Targeting glucose metabolism for healthy aging

Brewer, Rachel A.; Gibbs, Victoria K.; Smith, Daniel L.

doi:10.3233/nha-160007

Cited by 61 publications

(52 citation statements)

References 205 publications

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“…T cells utilize a variety of energy sources including glucose and lipids; however, their metabolic preferences are governed not only by their differentiation status but also by mitochondria fitness (Cui et al, ). Indeed, a lack of regulatory control over nutrient usage is a recurrent theme accompanying senescence and aging (Brewer, Gibbs, & Smith, ). We therefore sort to determine whether there were differences in glucose and fatty acid uptake in CD4 + and CD8 + EMRA T cell subsets.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial mass governs the extent of human T cell senescence

et al. 2019

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The susceptibility of human CD4+ and CD8+ T cells to senesce differs, with CD8+ T cells acquiring an immunosenescent phenotype faster than the CD4+ T cell compartment. We show here that it is the inherent difference in mitochondrial content that drives this phenotype, with senescent human CD4+ T cells displaying a higher mitochondrial mass. The loss of mitochondria in the senescent human CD8+ T cells has knock‐on consequences for nutrient usage, metabolism and function. Senescent CD4+ T cells uptake more lipid and glucose than their CD8+ counterparts, leading to a greater metabolic versatility engaging either an oxidative or a glycolytic metabolism. The enhanced metabolic advantage of senescent CD4+ T cells allows for more proliferation and migration than observed in the senescent CD8+ subset. Mitochondrial dysfunction has been linked to both cellular senescence and aging; however, it is still unclear whether mitochondria play a causal role in senescence. Our data show that reducing mitochondrial function in human CD4+ T cells, through the addition of low‐dose rotenone, causes the generation of a CD4+ T cell with a CD8+‐like phenotype. Therefore, we wish to propose that it is the inherent metabolic stability that governs the susceptibility to an immunosenescent phenotype.

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Section: Resultsmentioning

confidence: 99%

Mitochondrial mass governs the extent of human T cell senescence

et al. 2019

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“…The salutary healthful aging properties of the RGS14 KO are mediated by BAT, involving a SIRT3 mechanism and its ability to improve metabolism and mitochondrial function, also known to mediate healthful aging (Bratic & Trifunovic, 2010; Brewer, Gibbs & Smith, 2016; Herranz et al., 2010). The latter point was confirmed by experiments with BAT transplants, which reversed the phenotypes of the RGS14 KO and WT, such that the WT with the BAT transplant did not exhibit the adverse phenotype of aging and demonstrated improved cold exposure tolerance and oxygen consumption, whereas the RGS14 KO donors no longer possessed these features of healthful aging.…”

Section: Discussionmentioning

confidence: 99%

Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14

et al. 2018

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SummaryDisruption of the regulator for G protein signaling 14 (RGS14) knockout (KO) in mice extends their lifespan and has multiple beneficial effects related to healthful aging, that is, protection from obesity, as reflected by reduced white adipose tissue, protection against cold exposure, and improved metabolism. The observed beneficial effects were mediated by improved mitochondrial function. But most importantly, the main mechanism responsible for the salutary properties of the RGS14 KO involved an increase in brown adipose tissue (BAT), which was confirmed by surgical BAT removal and transplantation to wild‐type (WT) mice, a surgical simulation of a molecular knockout. This technique reversed the phenotype of the RGS14 KO and WT, resulting in loss of the improved metabolism and protection against cold exposure in RGS14 KO and conferring this protection to the WT BAT recipients. Another mechanism mediating the salutary features in the RGS14 KO was increased SIRT3. This mechanism was confirmed in the RGS14 X SIRT3 double KO, which no longer demonstrated improved metabolism and protection against cold exposure. Loss of function of the Caenorhabditis elegans RGS‐14 homolog confirmed the evolutionary conservation of this mechanism. Thus, disruption of RGS14 is a model of healthful aging, as it not only enhances lifespan, but also protects against obesity and cold exposure and improves metabolism with a key mechanism of increased BAT, which, when removed, eliminates the features of healthful aging.

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“…There is recognition across neurodegenerative diseases that glucoregulatory control decreases with aging, spawning clinical trials designed to ameliorate the effects of aging through the use of compounds like metformin (ClinicalTrials.gov Identifier: NCT02432287) or acarbose (Brewer et al, 2016). These trials do not address glaucoma in particular, but may impact the disease through improved glucoregulatory control.…”

Section: Resolving Metabolic Vulnerabilitymentioning

confidence: 99%

Metabolic Vulnerability in the Neurodegenerative Disease Glaucoma

Inman

Harun‐Or‐Rashid

2017

Front. Neurosci.

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Axons can be several orders of magnitude longer than neural somas, presenting logistical difficulties in cargo trafficking and structural maintenance. Keeping the axon compartment well supplied with energy also presents a considerable challenge; even seemingly subtle modifications of metabolism can result in functional deficits and degeneration. Axons require a great deal of energy, up to 70% of all energy used by a neuron, just to maintain the resting membrane potential. Axonal energy, in the form of ATP, is generated primarily through oxidative phosphorylation in the mitochondria. In addition, glial cells contribute metabolic intermediates to axons at moments of high activity or according to need. Recent evidence suggests energy disruption is an early contributor to pathology in a wide variety of neurodegenerative disorders characterized by axonopathy. However, the degree to which the energy disruption is intrinsic to the axon vs. associated glia is not clear. This paper will review the role of energy availability and utilization in axon degeneration in glaucoma, a chronic axonopathy of the retinal projection.

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Targeting glucose metabolism for healthy aging

Cited by 61 publications

References 205 publications

Mitochondrial mass governs the extent of human T cell senescence

Mitochondrial mass governs the extent of human T cell senescence

Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14

Metabolic Vulnerability in the Neurodegenerative Disease Glaucoma

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