the desynchronization of central and peripheral circadian systems contributes to the decline in optimal functioning of bodily systems . this includes changes in neuroendocrine circadian rhythms , insulin sensitivity , altered thermoregulation and acceleration of tumor growth ( cincotta et al . , 1993 ; touitou and haus , 2000 ; hastings et al . , 2003 ; straub and mocchegiani , 2004 ; cretenet et al . , 2010 ; heller et al . , 2011 these are complex interactions and dysfunction can be due to targeted disruption of neurons , neurotransmitter or neuropeptide production , transport or secretion . it is reasonable to expect that the neuronal activity or expression of circadian clock genes be reduced or rhythms phase shifted ( kolker et al . , 2003 ) . additionally , the connections between central and peripheral oscillators may be degraded or less functional ( morales et al . , 1987 ) . any one or a combination of these abnormalities may result in the decoupling of the circadian oscillators and the ensuing pathologies . the master central pacemaker is the suprachiasmatic nucleus ( scn ) which controls circadian rhythmicity . rhythmicity can dampen and/or elongate / shift with age but the number or cell size of neurons in the scn does not change . , 1993 ; madeira et al . , 1995 ) . additionally , glucose uptake decreases in the scn in aged animals ( wise et al . , 1988 ) and the expression of neuropeptides also diminishes . vasoactive intestinal polypeptide ( vip ) expressing neurons of the scn are retinorecipient and vasopressin ( avp ) expressing neurons of the scn modulate rhythmicity ( wu et al . , 2007 ) . in aged male humans , the number of scn neurons that express vip decreases and in aged female rats the expression becomes arrhythmic ( zhou et al . both genders also express less avp protein , less mrna ( roozendaal et al . , 1987 ; zhou et al . , 1995 ) and the normal daytime peak of avp is reduced ( hofman and swaab , 1994 ; liu et al . , 2000 ) . decreases in the neuroendocrine output of the scn may directly or indirectly affect the coupling of central and peripheral oscillators . in the scn , clock genes constitute the core clock mechanism of the mammalian timekeeping system . though the system is fairly complex , for brevity the simplest model is described . bmal1 and clock proteins dimerize and induce the transcription of period ( per ) and cryptochrome ( cry ) genes . in a negative feedback loop , levels of per and cry proteins increase and at a certain threshold form heterodimers which turn off the clock bmal1 regulated transcription of per and cry genes . this process takes roughly 24  h ( ko and takahashi , 2006 ) . in aged animals the expression of certain clock genes changes in the scn . per1 , per2 , and cry1 expression does not change significantly with age , but the normal photic stimulation of per1 expression is reduced ( asai et al . . additionally , the free - running period of per1luc rhythmicity is shortened in aged animals ( yamazaki et al . , 2002 ) and the amplitude of clock and bmal1 expression is decreased ( kolker et al . , 2003 ) . changes in clock gene expression in peripheral tissues do not always reflect what is seen in the scn ( yamazaki et al . , 2000 ) , and may result from a disruption of signals to these tissues or the tissues themselves , which are more susceptible to the aging process . furthermore , projections to and from the scn including peripheral oscillators may change with age . in motoneurons , aging results in a shortening in delay of spike potentials between axon and soma , as well as decreases in axon conduction velocity and increases in input resistance ( morales et al . the output from circadian and peripheral oscillators do not only influence the sleep / wake cycle , but regulates metabolism and reproduction . studies indicate that some tissues retain the ability to oscillate , even if connections from the master pacemaker have been degraded . peripheral tissues in vitro that have become arrhythmic can be chemically induced to oscillate ( yamazaki et al . however , in aged animals exhibiting a decreased photic response , retinal projections to the scn are not degraded and must be related to either the retina or scn clock functions ( zhang et al . , it is increasingly evident that determining the source of age - related sleep / wake or circadian dysfunctions is rather complex . another