,

*Pennington Biomedical Research Center/Louisiana State University System, Baton Rouge, Louisiana,

USA

�Instituto de Investigaciones Bioquımicas de Bahıa Blanca, Universidad Nacional del Sur and Consejo

Nacional de Investigaciones Cientıficas y Tecnicas, Bahıa Blanca, Argentina

What causes the brain to age?

Aging is a largely hypothetical construct that has a widerange of working definitions. For example, aging can bedefined as the collection of changes that increase over timeto promote morbidity and consequently render individualsprogressively more likely to die (Medawar 1952). Alter-natively, aging has been defined as a gradual deteriorationof physiological function with age (Partridge and Mangel1999). With regards to the aging of tissues, aging can bedefined as an intrinsic and potentially irreversible set ofprocesses which result in a loss of viability and increasedvulnerability (Comfort 1964). With specific regards to thebrain, it is well established that as the result of increasedchronological aging the brain undergoes numerous altera-tions at the molecular, cellular, and structural level. In thisreview we will discuss the potential roles of metabolicperturbations such as obesity and insulin resistance,serving as modulators for multiple aspects of brain aging.In addition, the links between high-fat diet consumption

and metabolic dysfunction are discussed in the context ofbrain aging.

Molecular and cellular changes in the aging brain

In regards to brain aging some of the most studied molecularand cellular changes can be grouped as being alterations inneurotransmitter signaling, increases in inflammatory signal-ing, and increases in oxidative stress (Fig. 1). Each of theseis discussed below and in later sections in the context of ageand diet-induced metabolic dysfunction.

Received April 3, 2010; revised manuscript received April 27, 2010;accepted April 29, 2010.Address correspondence and reprint requests to Dr. Jeffrey N. Keller,

Pennington Biomedical Research Center/LSU System, 6400 PerkinsRoad, Baton Rouge, LA 70808-4124, USA.E-mail: jeffrey.keller@pbrc.eduAbbreviations used: AD, Alzheimer’s disease; BBB, blood brain

barrier; CRP, C-reactive protein; HFD, high-fat diet; IL, interleukin;sICAM-1, soluble intracellular adhesion molecule-1.

Abstract

Deleterious neurochemical, structural, and behavioral alter-

ations are a seemingly unavoidable aspect of brain aging.

However, the basis for these alterations, as well as the basis

for the tremendous variability in regards to the degree to

which these aspects are altered in aging individuals, remains

to be elucidated. An increasing number of individuals regu-

larly consume a diet high in fat, with high-fat diet con-

sumption known to be sufficient to promote metabolic

dysfunction, although the links between high-fat diet con-

sumption and aging are only now beginning to be elucidated.

In this review we discuss the potential role for age-related

metabolic disturbances serving as an important basis for

deleterious perturbations in the aging brain. These data not

only have important implications for understanding the basis

of brain aging, but also may be important to the develop-

ment of therapeutic interventions which promote successful

brain aging.

Keywords: aging, brain, diabetes, insulin resistance, metab-

olism, neurodegeneration, obesity.

J. Neurochem. (2010) 114, 344–361.

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344 Journal Compilation � 2010 International Society for Neurochemistry, J. Neurochem. (2010) 114, 344–361� 2010 The Authors

Changes in neurotransmitter signaling within the agingbrainIn the aging brain, there are well documented changes inmultiple aspects of neurotransmitter signaling. For example,declines in the levels of neurotransmitters such as acetyl-choline are well documented in the aging brain (Gibson andPeterson 1981; Gibson et al. 1981; Bartus et al. 1982;Vannucchi and Pepeu 1987; Wu et al. 1988; Ogawa 1989;Terry and Buccafusco 2003) and age-related neurodegener-ative disorders such as Alzheimer’s disease (AD) (Bartuset al. 1982; Ogawa 1989; Tohgi et al. 1994; Terry andBuccafusco 2003; Jia et al. 2004). In addition, the levels anddensity of key neurotransmitters such as dopamine have beendemonstrated to be decreased in the aging brain (Carlsson1987; Volkow et al. 1996; Bannon and Whitty 1997; Wanget al. 1998; Meng et al. 1999). In contrast, studies indicate arole for excessive glutamate signaling occurring in the agingbrain, especially in age-related disorders such as AD,culminating in the development of neuron death throughexcitotoxicity (Coyle et al. 1981; Mattson et al. 1992,1995a,b; Coyle and Puttfarcken 1993; Sattler and Tymianski2000; Hynd et al. 2004). Together, these data point to grossimbalances in neurotransmitters occuring during brain agingand age-related diseases of the brain.

In addition to having an imbalance in the level ofneurotransmitters within the brain, additional studies havedocumented that there is a deleterious change in the levels ofkey neurotransmitter receptors during aging. For example, ithas been demonstrated that the glutamate receptor subunits(NR1, NR2A, and NR2B), and the a-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor decline with age(Clark et al. 1992; Gazzaley et al. 1996; Morrison and Hof1997; Eckles-Smith et al. 2000; Magnusson 2000; Sonntag

et al. 2000; Wenk and Barnes 2000; Clayton and Browning2001; Clayton et al. 2002; Shi et al. 2007; Adams et al.2008; Newton et al. 2008). Similarly, a number of studieshave also reported significant age-related decreases in thelevels of dopamine receptors D1, D2, and D3 (Wong et al.1984; Rinne et al. 1990; Iyo and Yamasaki 1993; Wanget al. 1998; Kaasinen et al. 2000). Decreasing levels ofdifferent serotonin receptors have also been shown to occurwith age. Particularly, humans studied by positron emissiontomography have shown that S2 serotonin receptors in thecaudate nucleus, putamen, and frontal cerebral cortex declinewith age (Wong et al. 1984). Regarding the levels ofcholinergic receptors, however, the effects of aging are stillunclear. Most studies seem to agree that there is a decrease inmuscarinic binding in rodent aging brain, but there iscontroversy as to which regions show a significant reductionin receptor density (James and Kanungo 1976; Freund 1980;Morin and Wasterlain 1980; Lippa et al. 1981; Pedigo et al.1984). Taken together, these data point to disturbances inboth neurotransmitters and neurotransmitter receptors occur-ring in the aging brain.

