Brain functions, including cognition, emotion, circadian behaviours and autonomic function, decline with age and cause significant impairment in quality of life owing to social, cognitive and physical disability. For instance, in 2002, approximately 5.4 million people (22.2%) older than 71 years of age in the United States were reported to have cognitive impairment, even excluding dementia1. Even among people older than 70 years of age with normal cognitive function, abnormalities in brain glucose metab-olism have been found, and these abnormalities are signif-icantly associated with depressive and anxiety symptoms2. Furthermore, it has been suggested that age-related sleep deterioration contributes to physical disabilities including skeletal muscle decline, increasing the risk of sarcopenia in the elderly3. Indeed, ageing is also the greatest risk factor for neurodegenerative diseases4. Over the past 20 years, there has been a vast amount of progress in our under-standing of ageing and longevity control in diverse model organisms5, remarkably revealing that the brain has a cen-tral role in the regulation of ageing and longevity6. Indeed, brain-specific genetic manipulations in mice have been shown to produce significant improvement in several physiological functions and lifespan extension (TABLE 1).

In addition to these genetic influences, recent findings have also revealed a range of cellular influences on the aging process, such as microglia. Microglia are immune cells in the brain that are emerging as key modulators of pathological brain states involving immune system acti-vation7,8. In particular, chronic microglial activation exac-erbates brain ageing by inducing inflammation8, which causes progressive damage in the brain. In addition to the effect of microglia, circulating factors (for example, myokines, hepatokines, adipokines, cytokines and their metabolites) have been reported to significantly affect brain function. However, the molecular mechanisms by which the brain modulates inflammation and responds to circulating factors are not fully elucidated.

One important class of proteins governing the effects of the brain on ageing is the sirtuin family. Sirtuins are an evolutionally conserved family of NAD+-dependent deacylases and play a critical part in ageing and longev-ity control in diverse model organisms including yeast, worms, flies and mice9–11. Sirtuins interact with other pathways that also contribute to the control of ageing, such as the insulin–forkhead box protein O (FOXO) and mechanistic target of rapamycin (mTOR) path-ways, in many cellular contexts12–14. Neuron-specific or brain-specific genetic manipulation of sirtuins mod-ulates not only the neuronal activity itself but also the function of peripheral tissues. For example, several papers have demonstrated that hypothalamic SIRT1 has roles in metabolic events in peripheral organs, includ-ing brown adipose tissue remodeling15, insulin sensi-tivity16, and systemic glucose and lipid metabolism17. Therefore, it is likely that the brain, via sirtuin signalling, is an important part of a network that regulates ageing throughout the body.

These findings, combined with a growing ageing human population, create a pressing need to further investigate the role of the brain in ageing and longevity control and understand the mechanisms that underlie age-associated brain pathophysiologies. Further elucida-tion of sirtuin function in the brain will also shed light on the systemic regulatory mechanisms of ageing and longevity. Such efforts will stimulate the development of preventive and therapeutic interventions to maintain the proper function of the brain in the elderly. Here, we describe how brain function is altered during the ageing process and how these alterations are exacerbated through mechanisms involving neurons and microglia. We also discuss the molecular mechanisms by which specific sig-nalling pathways in the mammalian brain modulate sys-temic ageing and affect longevity, focusing particularly on the function of brain sirtuins. Finally, we discuss putative

1Department of Developmental Biology, Washington University School of Medicine, Campus Box 8103, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.2Department of Biology, The Paul F. Glenn Center for the Science of Aging, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Bldg 68–280 Cambridge, Massachusetts 02139, USA.3Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Kendall Square, Cambridge, Massachusetts 02139, USA.4National Center for Geriatrics and Gerontology, Sleep and Aging Regulation Research Project Team, 7–430 Morioka-cho, Obu, Aichi 474–8511, Japan.

Correspondence to L.G.  leng@mit.edu

doi:10.1038/nrn.2017.42Published online 18 May 2017

MyokinesBiologically active peptides produced and secreted by muscle cells that mediate a range of biological effects in both original and remote tissues and organs.

