Age-Dependent Nonlinear Protein Aggregation: A Mathematical Model of Gut-Brain Axis Mediated Neurodegeneration
Abstract
Amishi and Himadri B. Bohidar*
Structural changes caused by misfolding, aggregation and clumping of proteins can manifest in serious pathological conditions. These also have a significant bearing on the biological activity of intrinsically disordered proteins (IDPs). Developing a general understanding of the neurodegenerative diseases by moving beyond the isolated age-based paradigms is one of the challenges of molecular biophysics. Herein, we propose a simple dynamic system level model that incorporates hormonal control, genetic predisposition, immune decline and the gut-brain axis as well as their interactions, to show that aggregation accelerates through critical tipping points rather than progressing steadily over time. Most strikingly, the model identifies a universal convergence around midlife, near the age of 47 years, when gender- specific protections fade and disease risk equalizes, and reveals gut dysbiosis as a dominant driver that can enhance protein clumping between age of 45 - 65 years. These findings shift the therapeutic focus from late-stage symptom management to proactive, stage-specific intervention, highlighting early immune support, midlife gut restoration, and late-stage clearance enhancement as key opportunities. Ultimately, the work presented in this study positions the gut- brain axis as an important lever to prevent the development of neurodegeneration decades prior to the onset of clinical symptoms. Furthermore, the generalized and simple model proposed herein can be modified to address an array of problems associated with the IDPs by suitably choosing the lever parameters.