Caloric restriction increases ketone bodies metabolism and preserves blood flow in aging brain

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Abstract

Caloric restriction (CR) has been shown to increase the life span and health span of a broad range of species. However, CR effects on in vivo brain functions are far from explored. In this study, we used multimetric neuroimaging methods to characterize the CR-induced changes of brain metabolic and vascular functions in aging rats. We found that old rats (24 months of age) with CR diet had reduced glucose uptake and lactate concentration, but increased ketone bodies level, compared with the age-matched and young (5 months of age) controls. The shifted metabolism was associated with preserved vascular function: old CR rats also had maintained cerebral blood flow relative to the age-matched controls. When investigating the metabolites in mitochondrial tricarboxylic acid cycle, we found that citrate and α-ketoglutarate were preserved in the old CR rats. We suggest that CR is neuroprotective; ketone bodies, cerebral blood flow, and α-ketoglutarate may play important roles in preserving brain physiology in aging.

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Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization.

L Pellerin, P. Magistretti (1994)

Glutamate, released at a majority of excitatory synapses in the central nervous system, depolarizes neurons by acting at specific receptors. Its action is terminated by removal from the synaptic cleft mostly via Na(+)-dependent uptake systems located on both neurons and astrocytes. Here we report that glutamate, in addition to its receptor-mediated actions on neuronal excitability, stimulates glycolysis--i.e., glucose utilization and lactate production--in astrocytes. This metabolic action is mediated by activation of a Na(+)-dependent uptake system and not by interaction with receptors. The mechanism involves the Na+/K(+)-ATPase, which is activated by an increase in the intracellular concentration of Na+ cotransported with glutamate by the electrogenic uptake system. Thus, when glutamate is released from active synapses and taken up by astrocytes, the newly identified signaling pathway described here would provide a simple and direct mechanism to tightly couple neuronal activity to glucose utilization. In addition, glutamate-stimulated glycolysis is consistent with data obtained from functional brain imaging studies indicating local nonoxidative glucose utilization during physiological activation.

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The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR.

Randall Chin, Xudong Fu, Melody Pai … (2014)

Metabolism and ageing are intimately linked. Compared with ad libitum feeding, dietary restriction consistently extends lifespan and delays age-related diseases in evolutionarily diverse organisms. Similar conditions of nutrient limitation and genetic or pharmacological perturbations of nutrient or energy metabolism also have longevity benefits. Recently, several metabolites have been identified that modulate ageing; however, the molecular mechanisms underlying this are largely undefined. Here we show that α-ketoglutarate (α-KG), a tricarboxylic acid cycle intermediate, extends the lifespan of adult Caenorhabditis elegans. ATP synthase subunit β is identified as a novel binding protein of α-KG using a small-molecule target identification strategy termed drug affinity responsive target stability (DARTS). The ATP synthase, also known as complex V of the mitochondrial electron transport chain, is the main cellular energy-generating machinery and is highly conserved throughout evolution. Although complete loss of mitochondrial function is detrimental, partial suppression of the electron transport chain has been shown to extend C. elegans lifespan. We show that α-KG inhibits ATP synthase and, similar to ATP synthase knockdown, inhibition by α-KG leads to reduced ATP content, decreased oxygen consumption, and increased autophagy in both C. elegans and mammalian cells. We provide evidence that the lifespan increase by α-KG requires ATP synthase subunit β and is dependent on target of rapamycin (TOR) downstream. Endogenous α-KG levels are increased on starvation and α-KG does not extend the lifespan of dietary-restricted animals, indicating that α-KG is a key metabolite that mediates longevity by dietary restriction. Our analyses uncover new molecular links between a common metabolite, a universal cellular energy generator and dietary restriction in the regulation of organismal lifespan, thus suggesting new strategies for the prevention and treatment of ageing and age-related diseases.

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Attenuation of age-related changes in mouse neuromuscular synapses by caloric restriction and exercise.

Gregorio Valdez, Juan Tapia, Hyuno Kang … (2010)

The cellular basis of age-related behavioral decline remains obscure but alterations in synapses are likely candidates. Accordingly, the beneficial effects on neural function of caloric restriction and exercise, which are among the most effective anti-aging treatments known, might also be mediated by synapses. As a starting point in testing these ideas, we studied the skeletal neuromuscular junction (NMJ), a large, accessible peripheral synapse. Comparison of NMJs in young adult and aged mice revealed a variety of age-related structural alterations, including axonal swellings, sprouting, synaptic detachment, partial or complete withdrawal of axons from some postsynaptic sites, and fragmentation of the postsynaptic specialization. Alterations were significant by 18 mo of age and severe by 24 mo. A life-long calorie-restricted diet significantly decreased the incidence of pre- and postsynaptic abnormalities in 24-mo-old mice and attenuated age-related loss of motor neurons and turnover of muscle fibers. One month of exercise (wheel running) in 22-mo-old mice also reduced age-related synaptic changes but had no effect on motor neuron number or muscle fiber turnover. Time-lapse imaging in vivo revealed that exercise partially reversed synaptic alterations that had already occurred. These results demonstrate a critical effect of aging on synaptic structure and provide evidence that interventions capable of extending health span and lifespan can partially reverse these age-related synaptic changes.

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Author and article information

Journal

Journal ID (nlm-journal-id): 8100437

Journal ID (pubmed-jr-id): 6047

Journal ID (nlm-ta): Neurobiol Aging

Journal ID (iso-abbrev): Neurobiol. Aging

Title: Neurobiology of aging

ISSN (Print): 0197-4580

ISSN (Electronic): 1558-1497

Publication date Nihms-submitted: 23 April 2015

Publication date (Electronic): 25 March 2015

Publication date (Print): July 2015

Publication date PMC-release: 01 July 2016

Volume: 36

Issue: 7

Pages: 2296-2303

Affiliations

[a ] Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA

[b ] Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA

[c ] Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

[d ] Institutional Mass Spectrometry Laboratory, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

[e ] Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

[f ] Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

Author notes

[* ] Corresponding author at: Sanders-Brown Center on Aging, University of Kentucky, 800 S. Limestone, Lexington, KY 40536, USA. Tel.: +1859 323 6671; fax: +1 859 257 4136. ailing.lin@ 123456uky.edu (A.-L. Lin).

Article

Manuscript ID: NIHMS682669

DOI: 10.1016/j.neurobiolaging.2015.03.012

PMC ID: 4457572

PubMed ID: 25896951

SO-VID: d0c5bb16-35b4-4d94-93d4-25149ebac72f

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This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

Caloric restriction increases ketone bodies metabolism and preserves blood flow in aging brain

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Most cited references 45

Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization.

The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR.

Attenuation of age-related changes in mouse neuromuscular synapses by caloric restriction and exercise.

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