source of sleep / wake changes can likely be attributed to age - related neuronal dysfunction in the arousal and sleep promoting areas of the brain . the scn directly or indirectly communicates with the sleep and wake promoting systems ( abrahamson et al . , 2001 ; aston - jones et al . , 2001 orexinergic ( or hypocretinergic ) neurons are known to stabilize or maintain wake ( saper et al . , 2001 , 2005 ) . these cells receive input from the scn via the dorsomedial hypothalamus ( dmh ) and are localized in the perifornical and lateral hypothalamus ( lh ) . there are two forms of the neuropeptide orexin / hypocretin ( a and b ) and two receptors . though the neurons are limited to a discrete area , both orexinergic fibers and receptors are widely distributed throughout the brain . in diurnal and nocturnal rodents , orexinergic neurons are most active during the active phase ( martinez et al . , 2002 ) . hypothalamic microdialysate analysis shows orexin-1 levels increase during wake and rem in adult animals ( kiyashchenko et al . , 2002 ) . mammals with no orexin or dysfunctional orexin / hypocretin receptors have disrupted sleep / wake cycles and narcoleptic symptoms . when orexin is decreased , the circadian rhythm of the sleep / wake cycle is disrupted . the flip  flop model of sleep / wake control suggests that there is a mutual inhibition between the areas that control sleep and the areas that control the wake state ( saper et al . , 2001 ) . in short , the ventrolateral preoptic area ( vlpo ) controls sleep and the brainstem cholinergic and monoaminergic systems control waking . flipping weight between these areas blocking or destroying these neurons or the orexin receptor 2 may flip the animal s state quickly from waking to sleep and vice versa , such as what occurs in narcoleptic individuals , orexin knockout mice , and canine narcolepsy ( chemelli et al . , 1999 ; lin et al . , 1999 ; peyron et al . , 2000 ; a disruption in orexin function or a reduction in orexin levels leads to less stable sleep / wake cycles such as that seen in many elderly patients with sleep disorders ( porkka - heiskanen , 2003 ) . additionally , decreases in excitatory orexin innervation to the noradrenergic locus coeruleus ( lc ) is thought to be a contributing factor of poor sleep / wake quality in aged cats ( zhang et al . orexin b immunoreactive ( -ir ) axon density was determined to be significantly lower in the lc of aged macaques than that observed in the young or adult animals ( 43 and 35% decrease respectively ; downs et al . , 2007 ) . real time pcr studies showed that preprohypocretin mrna does not change in the aged hypothalamus ( terao et al . , 2002 ) but in situ hybridization studies show that at the single cell level , preproorexin gene expression does decrease in cell count and optical density ( porkka - heiskanen et al . , 2004 ) . furthermore , orexin a and b protein expression as measured by radioimmunoassay was decreased in the lh ( porkka - heiskanen et al . , the number of orexinergic - ir neurons as well as the optical density of respective fibers in the lh is reduced in aged animals ( brownell and conti , 2010 ; sawai et al . , 2010 ) . it is interesting to note that orexinergic innervation of the cholinergic basal forebrain , which modulates wake and rem sleep , is reduced in aged guinea pigs ( zhang et al . , 2005 ) . hypocretin receptor 1 mrna is reduced in the hippocampus and hypocretin receptor 2 mrna is significantly reduced in thalamic areas , hippocampus , and the brainstem ( terao et al . , 2002 ) . neural activity measured by c - fos immunoreactivity is reduced in orexinergic neurons of mice at 24  months ( naidoo et al . , 2011 ) . changes are also seen in the cholinergic and monoaminergic wake active areas of aged animals . nicotinic and muscarinic receptors of the acetylcholinergic system decrease in the scn with age ( van der zee et al . , 1991 ) . in young animals , the noradrenergic neurons of the lc are important in wake promotion , receive direct input from the scn and follow a circadian pattern of activation ( aston - jones et al . , 2001 ) . in aged rats , lc projections to the frontal cortex and dentate gyrus decrease but axonal branching increases depending on the target and age . this is suggested to be a compensatory mechanism ( shirokawa et al . , 2000 ) . in the ventral periaqueductal gray ( vpag ) the