Increases in inflammatory signaling within the aging brainIncreased levels of inflammatory signaling are necessary formaintaining the function of all tissues, including the brain.However, in aging the brain appears to undergo at least threenegative perturbations in inflammatory signaling and im-mune function. The first of these negative alterations is thepresence of a chronic elevation in the levels of inflammatorysignaling. Increases in multiple aspects of inflammatorysignaling have been reported with aging including increasedlevels of tumor necrosis factor-a, interleukin (IL)-1, and IL-6(Ye and Johnson 1999; Tha et al. 2000; Terao et al. 2002;

Fig. 1 Interplay between metabolic dysfunction, high-fat diets (HFDs)

and brain aging. Consumption of a high-fat diet and the presence of

metabolic dysfunction (insulin resistance, adiposity, etc.) are associ-

ated with pathological brain aging. Pathological brain aging is linked to

excessive cognitive decline, high oxidative stress, alterations in brain

structure, and increased inflammatory signaling. In contrast, con-

sumption of a low-fat diet, caloric restriction, and maintenance of

metabolic function results in successful brain aging. The successful

brain aging is defined as preserved cognition, decreased oxidative

stress, preserved structure, and reduced inflammatory signaling.

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Spulber and Schultzberg 2010). Furthermore, studies havelinked increases in each of these factors to the developmentof neuropathology and neuronal dysfunction in the agingbrain (Strauss et al. 1992; Griffin et al. 1995; Patterson1995). In addition, the levels of cyclooxygenase andlipoxygenase, and their corresponding prostanoids andeicosanoids, are known to be chronically increased duringbrain aging (Uz et al. 1998; Manev et al. 2000; Qu et al.2000; Leone et al. 2007).

In addition to having a sustained increase in the basallevels of inflammatory signaling, aging is also known toimpair the coordinated nature of the immune response(Giunta 2008; Desai et al. 2010). In this model, multipleaspects of an immune response (time required to mount aresponse, the extent to which the response is activated, andthe rapidity to which the response is down-regulatedfollowing the triggering event) are adversely affected byage. This promotes a more inefficient and ineffectiveinflammatory signaling within aging tissues such as thebrain. Finally, aging appears to alter the magnitude ofperipheral immune cell infiltration into the brain followinginjury (Bolton and Perry 1998). Presumably, these cellscontribute to the modulation of resident immune signalingwithin the aging brain, although the potential role of thisobservation to age-related brain inflammation remains to befully elucidated.

Increases in oxidative stress within the aging brainOxidative stress occurs when the levels of oxidative damagereach a point that they promote the development of cellularand/or tissue dysfunction (Ding et al. 2006; Calabrese et al.2010). An increase in oxidative damage to proteins, lipids,nucleic acids, and sugars in the aging and AD brain is welldocumented (Adelman et al. 1988; Stadtman and Oliver1991; Sohal et al. 1995; Cai et al. 1996; Good et al. 1996;Smith et al. 1996; Berlett and Stadtman 1997; Sayre et al.1997; Gabbita et al. 1998; Perry et al. 1998; Nunomuraet al. 1999; Finkel and Holbrook 2000; Stadtman and Levine2000). Furthermore, studies have demonstrated that each ofthese forms of oxidative damage is sufficient to result indecreased function of essential proteins and organelles, andthereby contributing to the development of brain aging.Studies on the levels and activity of antioxidants andantioxidant enzymes in the aging and AD brain havedemonstrated a mixed bag of results (Calabrese et al. 2000,2003, 2004, 2006; Kitani et al. 2001; Maier and Chan 2002;Schmitt-Schillig et al. 2005; Droge and Schipper 2007;Navarro and Boveris 2008; Massaad et al. 2009) and itremains unclear to what extent decreased levels of antiox-idants may drive age-related increases in oxidative stress inthe brain. Perhaps most importantly for the purposes of thisreview, the oxidative stress has been implicated in mediatingthe effects of neurotransmitter dysregulation and increasedinflammatory signaling within the aging brain. Together,

these data highlight a model for interplay between each ofthese cellular processes and the modulation of brain aging.

Structural changes in the aging brain

In the context of brain aging the best studied structuralchanges include synaptic changes, white matter changes, andvascular changes. Each of these changes is outlined below,and then later in the review is discussed in the context ofaging and metabolic perturbations below.

Synaptic changesStudies have documented an aging-related decrease insynaptic number occurring in specific domains within bothexperimental animal studies as well as studies of humanbrains (Bertoni-Freddari et al. 2006). However, the size ofthese synapses has been found to be increased in theseexperimental settings (Bertoni-Freddari et al. 1990, 1992,1996). In both normal aging and AD brains, a negativecorrelation has been found between synapse number andsynapse size. This appears to potentially be a compensatoryresponse to minimize the effects of decreased synapsenumber, specifically to attempt to maintain the flux ofinformation at the junctional zones, and to stabilize thesynaptic contact per unit area (Scheff et al. 1990). However,ultimately the ability of the cortex to compensate seems to beexceeded and promote a decline in function (DeKosky andScheff 1990).

The mechanisms responsible for synaptic changes duringaging and AD are not clearly established. However, it hasbeen demonstrated that oxidative stress may contribute to thepathophysiology of aging. However, the contribution ofoxidative stress to the regulation of synaptic function isclearly complex. For example, it has been shown thatsuperoxide is necessary for synaptic plasticity and memory inyoung animals (Klann 1998; Klann et al. 1998; Thiels et al.2000; Knapp and Klann 2002; Thiels and Klann 2002), whilechronically elevated levels of superoxide likely contribute tosynaptic dysfunction during aging (Hu et al. 2006).

