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Nature. 2010 March 25; 464(7288): 529–535. doi:10.1038/nature08983.

Neural mechanisms of ageing and cognitive decline

Nicholas A. Bishop, Tao Lu, and Bruce A. Yankner

Abstract
During the past century, treatments for the diseases of youth and middle age have helped raise life
expectancy significantly. However, cognitive decline has emerged as one of the greatest health
threats of old age, with nearly 50% of adults over the age of 85 afflicted with Alzheimer’s disease.
Developing therapeutic interventions for such conditions demands a greater understanding of the
processes underlying normal and pathological brain ageing. Recent advances in the biology of
ageing in model organisms, together with molecular and systems-level studies of the brain, are
beginning to shed light on these mechanisms and their potential roles in cognitive decline.

Cognitive frailty is emerging as one of the greatest health threats of the twenty-first century.
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As the life expectancy of the population has increased, so too has the prevalence of
cognitive decline and dementia, largely in the form of Alzheimer’s disease, which now
affects almost 50% of adults over the age of 85 in the United States (1). This startling figure
can only grow as the average age of the population rises, so understanding the basis of
cognitive decline during ageing is critical. The greatest risk factor for cognitive decline and
Alzheimer’s disease in older adults is age itself. Therefore, the development of these
pathologies must be understood in the context of the molecular biology of the ageing
process.

Fortunately, the past 15 years have witnessed a great increase in our knowledge of the basic
molecular mechanisms of ageing. Most remarkably, functional genetic analysis has
identified signalling pathways that act as master regulators of ageing and lifespan and that
are conserved in yeast, nematodes, flies and mammals. Analysis of these model systems
suggests that the rate of ageing is not inevitably fixed but is plastic and open to modification.
Similarly, cognitive decline associated with mammalian brain ageing also seems to be
variable and possibly open to modification (Table 1). An important question is whether age-
related cognitive changes are mediated by any of the master regulators of ageing and
lifespan identified in model organisms. Moreover, recent studies have implicated these
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pathways in the control of age-related brain pathology, raising the possibility that altered
regulation of fundamental mechanisms of ageing may contribute to the pathogenesis of
neuro degenerative disorders.

Two important technical advances have provided new insight into the biology of brain
ageing. Microarray technology has made global gene expression analysis possible in humans
and model organisms, leading to the identification of evolutionarily conserved changes
during ageing. Concurrently, improvements in functional brain imaging have afforded us an
unprecedented view of the workings of large-scale cognitive networks in the ageing human
brain. An important challenge is to unify these two levels of analysis to obtain a more global
view of brain and organismal ageing in humans.

In this Review, we explore the basic molecular mechanisms of the ageing process in the
brain. We begin with a brief description of large-scale functional alterations in human brain
ageing. Then we turn to a discussion of conserved mechanisms of ageing that may underlie
the changes observed in the ageing brain, with a focus on mitochondrial function and
oxidative stress, autophagy and protein turnover, insulin/IGF signalling, target of rapamycin
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(TOR) signalling and sirtuin function. To begin to understand the ageing of the brain in the
context of the entire organism, we discuss how the brain might coordinate the ageing
process by acting as a primary sensor of physiological and environmental stressors through
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the action of conserved signalling pathways. There is hope that our growing understanding
of the molecular basis of brain ageing and the role of the brain in the ageing body will allow
us to rise to the challenge of treating and preventing cognitive decline and Alzheimer’s
disease.

Trajectory of ageing in the human brain

Ageing in humans is accompanied by stereotypical structural and neuro physiological
changes in the brain and variable degrees of cognitive decline. Functional imaging studies of
the human brain have recently provided an unprecedented systems view of neural activity
and how it changes with ageing (Fig. 1). These studies have revealed that separate brain
regions that interact to subserve higher-order cognitive functions show less-coordinated
activation with ageing, suggesting a global loss of integrative function (2). Importantly, this
reduced coordination of brain activity is associated with poor performance in several
cognitive domains (2). In addition to being less integrated, neural activity also becomes less
localized in some brain regions, particularly the prefrontal cortex, in response to executive
level tasks (3,4). By contrast, young adults activate more-discrete brain regions to perform
the same tasks and integrate these regions more closely with other brain regions. Aged
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individuals who exhibit delocalized activity show better cognitive performance than aged
individuals with more localized activity, consistent with the idea that delocalization may be
a compensatory response (3,5). These observations suggest that the higher-order systems
biology of the brain is significantly altered by normal ageing in the absence of disease.

