. Holding Onto Youth. Cell Metab. 2017 Aug 1;26(2):284-285. PubMed.

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  1. I am a big fan of the work Marc Raichle and his colleagues have done relating to both the default mode network and aerobic glycolysis. It is an understudied process that may be of great importance to brain development, brain aging, and the predisposition to AD.

    In previous studies, Dr. Raichle and his colleagues found that the pattern of aerobic glycolysis in young adults (highest in precuneus, posterior cingulate, and frontal regions) is similar to, and predictive of, the earliest pattern of amyloid plaque deposition at older ages. This raises questions about the mechanisms underlying aerobic glycolysis that conspire with age to provide a foothold for preferential vulnerability to amyloid plaques.

    In the present study, they seem to show that those same regions associated with highest aerobic glycolysis in young adults are also associated with the greatest declines with aging, even in the absence of amyloid plaque deposition. The findings raise interesting and important questions about the relationship of these physiological changes to other biological changes associated with normal brain aging, such as declines in the density, connectivity, function, or turnover of terminal neuronal fields that innervate these regions or the density, connectivity, or function of peri-synaptic astroglial cells.

    For instance, prior studies of normal aging have noted a preferential reduction of terminal neuronal fields innervating frontal cortex—not to mention how some of these changes may conspire with other factors in the predisposition to Alzheimer’s disease.

    View all comments by Eric M. Reiman
  2. While the physiologic phenomenon of aerobic glycolysis (AG) may seem somewhat obscure to a clinical audience, what it represents seems far more tangible. The authors brilliantly articulate the relationship between AG and transcriptional “neoteny,” that is, the relative persistence of childhood developmental gene expression.

    At a macro level they describe a gradual “flattening” with age of the topographic variability of AG that characterizes the young brain, perhaps reflecting a reduction in synaptic and dendritic spine development with age. 

    While this may be a normal physiological development of old age, an associated aspect of decreasing AG is a loss of neuroprotection via the pentose phosphate pathway that protects against oxidative stress, thus increasing the risk for oxidative damage. This, in turn, may be a key predisposing factor to neurodegenerative diseases such as Alzheimer’s and Parkinson’s and may be one reason why these diseases are age-related.

    View all comments by Richard Caselli
  3. Aerobic glycolysis (AG) is thought to play a crucial role for the metabolic demands of the developing brain, including those required by synaptic plasticity and myelination, and for neuroprotection. Goyal et al. here demonstrate in this study a clear relationship between brain aging and decrease of AG. These important findings elegantly draw on the previous work from the same team, where they had showed a similar association between AG and brain development.

    Notably, in both studies, they have been able to correlate the spatial distribution of AG in the brain to gene expression related to prolonged development. In this current work, they have also shown that age-related, regional changes of AG are very strongly associated with those levels of AG at young adulthood. 

    Altogether, this provides a strong metabolic hypothesis as to why the regions of the brain that develop later might be the ones more vulnerable to oxidative stress and age-related neurodegeneration (something we, and others, have previously observed). 

    It will be very interesting to see, as the authors point out, whether this might also be related to loss of myelination. This is something for which Big Data imaging projects, such as the Lifespan Human Connectome Project or the U.K. Biobank Brain Imaging Study, might provide direct, quantifiable answers.

    View all comments by Gwenaelle Douaud
  4. This article describes the evolution of aerobic glycolysis (AG) in the brain during normal aging. The term aerobic glycolysis refers to the non-oxidative metabolism of glucose before its oxidative phosphorylation (a deeper description of the process can be found in a previous article from the authors, Vlassenko and Raichle, 2015). AG results in the formation of lactate, despite adequate levels of available oxygen that could potentially lead to oxidative phosphorylation processes. PET can provide measurement of not only metabolic rate of glucose (CMRGlu) but also metabolic rate of oxygen (CMRO2), which allows estimation of glucose metabolism outside of oxidative phosphorylation, or aerobic glycolysis (AG). The authors developed methods to measure AG.

    In a previous article (Goyal et al., 2014), they showed that AG occurs in the brain in the context of neoteny. This term means that the developmental processes are prolonged after the birth. Cerebral neoteny is one of the particularities of human species. In other words, the developing human brain requires AG. The functions of metabolic products from AG (lactate or other products) are thus probably critical for brain development and plasticity (see for example, Magistretti, 2016). 

    Here, the authors describe various levels of AG in different brain regions of young subjects and its high occurrence in neotenic cerebral areas. They also show that AG maps flatten with aging, mainly because of AG decrease in the neotenic areas. The age-related decrease of AG occurs independently of the presence of amyloid plaques. However, in previous articles the authors showed that amyloid plaques occurs in the regions with high AG in young subjects (see Vlassenko et al., 2010). They also showed that regions with high AG in young subjects are close to the regions involved in resting state networks which are supposed to be very active in the normal brain (see Vlassenko and Raichle, 2015). These are the same regions in which amyloid deposits in AD patients. The relationship between all these events remains unclear but this article further emphasizes the need to better evaluate the impact of alteration of glucose metabolism and its various sub-entities such as aerobic glycolysis on the occurrence of neurodegenerative processes. The authors have already been working on the relationships between changes in glucose metabolisms and amyloid deposition (see Macauley et al., 2015). In any case, the article is interesting as it points to a mechanism that might be central to the initiation of amyloid deposition in non-genetic forms of AD. 

    References:

    . Brain aerobic glycolysis functions and Alzheimer's disease. Clin Transl Imaging. 2015 Feb 1;3(1):27-37. Epub 2014 Dec 10 PubMed.

    . Aerobic glycolysis in the human brain is associated with development and neotenous gene expression. Cell Metab. 2014 Jan 7;19(1):49-57. PubMed.

    . Imaging brain aerobic glycolysis as a marker of synaptic plasticity. Proc Natl Acad Sci U S A. 2016 Jun 28;113(26):7015-6. Epub 2016 Jun 17 PubMed.

    . Spatial correlation between brain aerobic glycolysis and amyloid-β (Aβ ) deposition. Proc Natl Acad Sci U S A. 2010 Oct 12;107(41):17763-7. PubMed.

    . Hyperglycemia modulates extracellular amyloid-β concentrations and neuronal activity in vivo. J Clin Invest. 2015 Jun;125(6):2463-7. Epub 2015 May 4 PubMed.

    View all comments by Marc Dhenain

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