White matter changesThrough the use of neuroimaging technologies considerableadvances have been made in our understanding of how whitematter is altered in the aging brain. For example, regionaldifferences in regards to age-related susceptibilities in whitematter loss are known to occur (Guttmann et al. 1998; Hsuet al. 2008; Kennedy and Raz 2009; Lee et al. 2009), withprefrontal white matter observed to be most sensitive to theeffects of aging (Gunning-Dixon et al. 2009). In addition tochanges in white matter density, it is known that aging isassociated with an increase in white matter lesions (Barberet al. 1999; Launer 2003; Roman 2004; Bugalho et al. 2007;Adami et al. 2008). These deleterious perturbations inconnectivity throughout the brain are presumed to contribute

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to impairments in brain function. Despite our progress inbeing able to detect and measure white matter changes, thereare two questions that need to be answered in this researcharea. First, the role of white matter structural alterations asmediators of cognitive disturbances in the aging brain remainto be clarified beyond the point of correlation studies.Second, the mediators of white matter changes remain to beelucidated, although a role for metabolic disturbances asmediators of white matter pathology is clearly emerging.

Vascular changesAging, as well as many neurodegenerative disorders, areassociated with structural and functional alterations of thecerebral vascularization (Behrendt and Ganz 2002; Aguero-Torres et al. 2006). Aging is characterized by a loss ofelongation in endothelial cells, decreased number of endo-thelial mitochondria, and progressive impairment in endo-thelium-dependent vasodilation (d’Alessio 2004; Brandeset al. 2005; Finch 2005). In addition, aging is associated withcerebral blood flow dysregulation and hypoperfusion, abnor-mal angiogenesis and remodeling, all of which may promoteneuronal injury and death (de la Torre 2004; Xiao et al.2004). It is thought that an augmented production of pro-inflammatory cytokines and vasoactive molecules could bethe responsible of the cognitive decline, potentially through amechanism of suppression of cerebral blood flow andamplification of cellular stress (Zlokovic 2005).

Another feature of senescent endothelial cells is theincreased generation of endothelial adhesion molecules(d’Alessio 2004), markers of endothelial inflammation.Increased levels of blood adhesion molecules have beenreported in several brain disorders, namely atherosclerosis,ischemic stroke, cerebrovascular disease and AD (Frohmanet al. 1991; Fassbender et al. 1999; Roher et al. 2004). Inaddition, soluble intracellular adhesion molecule-1 (sICAM-1) has been shown to be present in high levels incerebrospinal fluid of individuals with inflammatory diseasesof the central nervous system, and it has been suggested thatcerebral endothelial cells are the primary source of sICAM-1(Roher et al. 2004). This raises the possibility for moleculessuch as sICAM-1 contributing to vascular reactivity in theaging brain.

An increase in blood brain barrier (BBB) permeability hasbeen documented to occur during aging in healthy individ-uals. Morphological changes of BBB have been also shownin rodent models of aging (Hosokawa and Ueno 1999). Assome of these models exhibit increased oxidative stress at anearly age (Yasui et al. 2003) prior to the development ofother pathological features, it has been suggested thatalterations in BBB could be promoted via oxidative stress-mediated mechanisms. On the other hand, it has beendemonstrated that hypertension, a common feature of olderpeople, can induce BBB alterations (Baumbach and Heistad1988; Nag and Kilty 1997). Taken together, these findings

highlight the complexity in understanding the relationshipbetween oxidative stress and morbidities such as hyperten-sion in regulating the biological aging of the brain.

Variability in rates and extent of brain aging

While it is clear that chronological aging promotes ageneralized aging phenotype in the brain, it is equally clearthat there is dramatic and significant variability in both therate and severity of such alterations. For example, studies inhumans document that there is considerable variability inregards to deterioration in cognitive performance withadvancing age (Hultsch et al. 2002; Williams et al. 2005).As variability at the performance level could be reflectingvariations and alterations at a cellular and system level in thebrain, understanding the basis for this observation is likelyimportant to understanding the basis of brain aging, anddeveloping interventions for promoting successful brainaging.

Our laboratory, as well as numerous other laboratories,believes there is an important role for age-related metabolicperturbations in mediating not only brain aging, but also inexplaining the basis for the variability in the rates of brainaging. There is mounting evidence for metabolic dysfunc-tion, in particular conditions such as obesity and insulinresistance, as significant contributors to the aging of modernwesternized societies.

It is well known that aging is associated with theprogressive development of generalized insulin resistance(DeFronzo 1981; Elahi et al. 2002), inhibition of lipolysis(Miller and Allen 1973; Nyberg et al. 1976; Kumar et al.1999) and a loss in hepatic control of glucose production(Gupta et al. 2000) and triglyceride secretion (Bravo et al.1996). Cumulatively, each of these manifestations is suffi-cient to promote an increase in a number of morbidity factorsincluding cardiovascular and cerebrovascular diseases, gas-trointestinal and respiratory alterations, cancer, and cognitivedecline and dementia (Perlmuter et al. 1988; Haslam andJames 2005; Qiu et al. 2007). Moreover, people fromcountries with traditionally higher mean lifespan are knownto undergo an increase in a number of morbidities afterchanging their nutritional intake towards energy-rich diets.However, the availability of pharmacological treatments forthese morbidities has allowed for these deleterious morbid-ities to not significantly decrease lifespan in the population(Picard and Guarante, 2005). Despite such progress, itremains unclear whether pharmacological management ofmetabolic disorders (obesity, insulin resistance, etc.) is ableto also preserve brain function as these same individuals age.