Age-dependent breakdown in higher-order brain systems may relate, in part, to disruption of

myelinated fibres that connect neurons in different cortical regions (2). Although neuronal
loss is minimal in most cortical regions of the normal ageing brain (6), changes in the
synaptic physiology of ageing neurons may contribute to altered connectivity and higher-
order integration. Gene expression profiling studies of ageing mouse, rat, monkey and
human brains have shown significant changes in the expression of synaptic genes (7–13). In
the human and rhesus macaque prefrontal cortex, many genes involved in inhibitory
neurotransmission mediated by GABA (γ-aminobutyric acid) are strongly downregulated
with age, potentially altering the balance between inhibitory and excitatory
neurotransmission (13). This may contribute to increased neural activity in the prefrontal
cortex of aged individuals, a systems-level change that may initially be compensatory but
could predispose the individuals to excitotoxicity and neurodegenerative pathology.
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A central question is whether these functional changes, which appear in most ageing
individuals, are clearly distinct from pathological processes associated with
neurodegenerative disorders such as Alzheimer’s disease. Functional magnetic resonance
imaging studies suggest that changes in the activity of the hippocampus and associated
cortical regions can distinguish normal ageing from pathological ageing. Normal ageing is
associated with reduced metabolic activity in the subiculum and the dentate gyrus, whereas
reduced activity in the entorhinal cortex may be an early indicator of Alzheimer’s disease
(14). At the histopathological level, neuronal loss, beginning in the entorhinal cortex and the
CA1 field of the hippocampus, together with volume loss in the medial temporal lobe,
distinguishes normal ageing from the cognitive decline associated with Alzheimer’s disease
(15–18). However, other pathological hallmarks of Alzheimer’s disease (such as synapse
loss, amyloid plaques and neurofibrillary tangles) can correlate with cognitive decline and
become extensive in Alzheimer’s disease but are detected to varying degrees in many aged
individuals in the absence of cognitive decline. To understand the relationship between

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Alzheimer’s disease and normal brain ageing, we must gain a greater understanding of the
mechanistic basis of the ageing process. The identification of ageing pathways in model
organisms is beginning to shed light on this fundamental question.
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Conserved pathways of ageing in the brain

Genome-wide gene expression studies during ageing of the nematode Caenorhabditis
elegans, the common fruitfly (Drosophila melanogaster) and the brains of mice, rats,
chimpanzees and humans have revealed a few broadly conserved functional categories of
genes with age-dependent expression changes (6,19) (Table 2 and Fig. 2). In particular, most
of these studies provide evidence of reduced mitochondrial function during ageing.
Furthermore, reduced expression of genes involved in mitochondrial energy metabolism
may become more pronounced in humans with cognitive decline and Alzheimer’s disease
(20–22). Another universally conserved feature of ageing is increased expression of genes
involved in stress-response pathways. In a transcriptional profiling study of the ageing
cortex in mice, rhesus macaques and humans, the greatest conserved change was age-
dependent upregulation of the apolipoprotein D gene (13). Apo lipoprotein D expression
extends lifespan in Drosophila, and the protein functions as a lipid antioxidant conferring
resistance to oxidative stress (23,24). Moreover, apolipoprotein D expression is induced in
the brains of individuals with Alzheimer’s disease (25). Hence, conserved mechanisms of
stress resistance during ageing may also be used by the brain to protect against the pathology
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of neurodegenerative disorders.

Despite clear evidence of conservation of some ageing pathways and gene expression
signatures, a recent study directly comparing gene expression during ageing in mouse,
rhesus macaque and human brain has revealed a major evolutionary divergence (13). More
than 150 genes were found to undergo age-dependent expression changes in all three
organisms. Not all of these genes changed expression in the same direction in all three
organisms. A significant fraction of age-regulated genes, mostly predicted to participate in
neuronal functions, are upregulated with age in mice but downregulated with age in humans.
This suggests an evolutionary shift since the divergence of the rodent and human lineages,
resulting in coordinate repression, rather than activation, of many neuronal genes during
ageing. Biochemical and stereological neuronal counting studies of the ageing human cortex
suggest that this is unlikely to reflect neuronal loss (6,13). It is important to appreciate the
evolution of these gene expression changes, as they may contribute to the apparent human
specificity of certain neurodegenerative disorders, such as Alzheimer’s disease.

