Elevating acetyl-CoA levels reduces aspects of brain aging

Because old age is the greatest risk factor for dementia, a successful therapy will require an understanding of the physiological changes that occur in the brain with aging. Here, two structurally distinct Alzheimer's disease (AD) drug candidates, CMS121 and J147, were used to identify a unique molecular pathway that is shared between the aging brain and AD. CMS121 and J147 reduced cognitive decline as well as metabolic and transcriptional markers of aging in the brain when administered to rapidly aging SAMP8 mice. Both compounds preserved mitochondrial homeostasis by regulating acetyl-coenzyme A (acetyl-CoA) metabolism. CMS121 and J147 increased the levels of acetyl-CoA in cell culture and mice via the inhibition of acetyl-CoA carboxylase 1 (ACC1), resulting in neuroprotection and increased acetylation of histone H3K9 in SAMP8 mice, a site linked to memory enhancement. These data show that targeting specific metabolic aspects of the aging brain could result in treatments for dementia.

Download Full-text

Effect of phenylpyruvate on enzymes involved in fatty acid synthesis in rat brain

Biochemical Journal ◽

10.1042/bj1340545 ◽

1973 ◽

Vol 134 (2) ◽

pp. 545-555 ◽

Cited By ~ 24

Author(s):

John M. Land ◽

John B. Clark

Keyword(s):

Fatty Acid ◽

Citrate Synthase ◽

Mitochondrial Protein ◽

Fatty Acid Synthetase ◽

Acetyl Coa Carboxylase ◽

Acetyl Coa ◽

Adult Rats ◽

Malonyl Coa ◽

Old Rats ◽

The Brain

1. The activities of, and the effects of phenylpyruvate on, citrate synthase (EC 4.1.3.7), acetyl-CoA carboxylase (EC 6.4.1.2) and fatty acid synthetase derived from the brains of 14-day-old and adult rats were investigated. 2. The brain citrate synthase from 14-day-old rats had a Km for oxaloacetate of 2.38μm and for acetyl-CoA of 16.9μm, and a Vmax. of 838nmol of acetyl-CoA incorporation/min per mg of mitochondrial protein. From adult rat brain this enzyme had a Km for oxaloacetate of 2.5μm and for acetyl-CoA of 16.6μm and a Vmax. of 1070nmol of acetyl-CoA incorporated/min per mg of mitochondrial protein. Phenylpyruvate inhibited the enzyme from adult and young rat brains in a competitive fashion with respect to acetyl-CoA, with a Ki of 700μm. 3. The brain acetyl-CoA carboxylase from 14-day-old rats had a Km for acetyl-CoA of 21μm and a Vmax. of 0.248nmol/min per mg of protein, and from adult rats a Km for acetyl-CoA of 21μm and a Vmax. of 0.173nmol/min per mg of protein. The enzyme from young and adult rats required citrate (Ka=3mm) for activation and were inhibited non-competitively by phenylpyruvate, with a Ki of 10mm. 4. The brain fatty acid synthetase from 14-day-old rats had a Km for acetyl-CoA of 7.58μm and a Vmax. of 1.1 nmol of malonyl-CoA incorporated/min per mg of protein, and from adult rats a Km for acetyl-CoA of 4.9μm and a Vmax. of 0.48nmol of malonyl-CoA incorporated/min per mg of protein. Phenylpyruvate acted as a competitive inhibitor with respect to acetyl-CoA with a Ki of 250μm for the enzyme from 14-day-old rats. 5. These results are discussed with respect to phenylketonuria, and it is suggested that the inhibition of the brain fatty acid synthetase and possibly the citrate synthetase by phenylpyruvate could explain the defective myelination characteristic of this condition.

Download Full-text

Insulin activation of lipogenesis in isolated mammary acini from lactating rats fed on a high-fat diet. Evidence that acetyl-CoA carboxylase is a site of action

Biochemical Journal ◽

10.1042/bj2420905 ◽

1987 ◽

Vol 242 (3) ◽

pp. 905-911 ◽

Cited By ~ 16

Author(s):

M R Munday ◽

D H Williamson

Keyword(s):

Glucose Uptake ◽

High Fat Diet ◽

Acetyl Coa Carboxylase ◽

High Fat ◽

Acetyl Coa ◽

Carboxylase Activity ◽

Glucose Incorporation ◽

Site Of Action ◽

A Site

Feeding lactating rats on high-fat cheese crackers in addition to laboratory chow increased the dietary intake of fat from 2 to 20% of the total weight of food eaten and decreased mammary-gland lipogenesis in vivo by approx. 50%. This lipogenic inhibition was also observed in isolated mammary acini, where it was accompanied by decreased glucose uptake. These inhibitions were completely reversed by incubation with insulin. Insulin had no effect on the rate of glucose transport into acini, nor on pyruvate dehydrogenase activity as estimated by the accumulation of pyruvate and lactate, suggesting that these are not the sites of lipogenic inhibition. Insulin stimulated the incorporation of [1-14C]acetate into lipid in acini from high-fat-fed rats. In the presence of alpha-cyanohydroxycinnamate, a potent inhibitor of mitochondrial pyruvate transport, and with glucose as the sole substrate, neither [1-14C]glucose incorporation into lipid nor glucose uptake were stimulated by insulin. Insulin did stimulate the incorporation of [1-14C]acetate into lipid in the presence of alpha-cyanohydroxycinnamate, and this was accompanied by an increase in glucose uptake by the acini. This indicated that increased glucose uptake was secondary to the stimulation of lipogenesis by insulin, which therefore must occur via activation of a step in the pathway distal to mitochondrial pyruvate transport. Insulin stimulated acetyl-CoA carboxylase activity measured in crude extracts of acini from high-fat-fed rats, restoring it to values close to those of chow-fed controls. The effects of insulin on acetyl-CoA carboxylase activity and lipogenesis were not antagonized by adrenaline or dibutyryl cyclic AMP.

Download Full-text

Impaired Mitophagy in Neurons and Glial Cells during Aging and Age-Related Disorders

International Journal of Molecular Sciences ◽

10.3390/ijms221910251 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10251

Author(s):

Vladimir Sukhorukov ◽

Dmitry Voronkov ◽

Tatiana Baranich ◽

Natalia Mudzhiri ◽

Alina Magnaeva ◽

...

Keyword(s):

Glial Cells ◽

Brain Aging ◽

Cellular Level ◽

Aging Brain ◽

The Past ◽

Age Related ◽

Accumulation Of Damage ◽

Quantity Control ◽

The Brain

Aging is associated with a decline in cognitive function, which can partly be explained by the accumulation of damage to the brain cells over time. Neurons and glia undergo morphological and ultrastructure changes during aging. Over the past several years, it has become evident that at the cellular level, various hallmarks of an aging brain are closely related to mitophagy. The importance of mitochondria quality and quantity control through mitophagy is highlighted by the contribution that defects in mitochondria–autophagy crosstalk make to aging and age-related diseases. In this review, we analyze some of the more recent findings regarding the study of brain aging and neurodegeneration in the context of mitophagy. We discuss the data on the dynamics of selective autophagy in neurons and glial cells during aging and in the course of neurodegeneration, focusing on three mechanisms of mitophagy: non-receptor-mediated mitophagy, receptor-mediated mitophagy, and transcellular mitophagy. We review the role of mitophagy in neuronal/glial homeostasis and in the molecular pathogenesis of neurodegenerative disorders, such as Parkinson’s disease, Alzheimer’s disease, and other disorders. Common mechanisms of aging and neurodegeneration that are related to different mitophagy pathways provide a number of promising targets for potential therapeutic agents.

Download Full-text

Neuronal induction of BNIP3-mediated mitophagy slows systemic aging in Drosophila

10.21203/rs.3.rs-438556/v1 ◽

2021 ◽

Author(s):

Edward Schmid ◽

Jung-Hoon Pyo ◽

David Walker

Keyword(s):

Brain Aging ◽

Mitochondrial Outer Membrane ◽

Concomitant Increase ◽

Mitochondrial Content ◽

Mitochondrial Quality Control ◽

Interacting Protein ◽

Mitochondrial Homeostasis ◽

Effects Of Aging ◽

The Brain ◽

Novel Therapeutic

Abstract The effects of aging on the brain are widespread and present at both the cellular and functional level. Mitochondrial dysfunction is a hallmark of brain aging, but, the interplay between mitochondrial quality control, neuronal aging, and organismal health is not well understood. Here, we show that aging leads to a decline in mitochondrial autophagy (mitophagy) in the Drosophila brain and a concomitant increase in mitochondrial content. We find that induction of BCL2-interacting protein 3 (BNIP3), a mitochondrial outer membrane protein, in the adult nervous system induces mitophagy and prevents the accumulation of dysfunctional mitochondria in the aged brain. Importantly, neuronal induction of BNIP3-mediated mitophagy increases organismal longevity and healthspan. Furthermore, neuronal BNIP3-mediated mitophagy improves mitochondrial homeostasis and proteostasis in aged muscle, indicating cell non-autonomous effects. In addition, neuronal BNIP3-mediated mitophagy improves intestinal homeostasis in aged flies. Our findings identify BNIP3 as a novel therapeutic target to counteract brain aging and prolong overall organismal health with age.

Download Full-text

Bioinformatic Analysis Reveals Key Genes and Pathways in Aging Brain of Senescence-accelerated Mouse P8 (SAMP8)

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527317666180816094741 ◽

2018 ◽

Vol 17 (9) ◽

pp. 712-722 ◽

Cited By ~ 5

Author(s):

Jiaqi Li ◽

Yuzhi Zhou ◽

Guanhua Du ◽

Xuemei Qin ◽

Li Gao

Keyword(s):

Signaling Pathway ◽

Gene Network ◽

Brain Aging ◽

Aging Brain ◽

Hub Genes ◽

Qrt Pcr ◽

Key Genes ◽

Samp8 Mice ◽

Key Pathways ◽

Senescence Accelerated Mouse

Background: Aging is a complex process accompanied with the decline of the different physiological functions. Numerous differentially expressed genes (DEGs) have been found in the aging brain of senescence-accelerated mouse P8 (SAMP8), however, it was challenging to screen out the crucial ones. Objective: This study aimed to explore the crucial genes and pathways in aging brain of SAMP8 mice, which would be beneficial for understanding the pathogenesis of brain aging. Methods: Firstly, 430 genes that are differentially expressed in SAMP8 mice versus SAMR1 mice were obtained from 9 gene expression studies, and gene-gene network was constructed. Clustering analysis and topological analysis were used to single out the hub genes from this network. Secondly, pathway enrichment analysis was utilized to identify the key pathways from the 430 DEGs, and the DEGs in key pathways were considered as functional genes. Thirdly, the inner-network between hub genes and functional genes was constructed, and the key genes were predicted. Parts of the key genes were experimentally verified by quantitative real-time PCR (qRT-PCR), and the associated transcription factors (TFs) were predicted. Results: Our results revealed that 12 crucial genes might affect brain aging, including Trp53, Bcl2, Tnf, Casp9, Fos, Il6, Ptgs2, Il1b, Bdnf, Cdkn1a, Pik3c3, Rps6ka1, among which Casp9, Fos, Ptgs2, Cdkn1a, Pik3c3, and Rps6ka1 had been verified by qRT-PCR in 10-moth-old SAMP8 mice. Five functional groups including mitogen-activated protein kinase (MAPK) signaling pathway, neurotrophin signaling pathway, Hepatitis B, Alzheimer's disease and Oxytocin signaling pathway were significantly changed during aging process in SAMP8 mice. Two key transcription factors of c-Fos and C/EBPbeta were predicted by constructing a TF-target gene network. Conclusion: These putative genes and pathways are closely related to brain senescence and our results would gain new insight into the pathogenesis of brain aging.

Download Full-text

Characterization of a far upstream located promoter expressing the acetyl-CoA carboxylase-alpha in the brain of cattle

Gene ◽

10.1016/j.gene.2012.12.033 ◽

2013 ◽

Vol 515 (2) ◽

pp. 266-271 ◽

Cited By ~ 1

Author(s):

Xuanming Shi ◽

Cornelia C. Metges ◽

Hans-Martin Seyfert

Keyword(s):

Acetyl Coa Carboxylase ◽

Acetyl Coa ◽

The Brain

Download Full-text

Metabolic triad in brain aging: mitochondria, insulin/IGF-1 signalling and JNK signalling

Biochemical Society Transactions ◽

10.1042/bst20120260 ◽

2013 ◽

Vol 41 (1) ◽

pp. 101-105 ◽

Cited By ~ 45

Author(s):

Fei Yin ◽

Tianyi Jiang ◽

Enrique Cadenas

Keyword(s):

Functional Outcomes ◽

Redox Regulation ◽

Brain Aging ◽

Second Messengers ◽

Cell Signalling ◽

Signalling Pathways ◽

Aging Brain ◽

Phosphatidylinositol 3 Kinase ◽

The Brain ◽

Kinase Pathway

Mitochondria generate second messengers, such as H2O2, that are involved in the redox regulation of cell signalling and their function is regulated by several cytosolic signalling pathways. IIS [insulin/IGF1 (insulin-like growth factor 1) signalling] in the brain proceeds mainly through the PI3K (phosphatidylinositol 3-kinase)–Akt (protein kinase B) pathway, which is involved in the regulation of synaptic plasticity and neuronal survival via the maintenance of the bioenergetic and metabolic capacities of mitochondria. Conversely, the JNK (c-Jun N-terminal kinase) pathway is induced by increased oxidative stress and JNK translocation to the mitochondrion results in impairment of energy metabolism. Moreover, IIS and JNK signalling interact with and antagonize each other. This review focuses on functional outcomes of a metabolic triad that entails the co-ordination of mitochondrial function (energy transducing and redox regulation), IIS and JNK signalling, in the aging brain and in neurodegenerative disorders, such as Alzheimer's disease.

Download Full-text

The neural economics of brain aging

Scientific Reports ◽

10.1038/s41598-021-91621-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jacob Kosyakovsky

Keyword(s):

Brain Aging ◽

Simultaneous Equation ◽

Equation Model ◽

Aging Brain ◽

Human Lifespan ◽

Linear Simultaneous Equation ◽

Brain Changes ◽

Changes Over Time ◽

The Brain ◽

Resource Budget

AbstractDespite remarkable advances, research into neurodegeneration and Alzheimer Disease (AD) has nonetheless been dominated by inconsistent and conflicting theory. Basic questions regarding how and why the brain changes over time remain unanswered. In this work, we lay novel foundations for a consistent, integrated view of the aging brain. We develop neural economics—the study of the brain’s infrastructure, brain capital. Using mathematical modeling, we create ABC (Aging Brain Capital), a simple linear simultaneous-equation model that unites aspects of neuroscience, economics, and thermodynamics to explain the rise and fall of brain capital, and thus function, over the human lifespan. Solving and simulating this model, we show that in each of us, the resource budget constraints of our finite brains cause brain capital to reach an upper limit. The thermodynamics of our working brains cause persistent pathologies to inevitably accumulate. With time, the brain becomes damaged causing brain capital to depreciate and decline. Using derivative models, we suggest that this endogenous aging process underpins the pathogenesis and spectrum of neurodegenerative disease. We develop amyloid–tau interaction theory, a paradigm that bridges the unnecessary conflict between amyloid- and tau-centered hypotheses of AD. Finally, we discuss profound implications for therapeutic strategy and development.