Age-related neurologic manifestations include sensorydeficits (taste, smell, vibration, vision, and hearing), distur-bances in sensing pain, motor dysfunction (altered gait andposture), sleep disturbances, and impaired memory andcognition. For example, aging promotes the slowing of

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central processing and therefore may prolong the time ittakes to complete tasks. Declines in motor strength, reflexresponses, and reaction time with aging are related to sensori-motor changes. Changes associated with aging also includemild forgetfulness, a decrease in vocabulary, and learningdifficulties (Braun and Anderson 2006). These changestypically occur by the seventh decade of life, but have a greatdeal of heterogeneity and variability in regards to the severityof dysfunction which is observed in elderly individuals(McClearn 1997). While the basis for the variability in brainaging is not known, one possible mediator is metabolicdysfunction, with increased levels of dietary fat intakeserving as a potential mediator of metabolic dysfunction. Forexample, high-fat diets are known to be sufficient to promoteinsulin resistance and obesity in both humans and rodents(Oakes et al. 1997; Tschop and Heiman 2001; Buettner et al.2007; Damjanovic and Barton 2008). What is less known iswhat effect high-fat diets have on aging, particularly brainaging. With the intersection of an increasing aging and obesesociety, that increasingly regularly consumes a high fat diet,it is clear that understanding the impact of diet-inducedmetabolic perturbations on the aging brain is of mountingclinical importance. The possible contribution of metabolicdysfunction as a modulator of brain aging raises thepossibility that factors such as diet may be centrally linkedto the regulation of brain aging. In particular, diet-inducedmetabolic dysfunction likely serves as a pro-aging stimulusfor multiple aspects of brain biochemistry and physiology.Interestingly, several clinical and epidemiological studies, aswell as experimental evidence in rodents, suggest that thepresence of Western diet-induced metabolic dysfunction issufficient to promote cognitive decline and even dementia,thus accelerating the normal process of aging.

Several abnormalities of carbohydrate and lipid metabo-lism have been commonly observed to increase in Westernsocieties with age, namely insulin resistance, hyperglycemia,hyperinsulinemia, dyslipemia, triglyceridemia, and free fattyacid alterations (Bullo et al. 2007; Matia et al. 2007;Steemburgo et al. 2007; Astrup et al. 2008; Pasinetti andEberstein 2008). However, it is not yet completely under-stood whether these alterations become manifest as aconsequence of the molecular mechanisms operating in theaging process or as a result of the influence of many cultural/environmental factors such as diet and a decrease in physicalactivity (Paolisso et al. 1995).

In the context of brain aging metabolic dysfunction mustbe understood not only in terms of diabetes but also in termsof pre-diabetic states where individuals exhibit hyperinsul-emia but remain euglycemic. A high concentration ofcirculating insulin (hyperinsulinemia) may represent a failurein insulin metabolism as well as a compensatory response toinsulin resistance. In either case, hyperinsulinemia is corre-lated with insulin resistance in pre-diabetic individuals(Laakso 1993; Howard et al. 1998). At this point it is worth

to mention that many studies have reported that the elderlyare more insulin resistant that young individuals (DeFronzo1979; Rowe et al. 1983; Chen et al. 1985; Coon et al. 1992;O’Shaughnessy et al. 1992; Ferrannini et al. 1996), althoughthis point remains controversial (Pacini et al. 1988; Brough-ton et al. 1991; Boden et al. 1993; Ahren and Pacini 1998;Dechenes et al. 1998). Important to take into account is thatseveral factors may influence insulin action and secretion,including the degree and type of obesity (Peiris et al. 1986),level of fitness (Kirwan et al. 1993; Miller et al. 1994), andcirculation hormone profiles (Rizza et al. 1982a,b; Nielsenet al. 1997). In addition, some studies have shown thatcentral obesity (increased waist-to-hip ratio) is associated toinsulin resistance and aging. Furthermore, the intra-abdom-inal fat depot in central-obesity has been postulated tocontribute most to the development of insulin resistance, andtherefore the insulin resistance observed in aging may berelated more to changes in body composition during agingthan to aging per se. Moreover, intra-abdominal fat has beenpostulated to be the most metabolically active of the adiposedepots and correlates with insulin resistance and age inhealthy non-diabetic individuals regardless of gender andafter controlling for obesity (Cefalu et al. 1995; Cefalu2001).

Adiposity

Adipose tissue has long been considered as a mere energy-store but is increasingly appreciated for its roles in partic-ipating in several physiological events such as inflammation,angiogenesis, hypertension, and vascular homeostasis(Fruhbeck 2008). Moreover, the adipose tissue synthesizesand secretes a large number of factors collectively termed‘adipokines’ (Fruhbeck 2008). More than 50 differentadipokines have been identified and characterized for theirrole in influencing energy homeostasis and feeding behaviour(Ahima and Osei 2008). However, an increasing number ofstudies have identified that adipokines may play a role inmediating long-term potentiation, neuroprotection, andneuroinflammation.

A major role for adipose tissue (adipocytes) is to sequesterand store circulating lipid, which protects other cells andtissues in the body from the cytotoxic effects of free fattyacids in the circulation. Failure of adipocytes to effectivelyremove free fatty acids from the circulation is believed tocontribute to a variety of health complications includinghypertension, atherosclerosis, and ultimately the develop-ment of metabolic syndrome (Fagot-Campagna et al. 1998;Moller and Kaufman 2005; Smith and Wilson 2006; Wanget al. 2008). Conversely, the deposition of adipose/lipid intomuscle, liver, or bone marrow is known to promote not onlymetabolic syndrome but localized tissue dysfunction (Kuket al. 2009). Therefore, it is clear that adipocytes performessential functions for the overall well being of individuals,

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but it is equally clear that adipose in the incorrect places or inexcessive quantity also negatively impacts the health of anindividual.