The brain, sirtuins, and ageingAkiko Satoh1,4, Shin-ichiro Imai1 and Leonard Guarente2,3

Abstract | In mammals, recent studies have demonstrated that the brain, the hypothalamus in particular, is a key bidirectional integrator of humoral and neural information from peripheral tissues, thus influencing ageing both in the brain and at the ‘systemic’ level. CNS decline drives the progressive impairment of cognitive, social and physical abilities, and the mechanisms underlying CNS regulation of the ageing process, such as microglia–neuron networks and the activities of sirtuins, a class of NAD+-dependent deacylases, are beginning to be understood. Such mechanisms are potential targets for the prevention or treatment of age-associated dysfunction and for the extension of a healthy lifespan.

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mailto:leng%40mit.edu?subject=http://dx.doi.org/10.1038/nrn.2017.42

HepatokinesBiologically active peptides produced and secreted by hepatocytes that mediate a range of biological effects in both original and remote tissues and organs.

AdipokinesBiologically active peptides produced and secreted by adipocytes that mediate a range of biological effects in both original and remote tissues and organs.

CytokinesGeneral terms for small-size cell signalling peptides such as lymphokines, monokines, chemokines and interleukins (cytokines produced by lymphocytes, monocytes, chemocytes and leukocytes, respectively).

Brain atrophyShrinkage of the brain described as a loss of neurons and connections between neurons.

systemic factors from peripheral tissues that may act as feedback signals to influence brain function during the ageing process.

Brain ageing and sirtuinsCellular brain ageing. Age-associated neuronal dysfunc-tion is due to a range of morphological and functional alterations in the brain. These macroscopic and micro-scopic alterations are often associated with ultrastructural changes in neurons and glia. For example, brain atrophy occurs during the process of ageing, especially in the prefrontal cortex and the hippocampus18. In some cases, plaques and tangles develop outside and inside of neu-rons19, probably promoting neuronal cell death during the ageing process. Neurons also show alterations in synaptic structures20 (for example, decreases in synaptic density and synaptic terminals) and reduced neurotransmitter produc-tion. Another notable physiological change in the ageing brain is reduced neurogenesis21, the process of generating functional neurons from adult neural stem cells (NSCs). Adult neurogenesis in rodents, primates and humans22–26 is mainly restricted to the subgranular zone of the dentate gyrus of the hippocampus and to the subventricular zone of the lateral ventricles. Moreover, there is some evidence for the presence of NSCs and adult neurogenesis in other brain regions, including the striatum, cerebral cortex, sep-tum, spinal cord, hypothalamus and white matter (regions of myelination)27, and it has been suggested that reduced adult neurogenesis in these regions might play a part in neurodegenerative diseases25,28, repair of neural circuitry29 and weight control30. Synaptic plasticity also declines with

age, resulting in loss of neuronal networks and impaired cognitive function and emotion. Notably, increasing adult neurogenesis has the potential to both restore synaptic plasticity and increase cognitive function31.

The ageing brain exhibits abnormal increases in the number of the two main types of glia in the brain: astrocytes and oligodendrocytes (astrogliosis and oli-godendrogliosis, respectively); altered myelination and reduced nerve growth factor concentration are also found in the aging brain18 (FIG. 1). Such changes contribute to the destruction of the connectivity and high-order inte-gration of the neuronal network in the brain. Therefore, strategies that preserve adult neurogenesis and reduce gliosis would maintain brain function during ageing.

Roles of sirtuins in the brain. Sirtuins have been shown to have distinct roles in the mammalian brain. For example, SIRT1 promotes neurite outgrowth and axon development32, and also regulates dendritic arborization, long-term potentiation, and learning and memory33,34. In addition, in mouse models of Alzheimer disease and Huntington disease, SIRT1 promotes neuroprotective effects and cognitive functions35–37. Sirtuins have also been shown to be crucial in regulating circadian rhythm via the suprachiasmatic nucleus (SCN), in regulating other body functions via other hypothalamic regions, in determining addictive responses to opiates and in hear-ing6,32. Finally, SIRT1 and SIRT2 have been linked to the regulation of neural stem and/or progenitor cells and to the modulation of depressive behaviours38–42. The details of sirtuin functions in the brain are discussed below.