Mitochondrial dysfunction
Gene expression studies suggest that reduced expression of mitochondrial genes is a
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strongly conserved feature of ageing in organisms ranging from C. elegans to humans

(6,19). In particular, organ-specific analysis of brain ageing has revealed a progressive
decline in mitochondrial gene expression in rats, rhesus macaques and humans (7,10,13).
Mitochondrial function seems to be an important modulating influence on the ageing
process in all species tested, and it can have either positive or negative effects on lifespan,
depending on the context (26).

Reduction of mitochondrial function would be expected to impair health and shorten

lifespan. Indeed, there are examples in invertebrates and mammals where this is the case.
Severe reduction of mitochondrial function in worms shortens lifespan significantly (27).
Mice that have been engineered to accumulate mitochondrial DNA mutations at an elevated
rate show reduced electron transport chain function, signs of accelerated ageing and
shortened lifespan (28,29). Conversely, augmentation of mitochondrial function has been
shown to extend lifespan. Targeted overexpression of the antioxidant enzyme catalase

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specifically in mitochondria is sufficient to extend mouse lifespan (30). Furthermore,

artificially elevating the rate of mitochondrial respiration is sufficient to increase replicative
lifespan in yeast (31). Although the actual mechanisms that underlie lifespan extension in
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these experimental models are not entirely clear, one hypothesis is that efficient electron
transport chain function reduces the generation and release of damaging reactive oxygen
species (ROS).

Brain and muscle are particularly susceptible to defective mitochondrial function. The
human mitochondrial encephalomyopathies are inherited disorders caused by deletions or
mutations of mitochondrial DNA. These mitochondrial defects lead to varied neurological
and muscle-related impairments that depend on the number of mitochondria affected per cell
(32,33). Importantly, this dependence on the number of affected mitochondria also regulates
the age of onset of clinical symptoms. Hence, it has been suggested that a normal decrement
in mitochondrial function may also contribute to age-dependent functional deficits in
neurons and myocytes. Evidence in support of this notion comes from studies of Drosophila,
in which the orthologue of the mammalian brain-specific mitochondrial uncoupling protein
UCP5 functions specifically in neurons to regulate metabolism and lifespan (34). In the
human brain, declining mitochondrial function may selectively affect neuronal populations
with large bio energetic demands, such as the large pyramidal neurons that degenerate in
Alzheimer’s disease. Thus, declining mitochondrial function may contribute to brain ageing
and render neurons vulnerable to age-dependent pathology.
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Unexpectedly, reduced mitochondrial function can, in some circumstances, increase

lifespan. One of the earliest suggestions of this came from analysis of clk-1 mutant worms
(35). CLK-1 is required for synthesis of ubiquinone, which has an important role in
mitochondrial respiration, and clk-1 mutant worms have reduced respiratory rates. These
worms also have long lifespans, as well as generally slow developmental and behavioural
rates. Subsequent RNA interference screens found that reduction of function in many genes
affecting the electron transport chain can increase lifespan (36,37). This effect seems to be
crucially dose dependent, because a modest reduction in electron transport chain activity can
increase lifespan, whereas a more severe reduction shortens it (27). Recent evidence
suggests that this lifespan extension may be mediated by a nuclear transcriptional response
to mitochondrial defects, termed the retrograde response, involving the induction of
oxidative stress resistance and xenobiotic detoxification genes (38). In Drosophila, reduced
expression of electron transport chain components specifically in adult neurons is sufficient
to extend lifespan (39). This phenomenon may also occur in mammals, because Coq7
heterozygous mutant mice (Coq7 being the mouse orthologue of clk-1) are long lived (40).
Furthermore, a mouse model with reduced activity of the cytochrome c oxidase complex, a
component of the electron transport chain, shows increased lifespan (41). Intriguingly, this
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mouse also exhibits protection against neuronal excitotoxicity in the brain. Although the
signaling mechanisms mediating increased longevity in this context are not well understood,
one possibility is that ROS in a modestly increased concentration act as signalling molecules
to activate survival pathways and promote longevity.

