<aside> 🌱 “Truly, what is stiff and hard is a companion of death; what is soft and weak is a companion of life.” — Tao Teh Ching.
</aside>
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 are useful for contextualizing geroscience research, the framework itself does not explain what fundamentally causes them to emerge in the first place.
I propose a theorem that aims to explain the emergence of the hallmarks of aging as phenomena secondary to extracellular matrix chemical crosslinking, suggesting that the ensuant age-related extracellular matrix stiffening is a causative upstream agent in the aging process.
Mechanisms of aging have been conceptually organized into the framework of hallmarks (López-Otín et al., 2023). Although being an excellent introduction to biogerontology, the hallmarks concept does not conform to a full-fledged scientific paradigm, leaving out a few prominent characteristics of the aging process and not comprehensively explaining why the hallmarks emerge in the first place (Gems & de Magalhães, 2021; Keshavarz et al., 2022). At the same time, the mechanical properties of cells and their environment have been recognized as an important factor for a panoply of age-related derailments (Phillip et al., 2015). Despite the importance, the biogerontology field chronically neglects to include changes in extracellular matrix (ECM) biomechanics on the hallmarks list.
Such short-sightedness can be explained by the current predominantly cell-centric sentiment on aging. I would argue that without taking into account the cellular environment the said view on tissue aging biology is incomplete. It’s notable that some forms of chemical damage to the ECM components, i.e. sugar-derived crosslinks, accrue linearly with age and, when normalized by the component tissue residence time (turnover), proceed at the same rate regardless of the location in the body (Verzijl et al., 2000; Monnier & Sell, 2006).
Aging has been conceptualized as both time-dependent damage accumulation (Moqri et al., 2023) and the increase in intracellular entropy (Lu et al., 2023); although as of writing there is no field consensus on what aging is (Gladyshev et al., 2024). Below, I propose a theorem that aims to serve as a conceptual ground to incorporate the notion of ECM mechanics into the current biogerontology research framework by interpreting the hallmarks of aging as emergent and subordinate entropic events in relation to age-related ECM stiffening, resulting from the chemical crosslink accumulation.
Please see the preprint for details.