wake active dopaminergic neurons we have recently reported a reduction in the neural activity of these dopaminergic neurons of the vpag and the noradrenergic neurons of the lc in aged mice ( naidoo et al . , 2009 , 2011 ) . the wake active histaminergic system originates in the tuberomammillary nucleus ( tmn ) and sends widespread projections to areas that include the cortex , thalamus and brainstem . histamine levels were found to be increased in middle aged rats when compared to young , and the level of histamine methyl transferase was decreased ( mazurkiewicz - kwilecki and prell , 1984 ) . histamine h1 , h2 and h3 receptor mrna is decreased in the aging brain ( terao et al . , 2004 ) . given these changes in the aging wake promoting neurotransmitter systems as well as wake maintaining systems , it is clear that therapies to alleviate or attenuate these changes need to be developed . , 1996 ; szymusiak et al . , 1998 ) and when lesioned results in insomnia ( lu et al . , 2000 ) . gabaergic and galaninergic inhibitory neurons from this area project to wake active histaminergic neurons ( sherin et al . , 1996 ) . interestingly , the number of activated vlpo neurons during sleep does not change in old rats ( shiromani et al . , 2000 ) although connections between these areas may become dysfunctional or degraded with age . the scn has a minor input into the vlpo , but substantial direct and indirect inputs to the dmh ( novak and nunez , 2000 ; chou et al . , 2002 ) . the dmh heavily inputs the vlpo and it would be beneficial if these pathways were examined during aging . age - associated changes in the serotonergic system affect the function of respiratory motor output during sleep . serotonergic input to the hypoglossal nucleus decreases , which is thought to lead to a decline in upper airway muscle performance ( behan and brownfield , 1999 ) . in aged rhesus monkeys , serotonin receptor 2 density reduces in the occipital and parietal cortex including the deep layers of the motor cortex ( wenk et al . , 1989 ; bigham and lidow , 1995 ) . serotonin levels also decrease in the occipital areas but do not change in the cingulate cortex in aged monkeys ( beal et al . , 1991 ) . it is likely with normal aging that changes in any neurotransmitter system affecting sleep vary across the brain . in many patients afflicted with neurodegenerative diseases the physical and mental consequences lead to sleep disorders ( table 1 ) . for example , sleep fragmentation can occur if the patient can not move well or insomnia may develop due to depression or feelings of helplessness . medications used to alleviate some of the motor or cognitive symptoms such as levodopa in parkinson s disease ( pd ) can also contribute to disruptions in normal sleep / wake behaviors . however , some research indicates that sleep disturbances may predict manifestation of neurodegenerative diseases ( postuma and montplaisir , 2009 ) . sleep disturbance or loss also affects metabolic and immune function ( krueger et al . , 1998 ; knutson et al . , 2007 chronic sleep loss could lead to neuronal damage resulting in altered hypothalamic pituitary adrenal axis function , cognitive deficits and memory loss . increases in the number of patients with neurodegenerative diseases may be related to or the result of a society that does not sleep . da , dopamine ; inos , inducible nitric oxide synthase . sturrock and rao ( 1985 ) , zhang et al . ( 1982 ) , foley et al . ( 2007 ) , magri et al . ( 1997 ) , touitou ( 1995 ) , whitehead et al . ( ( 1998 ) , feinberg et al . ( 1967 ) , myers and badia ( 1995 ) , brun and englund ( 1981 ) , teipel et al . ( 1985 ) , kremer et al . ( 1991 ) , arnulf et al . initially there is an increase in nighttime arousals and a decrease in sws ( vitiello et al . , 1991 ) . in the later stages , circadian disruption , severe daytime wakefulness and a reduction in rem sleep occurs , likely due to a reduction in acetylcholine ( dykierek et al . , circadian rhythm dysfunction has been proposed to be due to changes in scn and pineal functions ( wu et al . , 2007 ) . degeneration of cholinergic input from the nucleus basalis of meynert to the cortex may be responsible for some of the sleep / wake changes ( montplaisir et al . , 1995 ) . neurofibrillary tangles found in the histaminergic tmn of ad patients and amyloid- peptide ( a ) aggregation also contributes to