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Nourishing the Aging BrainResearch reveals how the brain changes as we age and hints at ways to slow the decline.

By Morten ScheibyeKnudsen | March 1, 2015

he quest for immortality has inspired humankind since the dawn of civilization. Diverse ancient mythsand religious stories tell of miracle drinks that bestowed eternal life on the gods, while kings across the

ages have quested for comparable reallife elixirs. Chinese emperors, drawn by the promise of eternal life,swallowed concoctions containing everything from gold to arsenic and mercury, an often lethal cocktail.More recently, the late North Korean dictator Kim IlSung purportedly received transfusions of blood fromyoung donors in hopes of extending his life. All these failed attempts at achieving longevity underscore theharsh truth that death will, inevitably, overtake us. Nevertheless, a century of research has brought uscloser than ever to understanding what causes aging and what might be done to postpone its ultimateoutcome.

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Restricting the caloric

intake of rats increases

their life span by up to 50

percent, an observation

that has been repro duced

in organisms as distantly

related as yeast,

Drosophila, and

Caenorhabditis ele gans.

One of the earliest successful attempts to extend life in the lab came from Cornell biochemist andnutritionist Clive McCay some 80 years ago, when he discovered that restricting the caloric intake of ratsincreased their life span by up to 50 percent. This observation has since been reproduced in organisms asdistantly related as yeast, Drosophila, and Caenorhabditis elegans. But despite a wealth of research intowhy caloric restriction extends life, we are still rather far from pinpointing the mechanism behind thelongevity effect of this dietary intervention. Of significant interest is how diets may affect aging in thebrain, which is particularly sensitive to alterations in energy availability. Caloric restriction attenuates theprogression of Alzheimer’s disease in mouse models, for example, while dietinduced obesity exacerbatessymptoms. Conversely, recent findings from our lab suggest that accelerated brain aging, as seen in theprematureaging disease Cockayne syndrome, may be slowed through increased caloric and fat intake,while caloric restriction accelerates disease progression.1

Clearly, caloric restriction is not universallybeneficial. But by studying the influence of diet onaging in the brain, researchers have discovered anumber of bioenergetic molecules and druggabletargets that may serve as candidates forinterventions to delay the onset ofneurodegenerative disorders. Thus, whileimmortality remains a fantasy, living a longerhealthy life may be an achievable goal.

Caloric restriction and health

Of the many benefits of caloric restriction,improved ability to maintain glucose homeostasis isprobably the best established. Caloric restrictionimproves glucose tolerance, decreases insulinsecretion from the pancreas, and increases insulinsensitivity in the peripheral tissues in modelorganisms as well as in humans. Not surprisingly,mice and humans on caloric restriction are alsoleaner, with reduced fat accumulation in the liver, resulting in a decreased risk of developing fatty liverdisease. Markers of inflammation also decrease, and cardiovascular parameters such as blood pressureimprove—effects that can also be explained by improved insulin signaling and glucose homeostasis.

In addition, calorierestricted animals are smaller than their wellfed counterparts, perhaps correspondingto decreased cell proliferation, a phenomenon that occurs in response to energy deficits in both normal andcancer cells. Decreased cell proliferation may be important, since a cell can only undergo a finite number ofdivisions before it ceases to divide, a phenomenon called cellular senescence. In simple organisms such asyeast, two types of life span can be defined: a chronological life span, or the length of time a yeast cell cansurvive, and a replicative life span, or the number of cell divisions a yeast cell can undergo. Limitedreplicative potential is also observed in mammalian cells, where it is referred to as the Hayflick limit. (See“Of Cells and Limits.”) Decreased cell proliferation also leads to slower division of stem cells, allowing theseprogenitor cell populations to supply the various cell types of the body for longer periods of time. Thissparing of stemcell pools could explain why dietary restriction is particularly effective in maintaining tissuehomeostasis in rapidly proliferating tissues such as skin, hair, and bone marrow.

Neural tissues, such as the brain and spinal cord, have a limited capacity to rejuvenate themselvesthrough stemcell renewal, however, perhaps explaining why dietary restriction may not impact theseareas of the body as much as others. To complicate matters, rodents and many other model organisms donot normally suffer from neurodegeneration, and a possible neuroprotective effect of caloric restrictiontherefore cannot be extrapolated from longevity studies interrogating dietary interventions in thosemodels. In order to circumvent this problem, researchers are studying neurodegenerative and prematureaging diseases in humans to understand the effect of diet on brain health and aging.

