M. Balietti, B. Giorgetti, P. Fattoretti, Y. Grossi, F. Orlando, M. Solazzi, D. Platano, G. Aicardi, C. Bertoni-Freddari

Ketogenic diets (KD), successfully used in the treatment of some forms of pediatric epilepsy, have recently been tested in the therapy of other diseases, including traumatic brain injuries, hypoxia-ischemia, mitochodriopathies, and cancer. To date, little is known about their consequences on aging. Thus, to investigate the effect on brain aging, late-adult (19-month-old) Wistar rats were fed with a medium chain triglycerides KD (MCT-KD) for 8 weeks, and the ultrastructural features of synapses and synaptic mitochondria were studied by electron microscopy in the granule cell layer of the cerebellar cortex (GCL-CCx) and stratum moleculare of the hippocampal CA1 area (SM CA1). Young (5-month old) and late-adult animals fed with a commercial laboratory chow were used as control groups. The average area of the synaptic contact zones (S), the numeric density of contacts (Nvs: number of synapses/cubic micron of tissue), the synaptic surface density (Sv: overall area of synaptic junctional zones/cubic micron of tissue), the average volume of mitochondria (V), the numeric density of organelles (Nvm: number of mitochondria/cubic micron of tissue), as well as the mitochondrial volume density (Vv: overall volume of mitochondria/cubic micron of tissue) were measured. In GCL-CCx, no significant differences for either synapses or mitochondria were found among the groups. On the contrary, in SM CA1 of the rats fed with MCT-KD, S and Sv were significantly increased, Nvm was significantly decreased, and V was increased but not significantly. Nvs and Vv were similar in treated and control rats. No statistical differences were found in SM CA1 between the two control groups. Since significant enlargement of synaptic and mitochondrial size has been reported to occur in older animals, MCT-KD appears to induce aging-like alterations in SM CA1, but not in GCL-CCx. The present findings advice, for the first time, that the use of MCT-KD implies potential risks for the normal aging process of the brain, possibly as a consequence of the decline of the adaptive capacities necessary to support the metabolic shift.

Keywords (Optional): 
ketogenic diet
synaptic morphology
synaptic mitochondria
brain aging