the ad pathology . normally in the interstitial fluid a has a diurnal fluctuation with low levels during sleep and peak levels during wake . recently one study showed that prolonged wake and/or orexin administration increased levels of the a in the interstitial fluid of the brain in mice ( kang et al . administration of an orexin antagonist reduced amyloid deposits in several brain areas suggesting that manipulating sleep or the orexin system in ad patients could improve symptoms ( kang et al . , 2009 ) . although the research is sparse , melatonin , phototherapy and exercise have all had positive effects in the treatment of circadian and sleep / wake disorders of ad patients ( wu and swaab , 2007 ) . as one in three americans develops ad , there is a crucial need for more research in these therapies . rem sleep behavior disorder ( rbd ) has been associated with pd and thought to be an early manifestation ( schenck et al . , 1996 ; boeve et al . , 2003 ; postuma and montplaisir , 2009 ) . sleep attacks and excessive daytime sleepiness ( eds ) are also commonly seen in patients with pd ( factor et al . , 1990 ; diederich et al . , the degeneration begins at the brainstem and progresses rostrally , although degeneration of the dopaminergic neurons of the substantia nigra pars compacta is the main contributor to pd characteristics ( braak et al . , rbd results from pedunculopontine dysfunction and likely explains rbd manifesting previous to pd ( rye , 1997 ; boeve et al . , 2007 ) . some studies have successfully seen bright light therapy or sleep modifications reduce the symptoms of pd ( hogl et al . , 1998 ; willis and turner , 2007 ) . huntington s disease ( hd ) is a genetic disorder characterized by a polyglutamine ( cag ) repeat ( scherzinger et al . , 1999 ) . neurodegeneration is extensive throughout the brain , affecting cortical and subcortical areas but primarily affects the basal ganglia ( vonsattel et al . , 1985 ) . sleep and wake regions of the brain including the brainstem , thalamus , hypothalamus and cortex are also affected in hd ( kremer et al . , 1991 ) . the scn pacemaker is functional in mouse models of hd , so a dysfunction of the circadian circuitry is proposed to contribute to circadian abnormalities ( pallier et al . , 2007 ) . central and peripheral clock gene expression is altered as well ( morton et al . , 2005 ; maywood et al . , 2010 ) . the sleep / wake cycle is disrupted in hd patients characterized by self - reported eds , sleep fragmentation at night , and delayed sleep phase ( arnulf et al . , 2008 ; videnovic et al . , 2009 ; aziz et al . , sleep is lighter with an increase in stage 1 and a decrease in rem sleep ( arnulf et al . , 2008 ) . disruptions in the circadian and sleep / wake cycles of these patients exacerbate symptoms , increasing depression , cognitive deficits and metabolic dysfunctions ( aziz et al . , 2010 ) . it is important to note that pharmacological and behavioral manipulation of sleep and wake reduces disease progression and improves cognitive function and circadian gene expression in a mouse model of hd ( hockly et al . , 2002 ; pallier et al . , 2007 ; pallier and morton , 2009 ; maywood et al . , 2010 ) amyotrophic lateral sclerosis ( als ) is considered an age - associated neurodegenerative disease with the age of onset ranging from 40 to 70 . most als cases are sporadic and about 10% are familial . also called lou gehrig s or motor neuron disease ( boillee et al . , 2006 ) , both upper and lower motor neurons are affected . motor neurons of the motor cortex , brainstem and spinal cord gradually degenerate leading to muscle weakness , sleep disordered breathing ( sdb ) and paralysis ( kimura et al . , 1999 ) . additionally , sleep is reduced in both rem and sws stages with resulting eds ( barthlen and lange , 2000 ; lo coco et al . , 2011 ) . some patients find relief using assisted breathing such as continuous positive airway pressure ( cpap ) or bilevel positive airway pressure ( bipap ; howard et al . , 1989 ; david et al . , 1997 ; barthlen and lange , 2000 ) . amyotrophic lateral sclerosis is a complex disease of many subtypes with various genetic and environmental contributing factors . one such factor is glutamate toxicity which is decreased using the drug riluzole ( shaw and ince , 1997 ) . levels of serotonin are decreased in als patients and compensatory increases in