Table 1 | Longevity studies with brain-specific genetically engineered mice

Mouse model

Promoter Gene targeted or modified

Mouse strain

Sex Median lifespan (percentage increase or decrease compared with control)

Maximum lifespan

Refs

αMUPA α-crystallin A chain uPA overexpression FVB/N Female Extension (16%) Extension 182

UCP2 Tg brain

Hcrt Ucp2 overexpression

C57BL/6 Male Extension (12%) Extension 183

Female Extension (20%) Extension

bIrs2-KO Nestin Irs2 overexpression C57BL/6 Combined Extension (Het) (18%) Extension 184

Extension (Homo) (14%) Extension

bIGF1RKO Nestin Igf1r knockout C57BL/6 Combined Extension* (9%) No extension 185

Male Extension* (13%) No extension

Female Extension* (8%) No extension

N/Ikbkblox/lox Nestin Ikbkb inactivation C57BL/6 Combined Extension (23%) Extension (Data in males only)

127,186

MBH-IκB-α Synapsin promoter-directed lentiviral

Dominant negative Ikba

C57BL/6 Male Extension (p > 0.0001) Extension 127,186

MBH-IKK-β Synapsin promoter-directed lentiviral

Constitutively active IKBKB

C57BL/6 Male Shorten (p > 0.05) Shorten 127,186

BRASTO Prion Sirt1 overexpression

C57BL/6 Combined Extension (11%) Extension 11

Male Extension (9%) A trend of extension

Female Extension (16%) Extension

*Only mean lifespans are provided. Hcrt, hypocretin; Igf1r, insulin-like growth factor 1 receptor; Ikbkb, inhibitor of nuclear factor-κB (NF-κB) kinase subunit-β; Irs2, insulin receptor substrate 2; IκBa, NF-κB inhibitor-α; Tg, transgenic; Ucp2, uncoupling protein 2; uPA, urokinase-type plasminogen activator.

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b Functional changes during normal aging

a Histological changes during normal ageing

Mental deficits• Anxiety• Depression

Sleep disruption• Poor sleep quality• Delayed sleep onset latency

Circadian dysfunctionDisruption of amplitudeand period length ofcircadian behaviour

Cognitive decline• Vocabulary• Conceptual reasoning• Memory• Processing speed

Nature Reviews | Neuroscience

↑ Plaque and tangles↓ Adult neurogenesis ↑ Chronic inflammation↓ Nerve growth factor

Myelin

↑ Microglial activation↑ Chronic inflammation

Neuron

↑ Abnormal myelination

↑ Oligodendrogliosis Oligodendrocyte

↓ Neurotransmitter↓ Synaptic plasticity

Synapse

MicrogliaAstrocyte↑ Astrogliosis

Cognitive decline. Cognitive decline is a normal part of ageing and includes deficits in vocabulary, concep-tual reasoning, memory and processing speed. A recent study using whole-genome sequencing of a healthy age-ing cohort (the ‘wellderly’, individuals who live into their ninth decade without developing a significant chronic medical condition) identified common and rare genetic variants associated with a slower decline in cognitive function compared with controls43. Therefore, main-tenance of cognitive function might be important for healthy ageing.

Sirtuins contribute to age-associated cognitive decline through the regulation of synaptic plasticity and adult neurogenesis32. In the hippocampus, SIRT1

regulates synaptic plasticity33,34. SIRT1‑deficient mice have impaired hippocampal-dependent memory that is associated with decreased long-term potentiation (the reinforcement of synapses with repeated stimula-tion) in the CA1 region of the hippocampus33,34. In this region, SIRT1 positively regulates synaptic plasticity via a repressor complex containing the transcription factor Yin and Yang 1 (YY1), which represses the expression of microRNA-134 (miR-134). This brain-specific microRNA downregulates cAMP-responsive element-binding pro-tein (CREB) and brain-derived neurotrophic factor (BDNF) mRNA expression33. CREB and BDNF are important for synapse formation and long-term potenti-ation. In addition to its crucial role in synaptic plasticity, SIRT1 has been shown to regulate adult neurogenesis44–47. From a mechanistic point of view, SIRT1 can suppress NSC differentiation45,48,49 and self-renewal50. It has also been reported that both SIRT1 and SIRT2 can mediate neural stem and/or progenitor cell fate decisions into oli-godendrocytes51. Animals with high level of hippocam-pal neurogenesis are highly adaptable for learning and memory52, whereas decreased hippocampal neurogen-esis results in impaired spatial learning and a significant reduction in long-term potentiation in the dentate gyrus of the hippocampus53,54.