The observation that modestly reduced mitochondrial function can activate longevity
pathways raises the interesting possibility that the initial decline in mitochondrial gene
expression observed during brain ageing may be part of an active compensatory mechanism
that increases stress resistance. Such a compensatory response might be effective in resisting
transient stress. However, persistent stress associated with ageing may further reduce
mitochondrial function, leading to a self-reinforcing cycle of detrimental decline (Fig. 3).

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Oxidative stress and epigenetic changes

Multiple lines of evidence suggest that progressive oxidative damage is a conserved, central
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mechanism of age-related functional decline (42). Gene expression studies of whole-

organism ageing in worms and flies and brain-specific ageing in mice, rats, chimpanzees and
humans reveal that all six organisms show an age-dependent upregulation of oxidative
stress-response genes (reviewed in ref. 6). Moreover, genes that mediate oxidative stress
responses and DNA damage repair constitute the largest class of genes upregulated in the
ageing human prefrontal cortex (7,11). Dietary antioxidants can suppress many age-related
gene expression changes in the mouse brain (43) and can reduce cognitive decline and
prevent oxidative damage to the brain in ageing rats (44).

In the ageing human brain, oxidative damage to specific gene promoters results in gene
silencing (7). It may be that irreplaceable post-mitotic cells, such as neurons, respond to
unrepaired DNA damage by silencing expression of the affected genomic region, rather than
by undergoing apoptosis. The mechanism of silencing may be epigenetic; specifically, it
may be a transition to a more repressive transcriptional state (7,13). Recent studies have
shown that DNA damage can induce changes in gene expression and histone modification
patterns that may be mediated, in part, by the conserved lifespan regulatory gene SIRT1 (see
below), suggesting a possible mechanistic link between DNA damage, epigenomic state and
ageing (45,46). Consistent with this idea, the yeast homologue of SIRT1, SIR2, is a long-
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established regulator of lifespan, DNA damage repair and epigenetic gene silencing (47).
Furthermore, a number of chromatin-remodelling factors regulate lifespan in C. elegans
(48). These considerations argue strongly for a conserved role of epigenome dynamics in the
ageing process.

A recent study demonstrated the importance of altered epigenetic state in the control of brain
neuronal gene expression underlying synaptic plasticity and memory. The study used a
mouse model in which inducible expression of p25, an allosteric regulator of cyclin-
dependent kinase 5 (CDK5), elicits neurodegeneration. A transient period of p25 expression
in the adult mouse resulted in some degree of neurodegeneration and synapse loss in the
hippocampus, together with memory loss (49). Environmental enrichment promoted the
recovery of lost memories, which was accompanied by increased synaptic plasticity and the
induction of activating histone acetylation marks. Remarkably, treatment with a
pharmacological histone deacetylase inhibitor was able to mimic environmental enrichment
and promote neuronal plasticity and recovery of memory function. These findings highlight
the role of epigenetic changes in memory loss associated with neurodegeneration. In
addition, they suggest that loss of memory storage is distinct from loss of neural pathways
that access stored memory. Given that human brain ageing is accompanied by memory loss
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and reduced synaptic connectivity, but not significantly by neuronal loss, it is probable that
loss of the ability to access stored memories underlies age-dependent memory deficits. If
this is so, there is hope that pharmacological interventions affecting epigenetic state could
ameliorate some of the cognitive deficits associated with ageing and neurodegenerative
disorders.

Autophagy and protein turnover

Studies in model organisms have implicated autophagy as a crucial regulator of the ageing
process. In worms, increased autophagy is necessary for lifespan extension by reduced
insulin-like signaling (50) and dietary restriction (51). In flies, increasing autophagy in
neurons alone is sufficient to extend lifespan (52), and reducing autophagy shortens lifespan
and gives rise to neurodegeneration (52,53). Reduced basal autophagy in the mouse nervous
system similarly leads to neurodegeneration (54,55). In autophagy-deficient flies and mice,

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neurodegeneration is accompanied by the accumulation of ubiquitylated protein aggregates,

similar to those observed in human neurodegenerative disorders such as Huntington’s
disease and Alzheimer’s disease. Consistent with this, the expression of BECN1, a key
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regulator of autophagy, is directly related to efficient clearance of aggregated mutant

huntingtin protein in Huntington’s disease (56). Expression of BECN1, as well as a number
of other key genes in the autophagic pathway, declines with ageing in the human brain (T.L.
and B.A.Y., unpublished observations), potentially increasing neuronal vulnerability to the
toxic effects of protein aggregates.

