Fasting, Autophagy and Neurodegenerative Diseases

Increasing evidence suggests that dysregulation of autophagy results in the accumulation of abnormal proteins and/or damaged organelles, which is commonly observed in neurodegenerative diseases, such as Alzheimer, Huntington’s, and Parkinson’s diseases  (Banerjee, Beal, and Thomas 2010).

Impaired protein homeostasis and accumulation of damaged or abnormally modified protein are common disease mechanisms in many neurodegenerative disorders, including Parkinson's disease. As one of the major degradation pathways, autophagy plays a pivotal role in maintaining effective turnover of proteins and damaged organelles in cells. Several decades of research efforts led to insights into the potential contribution of impaired autophagy machinery to alpha-synuclein accumulation and the degeneration of dopaminergic neurons, two major features of Parkinson's disease pathology (Hou et al. 2020).

Animal studies have shown that prolong fasting induces autophagy by downregulating the nutrient sensing pathway, mTOR (Cuervo et al. 2005).

Autophagy can be monitored by indirectly measuring degradation of protein p62, an autophagy receptor. The fasting mimicking diet (FMD) has been shown to maintain normal expression of p62 (a measure of functioning autophagy) (Brandhorst et al. 2015).

FMD has furthermore been shown to induce neurogenesis in adult mice. In old mice, cycles of the FMD was shown to improve hippocampal neurogenesis, lower IGF-1 levels and PKA activity, elevate NeuroD1, and improve cognitive performance (Brandhorst et al. 2015).

References

Banerjee, R., M. F. Beal, and B. Thomas. 2010. 'Autophagy in neurodegenerative disorders: pathogenic roles and therapeutic implications', Trends Neurosci, 33: 541-9.

Brandhorst, S., I. Y. Choi, M. Wei, C. W. Cheng, S. Sedrakyan, G. Navarrete, L. Dubeau, L. P. Yap, R. Park, M. Vinciguerra, S. Di Biase, H. Mirzaei, M. G. Mirisola, P. Childress, L. Ji, S. Groshen, F. Penna, P. Odetti, L. Perin, P. S. Conti, Y. Ikeno, B. K. Kennedy, P. Cohen, T. E. Morgan, T. B. Dorff, and V. D. Longo. 2015. 'A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan', Cell Metab, 22: 86-99.

Cuervo, A. M., E. Bergamini, U. T. Brunk, W. Droge, M. Ffrench, and A. Terman. 2005. 'Autophagy and aging: the importance of maintaining "clean" cells', Autophagy, 1: 131-40.

Hou, X., J. O. Watzlawik, F. C. Fiesel, and W. Springer. 2020. 'Autophagy in Parkinson's Disease', J Mol Biol, 432: 2651-72.