Given these crucial roles for sirtuins in the adult CNS, in particular the evidence that adult neurogene-sis is important for the maintenance of hippocampal and olfactory bulb functions55, the decline in the level of hippocampal SIRT1 activity with age is likely to have important and detrimental consequences56, and amelio-ration of age-related neurogenesis decline obtained by targeting sirtuins could be an effective intervention to improve age-related cognitive defects. Indeed, long-term administration of nicotinamide mononucleotide (NMN), a key NAD+ intermediate that can enhance sirtuin activ-ity, significantly increases the NSC pool in the dentate gyrus of aged mice51, and whether this restoration results in cognitive improvements is currently under investiga-tion. The importance of NAD+ biosynthesis in ageing is further discussed here below.

Compared to young individuals, about 20% of peo-ple at 55 years and older develop some kind of mental health disorder57, such as anxiety or depression, which also severely affects other physiological functions in the elderly. Therefore, maintaining mental health is essen-tial to achieve healthy ageing. Anxiety is one important mental health issue that tends to have an increased inci-dence in the elderly compared with younger adults. The pathology of anxiety disorders has been linked to neural systems such as GABAergic, noradrenergic and seroton-ergic signalling58. For example, downregulation of GABA type A receptor reduces the extent of anxiety in patients with anxiety disorder. In addition, α2-adrenergic recep-tor antagonists increase the firing of noradrenergic neu-rons in the locus coeruleus and induce anxiety, whereas α2-adrenergic receptor agonists reduce symptoms of anxiety58. Furthermore, presynaptic 5-hydroxytryptamine (5-HT; also known as serotonin) receptor subtype 1 (5-HT1) and postsynaptic 5-HT2 are principally involved in the modulation of anxiety59.

Figure 1 | Cellular, histological and functional changes in normal brain ageing. a | During the ageing process, amyloid plaques and neurofibrillary tangles are generated inside and outside of neurons, adult neurogenesis and nerve growth factor concentration decline, and chronic low-grade inflammation persists as a result of microglial activation. In addition, neurotransmitter production and synaptic plasticity are significantly reduced with age. Correct myelination of CNS neurons can also become disrupted with age along with increased brain oligodendrogliosis and astrogliosis. b | Age-associated alterations of brain function include cognitive and mental deficits, sleep disruption and circadian dysfunction. Cognitive functions that are affected by age include vocabulary, conceptual reasoning, memory and processing speed. Mental health concerns (for example, anxiety or depression) and sleep disruption (for example, poor sleep quality or delayed sleep onset latency) are significantly increased in elderly. Finally, age-associated circadian dysfunction is suggested to cause disruption of amplitude and period length of circadian behaviours.

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Circadian clockCentral mechanisms that drive circadian rhythm.

Additional evidence strengthens the case that brain sirtuins are involved in mechanisms underlying depres-sive disorders. A recent genome-wide association study (GWAS) of Han Chinese women identified two loci con-tributing to the risk of major depressive disorder (MDD) on chromosome 10. One is near the SIRT1 gene, and the other is near the LHPP gene38. In particular, GWAS of individuals with severe subtype of MDD revealed an association with a single-nucleotide polymorphism (SNP) at the SIRT1 locus38. Another study found that genetic variations in SIRT1 have been associated with depression in the Japanese population39,40. These studies suggest that an abnormal level of activity of SIRT1, possibly due to an increase in gene expression, could contribute to depres-sion. Consistent with these GWAS studies, brain-specific Sirt1‑knockout mice are less susceptible to depression than control mice42. Interestingly, electroconvulsive ther-apy (ECT), which is one of the most efficient treatments available for depression, increases SIRT1 immunoreac-tivity in the hippocampus and hypothalamus of mice, although this effect may not contribute to the antidepres-sive activity of ECT60. Opposite to SIRT1, inhibition of SIRT2 by tenovin-D3 results in depressive-like behaviours and impaired hippocampal neurogenesis, whereas over-expression of SIRT2 triggered by intra-hippocampal infu-sion of a Sirt2-expressing adeno-associated virus reverses chronic stress-induced depressive-like behaviours and promotes neurogenesis41. Whether the roles of SIRT1 and SIRT2 in hippocampal neurogenesis are related to their role in depression is not yet clear.