Aging is known to impair the ability of adipocytes tosequester free fatty acids, and promote the release of pro-inflammatory signals from adipose tissue. Many studies havesuggested that the decline in specific adipose depots isbecause of a decrease in adipocyte size and not a reduction innumber. Additional studies have demonstrated that agingimpairs the process of adipocyte differentiation resulting inan increase in more highly reactive pre-adipocytes. Pre-adipocytes do not have the capacity to sequester free fattyacids from the circulation to the same degree as matureadipocytes, and an age-related increase in pre-adipocytesmay therefore result in promotion of adverse events inregards to the regulation of circulating lipids. Taken together,these studies strongly suggest that aging has direct andcomplex effects on adipose tissue including a redistributionof adipose depots as well as fundamental alterations in thecell biology of adipocytes, which together may promotemetabolic dysfunction and inflammatory signaling through-out the body.

An increase in visceral adiposity is a common feature ofaging, and epidemiological evidence supports its role as aprominent risk factor for insulin resistance, diabetes, andmortality from atherosclerotic cardiovascular disease (Shim-okata et al. 1989; Cefalu et al. 1995; Ferrannini et al. 1997;Lamarche 1998; Fujimoto et al. 1999). Typically, elderlypeople have a lighter body weight as compared to youngerindividuals but increased waist circumference, consistentwith elevated levels of abdominal adipose tissue. It has beenobserved that a complex relationship exists between aging,obesity and increased visceral fat which is not alwayssufficient to promote insulin resistance (Carr et al. 2004). Ithas been reported that caloric restriction extends life in avariety of species and decreases the development of mostage-related diseases, and it is believed that these effects maybe because of the ability of dietary restriction to reduce fatstores, especially visceral fat. In addition, the removal ofvisceral fat in rats has demonstrated to improve insulinaction, delay the onset of age-dependent insulin resistance,glucose intolerance and diabetes, as well as increase in meanand maximum lifespan in rodent models of obesity anddiabetes (Barzilai et al. 1999; Gabriely et al. 2002). Visceralfat removal has shown to improve metabolism even withoutany changes in body weight, fat mass, and lean body mass(Gabriely et al. 2002). It is thought that surgical removal ofvisceral fat depots disrupts a cross-talk between fat depotsand multiple sites within the body (Wang et al. 1999).

The issue of adiposity itself in aging is a complexbiological problem to study. For example, total fat mass isknown to peak at middle age in both humans and rodents,which is followed by a precipitous decline with advancingage. However, the decline in fat mass with age does not

coincide with a decrease in percent body fat because leanmuscle mass is also decreased with age. Therefore, bodymass index and other such measures do not do an accurateidentification of the dramatic increase in ectopic fat andvisceral fat deposition that occurs in aging. In addition, it ispoorly understood how such changes in adiposity contributeto the development of chronic disease in the elderly, or thedevelopment of metabolic syndrome which occurs in 40–70% of the elderly.

Impact of high-fat diets on aspects of aging

High-fat diets (HFDs) have been used for many years tostudy the effects of increased adiposity, dyslipidemia andinsulin resistance in rodents. It has been shown that thedisturbances originated by high-fat feeding closely resemblethe metabolic disturbances observed in humans (Woods et al.2003). Several different types of HFDs are commonlyutilized in the study of diet-induced obesity and insulinresistance. One problem with this literature is that all of theeffects of these various HFDs (which vary in the amount andsource of dietary fat) have all been summarized as being‘HFD effects’. This has inevitably been source of greatvariability in the findings reported. In addition, many studieshave contrasted the effects of HFD to animals fed a standardchow diet, which dramatically affects the interpretation offindings as compared to using appropriate low fat controldiets. This is because standard chow diets differ in theamount and source of dietary fat, as well as other dietarycomponents, and therefore do not allow controlled studies onthe specific effect elevated dietary fat has on individualparameters.

Despite the tremendous progress which has been made inour understanding of dietary fat and obesity/diabetes withusing these different HFDs, it is important to point out thatrelatively little is currently available in regards to the study ofHFDs and brain aging. For example, studies have not firmlyestablished the ability of HFDs to promote or acceleratedifferent aspects of brain aging. In addition, studies have notexamined in a comprehensive manner what specific aspectsof perturbed metabolism (high fasting glucose, hyperinsul-emia, elevated adiposity, cholesterol level, fatty acid levels,etc.) may be most involved in the promotion of brain aging.

In addition to the use of diets, many rodent strains havebeen utilized as models of obesity, and the use of thesemodels has contributed strongly to the understanding ofobesity (Wu et al. 2004; Kanoski et al. 2007). In particular,the ob/ob mouse, which is characterized by an increase inboth number and size of adipocytes, and also by itsperturbations in leptin treatment, has been used to test theeffects of obesity on the brain (Itateyama et al. 2003; Teraoet al. 2008). However, because of the polygenic character ofthis disorder and the numerous congenic perturbationsobserved in these rodent models (ob/ob mice, fa/fa Zucker

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rats) they have an obvious limitation in the study of brainaging. Thus, HFD-induced models of metabolic dysfunctionshould be considered the best option for studying the effectsof metabolic dysfunction on human brain aging.

HFD can accelerate age-related adiposityAs pointed out above, aging leads to a redistribution of bodyfat, with a stabilization or enhancement of visceral fat and fatdeposition into tissues such as liver, muscle, and bone.Similarly, HFD consumption has been also found to increasevisceral fat mass (Park et al. 2001). This increased amount ofvisceral adipose tissue usually results in elevated concentra-tions and flux of circulating free fatty acids into the portalcirculation (Bjorntorp 1990), as the abdominal fat has a highlipolytic activity and is very sensitive to adrenergic stimu-lation because of the peculiarities of the lipolytic cascade(Wahrenberg et al. 1989). This elevation of circulating freefatty acids is associated with increased hepatic glucoseproduction (Ferrannini et al. 1983), reduced hepatic insulinclearance (Svedberg et al. 1990), decreased peripheral glu-cose uptake (Ferrannini et al. 1983), and increased very-low-density lipoprotein-triglyceride synthesis (Kissebah et al.1976). Thus a higher rate of lipolysis is able to cause thedisturbances in glucose and lipoprotein metabolism associ-ated with diet-induced obesity. HFD consumption is there-fore capable of promoting novel metabolic perturbations aswell as accelerate individual aspects of age-related metabolicdisturbances.

