Fundamental Clock of Biological Aging: Convergence of Molecular, Neurodegenerative, Cognitive and Psychiatric Pathways: Non-Equilibrium Thermodynamics Meet Psychology

Abstract

In humans, age-associated degrading changes, widely observed in molecular and cellular processes underly the time-dependent decline in spatial navigation, time perception, cognitive and psychological abilities, and memory. Cross-talk of biological, cognitive, and psychological clocks provides an integrative contribution to healthy and advanced aging. At the molecular level, genome, proteome, and lipidome instability are widely recognized as the primary causal factors in aging. We narrow attention to the roles of protein aging linked to prevalent amino acids chirality, enzymatic and spontaneous (non-enzymatic) post-translational modifications (PTMs SP), and non-equilibrium phase transitions. The homochirality of protein synthesis, resulting in the steady-state non-equilibrium condition of protein structure, makes them prone to multiple types of enzymatic and spontaneous PTMs, including racemization and isomerization. Spontaneous racemization leads to the loss of the balanced prevalent chirality. Advanced biological aging related to irreversible PTMs SP has been associated with the nontrivial interplay between somatic (molecular aging) and mental (psychological aging) health conditions. Through stress response systems (SRS), the environmental and psychological stressors contribute to the age-associated “collapse” of protein homochirality. The role of prevalent protein chirality and entropy of protein folding in biological aging is mainly overlooked. In a more generalized context, the time-dependent shift from enzymatic to the non-enzymatic transformation of biochirality might represent an important and yet underappreciated hallmark of aging. We provide the experimental arguments in support of the racemization theory of aging.

Fundamental Cause of Bio-Chirality: Space-Time Symmetry—Concept Review

“…It is beyond this article's scope to elucidate the physical significance of STS in the mathematical language of the Standard Model (SM) and String Theory (StrT) (see, [37][38][39]), but the logical ground for understanding is provided. The family of SM elementary particles (EPs) (see Figures 1 and 2) adequately describes the physical world at microscopic and cosmological scales [40][41][42][43]. However, much more remains to be understood.…”

“…The biological systems, representing thermodynamically open non-equilibrium states characterized by the bio-molecular phase transitions, are commonly associated with symmetry transformations (symmetry changes or "breaking") [165][166][167][168] and not trivial bidirectional behavior of entropy [123,171]. Notably, the evolution of galaxy clusters exhibits similar bi-directional (decreasing and increasing stages) entropy patterns [43,[172][173][174]. The fundamental significance of biochirality at the molecular and cellular levels assumes the mechanisms of the organism/brain morphology, behavior, cognition, and consciousness are grounded on basic principles of spatial organization and function.…”

Arrow of Time, Entropy, and Protein Folding: Holistic View on Biochirality

“…The most frequently occurring PTMs Enz are protein phosphorylation and dephosphorylation, which provide the switch between active and inactive states of proteins. The interplay between enzymatic PTMs (e.g., phosphorylation) and spontaneous racemization has been shown to be a principal determinant of the age-associated pathogenic pathways [ 57 ]. There is now general agreement that the long-lived proteins (LLPs) are inherently vulnerable to various time-dependent non-enzymatic modifications, including unfolding, misfolding, damage, and pathological aggregation [ 58 , 59 ].…”

“…Protein folding pathways are prone to malfunction, driven by a pathogenic spontaneous stereoselective reaction, accompanied by aberrant liquid-to-solid phase transitions (PhTs), leading to stepwise, age-associated misfolding, including fibrillization and aggregation. During a lifetime, spontaneous racemization is an inevitable factor, contributing to proteins, cells, and organism aging [ 57 ]. Spontaneous racemization frequently coexists with the abnormal PTM Enz , especially phosphorylation.…”

Exploring the aging process of cognitively healthy adults by analyzing cerebrospinal fluid metabolomics using liquid chromatography-tandem mass spectrometry

“…Aging-related degradation of molecular and cellular processes contribute to genome, proteome, and lipidome instability, and the minor changes of these upstream molecules can cause significant metabolite alterations [ 8 ]. Because perturbations in metabolic pathways can be one of the first measurable alteration before disease manifestations, metabolomics can be used to characterize the dynamic biological aging processes.…”