Recent studies have demonstrated one molecular mechanism by which sirtuins may be linked to anxiety42. Upregulation of SIRT1 leads to anxiety by activating the transcription of monoamine oxidase type A (MAO-A)42, which degrades neurotransmitters such as 5-HT. Because MAO inhibitors maintain consistent 5-HT levels, these inhibitors are clinically relevant for the treatment of patients with anxiety and depression61. In addition, both common and rare genetic polymorphisms in SIRT1 have been found to be associated with anxiety and other psy-chiatric disorders42. In the same vein, SIRT6 may regulate anxiety-like behaviour induced by prolonged exposure of the central amygdala to corticosteroid62. Corticosteroids activate the glucocorticoid receptor (GR), which local-izes in the nucleus and suppresses corticotropin-releasing factor (CRF), thereby reducing anxiety. A SIRT6–nuclear factor-κB (NF-κB) complex binds to the promoter region of the GR gene and suppresses expression through deacetylation of histone H3 lysine 9 (H3K9), leading to CRF expression62. Thus, inhibition of a specific sirtuin activity might be beneficial to attenuate anxiety-like behaviours, promoting healthy ageing.

Circadian dysfunction. Living organisms have daily rhythms (circadian rhythms) controlled by the master clock in the SCN, which maintains their physiological behaviours and homeostasis in response to environmen-tal changes. With age, the number of neurons in the SCN declines in rats63 and rhesus monkeys64. The expression of glial fibrillary acidic protein (GFAP), a marker of astro-cytes, increases in the SCN of rats and rhesus monkeys,

especially in the dorsomedial part of this nucleus63,64, whereas electrical activity in SCN neurons decreases in aged animals65,66. In the SCN, expression of neuro-transmitters, including vasoactive intestinal peptide, vasopressin, 5-HT, GABA and other neurochemical compounds, such as calbindin, also declines with age. Such age-associated alterations of SCN neurons cause the functional decline in the SCN, leading to disruption of amplitude and period length of circadian behaviours. These changes have been linked to age-associated alter-ations in the expression of circadian clock-related genes. In mammals, the circadian clock is regulated by specific patterns of expression of clock genes encoding positive regulators of transcription, such as circadian locomoter output cycles protein kaput (CLOCK), brain and muscle ARNT-like 1 (BMAL1), neuronal PAS domain-containing protein 2 (NPAS2) and retinoid-related orphan receptors (RORs), and negative regulators of transcription, such as cryptochromes (CRYs), period circadian protein homologues (PERs) and Rev-ErbA-α.

A recent study has demonstrated that SIRT1 medi-ates central circadian control in the SCN. Brain-specific Sirt1‑overexpressing transgenic mice show decreases in the level of acetylated BMAL1 in SCN neurons, whereas brain-specific Sirt1‑knockout mice show increases in BMAL1 acetylation in those neurons67. SIRT1 also directly activates Bmal1 transcription, which is positively regu-lated by the nuclear receptor RORα, and this activation requires peroxisome proliferator-activated receptor-γ co-activator 1α (PGC1α)67. The protein levels of SIRT1 decrease in SCN neurons with advanced age, leading to the reduction in BMAL1 and PER2 protein levels in these neurons. Indeed, old mice (22–24 months) display a more disrupted behavioural pattern and an inability to adapt to changes in the light entrainment schedule67. Interestingly, brain-specific Sirt1-knockout mice phenocopy these age-dependent circadian changes, whereas mice overex-pressing Sirt1 in the brain are protected from such effects of ageing67. These results indicate that maintaining SIRT1 function in the SCN could delay the ageing process and might potentially promote lifespan.

In a separate study, mice with an innate circadian period close to 24 hours (as revealed in a constant dark environment) lived longer in the normal laboratory set-ting of a 12-hour light and 12-hour dark cycle than mice with circadian period significantly longer or shorter than 24 hours68. This finding suggests that mice forced to reset their clocks daily experience faster ageing, perhaps due to a desynchronization between their circadian cycle and the light cycle. We infer that an ability to adapt well to a changing light environment may be one factor favouring longevity in the wild. This may be most crucial at later ages, when the function of the SCN is deteriorating.

Sleep disruption. Sleep is one of the vital circadian behav-iours in organisms. Notable alterations of sleep with age are poor sleep quality and delayed sleep onset latency, which is the length of time to accomplish the transition from wakefulness to sleep. Quality of sleep is determined by the quantity of delta waves (in NREM (non-rapid eye movement) sleep) in the electroencephalogram69,70.

