PMID- 38106160
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240416
DP  - 2023 Dec 4
TI  - A ketogenic diet reduces age-induced chronic neuroinflammation in mice Running 
      title: ketogenic diet and brain inflammaging.
LID - 2023.12.01.569598 [pii]
LID - 10.1101/2023.12.01.569598 [doi]
AB  - Beta-hydroxybutyrate (BHB) is a ketone body synthesized during fasting or 
      strenuous exercise. Our previous study demonstrated that a cyclic ketogenic diet 
      (KD), which induces BHB levels similar to fasting every other week, reduces 
      midlife mortality and improves memory in aging mice. BHB actively regulates gene 
      expression and inflammatory activation through non-energetic signaling pathways. 
      Neither of these activities has been well-characterized in the brain and they may 
      represent mechanisms by which BHB affects brain function during aging. First, we 
      analyzed hepatic gene expression in an aging KD-treated mouse cohort using bulk 
      RNA-seq. In addition to the downregulation of TOR pathway activity, cyclic KD 
      reduces inflammatory gene expression in the liver. We observed via flow cytometry 
      that KD also modulates age-related systemic T cell functions. Next, we 
      investigated whether BHB affects brain cells transcriptionally in vitro. Gene 
      expression analysis in primary human brain cells (microglia, astrocytes, neurons) 
      using RNA-seq shows that BHB causes a mild level of inflammation in all three 
      cell types. However, BHB inhibits the more pronounced LPS-induced inflammatory 
      gene activation in microglia. Furthermore, we confirmed that BHB similarly 
      reduces LPS-induced inflammation in primary mouse microglia and bone 
      marrow-derived macrophages (BMDMs). BHB is recognized as an inhibitor of histone 
      deacetylase (HDAC), an inhibitor of NLRP3 inflammasome, and an agonist of the 
      GPCR Hcar2. Nevertheless, in microglia, BHB's anti-inflammatory effects are 
      independent of these known mechanisms. Finally, we examined the brain gene 
      expression of 12-month-old male mice fed with one-week and one-year cyclic KD. 
      While a one-week KD increases inflammatory signaling, a one-year cyclic KD 
      reduces neuroinflammation induced by aging. In summary, our findings demonstrate 
      that BHB mitigates the microglial response to inflammatory stimuli, like LPS, 
      possibly leading to decreased chronic inflammation in the brain after long-term 
      KD treatment in aging mice.
FAU - Nomura, Mitsunori
AU  - Nomura M
AUID- ORCID: 0000-0002-1811-4917
AD  - Buck Institute for Research on Aging, Novato, CA, USA.
FAU - Murad, Natalia Faraj
AU  - Murad NF
AD  - Buck Institute for Research on Aging, Novato, CA, USA.
FAU - Madhavan, Sidharth S
AU  - Madhavan SS
AUID- ORCID: 0000-0001-8163-0917
AD  - Buck Institute for Research on Aging, Novato, CA, USA.
AD  - Leonard Davis School of Gerontology, University of Southern California, Los 
      Angeles, CA, USA.
FAU - Eap, Brenda
AU  - Eap B
AUID- ORCID: 0000-0001-6457-2436
AD  - Buck Institute for Research on Aging, Novato, CA, USA.
AD  - Leonard Davis School of Gerontology, University of Southern California, Los 
      Angeles, CA, USA.
FAU - Garcia, Thelma Y
AU  - Garcia TY
AD  - Buck Institute for Research on Aging, Novato, CA, USA.
FAU - Aguirre, Carlos Galicia
AU  - Aguirre CG
AD  - Buck Institute for Research on Aging, Novato, CA, USA.
AD  - Leonard Davis School of Gerontology, University of Southern California, Los 
      Angeles, CA, USA.
FAU - Verdin, Eric
AU  - Verdin E
AUID- ORCID: 0000-0003-3703-3183
AD  - Buck Institute for Research on Aging, Novato, CA, USA.
FAU - Ellerby, Lisa
AU  - Ellerby L
AUID- ORCID: 0000-0002-9050-7977
AD  - Buck Institute for Research on Aging, Novato, CA, USA.
FAU - Furman, David
AU  - Furman D
AUID- ORCID: 0000-0002-3654-9519
AD  - Buck Institute for Research on Aging, Novato, CA, USA.
FAU - Newman, John C
AU  - Newman JC
AUID- ORCID: 0000-0002-8455-0100
AD  - Buck Institute for Research on Aging, Novato, CA, USA.
AD  - Division of Geriatrics, University of California, San Francisco, San Francisco, 
      CA, USA.
LA  - eng
GR  - R01 AG067333/AG/NIA NIH HHS/United States
GR  - R01 AG068025/AG/NIA NIH HHS/United States
GR  - T32 AG000266/AG/NIA NIH HHS/United States
GR  - T32 AG052374/AG/NIA NIH HHS/United States
PT  - Preprint
DEP - 20231204
PL  - United States
TA  - bioRxiv
JT  - bioRxiv : the preprint server for biology
JID - 101680187
PMC - PMC10723274
OTO - NOTNLM
OT  - Beta-hydroxybutyrate (BHB)
OT  - brain
OT  - inflammaging
OT  - ketogenic diet
COIS- Conflict of Interest J.C.N. and E.V. are co-founders, hold stock, and 
      co-inventors on patents licensed to BHB Therapeutics, Ltd., and Selah 
      Therapeutics Ltd., which develop ketone esters for consumer and therapeutic use.
EDAT- 2023/12/18 06:42
MHDA- 2023/12/18 06:43
PMCR- 2023/12/15
CRDT- 2023/12/18 04:34
PHST- 2023/12/18 06:42 [pubmed]
PHST- 2023/12/18 06:43 [medline]
PHST- 2023/12/18 04:34 [entrez]
PHST- 2023/12/15 00:00 [pmc-release]
AID - 2023.12.01.569598 [pii]
AID - 10.1101/2023.12.01.569598 [doi]
PST - epublish
SO  - bioRxiv [Preprint]. 2023 Dec 4:2023.12.01.569598. doi: 10.1101/2023.12.01.569598.