The signalling pathway of the kinase TOR is a central regulator of protein homeostasis that
acts to inhibit autophagy and messenger RNA translation. Reduced TOR signalling has been
shown to extend lifespan in yeast, worms and flies (reviewed in ref. 57). Moreover, it was
recently shown that the TOR inhibitor rapamycin extends lifespan in mice even when
treatment is initiated late in life (58). The extent to which TOR signalling in neurons
contributes to the observed lifespan effects is unknown, but there is evidence that TOR
signalling and autophagy have significant effects on pathological protein aggregates
associated with age-dependent neuro degenerative diseases. For example, rapa mycin has
been shown to reduce toxic-aggregate formation and disease progression by increasing
autophagy in mouse and fly models of Huntington’s disease and tauopathy (59). These
results suggest that the TOR pathway may modulate pathological protein aggregation
associated with neurodegenerative disorders.
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Accumulation of ubiquitylated protein aggregates can occur during normal human brain
ageing and reaches pathological levels in neurodegenerative disorders such as Alzheimer’s
disease and tauopathies. A recent study found that a mouse model of chronically reduced
proteasomal activity in the brain showed elevated concentrations of several proteins, some
of which had previously been found to alter expression in the brain in Alzheimer’s disease
(60). Furthermore, these mice had deficits in spatial memory, consistent with a potential role
for defective proteasome function in cognitive decline associated with Alzheimer’s disease.
Ubiquitylated protein aggregates are not as prevalent in other ageing tissues, which may
reflect the unusual longevity of post-mitotic neurons (which survive for an entire human
lifetime in a metabolically active state).

Insulin/IGF signalling
Reduced signalling through the insulin/IGF-1 signalling (IIS) pathway is a strongly
conserved mechanism of lifespan extension in worms, flies and mammals (reviewed in ref.
61). Polymorphisms in two IIS pathway genes, the IGF-1 receptor and the downstream
FOXO3 transcription factor, have been associated with longevity and healthy ageing in
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humans (62–64). Importantly, reduced IIS specifically in the nervous system is sufficient to
extend lifespan in several model systems. In worms, for example, reduced IIS in the nervous
system accounts for a portion of the lifespan extension in IIS mutants (65,66). Furthermore,
ablation in the fly brain of specific neurosecretory cells that produce insulin-like peptides is
sufficient to extend lifespan (67).

In mammals, insulin and IGF-1 are neurotrophic and promote neuronal survival by
inhibiting apoptosis (68). Insulin and IGF-1 can also promote learning and memory in
humans and animal models (61,68). By contrast, reduction of IIS by neuron-specific
knockout of the insulin receptor substrate Irs2 is sufficient to extend mouse lifespan (69).
There is a dichotomy, therefore, between the neuroprotective effects of insulin and IGF-1
signalling and their apparently deleterious effects on organismal lifespan. Interestingly, the
effects on lifespan parallel the effects on neurodegenerative pathology. In worms, reduced
insulin signalling can ameliorate amyloid-β aggregation and cytotoxicity (70). Similarly,

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knockout of Irs2 or the IGF-1 receptor can reduce cognitive impairment, neurodegeneration
and premature mortality in mouse models of Alzheimer’s disease (71,72). In patients with
Alzheimer’s disease, there is evidence of reduced expression of components of the IGF
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signalling pathway (73). It is unclear, however, whether this represents an active

neuroprotective response or a secondary manifestation of the neurodegenerative process.