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Nature Reviews | Neuroscience

Microglia

Aged brain

Pro-inflammatorycytokine releasefrom microglia• ↑ IL-1β • ↑ IL-6 • ↑ TNF

↑ BBB permeability

Myelin

Axon

• Synaptic damage• Neuronal death

Pathologies of age-associateddiseases

• MHCII • CD48• CD11b• CD11c

Pro-inflammatorycytokines fromperipheral immunesystem

• TLRs• CD86• CD40• ICAMs

Surface expression of:

• ↑ Neuroinflammation• ↓ IL-10• ↓ IL-4

Neuron

Figure 2 | Exacerbation of brain ageing through the activation of microglia. The aged brain is characterized by chronic low-grade inflammation and increased microglia reactivity (activated microglia), compared with the young brain. Activated microglia are marked by positive expressions of major histocompatibility complex class II (MHCII), CD48, CD11b, CD11c, toll-like receptors (TLRs), CD86, CD40 and intercellular adhesion molecules (ICAMs), and produce pro-inflammatory cytokines. Additional inflammatory cytokines are also recruited from the peripheral immune system, access the brain because of age-related increased blood–brain barrier (BBB) permeability and are maintained because of the reduced ability of phagocytosis in the aged brain. Elevated levels of interleukin-1β (IL-1β), IL-6 and tumour necrosis factor (TNF) are common in the aged brain and are accompanied by reduced levels of anti-inflammatory cytokines such as IL-10 and IL-4.

Human aetiological studies show a negative correlation between delta power and lifespan, and an inverse corre-lation between delta power and metabolic disorders71,72. In addition, recent GWAS studies reveal a close linkage between sleep–circadian-related genes and metabolism- related genes73. However, the molecular mechanisms behind these phenomena are not fully understood.

The sleep–wake cycle is controlled by circadian and homeostatic factors that are regulated by sirtuins. SIRT1 exists in wake-active neurons and is necessary for neu-rotransmitter synthesis in these neurons74. Conditional whole-brain Sirt1-knockout mice display a reduction in wake-time in both light and dark periods, and develop an accelerated accumulation of lipofuscin, an age-related marker, in wake-active neurons. Similar to Sirt1-knockout mice, Sirt3-knockout mice also display accelerated age-ing phenotypes, such as a deficit in adaptive antioxi-dant response, and oxidative injury in neurons of the locus coeruleus incurred during forced wakefulness75. Furthermore, knockdown of Sirt1 in mouse dorsomedial hypothalamic nucleus (DMH) and lateral hypothalamic nucleus (LH) decreases quality of sleep11. Therefore, eluci-dating the function of hypothalamic sirtuin-positive neu-rons in sleep–wake regulation is likely to shed new light on this fascinating connection between sleep, metabolism, ageing and longevity.

Effects of microglia on brain ageing. Brain microglia are immune cells that mediate the increased inflam-mation that occurs in the brain during ageing, result-ing in neuroinflammation. At the cellular level, this is characterized by chronic low-grade inflammation and increased microglial reactivity, compared to the young

brain. Such conditions are driven by increases in the level of cytokines in the brain, increased blood–brain barrier (BBB) permeability, microglial priming and phagocyto-sis. In young animals, peripheral cytokines induced by the innate immune system enter the CNS via saturable transport systems (for example, active transporter) and through restricted transmembrane diffusion across the BBB76–83. The aged brain is characterized by elevated levels of inflammatory cytokines such as interleukin-1β (IL-1β), IL-6 and tumour necrosis factor (TNF)84–86, and reduced levels of anti-inflammatory cytokines such as IL-10 and IL-4 (REFS 87,88). This phenomenon is partly explained by the significantly elevated permeability of the BBB, which is due to the age-related reduction in the expres-sion of BBB tight junction proteins89,90. In addition to the changes in the BBB, the increased inflammatory profile of the aged brain is associated with microglial priming, an exaggerated or heightened microglial response to inflam-matory stimuli (for example, lipopolysaccharide (LPS), a component of bacterial cell walls). By contrast, there is chronic expression of major histocompatibility complex class II (MHCII)91, CD68 (REF. 92), CD11b93, CD11c94, toll-like receptors (TLRs)95, CD86 (REF. 96), CD40 (REF. 96) and intercellular adhesion molecules (ICAMs)96 in aged rodent brains. Approximately 25% of microglia in mice at 18–20 months of age is MHCII positive, compared with only less than 3% of MHCII-positive microglia in mice at 3–4 months of age91. Moreover, microglia in the aged brain have impaired phagocytosis functions97,98. Such excessive and prolonged inflammation resulting from microglial priming causes neuroinflammation, resulting in synaptic damage, neuronal death during the ageing process and several age-associated diseases (FIG. 2).