Diet and disease

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BRAIN DRAIN: The brain has a remarkably highmetabolism, consuming some 20 percent of the totalbody energy under resting conditions. Largely unable tometabolize fatty acids for energy, the brain depends onglucose and secondary metabolites synthesized fromfatty acids called ketones. Studies of severalneurological disorders, which tend to be associatedwith increased basal metabolism, suggest that diseaseprogression can be influenced by switching the energysource from glucose to ketones.See full infographic: JPG | PDF© DUNG HOANG

Age-associated disorders

such as Alzheimer’s,

Parkinson’s, Huntington’s,

and ALS appear to be influ-enced by dietary energetic

intake.

University of California, Los Angeles, researcherRoy Walford, a pioneer in the field of caloricrestriction, felt so strongly about the benefits ofthis dietary intervention that he even practiced aversion of it himself, convinced that it would allowhim to live to age 120. Nevertheless, he wasdiagnosed with amyotrophic lateral sclerosis (ALS),a rapidly progressing neurodegenerative disorder,and died in 2004 at age 79. It is now relatively wellestablished that caloric restriction exacerbates theprogression of ALS, while increasing caloric intakeattenuates the disease. This may reflect anincrease in basal energy consumption in ALSpatients.2 Indeed, a recent study suggests that ALSpatients can ingest a highcalorie diet withoutdeveloping diseases such as obesity and diabetes.3

Unfortunately, the increased catabolism, incombination with progressive feeding difficulties,leads to significant weight loss in ALS patients.

These observations suggest that caloric intake canprofoundly alter neurological health, supporting theidea that the human brain may be particularlysensitive to alterations in energy homeostasis. Thissensitivity may stem from the organ’s remarkablyhigh metabolism: under resting conditions, thebrain consumes roughly 20 percent of total bodyenergy production, despite constituting only aminute fraction of body weight. In addition, thebrain does not store energy as glycogen or fats asother organs do. In fact, the nervous system islargely unable to metabolize fatty acids for energy.Thus, the brain is highly dependent on glucose as a fuel source. Likely due to this strong glucoserequirement for normal brain function, the majority of glucose uptake in the brain is insulin independent.Insulin increases brain glucose uptake by 10 to 20 percent, however, and central insulin resistance, whichmay occur in type2 diabetes, decreases this insulinstimulated glucose uptake.

As an alternative to glucose, the brain can drawenergy from ketones, a group of metabolitessynthesized from fatty acids in the liver.Interestingly, the addition of ketones as analternative fuel source for the brain attenuates theprogression of Alzheimer’s in a mouse model of thedisease.4 In contrast, fattyacid ingestion isassociated with the development of the disease,though likely only in carriers of the APOE4 riskallele. The mechanism for this is not wellunderstood but may involve the role of APOE4 inthe transport of cholesterol in the blood. Increasedingestion of fat leads to increases in circulatingcholesterol levels that may predispose individualswith APOE4 to atherosclerosis, which in the brain vasculature is an independent risk factor for thedevelopment of Alzheimer’s. Notably, diabetes, which leads to widespread atherosclerosis, is also anAlzheimer’s risk factor.

Although this is speculative, one could imagine a decrease in neuronal energetic availability, due to insulinresistance and atherosclerosis of the brain vasculature, being involved in the pathogenesis of Alzheimer’s



DNA DAMAGE IN AGING CELLS: A highfat diet, and inparticular a ketogenic diet, can rescue symptoms inanimal models of Cockayne syndrome, an acceleratedaging disorder caused by defects in DNA repair,suggesting that genome instability introduces metabolicalterations that occur in the aging process.Accumulation of damaged DNA leads to activation ofpolyADPribose polymerase 1 (PARP1). As aconsequence, levels of NAD+, a cofactor in glycolysis,and acetylCoA, an alternative to lactate as the outcomeof glycolysis, decline, as does the activity of mammaliansirtuin SIRT1, which normally metabolizes NAD+ todrive the deacetylation of proteins such as histones andtranscription factors. Pharmacological inhibition ofPARP1, restoration of NAD+ levels, increases in ketonelevels, and activation of SIRT1 have all shown promisein attenuating agerelated decline.See full infographic: JPG | PDF© DUNG HOANG

disease. Similarly, a failure to meet the neuronal energy requirement in ALS may lead to loss of motorneurons. Further evidence for the role of dysregulated energy homeostasis in the body’s neurons comesfrom Huntington’s disease, a neurodegenerative disorder characterized by loss of voluntary movements,dementia, and often psychiatric symptoms. Like ALS patients, those suffering from Huntington’scommonly have increased basal metabolism and unexplained weight loss. Interestingly, feeding aketogenic diet slows disease progression in mouse models of both ALS and Huntington’s diseases.5,6 And inParkinson’s patients, who also tend to show increased energy expenditure and weight loss, a ketogenic diethas likewise shown promising results.7

It is clear that certain ageassociated disorders such as Alzheimer’s, Parkinson’s, Huntington’s, and ALSappear to be influenced by dietary energy intake.8 (See illustration.) Nevertheless, little is known abouthow normal brain aging is modulated by dietary changes. Because many model systems, including rodents,do not naturally develop neurodegeneration, this has been a particularly challenging problem to address.

