Ketogenic Diet Reduces Age-Induced Chronic Neuroinflammation in Mice.

Autor:	Nomura M; Buck Institute for Research on Aging, Novato, CA, USA., Murad NF; Buck Institute for Research on Aging, Novato, CA, USA., Madhavan SS; Buck Institute for Research on Aging, Novato, CA, USA.; Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA., Mu WC; Buck Institute for Research on Aging, Novato, CA, USA., Eap B; Buck Institute for Research on Aging, Novato, CA, USA.; Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA., Garcia TY; Buck Institute for Research on Aging, Novato, CA, USA., Aguirre CG; Buck Institute for Research on Aging, Novato, CA, USA.; Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA., Verdin E; Buck Institute for Research on Aging, Novato, CA, USA., Ellerby L; Buck Institute for Research on Aging, Novato, CA, USA.; Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA., Furman D; Buck Institute for Research on Aging, Novato, CA, USA.; Stanford 1000 Immunomes Project, Stanford University School of Medicine, Stanford, CA, USA.; Instituto de Investigaciones en Medicina Traslacional, Universidad Austral, Consejo Nacional de Investigaciones Científicas y Técnicas, 1629, Pilar, Argentina., Newman JC; Buck Institute for Research on Aging, Novato, CA, USA.; Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.; Division of Geriatrics, University of California, San Francisco, CA, USA.
Jazyk:	angličtina
Zdroj:	Aging biology [Aging Biol] 2024; Vol. 2. Date of Electronic Publication: 2024 Dec 16.
DOI:	10.59368/agingbio.20240038
Abstrakt:	The ketone body beta-hydroxybutyrate (BHB) is an acidic energy metabolite that is synthesized during periods of fasting or exercise. Our previous study demonstrated that an every other week cyclic ketogenic diet (Cyclic KD), which induces blood BHB levels similar to those observed during fasting, reduces midlife mortality and improves memory in aging mice. In addition to its canonical role as an energy metabolite, BHB regulates gene expression and inflammatory activation through non-energetic signaling pathways. The precise mechanisms by which BHB or KD affects brain function during aging remain incompletely understood. Using bulk RNA-sequencing (RNA-Seq), we examined whole brain gene expression of 12-month-old C57BL/6JN male mice fed KD for either one week or 14 months. While one-week KD increases some inflammatory gene expression, the 14-month Cyclic KD largely reduces age-induced neuroinflammatory gene expression. Next, a gene expression analysis of human primary brain cells (microglia, astrocytes, and neurons) using RNA-Seq revealed that BHB alone induces a mild level of inflammation in all three cell types. However, BHB inhibits the more pronounced inflammatory gene expression induced by lipopolysaccharide (LPS) in microglia. BHB exhibits a comparable inhibitory effect on LPS-induced inflammation in mouse primary microglia, which we used as an in vitro model to test and exclude known mechanisms by which BHB regulates inflammation and gene expression as responsible for this modulation of LPS-induced inflammatory gene expression. An acidic milieu resulting from BHB may be required for or contribute to the effect. Overall, we observe that BHB has the potential to attenuate the microglial response to inflammatory stimuli, such as LPS. This may contribute to an observed reduction in chronic inflammation in the brain following long-term Cyclic KD treatment in aging mice. Competing Interests: Conflicts of Interest J.C.N. and E.V. are cofounders, stockholders, and coinventors on patents licensed to BHB Therapeutics, Ltd., and Selah Therapeutics Ltd., which develop ketone esters for consumer and therapeutic use.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu