Age-Dependent Nonlinear Protein Aggregation: A Mathematical Model of Gut-Brain Axis Mediated Neurodegeneration.

The structural alterations due to protein misfolding, aggregation and clumping could lead to a number of pathological diseases. They have a considerable influence on the biological function of the intrinsically disordered proteins (IDPs) as well. The development of a comprehensive theory about neurodegenerative diseases, moving beyond the aging-related paradigms, constitutes one of the tasks of molecular biophysics. In the present paper, we developed a parsimonious but highly predictive mathematical model that takes into account hormonal regulation, genetic predisposition, immune deficiency and gut-brain axis with the nonlinear interaction of these factors and proved that protein aggregation progresses through critical tipping points instead of steady-state progression. The most notable finding is the universal convergence which is modelled at midlife around the age of 47 years, where gender-based protective effect disappears and risks become the same and where gut dysbiosis emerges as a potentially modifiable factor that accelerates the clumping of proteins in the age range of 45-65 years. The results of our research change the focus of treatment from late-stage symptom management to a stage-specific preventive intervention by emphasizing early immune support, midlife gut restoration and late-stage clearance enhancement. In essence, this work suggests the gut-brain axis as a valuable tool for theoretical prevention of neurodegeneration decades before clinical symptoms emergence. Also, our mathematical model can be adapted to solve various problems related to IDPs by adjusting the lever parameters accordingly.