Premature aging

Another window into normal brain aging could bedisorders characterized by premature agerelatedchanges in the brain. Cockayne syndrome patients,for example, develop very severeneurodegeneration—in addition to a host of otherpremature aging symptoms and extreme weightloss—and usually die by their teenage years.9 Thedisease is exceedingly rare and is, in most cases,caused by mutations in the CSA or CSB genes,which encode two proteins involved in DNA repair.CSA and CSB proteins may also be involved in thecontrol of transcription and in remodeling proteinsthat bind and package DNA, such as histones. Still,there is no good mechanistic explanation for thepathogenesis of this disease.

One intriguing aspect of Cockayne syndrome is howsimilar its clinical presentation is to known primarymitochondrial disorder symptoms, includingprogressive atrophy of the brain, lactateaccumulation, hearing loss, and seizures. Sincemitochondrial dysfunction has long been suspectedto be a hallmark of the aging process, a defect inthis crucial organelle’s function could explain theaccelerated aging features in Cockayne syndrome.Indeed, mitochondrial dysfunction has beenobserved in cells from Cockayne patients as well asin mice that harbor a truncation mutation in themurine homologue of human CSB. Like Cockaynesyndrome patients, these mice show increasedbasal metabolism and loss of fat deposits. Feedingthese animals a highfat diet, however, rescuesthem from the disease phenotype, while caloricrestriction exacerbates features of acceleratedaging.

Because the mammalian brain does not metabolizefatty acids, a secondary metabolite, such asketones, could be responsible for the beneficial effect of the highfat diet. Indeed, ketones increase the lifespan of a shortlived nematode model of Cockayne syndrome. Ketones also ameliorate mitochondrial



changes in models of Cockayne syndrome and have recently been shown to have life spanextendingproperties in wildtype C. elegans. Interestingly, ketogenesis, the production of ketones as a result of fattyacid breakdown, can be induced by fasting, suggesting that ketones could play a central role in theincreased longevity effects of caloric restriction observed in the lab. Fasting, however, also leads to adecrease in blood glucose levels, perhaps leading to brain energy shortage in diseases such as Cockaynesyndrome, where energy demand is increased.

The observation that ketones may slow aging caused by defects in DNA repair also suggests a link betweengenome instability and metabolic alterations. Levels of lactate, formed from pyruvate during glycolysis, areincreased in the brain of Cockayne syndrome patients as well as in aged individuals. One factor influencingthese levels is the ratio of NAD+ to NADH, cofactors in the conversion of pyruvate to lactate.

NAD+ is a particularly interesting compound in the context of DNA repair. In the process of DNAdamagesignaling, this molecule is consumed by the enzyme polyADPribose polymerase 1 (PARP1), which haspreviously been shown to be increasingly activated with age. Indeed, PARP1 is hyperactivated in severalaccelerated aging disorders thought to be caused by defects in DNA repair and concomitant accumulationof DNA damage. Greater PARP1 activity uses up more NAD+, leading to a decrease in the NAD+/NADHratio and increased shunting of glucose to lactate. This also results in decreased production of acetylCoA,an alternative outcome of glycolysis and the fuel source for the mitochondrial citric acid cycle. (Seeillustration.) But cells can also get acetylCoA by metabolizing ketones and fatty acids, and it is likely thatthe beneficial effects of a highfat diet in Cockayne syndrome mouse models can be attributed to thenormalization of acetylCoA levels.

In addition to being an important redox factor and DNArepair metabolite, NAD+ is a required molecule forthe function of enzymes known as sirtuins, coded by a group of longevity genes, the activation of whichmay be central in the lifeextending effects of caloric restriction in nematodes and flies.10 These sirtuinenzymes metabolize NAD+ to drive the deacetylation of various proteins such as histones and transcriptionfactors. As a result of agerelated decline in NAD+, the activity of the mammalian sirtuin SIRT1 appears tobe decreased. Interestingly, reconstitution of NAD+ from precursor molecules can rescue such ageassociated phenotypes, and in mouse skeletal muscle this effect may depend on SIRT1.11

Recent data suggest that the lifeextending effects of ketones and NAD+ both converge on the activationof SIRT1.1 The role of SIRT1 in these processes may be of particular interest given that SIRT1 is highlyexpressed in the brain and represents a druggable target with multiple specific pharmacological activatorscurrently being developed.12 Indeed, several of these activators appear to be able to extend the life span ofrodents. The efficacy of these compounds in ameliorating brain aging will be a particularly exciting aspect toinvestigate in future studies.

