Regulation of metabolic health and aging by nutrient-sensitive signaling pathways

Cummings, Nicole E.; Lamming, Dudley W.

doi:10.1016/j.mce.2016.11.014

Cited by 69 publications

(48 citation statements)

References 137 publications

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“…mTORC1 inactivation during nutrient starvation and ER stress due to misfolded protein accumulation – the unfolded protein response (UPR) – both converge on the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which decreases protein translation while increasing translation of ATF4, the master transcriptional regulator of stress adaptation genes including autophagy genes (Cummings and Lamming, 2016; Saxton and Sabatini, 2017). We observed prominent eIF2α phosphorylation in response to live but not dead L. innocua (Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

STING Senses Microbial Viability to Orchestrate Stress-Mediated Autophagy of the Endoplasmic Reticulum

Moretti

Roy

Bozec

et al. 2017

Cell

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282

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SUMMARY Constitutive cell-autonomous immunity in metazoans predates interferon-inducible immunity and comprises primordial innate defense. Phagocytes mobilize interferon-inducible responses upon engagement of well-characterized signaling pathways by pathogen-associated molecular patterns (PAMPs). The signals controlling deployment of constitutive cell-autonomous responses during infection have remained elusive. Vita-PAMPs denote microbial viability, signaling the danger of cellular exploitation by intracellular pathogens. We show that cyclic-di-adenosine monophosphate in live Gram-positive bacteria is a vita-PAMP engaging the innate sensor Stimulator of Interferon Genes (STING) to mediate endoplasmic reticulum (ER) stress. Subsequent inactivation of the mechanistic Target of Rapamycin mobilizes autophagy, which sequesters stressed ER membranes, resolves ER stress, and curtails phagocyte death. This vita-PAMP-induced ER-phagy additionally orchestrates an interferon response by localizing ER-resident STING to autophagosomes. Our findings identify stress-mediated ER-phagy as a cell-autonomous response mobilized by STING-dependent sensing of a specific vita-PAMP, and elucidate how innate receptors engage multilayered homeostatic mechanisms to promote immunity and survival after infection.

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Section: Resultsmentioning

confidence: 99%

STING Senses Microbial Viability to Orchestrate Stress-Mediated Autophagy of the Endoplasmic Reticulum

Moretti

Roy

Bozec

et al. 2017

Cell

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282

246

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“…Furthermore, enrichment analysis suggested that both epigenetic AA measures were associated to genetic variants in genes involved in pathways related to the regulation of cell metabolism and immune function. Among the gene sets associated to AgeAccel differences between T1 and T0, it is worth to note the presence of the mTOR pathway, which plays a pivotal role in the regulation of nutrients-sensing and energy metabolism during aging (Cummings and Lamming 2017;Tosti et al 2018;Lushchak et al 2019). In animal models, it has been previously demonstrated the influence of a genetic component in the response to a nutritional intervention, such as caloric restriction (CR) (Liao et al 2010).…”

Section: Discussionmentioning

confidence: 99%

One-year Mediterranean diet promotes epigenetic rejuvenation with country- and sex-specific effects: a pilot study from the NU-AGE project

et al. 2020

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Mediterranean diet has been proposed to promote healthy aging, but its effects on aging biomarkers have been poorly investigated. We evaluated the impact of a 1-year Mediterranean-like diet in a pilot study including 120 elderly healthy subjects from the NU-AGE study (60 Italians, 60 Poles) by measuring the changes in their epigenetic age, assessed by Horvath's clock. We observed a trend towards epigenetic rejuvenation of participants after nutritional intervention. The effect was statistically significant in the group of Polish females and in subjects who were epigenetically older at baseline. A genome-wide association study of epigenetic age changes after the intervention did not return significant (adjusted p value < 0.05) loci. However, we identified small-effect alleles (nominal p value < 10-4), mapping in genes enriched in pathways related to energy metabolism, regulation of cell cycle, and of immune functions. Together, these findings suggest that Mediterranean diet can promote epigenetic rejuvenation but with country-, sex-, and individual-specific effects, thus highlighting the need for a personalized approach to nutritional interventions.

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“…Dietary MR produces many beneficial effects on metabolic health in both rodents and humans, preventing weight gain and fat accretion, and improving control of blood glucose (10, 18, 43, 44). However, humans have significant difficulties in remaining compliant with severe dietary alterations.…”

Section: Discussionmentioning

confidence: 99%

Short‐term methionine deprivation improves metabolic health via sexually dimorphic, mTORCI‐independent mechanisms

Yang

Miller

et al. 2018

FASEB j.

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Obesity and diabetes are major challenges to global health, and there is an urgent need for interventions that promote weight loss. Dietary restriction of methionine promotes leanness and improves metabolic health in mice and humans. However, poor long-term adherence to this diet limits its translational potential. In this study, we develop a short-term methionine deprivation (MD) regimen that preferentially reduces fat mass, restoring normal body weight and glycemic control to diet-induced obese mice of both sexes. The benefits of MD do not accrue from calorie restriction, but instead result from increased energy expenditure. MD promotes increased energy expenditure in a sex-specific manner, inducing the fibroblast growth factor (Fgf)-21-uncoupling protein (Ucp)-1 axis only in males. Methionine is an agonist of the protein kinase mechanistic target of rapamycin complex (mTORC)-1, which has been proposed to play a key role in the metabolic response to amino acid-restricted diets. In our study, we used a mouse model of constitutive hepatic mTORC1 activity and demonstrate that suppression of hepatic mTORC1 signaling is not required for the metabolic effects of MD. Our study sheds new light on the mechanisms by which dietary methionine regulates metabolic health and demonstrates the translational potential of MD for the treatment of obesity and type 2 diabetes.-Yu, D., Yang, S. E., Miller, B. R., Wisinski, J. A., Sherman, D. S., Brinkman, J. A., Tomasiewicz, J. L., Cummings, N. E., Kimple, M. E., Cryns, V. L., Lamming, D. W. Short-term methionine deprivation improves metabolic health via sexually dimorphic, mTORC1-independent mechanisms.

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Regulation of metabolic health and aging by nutrient-sensitive signaling pathways

Cited by 69 publications

References 137 publications

STING Senses Microbial Viability to Orchestrate Stress-Mediated Autophagy of the Endoplasmic Reticulum

STING Senses Microbial Viability to Orchestrate Stress-Mediated Autophagy of the Endoplasmic Reticulum

One-year Mediterranean diet promotes epigenetic rejuvenation with country- and sex-specific effects: a pilot study from the NU-AGE project

Short‐term methionine deprivation improves metabolic health via sexually dimorphic, mTORCI‐independent mechanisms

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