No abstract

Background Biochirality, evident in the homochirality of deoxyribonucleic acid (DNA) and the prevalent chirality of amino acids (AAs) in a bilateral organism, represents a challenge for modern biochemistry and neuroscience. Attention to the spontaneous post translational racemization allow revealing the link between protein aging, cell aging, and decline of cognitive functions should be highlighted. Method Analytical review of current advances in the molecular biology, biophysics, and neuroscience. Result At the protein level, biochirality is closely associated with various post‐translational modifications (PTMs), which support the dynamic balance of the prevalent chirality of enzymes and their substrates. This review posits a racemization hypothesis of neurodegeneration (RHND) that focuses on the distinct forms of the aberrant PTMs, which critically impact enzymes‐substrate interaction named spontaneous racemization. From a thermodynamic perspective, the collapse of homochirality by racemization is the result of a conformational non‐equilibrium phase transition. At the cellular level, the concept of non‐equilibrium phase transitions (PhTs) is relevant to the biophysics of PTMs, physiology of membrane‐less organelles (MLO), and intrinsically disordered proteins (IDPs). MLOs, containing IDPs, represent coherent structures with distinct protein dynamics and biological functions. MLOs containing IDPs are implicated in protein folding and aberrant protein conformation leading to aggregation diseases. Spontaneous, non‐enzymatic PTMs within MLOs represent the internal determinants of protein aging, cell aging and age‐related diseases. Recently it has been shown that the racemization of the serine (Ser) residue occurs (preferably) in the flexible (unstructured or intrinsically disordered) regions of proteins. Conclusion The amyloid cascade hypothesis in Alzheimer’s disease (AD) needs to be reconciled with the failure of numerous Aβ targeting drug therapies in clinical trials. In our view, both neuroscience and thermodynamic advances are necessary for addressing the brain region, cell type, and age‐dependent racemization processes that critically influence nervous system functions. The link between protein aging, cell aging, and decline of cognitive functions should be highlighted. The chiral non‐equilibrium phase transitions (PhTs) concomitant with the protein misfolding and aggregation, evident in an increasing number of experimental results, convince as to introduce the RHND.

In humans, age-associated degrading changes are observed in molecular and cellular processes underly the time-dependent decline in spatial navigation, time perception, cognitive and psy-chological abilities, and memory. Cross talk of biological, cognitive, and psychological clocks provides an integrative contribution to healthy and advanced aging. At the molecular level, ge-nome, 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 chirali-ty, 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 re-lated to irreversible PTMs SP has been associated with the nontrivial interplay between poor so-matic and mental 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 un-der-appreciated hallmark of aging.