As the extracellular matrix gets crosslinked with age, leading to a smaller number of potential microscopic states therein, its entropy decreases. Since the entropy sum value is constant, this inevitably leads to an increase in entropy inside the cell, manifesting as the hallmarks of cellular aging. There are well-studied biochemical and mechanical events that reflect the change in intracellular entropy in response to the ECM rigidity, resulting in an increased rate of DNA double-strand breaks and subsequent epigenetic downshift, for example. The cell, in an attempt to "export" entropy away from the genetic material, produces matrix-remodeling enzymes, such as MMPs, to raise entropy in the ECM. Thus, age-dependent ECM remodeling is an adaptive response to preserve genetic integrity up to a point defined by evolutionary constraints. The response ensures short-term survival, but is pathological in the long term.
The delocalized entropy aging theorem (DEATh) is based on a supposition that the cell and its environment, represented by the extracellular matrix (ECM), are a single thermodynamic unit. In other words, from a thermodynamic perspective, the cell and processes therein cannot be regarded in separation from the cellular environmental context.
I further propose that the sum of entropies inside and outside the cell, $S_{CELL}$ and $S_{ECM}$ respectively, is some constant value, i.e. at some hypothetical point in time $t_0$, e.g. in a young organism, $S_{CELL} + S_{ECM} = const$ (see figure; left panel).
The implications of this supposition have a profound significance for our understanding of the aging process, specifically – the emergence of the hallmarks of aging. The latter, although an excellent framework for the systematization of the current knowledge on molecular-genetic manifestations of organismal senescence, does not go beyond that to explain why these manifestations, i.e. the aforementioned hallmarks, occur in the first place.
The thermodynamic supposition I have proposed explains the emergent and subordinate nature of the hallmarks of aging as follows:
i. At $t_0$, $S_{CELL} + S_{ECM} = const$ (see figure; left panel).
ii. With age, the accumulation of chemical damage to the ECM proteins in the form of intermolecular crosslinks leads to the reduction of overall relative mobility of fibrillar matrix components—e.g. through decreased lateral sliding of collagens—negatively affecting ECM viscoelasticity and altering its mechanical properties towards tissue stiffening. The reduction in the said relative mobility is concurrent with the reduction of potential microscopic states in the ECM – in other words, diminished entropy. According to i., decreased ECM entropy, $S_{ECM}$, must result in increased entropy inside the cell, $S_{CELL}$, otherwise the supposition will not hold. Consequentially, the ensuing increase in entropy within the cell is what we observe as the hallmarks of aging (see figure; middle panel).
iii. The increased entropy in close proximity to the genetic material presents a vital threat to the cell’s survival and requires immediate action – the entropy must be “exported” away from crucial intracellular hotspots. This is done by mechanosensory pathways feeding into regulatory circuits governing the expression of ECM remodeling enzymes and ECM structural parts. The subsequent enzyme-mediated ECM fragmentation and aberrant de novo deposition of ECM constituents increases the entropy outside the cell, representing a survival strategy – within evolutionary constraints specific for a given species: as $S_{ECM}$ increases, $S_{CELL}$ must decrease. This swing in the opposite direction is a temporary solution at the expense of physiological tissue homeostasis, eventually resulting in pathology (see figure; right panel).
<aside> 🟥 Please note that the described flow of entropy—its delocalizedness—is not some magical process; it is tied to well-known biochemical and mechanosensory cascades that I will explain further. Stay tuned.
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