Caloric restriction and sirtuins

Caloric restriction — that is, the reduction of calorie intake without causing malnutrition —
is the only known intervention that robustly increases lifespan in many species (74).
Recently, this phenomenon has been extended to primates, in a long-term experiment
showing lifespan extension in calorie-restricted rhesus macaques (75). Caloric restriction has
also been widely documented to have beneficial effects on the function of the brain and its
vulnerability to age-dependent pathology. It prevents many age-dependent gene expression
changes in the mouse brain (8,43), reduces age-related brain atrophy in rhesus macaques
(75) and has significant beneficial effects on the age-dependent impairment of learning and
memory in rodents (76,77) and humans (78). Unexpectedly, a three-month period of caloric
restriction in healthy aged humans was sufficient to improve verbal memory by
approximately 20% (ref. 78). There is also evidence that caloric restriction may confer
resistance to Alzheimer’s-disease-type pathology: caloric restriction was found to reduce
amyloid-β deposition and improve learning and memory in transgenic mouse models of
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Alzheimer’s disease (79).

The molecular basis of the beneficial effects of caloric restriction has recently begun to be
elucidated (80). The NAD+-dependent deacetylase SIR2 was one of the earliest genes to be
implicated in the response to caloric restriction, initially in a yeast model (81). Homologues
of Sir2 (called sirtuins) have subsequently been shown to mediate some of the effects of
caloric restriction in flies (82) and mammals (83,84). It is important to note, however, that
the potential roles of sirtuins in caloric restriction are controversial and context dependent
(see page 480), differing markedly across genetic backgrounds in yeast (85) and tissue types
in mice (86). Similarly, SIRT1 can have either beneficial or detrimental effects in the brain.
Evidence for the benefits of SIRT1 in brain ageing includes the finding that increased SIRT1
activity protects against axon degeneration after injury in a mouse mutant known as
Wallerian degeneration slow (87). SIRT1 also protects against amyloid-β toxicity in cell
culture and neurodegeneration in the p25/CDK5 mouse model, which recapitulates aspects
of Alzheimer’s disease pathology and tauopathy (88). By contrast, SIRT1 may also have
some detrimental effects, as Sirt1 knockout mice show reduced oxidative stress and
increased neuroprotection in the ageing brain even though lifespan is shortened (89). Further
studies are required to better elucidate the roles of sirtuins in brain ageing and their
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therapeutic potential in neurodegenerative diseases.

Potential brain regulation of organismal ageing

There is increasing evidence that the nervous system may act as a central regulator of ageing
by coordinating the physiology of extraneural tissues. In worms, a number of different
mutations that disrupt the function of sensory neurons extend lifespan (90). Furthermore,
ablation of specific neurons can increase lifespan in worms (91) and flies (67). A notable
example of the central regulatory function of the nervous system was the finding that two
neurons in C. elegans, the ASI neurons, could mediate lifespan extension in response to
caloric restriction (92). Lifespan extension required ASI-neuron-specific activity of the
transcription factor SKN-1, a homologue of the mammalian NF-E2 related factor (NFE2L2),
with known functions in activating cellular defences against oxidative and xenobiotic stress.

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Interestingly, the ASI neurons regulate energy metabolism in C. elegans and may thus
represent a functional analogue of the mammalian hypothalamus.
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The hypothalamus functions as a central regulator of metabolism and energy use, and it
coordinates the physiological responses of the entire organism through hormonal signalling.
In mice, reducing the growth hormone signalling from the hypothalamic–pituitary axis
extends lifespan (93). Furthermore, overexpression of the mitochondrial uncoupling protein
UCP2 in specific cells in the murine hypothalamus is sufficient to extend lifespan (94).
These findings argue for a crucial role of hypothalamic hormonal signalling in the control of
organismal ageing.

Such hypothalamic regulation of hormonal pathways might have a role in cognitive decline
during brain ageing. The hypothalamus coordinates stress responses, in part through the
regulation of peripheral glucocorticoid secretion (95). Glucocorticoids can be sensed directly
by another part of the brain, the hippocampus, which then suppresses hypothalamic
stimulation of further glucocorticoid release in a negative feedback loop (Fig. 4). However,
excessive glucocorticoid production associated with chronic or severe stress may impair
hippocampal neuronal function and predispose the organism to neurodegeneration (96),
potentially disrupting the regulatory circuit that connects the hippocampus and the
hypothalamus. Furthermore, primary hippo campal neurodegeneration in individuals with
Alzheimer’s disease may also disrupt hippocampal–hypothalamic control of systemic
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physiological functions (97). Other brain-systemic circuits yet to be discovered may further
integrate higher-order brain function with systemic physiology. Thus, primary degenerative
changes in the brain could contribute to systemic breakdown in the regulation of
glucocorticoids and other crucial hormones, such as IGF-1. These systemic changes may, in
turn, predispose the individual to further neurodegenerative changes, setting up a
progressive cycle of physiological and neurological decline (Fig. 4).