glutamate lead to excitotoxicity . it has been suggested that motor neurons with a high density of serotonergic innervation are more susceptible to degeneration ( sandyk , 2006 ) . as melatonin has antioxidant properties and inhibits glutamate release , this reduction would further exacerbate degeneration . indeed , melatonin supplements slowed disease progression when given to a mouse model of familial als ( weishaupt et al . , 2006 ) . normally the scn is coupled to peripheral oscillators , although studies have shown that scn control is not necessary for sustaining oscillatory activity . if signals from central oscillators reduce in strength due to age or neurodegeneration , other cues may entrain the peripheral oscillators ( weinert , 2005 ) . unmasking mechanisms within sleep / wake systems is difficult due to the many checks and balances that ensure homeostasis . although compensation and plasticity occurs to a lesser extent in older animals , a relatively high degree is preserved ( van someren et al . , 2002 ) . this may not always be advantageous as epigenetic methylation of circadian genes has been associated with dementia ( liu et al . , 2008 ) . understanding how the aging brain can compensate and remain plastic will be beneficial to focus on more effective treatments for sleep / wake and neurodegenerative disorders . the co - morbidity of sleep disorders with neurodegenerative diseases suggests that changes in many of these neural areas manifests in sleep / wake and circadian dysfunction . effects on the sleep / wake and circadian systems may result from , or contribute to , the increasing pathology . some research has shown the benefit of pharmacologically or behaviorally restoring rhythms and sleep / wake for delaying pathologies ( table 1 ) . this is important to understand in a society where sleep is not considered a priority . a few points worth considering are as follows : sleep is a basic need that is made secondary to work schedules and some leisure activities for many adults . in developing children and adolescents , early school start times and late night extracurricular meetings contribute to a culture of sleep deprived , cognitively unhealthy americans . if restoring our circadian and sleep / wake cycles can ward off the deterioration of the brain , it is imperative to educate the public about the very real damage of abnormal sleep / wake cycles not only in aging individuals but at every age . the fragmented sleep / wake pattern seen in aging individuals can be due to the degeneration or dysfunction of the circadian and sleep / wake networks . uncoupling of the central and peripheral oscillators may exacerbate dysfunction via altered feedback signals or signaling pathways . it is likely that several brain regions are affected and that there are individual differences in how the sleep / wake and circadian networks degrade . additionally there may be differential plasticity and compensation in the integration of these neural systems , making the identification of applicable therapies very difficult . however , if mechanisms contributing to the normal aging process of these networks are identified , this may elucidate a general therapy for restoring sleep / wake and circadian homeostasis . it is crucial that we immediately invest our energies and resources in understanding these mechanisms as well as in the dissemination and implementation of current knowledge and therapies to the public . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
sleep / wake and circadian rest - activity rhythms become irregular with age . typical outcomes include fragmented sleep during the night , advanced sleep phase syndrome and increased daytime sleepiness . 
 these changes lead to a reduction in the quality of life due to cognitive impairments and emotional stress . 
 more importantly , severely disrupted sleep and circadian rhythms have been associated with an increase in disease susceptibility . 
 additionally , many of the same brain areas affected by neurodegenerative diseases include the sleep and wake promoting systems . 
 any advances in our knowledge of these sleep / wake and circadian networks are necessary to target neural areas or connections for therapy 
 . this review will discuss research that uses molecular , behavioral , genetic and anatomical methods to further our understanding of the interaction of these systems .