Dietary Restriction Extends Lifespan through Metabolic Regulation of Innate Immunity

Wu, Ziyun; Isik, Meltem; Moroz, Natalie; Steinbaugh, Michael J.; Zhang, Peng; Blackwell, T. Keith

doi:10.1016/j.cmet.2019.02.013

Cited by 133 publications

(150 citation statements)

References 77 publications

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“…The role of BHB in microglia and neuroinflammation has been previously studied in various disease models [ 26 , 36 , 38 , 53 , 54 , 55 , 56 , 57 ]. However, the metabolic effects of BHB on microglia activation and the underlying metabolic reprogramming remain unknown.…”

Section: Resultsmentioning

confidence: 99%

“…Dietary interventions have shown potential to alter the metabolic environment and subsequently fine-tune the immune system [ 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. Amongst these, ketogenic diets have been one of the most popular, particularly in the treatment of diseases of the brain like epilepsy and glioma [ 28 , 29 , 30 , 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

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β-Hydroxybutyrate Oxidation Promotes the Accumulation of Immunometabolites in Activated Microglia Cells

et al. 2020

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Metabolic regulation of immune cells has arisen as a critical set of processes required for appropriate response to immunological signals. While our knowledge in this area has rapidly expanded in leukocytes, much less is known about the metabolic regulation of brain-resident microglia. In particular, the role of alternative nutrients to glucose remains poorly understood. Here, we use stable-isotope (13C) tracing strategies and metabolomics to characterize the oxidative metabolism of β-hydroxybutyrate (BHB) in human (HMC3) and murine (BV2) microglia cells and the interplay with glucose in resting and LPS-activated BV2 cells. We found that BHB is imported and oxidised in the TCA cycle in both cell lines with a subsequent increase in the cytosolic NADH:NAD+ ratio. In BV2 cells, stimulation with LPS upregulated the glycolytic flux, increased the cytosolic NADH:NAD+ ratio and promoted the accumulation of the glycolytic intermediate dihydroxyacetone phosphate (DHAP). The addition of BHB enhanced LPS-induced accumulation of DHAP and promoted glucose-derived lactate export. BHB also synergistically increased LPS-induced accumulation of succinate and other key immunometabolites, such as α-ketoglutarate and fumarate generated by the TCA cycle. Finally, BHB upregulated the expression of a key pro-inflammatory (M1 polarisation) marker gene, NOS2, in BV2 cells activated with LPS. In conclusion, we identify BHB as a potentially immunomodulatory metabolic substrate for microglia that promotes metabolic reprogramming during pro-inflammatory response.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

β-Hydroxybutyrate Oxidation Promotes the Accumulation of Immunometabolites in Activated Microglia Cells

et al. 2020

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“…In fact, studies of caloric restriction have shown that feeding can induce adipose tissue DNL, increase RER above 1.0, and lead to innate immune modulation. [26,69]…”

Section: Discussionmentioning

confidence: 99%

Sleeve Gastrectomy enhances glucose utilization and remodels adipose tissue independent of weight loss

Harris

Mina

Čabarkapa

et al. 2019

Preprint

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Objective: Sleeve gastrectomy (SG) induces weight-loss independent improvements in glucose homeostasis by unknown mechanisms. We sought to identify the metabolic adaptations responsible for these improvements.Methods: Non-obese C57Bl6/J mice on standard chow underwent SG or sham surgery. Functional testing and indirect calorimetry were used to capture metabolic phenotypes. Tissuespecific glucose uptake was assessed by 18-FDG PET/CT and RNA sequencing was used for gene expression analysis.Results: In this model, SG induced durable improvements in glucose tolerance despite not causing lasting changes in weight, fat/lean mass, or food intake. Indirect calorimetry revealed post-SG animals had respiratory exchange ratios (RER) nearing 1.0 on average and had daily RER excursions above 1.0, indicating preferential glucose utilization and increased energy demand, respectively. Sham operated mice demonstrate normal RER feeding/fasting excursions. PET/CT showed increased avidity within white adipose depots. Finally, SG led to an upregulation in the transcriptional pathways involved in energy metabolism, adipocyte maturation, and adaptive and innate immune cell chemotaxis and differentiation within the visceral adipose tissue.Conclusions: SG induces a rapid, weight-loss independent shift towards glucose utilization and transcriptional remodeling of metabolic and immune pathways in visceral adipose tissue.

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“…We have recently shown that knocking down a serine-threonine kinase gene drl-1 using RNAi leads to a DR-like phenotype that extends life and health span (Chamoli et al 2014). Non-genetically, DR can be implemented by diluting bacteria in liquid media (Bishop and Guarente 2007;Panowski et al 2007) or on solid media plates (Greer et al 2007;Wu et al 2019), by peptone restriction (Hosono et al 1989), by feeding a non-hydrolysable glucose analog (Schulz et al 2007) or even by complete depletion of bacterial feed (Kaeberlein et al 2006). Interestingly but quite expectedly, the transcription factor requirements also vary with the model of DR. For e.g., the key transcription factor required in DR regime on solid plates is DAF-16 while for eat-2 mutants, drl-1 KD worms and for bacterial dilution in liquid, PHA-4 is required (Chamoli et al 2014;Greer et al 2007;Panowski et al 2007).…”

Section: Introductionmentioning

confidence: 99%

The genetic paradigms of dietary restriction fail to extend life span in cep-1(gk138) mutant of C. elegans p53 due to possible background mutations

Goyala

Baruah

Mukhopadhyay

2020

Preprint

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AbstractDietary restriction (DR) increases life span and improves health in most model systems tested, including non-human primates. In C. elegans, as in other models, DR leads to reprogramming of metabolism, improvements in mitochondrial health, large changes in gene expression, including increase in expression of cytoprotective genes, better proteostasis etc. Understandably, multiple global transcriptional regulators like transcription factors FOXO/DAF-16, FOXA/PHA-4, HSF1/HSF-1 and NRF2/SKN-1 are important for DR longevity. Considering the wide-ranging effects of p53 on organismal biology, we asked whether the C. elegans ortholog, CEP-1 is required for DR-mediated longevity assurance. We employed the widely-used TJ1 strain of cep-1(gk138). We show that cep-1(gk138) suppresses the life span extension of two genetic paradigms of DR, but two non-genetic modes of DR remain unaffected in this strain. We find that in cep-1(gk138), two aspects of DR, increased autophagy and the up-regulation of expression of cytoprotective xenobiotic detoxification program (cXDP) genes are dampened. Importantly, we find that background mutation(s) in the strain may be the actual cause for the phenotypic differences that we observed and cep-1 may not be directly involved in genetic DR-mediated longevity assurance in worms. Identifying these mutation(s) may reveal a novel regulator of longevity required specifically by genetic modes of DR.

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Dietary Restriction Extends Lifespan through Metabolic Regulation of Innate Immunity

Cited by 133 publications

References 77 publications

β-Hydroxybutyrate Oxidation Promotes the Accumulation of Immunometabolites in Activated Microglia Cells

β-Hydroxybutyrate Oxidation Promotes the Accumulation of Immunometabolites in Activated Microglia Cells

Sleeve Gastrectomy enhances glucose utilization and remodels adipose tissue independent of weight loss

The genetic paradigms of dietary restriction fail to extend life span in cep-1(gk138) mutant of C. elegans p53 due to possible background mutations

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