HFD can exacerbate peripheral inflammationHFD-induced metabolic dysfunction has been shown topositively correlate with markers of acute-phase responsesuch as C-reactive protein (CRP) (Mendall et al. 1996;Koenig et al. 1999) and fibrinogen (Juhan-Vague et al.1993). Elevated levels of CRP have been associated withhigh fasting glucose, high serum lipids, high body massindex (Mendall et al. 1996; Koenig et al. 1999; Yudkin et al.1999). It has been shown that chronic, subclinical inflam-mation is part of insulin resistance syndrome and thatdyslipidemia, abdominal obesity, low insulin sensitivity andhypertension parallel increasing levels of CRP (Festa et al.2000). It is possible that HFD consumption can provokecytokine secretion to the point it leads to insulin resistance,and may thereby accelerate age-related processes leading toinsulin resistance (Festa et al. 2000).

Decreased insulin sensitivity may be responsible of theincreased CRP expression, as the physiological effect ofinsulin on hepatic protein synthesis includes the stimulation ofalbumin synthesis and inhibition of fibrinogen synthesis (DeFeo et al. 1993). Resistance to insulin would then be expectedto lead to increased synthesis of acute-phase proteins, such asfibrinogen and CRP. In addition to these mechanisms, HFDsvia the acceleration of adipose reactivity may promote ageneralized increase in inflammatory signaling as the result of

adipose-derived adipokine signaling throughout the body. Allthese data indicate that subclinical inflammation would beexpected to be present early in HFD-induced metabolicdysfunction (such as elevated adiposity and insulin resistance),and thereby link HFD-induced modulation of metabolicdysfunction to age-related changes in inflammatory signaling.

Molecular pathways for HFD effects on metabolicdysfunction

Mitochondrial dysfunctionSeveral studies have related diet-induced metabolic distur-bances with mitochondrial alterations. For example, adecreased expression of genes involved in mitochondriabiogenesis has been observed following HFD consumption(Handschin and Spiegelman 2006; Nisoli et al. 2007; Shenet al. 2004). Similarly, HFDs have been demonstrated todecrease the levels of mitochondrial complex 1 activity(Nisoli et al. 2007). Complex I, also known as NADH-ubiquinone oxidoreductase, is a membrane enzyme complexof the mitochondrial electron transport chain that catalyzeselectron transfer from NADH to ubiquinone thus generatingproton motive force. Decreased levels of this complex willhave pronounced deleterious effects on mitochondrialenergy-generating efficiency, which together with an alteredbiogenesis, would be expected to compromise energyavailability in the aging brain. HFD effects on mitochondriamay therefore serve as a potential mechanism by whichmetabolic dysfunction induced by HFD consumption mod-ulates the rates of brain aging.

Oxidative stressOxidative stress is thought to be one of the earliest steps inHFD-induced pathogenesis (Matsuzawa-Nagata et al. 2008).Reactive oxygen species are normal byproducts of biologicalprocesses but are known to be capable of reactivity withproteins, nucleic acids, and lipids. Mitochondrial-derivedreactive oxygen species are believed to potentially be a majorsite of HFD-induced oxidative stress (Joseph et al. 2005;Cecarini et al. 2007; Lau et al. 2007), although studies havealso identified a role for NADPH oxidase in HFD-inducedoxidative stress (Bruce-Keller et al. 2010). Increased levelsof oxidative stress have been found in animals and humansfollowing HFD-induced metabolic dysfunction (Urakawaet al. 2003; Furukawa et al. 2004; Diniz et al. 2006;Fridlyand and Philipson 2006; Iqbal 2007; Yaffe 2007;Mantena et al. 2008; Matsuzawa-Nagata et al. 2008; More-ira et al. 2008). Taken together, these data suggest that HFDconsumption may play an important role in regulating age-related increases in oxidative stress.

Sirtuin signalingSirtuins are a family of NAD+-dependent histone/proteindeacetylases involved in a broad range of physiological

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functions, including control of gene expression, metabolism,and aging (Bordone and Guarente 2005). Many studies haveassociated sirtuins with caloric restriction-mediated healthbenefits including increased longevity (Smith et al. 2000;Tanner et al. 2000; Gray and Ekstrom 2001; Blander andGuarente 2004). Because of the ability of caloric restrictionto promote beneficial effects on metabolism and brain aging,these studies identify a potentially important role for sirtuinsin promoting the beneficial effects of caloric restriction onthe brain. Seven distinct sirtuins (Sirt1–Sirt7) have beendescribed in mammals, being Sirt1 expressed in severaltissues and implicated in effects such as stress resistance,reduced apoptosis, and metabolic changes associated withcalorie restriction (Blander and Guarente 2004).

Almost all Sirt1-deficient animals die during early post-natal development (Chen et al. 2005), with reduced trigly-cerides, insulin, and blood glucose observed in these sameanimals. Such findings further link Sirt1 to metabolicregulation. Sirt1 is also present in white adipose tissue,where has been shown to reduce adipogenesis and triglyc-eride accumulation in the lipid droplets of a cell model ofwhite adipocytes. These observations have been related todecreased expression of genes involved in fatty acidmetabolism, such as peroxisome proliferator-activated recep-tors gamma. In addition, in vivo, fasting induces Sirt1 andpromotes lipolysis by inhibiting proliferator-activated recep-tors gamma-mediated fatty acid trapping. The function ofSirt1 in the release of insulin by pancreatic b cells has alsobeen studied, and it has been found that reduction of Sirt1expression in b cell lines promotes a reduction in insulinsecretion (Bordone et al. 2006).

