Short Term Ketogenic Diet, five tissues, males and females, two arms study.

ABSTRACT: The ketogenic diet (KD) has an excellent safety profile and is a recognized neurotherapeutic diet for human epilepsy. In C57Bl6 mice, the Ketogenic Diet (KD) significantly extends lifespan and healthspan and extends memory in two mouse models of Alzheimer’s disease backcrossed to C57Bl6. We studied the effects of a short-term KD (STKD) of > 6 weeks in mice and human blood, and in 5 mouse tissues. In mouse and human blood STKD suppressed transcripts and pathways of myeloid-based inflammation in common. In human blood STKD suppressed transcripts downstream of myeloid hematopoietic stem cell (HSC) differentiation at a ratio of 26-myeloid to 1-non-myeloid. Despite this biased suppression of myeloid HSC transcripts that include red blood cells, no Complete Blood Count (CBC) parameter was significantly altered, consistent with KD’s known safety profile. New human blood biomarker transcripts of KD’s potential therapeutic effect were identified. STKD reduced transcripts of myeloid-expressed amyloid precursor protein (APP) and alpha synuclein (SNCA) connected to Alzheimer’s and Parkinson’s disease, the first known dietary suppression of these transcripts in human blood. In C57BL6 mice, transcriptomic effects of STKD were analyzed in hippocampus, cortex, liver and gastrocnemius muscle. STKD affected liver most of the 5 tissues, increasing transcripts of lipid oxidation and Beta-hydroxybutyrate (BHB) production and suppressing transcripts of de novo lipogenesis and glycolysis. While STKD of 6 weeks elicited significant suppression of myeloid inflammatory transcriptional pathways in blood of mice and humans, those pathways were not significantly suppressed in mouse brain, that requires a longer-term KD (LTKD) of at least 52 weeks as we and others have shown. The myeloid bias hypothesis proposes that the age-related clonal expansion of blood myeloid HSCs drives age-related proliferation of myeloid cells including microglia and monocytes, that mediate neuroinflammation in aging C57Bl6 mouse brain, ‘inflammaging’. We speculate that LTKD’s suppression of myeloid-specific neuroinflammatory transcripts in mouse brain is driven by KD’s myelosuppression in blood over time. Since humans also experience an age-related expansion of the HSC myeloid clone, we speculate that prolonged KD could produce anti-inflammatory anti-aging effects in human brains as well.

ORGANISM(S): Mus musculus

PROVIDER: GSE351630 | GEO | 2026/10/25

REPOSITORIES: GEO