Altered brain mitochondrial metabolism in healthy aging as assessed by in vivo magnetic resonance spectroscopy

Abstract

A decline in brain function is a characteristic feature of healthy aging; however, little is known about the biologic basis of this phenomenon. To determine whether there are alterations in brain mitochondrial metabolism associated with healthy aging, we combined (13)C/(1)H magnetic resonance spectroscopy with infusions of [1-(13)C]glucose and [2-(13)C]acetate to quantitatively characterize rates of neuronal and astroglial tricarboxylic acid cycles, as well as neuroglial glutamate-glutamine cycling, in healthy elderly and young volunteers. Compared with young subjects, neuronal mitochondrial metabolism and glutamate-glutamine cycle flux was approximately 30% lower in elderly subjects. The reduction in individual subjects correlated strongly with reductions in N-acetylaspartate and glutamate concentrations consistent with chronic reductions in brain mitochondrial function. In elderly subjects infused with [2-(13)C]acetate labeling of glutamine, C4 and C3 differed from that of the young subjects, indicating age-related changes in glial mitochondrial metabolism. Taken together, these studies show that healthy aging is associated with reduced neuronal mitochondrial metabolism and altered glial mitochondrial metabolism, which may in part be responsible for declines in brain function.

Figure 1

Typical position of the spectroscopic volume of interest (∼100 mL) and brain segmentation into gray matter (GM, left), white matter (WM, center), or cerebral spinal fluid (CSF, right) from two healthy young (top) and elderly volunteers (bottom). In spite of the overall brain atrophy in the elderly subjects, the proportion of gray and white matter in the volumes of interest was similar (Young: %GM=47±1% versus Elderly: %GM=49±2%).

Figure 2

Time courses of glutamate (A and B) and glutamine (C and D) ¹³C concentrations for C4 and C3 positions from one young (left, dark symbols) and one elderly (right, open symbols) volunteer during the infusion of [1-¹³C]glucose (top) and during the infusion of [2-¹³C]acetate (bottom). The corresponding best fits by the metabolic model are shown as solid lines through the data points. The scale for glutamine is adjusted to facilitate the visualization of the kinetics. Symbols: Glu-C4: squares (▪ and □); Glu-C3: diamonds (⧫ and ◊); Gln-C4: triangles (▴ and Δ); Gln-C3: circles. (○ and •).

Figure 3

Pearson's correlation coefficients. (A and B) calculated between neuronal metabolites Glu and NAA and V_TCAn, neuronal TCA cycle rate; (C) calculated between astroglial metabolite Ins and V_TCAg, glial TCA cycle rate. Closed circles: individual values measured for Elderly (n=7). Open circles: average values for the respective metabolite concentrations from a young cohort (n=7). Fluxes and metabolite concentrations are expressed as μmol per g per min, and μmol per g, respectively.

Figure 4

Neuronal-astroglial metabolic model and fluxes altered with aging. ¹³C label that is incorporated from [2-¹³C]acetate or [1-¹³C]glucose enters the mitochondrial TCA cycle of astroglia and neurons (primarily), respectively. The exchange of label into the glutamine pool that is localized to the astroglia and the glutamate pool that is primarily neuronal allows the rates of the astroglial and neuronal TCA cycles to be measured. Label will cross from the neurons to the astroglia and back through the glutamate–glutamine cycle in which released neurotransmitter glutamate is taken up by the astroglia, converted to glutamine, and then released back to the neuron for restoration of the glutamate pool. We found that both the neuronal TCA cycle and the glutamate–glutamine cycle were reduced, and that the astroglial TCA cycle was increased in healthy elderly subjects. The primary findings are a decrease in both V_cycle and V_TCAn in the elderly subjects. There was also a measured increase in the rate of the glial TCA cycle in the elderly subjects; however, we have placed it in parentheses because of the possibility of other changes in glial metabolic pathways accounting for the difference in labeling patterns, in particular anaplerosis. Left: neuronal compartment; Right: astroglial compartment. Abbreviations: Lac, lactate; Glc, glucose; Pyr, pyruvate; AcCoA, acetyl coenzyme A; OAA, oxaloacetate; αKG, α-ketoglutarate; Glu, glutamate; Gln, glutamine; Asp, aspartate; V_ac, acetate consumption rate; V_PDHn, flux through neuronal pyruvate dehydrogenase; V_PDHg, astroglial flux through the pyruvate dehydrogenase; V_TCAn, neuronal TCA cycle rate; V_TCAg, glial TCA cycle rate; V_PC, flux through pyruvate carboxylase; V_cycle, glutamate–glutamine cycle rate.