Download Full-text

Structure and function of the aging brain

10.31219/osf.io/25vbs ◽

2018 ◽

Cited By ~ 1

Author(s):

R. Nathan Spreng ◽

Gary R. Turner

Keyword(s):

Brain Aging ◽

American Psychological Association ◽

Functional Change ◽

Structure And Function ◽

Aging Brain ◽

Adult Lifespan ◽

Age Related ◽

Brain Changes ◽

And Function ◽

The Brain

In this opening section of the Aging Brain we set the stage for the contributions that follow by providing a broad overview of the latest advances in our understanding of how the brain changes, both structurally and functionally, across the adult lifespan. We leave domain-specific aspects of brain aging to the subsequent chapters, where contributors will provide more targeted accounts of brain change germane to their particular focus on the aging brain. Here we review the extant, and rapidly expanding literature to provide a brief overview and introduction to structural and functional change that occur with typical brain aging. We begin the chapter by looking back, to review some of the early discoveries about how the brain changes across the adult lifespan. We close the chapter by looking forward, towards new discoveries that challenge our core assumptions about the inevitability or irreversibility of age-related brain changes. These sections serve as bookends for the core of the chapter where we review the latest research advances that continue to uncover the mysteries of the aging brain. Spreng, R.N., Turner, G.R. (2019, forthcoming) Structure and function of the aging brain. In G Samanez-Larkin (Ed.) The aging brain. Washington DC: American Psychological Association.

Download Full-text

Cornel iridoid glycoside ameliorated Alzheimer's disease-like pathologies and necroptosis through RIPK1/MLKL pathway in young and aged SAMP8 mice

10.21203/rs.3.rs-230305/v1 ◽

2021 ◽

Author(s):

Denglei Ma ◽

Yanzheng Li ◽

Yanqiu Zhu ◽

Weipeng Wei ◽

Li Zhang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Brain Aging ◽

Neuronal Loss ◽

Iridoid Glycoside ◽

Intragastric Administration ◽

Cornel Iridoid Glycoside ◽

Samp8 Mice ◽

The Brain

Abstract Background Aging is an important risk factor for sporadic Alzheimer’s disease (AD) and other neurodegenerative diseases. Senescence-accelerated mouse-prone 8 (SAMP8) is used as an animal model for brain aging and sporadic AD researches. The aim of the current study was to investigate the pharmacological effects of cornel iridoid glycoside (CIG), an active ingredient of Cornus officinalis, on AD-type pathological changes in young and aged SAMP8 mice. Methods Nissl and immunohistochemical staining was applied to detect NeuN-labeled neurons and myelin basic protein-labeled myelin sheath,. Western blotting was used to detect the expression levels of related proteins of synapse, APP processing and necroptosis. Results The results showed that SAMP8 mice at the age of 6 and 14 months exhibited age-related neuronal loss, demyelination, synaptic damage, and APP amyloidogenic processing. In addition, the increased levels of receptor-interacting protein kinase-1 (RIPK1), mixed lineage kinase domain-like protein (MLKL) and p-MLKL indicating necroptosis were found in the brain of SAMP8 mice. Intragastric administration of CIG for 2 months alleviated neuronal loss and demyelination, increased the expression of synaptophysin, postsynaptic density protein 95 and AMPA receptor subunit 1, elevated the levels of soluble APPα fragment and a disintegrin and metalloproteinase 10 (ADAM10), and decreased the levels of RIPK1, p-MLKL and MLKL in the brain of young and aged SAMP8 mice. Conclusion This study denoted that CIG might be a potential drug for aging-associated neurodegenerative diseases such as AD.

Download Full-text