Studies have shown that a modest over-expression of Sirt1protects hepatic lipid and glucose metabolism from damagecaused by HFDs. In addition, Sirt1 has been found to beinvolved in the protection from metabolic syndrome. Sirt1activators have been found to be beneficial for mitochondrialand metabolic function in obese rodents and are currentlybeing studied as potential treatments for type-2 diabetes(Milne et al. 2007). It has been reported that moderate Sirt1over-expression in mice prevents HFD-induced glucoseintolerance and non-alcoholic fatty liver disease (Pflugeret al. 2008). Together, these data raise the possibility ofHFDs mediating their effects on the aging brain in a sirtuin-dependent manner, although more work in this area is clearlyneeded.

Evidence for HFD exacerbating brain aging

HFD consumption is thought to induce changes not only inenergy metabolism but also in brain function. Considerableclinical evidence suggests that HFD consumption and thepresence of metabolic dysfunction are sufficient to exacer-bate brain aging, promoting the development of cognitivealterations including dementia (Haan et al. 2003; Taylor and

MacQueen 2007; Yaffe 2007). Moreover, obese adults haveshown more severe brain atrophy than non-obese adults(Ward et al. 2005), further linking HFD consumption tobrain perturbations.

Insulin has been suggested to play important roles inregulating memory, so any disturbance in insulin signalingwould be expected to have a negative impact on memory(Luchsinger et al. 2004). Some studies have demonstratedthat HFDs are able to increase amyloid beta peptide (Ab)levels and Ab-neuropathy in brains of mice exhibitingAlzheimer’s disease (AD) pathology (Ho et al. 2004).Experimental evidence suggests that alterations in insulinmetabolism may influence the onset of AD through theirinfluence on the synthesis and degradation of Ab peptides.Moreover, high levels of circulating insulin may alsopromote the accumulation of Ab peptides by directlycompeting with Ab for the insulin-degrading enzyme,thereby limiting Ab degradation by insulin-degradingenzyme. However, whether the risk of AD is increased inhuman patients with diabetes mellitus is a matter of somedebate. Some studies have reported that diabetic patientshave elevated risk of developing AD (Leibson et al. 1997;Craft et al. 1998; Ott et al. 1999; Arvanitakis et al. 2004).However, several clinical studies have indicated that diabetesdoes not seem to be associated to AD (Curb et al. 1999;Tariot et al. 1999; MacKnight et al. 2002; Luchsinger et al.2004; Akomolafe et al. 2006). Moreover, almost all neuro-pathological studies so far have failed to detect anyassociations between AD-related pathology and diabetes(Heitner and Dickson 1997; Petrovitch et al. 2000; Peilaet al. 2002; Janson et al. 2004; Arvanitakis et al. 2006).Instead, diabetes has been associated to the presence ofcerebral infarcts (Peila et al. 2002; Arvanitakis et al. 2006).As diabetes present altered capillary blood vessels in theperipheral vasculature, it is not surprising that diabetespromotes changes in brain microvasculature. Interestingly,data from the Framingham study has demonstrated a linkbetween type-2 diabetes and lower cognition scores (Eliaset al. 1997), and hyperglycemia has been found to negativelyinfluence cognitive impairment in population-based studies(Franceschi et al. 1984; Robertson-Tchabo et al. 1986;Langan et al. 1991; Messier et al. 1999).

Another metabolic disturbance associated with HFDconsumption and obesity is hypertension which is considereda great risk factor for cerebral stroke (Rosamond et al. 2008).One possible mechanism by which obesity may increase therisk of stroke is via an alteration in cerebral perfusion.Cerebral perfusion is regulated through active constrictor anddilator mechanisms and by the physical properties of thecerebral vasculature, such as myogenic tone and vesselstructure. Increased myogenic tone has been reported tooccur in middle and posterior cerebral arteries from sponta-neously hypertensive rats, as well as vasopressin-deficient rat(Dunn et al. 1998; Gonzalez et al. 2008). In addition, a great

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body of evidence has reported vascular remodeling in thecerebral circulation in different models of hypertension,spontaneously hypertensive rats among them (Baumbach andHeistad 1989; Arribas et al. 1996; Dunn et al. 1998). Themost common changes in hypertensive populations aremechanical and architectural properties of the cerebralvasculature, particularly an inward remodeling of the largearteries (Baumbach and Heistad 1988, 1989; Baumbachet al. 1988). Inward remodeling not only increases the risk offlow obstruction but it is also detrimental in ischemicconditions. After ischemia, brain vessels are near-maximallyvasodilated, so reductions in maximum lumen diameterbecome a constraint on perfusion. In addition, it is wellknown that alterations of arterial pressure cause deleteriouschanges in vascular structure, as vessels become rigid, wallthickness can increase and lumen diameter can decrease(Baumbach and Heistad 1989; Heistad et al. 1990), causingan extra impairment of blood flow during ischemia. Inaddition, studies carried out in adult obese Zucker rats withmoderate hypertension and severe insulin resistance havedemonstrated an increased cerebral vascular myogenic tone,inward cerebral vascular remodeling, and increased cerebraltissue death after ischemia/reperfusion injury in these rodents(Osmond et al. 2009). Important to note, young obeseZucker rats, which are obese and insulin resistant but not yethypertensive, did not show any of those deficits (Osmondet al. 2009). In addition, other studies carried out in leptindeficient ob/ob mice and also in diet-induced obese micehave shown that obesity worsens the response to ischemia(Nagai et al. 2007; Terao et al. 2008). All these data togethersuggest that obesity together with prolonged moderatehypertension serve as risk factors for cerebral vasculardysfunction and stroke.