Future directions
The major risk factor for neurodegeneration and cognitive decline is the ageing of the brain.
Conserved pathways and mechanisms that control organismal ageing, such as insulin/IGF
signalling and mitochondrial function, can modulate pathology and cognitive decline in
mouse, fly and worm models of Alzheimer’s disease and other neurodegenerative disorders.
However, the role of these conserved pathways in the onset and progression of
neurodegenerative disorders in humans is still unclear. The resolution of this basic issue will
depend on future clinical interventions that target these pathways to ascertain their role in
both normal age-related cognitive decline and pathological neurodegeneration.

The role of the brain as a central integrator of physiological changes during ageing is just
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beginning to be explored. Recent findings suggest that higher-order brain systems become
less efficient with age, with some degree of disconnection between brain areas that normally
function together in young adults. This may reflect, in part, gene expression changes that
affect synaptic function, axonal integrity and myelination. An intriguing question is whether
functional disconnection in the brain leads to disruption of brain-systemic feedback loops
involving crucial hormonal and autonomic systems. Such a loss of integrated function may
contribute to age-related physiological changes, such as hypertension and insulin resistance,
and predispose individuals to age-related pathological changes in the brain. It will be
exciting to explore the extent of these functional connections in future studies.

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Figure 1. Altered functional activation of brain systems during brain ageing

Functional imaging of brain activation during task performance shows a change in activation
patterns as the human brain ages. a, Top: functional magnetic resonance imaging scans show
simultaneous activation of the medial prefrontal cortex (mPFC), posterior cingulate (pC) and
lateral parietal cortex (LP) in young adults, but this temporal correlation of activity is
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considerably reduced in aged individuals. (Images reproduced, with permission, from ref. 2.)
Bottom: hypothetical connections between areas of the mPFC, pC and LP may mediate the
coordinated activation in young adults, whereas declining function of such connections
could underlie the observed disruption in coordinated activity in ageing brains. (Images
courtesy of C. Koch, California Institute of Technology, Pasadena.) b, Positron emission
tomography shows that young adults performing a memory test exhibit right-lateralized
brain activation. Aged adults with poor performance in this test also had right-lateralized
PFC activity, but aged adults with good performance showed bilateral activation. Thus,
recruitment of additional brain areas may compensate for age-dependent functional decline
in the primary areas subserving cognitive abilities (3,5). (Images reproduced, with
permission, from ref. 5.)
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Figure 2. Evolutionary changes in gene regulation in the brain during ageing

A broad regulatory shift in age-related gene expression appears in the primate lineage.
Genes that change with ageing in the human and rhesus macaque cortex are predominantly
downregulated (pink), in contrast to the mouse cortex, where most age-regulated genes are
upregulated (green). This degree of gene repression is not observed in several other non-
neural human tissues, including peripheral blood mononuclear cells (T.L. and B.A.Y.,
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unpublished observations), muscle (98) and kidney (99).

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Figure 3. Conserved pathways that regulate organismal and brain ageing