In the hunt for youth

Although a wealth of knowledge regarding interventions in specific ageassociated diseases such asAlzheimer’s and Parkinson’s diseases have been reported, little is known about interventions that maymodulate normal brain aging. We are, however, getting closer to an understanding of fundamental aspectsof neurological aging, and we may soon be able to intervene in the aging process as a whole, perhaps withthe benefit of preventing Alzheimer’s, Parkinson’s, and other ageassociated neurological diseases.Increasing the level of circulating ketones, through dietary interventions or exogenous ketone sources,may be one relatively easy way to intervene, and could be efficacious either alone or in combination withother targeted interventions. Further studies are needed to understand the optimal dietary regimens andsupplements, but there are grounds for optimism.

Morten ScheibyeKnudsen is a research fellow at the National Institute on Aging. His research

has focused on brain aging and how various interventions might attenuate agerelated

neurological decline.

References



You

RosielakoPosts: 1

1. M. ScheibyeKnudsen et al., “A highfat diet and NAD(+) activate Sirt1 to rescue premature aging inCockayne syndrome,” Cell Metab, 20:84055, 2014.

2. L. Dupuis et al., “Energy metabolism in amyotrophic lateral sclerosis,” Lancet Neurol, 10:7582,2011.

3. A.M. Wills et al., “Hypercaloric enteral nutrition in patients with amyotrophic lateral sclerosis: arandomised, doubleblind, placebocontrolled phase 2 trial,” Lancet, 383:206572, 2014.

4. Y. Kashiwaya et al., “A ketone ester diet exhibits anxiolytic and cognitionsparing properties, andlessens amyloid and tau pathologies in a mouse model of Alzheimer’s disease,” Neurobiol Aging,34:153039, 2013.

5. D.N. Ruskin et al., “A ketogenic diet delays weight loss and does not impair working memory ormotor function in the R6/2 1J mouse model of Huntington’s disease,” Physiol Behav, 103:50107,2011.

6. Z. Zhao et al., “A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateralsclerosis,” BMC Neurosci: 7:29, 2006.

7. T.B. VanItallie et al., “Treatment of Parkinson disease with dietinduced hyperketonemia: afeasibility study,” Neurology, 64:72830, 2005.

8. V.D. Longo, M.P. Mattson, “Fasting: molecular mechanisms and clinical applications,” Cell Metab,19:18192, 2014.

9. M.A. Nance, S.A. Berry, “Cockayne syndrome: review of 140 cases,” Am J Med Genet, 42:6884,1992.

10. S. Imai, L. Guarente, “NAD+ and sirtuins in aging and disease,” Trends Cell Biol, 24, 46471, 2014.11. A.P. Gomes et al., “Declining NAD(+) induces a pseudohypoxic state disrupting nuclear

mitochondrial communication during aging,” Cell, 155:162438, 2013.12. D.A. Sinclair, L. Guarente, “Smallmolecule allosteric activators of sirtuins,” Annu Rev Pharmacol

Toxicol, 54:36380, 2014.

Clarification: An editorial change to this story may have given the incorrect impression that Morten

ScheibyeKnudsen headed the lab whose work was described. He was actually research associate at that

time. The Scientist regrets any misunderstanding.

Tags

premature aging disease, neurodegenerative diseases, Mitochondrial disease, metabolism, Glucosemetabolism, energy metabolism, energy, disease/medicine, brain and aging

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March 2, 2015

Interesting piece, thanks. I was recently diagnosed with normal pressurehydrocephalus, another neuro condition associated with aging, and oftenmistaken for AD or PD. Is anything known of energy metabolism inhydrocephalus patients?

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March 5, 2015

So all I get from http://en.wikipedia.org/wiki/Ketone is:

"Many sugars are ketones, known collectively as ketoses. The best knownketose is fructose "

Is ther ANY more info on what "foods" provide ketones ?

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March 6, 2015

Correct periodic fasting slows down aging

Michael Lerman, "The biological essence of resting cells in cell populations"

J. Theoretical Biopogy, 1978

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Nourishing the Aging Brain The Scientist Magazine®nadconcierge.com/wp-content/uploads/2016/01/...sirtuin SIRT1, which normally metabolizes NAD+ to drive the deacetylation of proteins