Dyslipidemia is another common disease associated withHFD consumption. More than 50% of the US populationolder than 20 years old have cholesterol levels of 200 mg/dLor higher, and more than 18% have levels of 240 mg/dL orhigher. The link between dyslipidemia and having a higherrisk of cognitive impairment or dementia is controversial(Wieringa et al. 1997; Kuo et al. 1998; Scacchi et al. 1998;Lesser et al. 2001). Reduced levels of high-density lipopro-tein cholesterol have been reported in some cases ofdementia (Muckle and Roy 1985; Kuriyama et al. 1992,1994; Wieringa et al. 1997; Kuo et al. 1998; van Exel et al.2002; Michikawa 2003) but not all cases of dementia.

Direct evidence for HFD promoting brain pathogenesisA large body of evidence from rodent and human studies hasdemonstrated that HFD-induced metabolic dysfunction pro-motes cognitive alterations and dementia (Kumari et al.2000; Craft 2005; Li et al. 2007; Pasinetti et al. 2007; Razayet al. 2007). Different studies have been performed on rats inorder to clarify the influence specific diets may have ondifferent aspects of cognition. Interestingly, it has been

documented that even maternal HFD consumption sensitizesoffspring to the deleterious consequences of HFD (Whiteet al. 2009). Studies carried out in rats have shown that, inagreement with biochemical and physiological evidence, adiet high in saturated fatty acids can impair learning andmemory functions (Greenwood and Winocur 1990; Gran-holm et al. 2008). Moreover, direct injection of triglyceridesinto the brain has shown to have detrimental consequencesfor learning and memory (Farr et al. 2008). In addition, thestrong relationship between obesity and cognitive impair-ment found in animals (Baran et al. 2005; Winocur andGreenwood 2005; Granholm et al. 2008; White et al. 2009)supports an association between obesity and deficits inlearning, memory, and executive functioning in humanpatients (Elias et al. 2003, 2005). At present, oxidativestress and brain inflammation are thought to play key roles inHFD-induced cognitive loss, as brain markers of oxidativestress and inflammation have been found to be increased inmice fed HFD which show clear cognitive impairment(Zhang et al. 2005; Souza et al. 2007; Pistell et al. 2010).Furthermore, HFD consumption has been shown to increaseage-related oxidative stress in the brain (Mattson et al. 2003;Perry et al. 2003). For example, rodents fed high-fat or high-calorie diets have shown to have increased levels of oxidativestress (Zhang et al. 2005) and protein oxidation (Souza et al.2007) in the brain. However, it is still unclear whetheroxidative stress in HFD models of obesity is the result ofobesity per se, or is more related to the associated metabolicdysfunction. Although there is a clear relation betweenobesity and brain inflammation, the real mechanisms where-by HFD contributes to brain inflammation and cognitiveimpairment also remain elusive. Certainly, brain function issensitive to inflammatory pathways and mediators. Forexample, IL-1b and IL-6 are able to alter physiologicmechanisms involved in cognition and memory (Bellingeret al. 1995; Jankowsky and Patterson 1999; Gemma andBickford 2007). Adiponectin and leptin, two well knownadipokines, could be considered as important links betweenobesity, insulin resistance and related inflammatory disorders(Fantuzzi 2005; Antuna-Puente et al. 2008). Adiponectin hasbeen shown to exhibit neuroprotective and anti-inflammatoryproperties in the brain (Chen et al. 2009) and to haveimportant roles against the development of insulin resistance,dyslipidemia and atherosclerosis (Rasouli and Kern 2008).Leptin has also been reported to have important roles incognition (Harvey et al. 2005; Oomura et al. 2006) and inthe modulation of inflammatory signaling in microglia(Pinteaux et al. 2007). Among the afferent inputs that thebrain uses to adjust food intake and energy metabolism,leptin is one of the best understood, supressing food intakeand increases energy expenditure (Friedman and Halaas1998). Studies such as these raise the possibility of roles forleptin in the aging brain that are independent of leptin effectsin the hypothalamus and the regulation of feeding behavior.

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There is also reasonable evidence for believing that insulinmight also play a role in mediating the effects of HFDconsumption on the brain, as insulin is known to act withinthe hippocampus. In vitro studies have shown that insulin canmodulate hippocampal synaptic plasticity (Izumi et al. 2003;Zhao et al. 2004; van der Heide et al. 2005). In addition, it isalso known that hippocampal cognitive performance stronglydepends on glucose supply (McNay et al. 2000; McNay andGold 2002; Gold 2005), which is regulated in larger part byperipheral insulin levels. It has been reported that hippo-campus of AD brains have lower levels of glucose utilizationand a corresponding impairment in insulin signaling (Frolichet al. 1998; Hoyer 2004; Steen et al. 2005).

Summary

Considerable evidence suggests a role for metabolic dys-function as a modulator of brain aging, and consequentlyraises the specter of stressors such as HFD consumption asmediators of accelerated brain aging. In this model HFDconsumption promotes a myriad of metabolic disturbancesduring aging, which directly and/or indirectly modulate therate the brain ages. Of particular interest is the possibility thatmetabolic dysfunction during aging (in response to HFDconsumption, genetics, physical activity, etc.) accounts forthe considerable variability in the rates of brain aging that areobserved in the elderly. Despite the progress made in thisresearch area, several key questions remain to be answered.For example, which component(s) of metabolic dysfunctionare responsible for the initiation/propagation of brain aging?How do individual aspects of metabolic dysfunction mediateneurochemical, structural, and/or functional changes in theaging brain? Answering these questions will likely contributeto not only our understanding of brain aging, but also to thedevelopment of therapeutic interventions which promotehealthy brain aging.

Acknowledgements

This work was supported by grants from the NIA (AG029885,

AG025771) and the Hibernia National Bank/Edward G Schlieder

Chair (J.N.K.).

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