Shown are mechanisms that involve mitochondrial function, oxidative stress, autophagy,
protein homeostasis, TOR signalling, insulin/IGF-1 signalling (IIS), caloric restriction (CR)
and sirtuins. Modest concentrations of ROS generated by mitochondria during normal
metabolism may induce stress-resistance pathways that scavenge ROS and repair damage.
However, progressive mitochondrial damage may lead to pathological concentrations of
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ROS production, which, in turn, may contribute to further mitochondrial damage. Damaged
mitochondria can be cleared by autophagy, which is promoted by CR and inhibited by TOR
signalling. CR improves overall mitochondrial function, in part, by promoting mitochondrial
biogenesis and reducing ROS production (100). ROS can damage other crucial
macromolecules, such as DNA and proteins. Unrepaired DNA damage may give rise to
epigenetic changes and gene silencing and may exacerbate mitochondrial impairment by
reducing the expression of nuclear-encoded mitochondrial genes. ROS can also modify
proteins, leading to protein unfolding and aggregation. Modified proteins can be removed by
a number of degradative pathways, including the ubiquitin proteasome pathway. Inadequate
clearance may lead to the accumulation of toxic protein aggregates. The dynamics of protein
clearance and aggregate formation may be modulated by the IIS pathway and by SIRT1 and
CR. The accumulation of damaged and toxic proteins may also be modified through the
regulation of messenger RNA translation by TOR signalling and CR.
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Figure 4. The brain as a potential regulator of organismal ageing

The ageing of the brain may be coordinated with the ageing of organ systems through
hormonal feedback circuits. The left-hand side of the diagram shows how glucocorticoid
hormonal signalling may contribute to brain ageing. Stressors induce hypothalamic
production of corticotropin-releasing hormone (CRH), leading to glucocorticoid release
from the adrenal glands. The hippocampus, in turn, senses glucocorticoid concentrations
through the glucocorticoid receptor (GR), resulting in feedback inhibition of glucocorticoid
release through the hypothalamus. Chronically elevated glucocorticoid concentrations
during ageing may be detrimental to hippocampal function, blunting the ability of the
hippocampus to repress glucocorticoid release and potentially setting up a self-reinforcing
process of hormonally mediated hippocampal decline. The right-hand side of the diagram
shows how hormonal feedback circuits, similar to the pathways shown on the left-hand side,
may be a general mechanism contributing to the decline of other functional systems in the
brain. Dashed arrows indicate effects that may be indirect and/or are poorly understood
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mechanistically.

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Table 1
Signalling pathways that influence ageing in model organisms and brain ageing in mammals
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Pathway Effects on ageing of model organism Effects on mammalian brain ageing

Insulin/IGF-1 signalling Decreased signalling promotes increased Decreased signalling promotes decreased Alzheimer’s disease
stress resistance and lifespan pathology; paradoxically, increased signalling may be
neuroprotective
TOR signalling Decreased signalling causes increased Regulation of autophagy and protein homeostasis may modulate
lifespan, increased autophagy and decreased toxic-protein aggregation in neurodegenerative disease
protein translation
Mitochondrial function Severely decreased function causes decreased Progressively decreasing function during ageing contributes to
lifespan, but modestly decreased function can decline and pathology. However, preliminary evidence suggests
cause increased lifespan that modestly decreased function may engage beneficial pathways
Sirtuins Can increase or decrease lifespan in different Can be neuroprotective or detrimental to neurons, depending on
contexts context
Caloric restriction Optimal caloric restriction causes increased Increased preservation of cognitive function during ageing
lifespan

IGF-1, insulin-like growth factor 1; TOR, target of rapamycin.

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Table 2
Evolutionary conservation of gene expression changes during brain ageing

Gene category Human (brain) Rhesus macaque (brain) Rat (brain) Mouse (brain) Fly (organism) Worm (organism)
Bishop et al.

Stress response ↑ ↑ ↑ ↑ ↑ ↑
Mitochondria ↓ ↓ ↓ ↓↑ ↓ ↓
Neural plasticity/synaptic function ↓ ↓ ↓ ↓ – –
Inhibitory interneuron function ↓ ↓ – – – –
Ubiquitin–proteasome pathway ↓ ↓ – ↓ – –
Immune/inflammatory response ↑ – ↑ ↑ ↑ –
Metal ion homeostasis ↑ – ↑ – – –
Myelin-related proteins ↑ – ↑ – – –
Glial genes ↑ – ↑ – – –

Some gene categories, such as those involved in stress responses and mitochondrial function, show conserved changes during ageing, whereas others, such as inhibitory interneuron function, exhibit primate-
specific changes. An upward arrow indicates that expression increases with age; a downward arrow indicates that expression decreases with age; and a dash indicates that no change in expression with age is
detected. In the ageing mouse brain, different subsets of mitochondrial genes are either age-upregulated or age-downregulated (13).

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