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By contrast, in the healthy young brain, microglial acti-vation and cytokine production are transient and are in response to an insult, and microglia return to a surveying state when the immune stimulus is resolved99.

Recent studies indicate that sirtuins are involved in the regulation of cytokine production from microglia and in microglial activation (TABLE 2). In rats, administration of LPS, which binds to TLR4 exclusively expressed on micro-glia in the rodent brain, induces NF-κB-dependent micro-glial activation in primary microglia100. The p65 protein

(also known as RelA) in the NF-κB protein complex is a well-known substrate of SIRT1 deacetylation, which leads to repression of NF-κB. LPS promotes notable upregu-lation of matrix metalloproteinase 9 (MMP9), inducible nitric oxide synthase (iNOS) and IL-1 through miR-204 activation101. The 3ʹ untranslated region (3ʹ UTR) of Sirt1 mRNA is directly bound to miR-204, which leads to sup-pression of Sirt1 expression101. Moreover, knockdown of Sirt1 increases levels of MMP9, iNOS and IL-1, whereas resveratrol, an activator of SIRT1, decreases them101.

Table 2 | Role of sirtuins in different brain functions

Cellular or behavioural parameter

Sirtuin Effects or role Downstream factors Refs

Adult neurogenesis SIRT1 NSCs differentiation, self-renewal and cell fate decisions leading to differentiation into oligodendrocytes

HES1, PAX2 and NOTCH 44–51

SIRT2 Cell fate decisions leading to differentiation into oligodendrocytes

Unknown 51

Hippocampal neurogenesis Unknown 41

Synaptic plasticity SIRT1 Increased synaptic formation and plasticity miR-134 33,34

Cognition SIRT1 Increased hippocampal-dependent memory CREB and BDNF 33,34

Emotion SIRT1 Anxiety MAO-A 42

MDD MAO-A 38–40,42

SIRT2 Depression-like behaviour Unknown 41

SIRT6 Anxiety-like behaviour GR 62

Circadian rhythms SIRT1 Circadian control in the SCN BMAL1 67

Sleep–wake patterns SIRT1 Increase in NREM delta power NKX2.1–OX2R 11

Determines duration of wakefulness Unknown 74

SIRT3 Adaptive response to forced wakefulness FOXO3a and PGC1α 75

Age-related hearing loss (BOX 1)

SIRT3 Reduction of cochlear degeneration Mitochondrial NADPH-dependent IDH2

121,122

Protection of cochlear hair cells against gentamicin ototoxicity by adjudin

Unknown 178

SIRT1 Protection of cochlear hair cells against age-related hearing loss

p53 and FOXO3 179,181

Microglial activation SIRT1 MMP9, iNOS and IL-1 production miR-204 101

IL-1 production IL-1β 102

SIRT2 LPS-induced microglial activation NF-κB 103

Neuroprotective effects SIRT1 Alzheimer disease Tau 102,105–108

Parkinson disease LC3–α-synuclein 109,110

Huntington disease TORC1, CREB and FOXO3a 35,36,111–113

Amyotrophic lateral sclerosis p53 and FOXO3 106,114,115

SIRT2 Parkinson disease Unknown 116

Huntington disease SREBP2 117–119

SIRT3 Protection against excitotoxic injury Unknown 123

Amyotrophic lateral sclerosis Unknown 124

Metabolic events in peripheral tissues

SIRT1 Brown adipose tissue-remodelling Unknown 15

Increases insulin sensitivity Unknown 16

Regulates systemic glucose and lipid metabolism Unknown 17

BDNF, brain-derived neurotrophic factor; BMAL1, brain and muscle ARNT-like 1; CREB, cAMP-responsive element-binding protein; FOXO3, forkhead box protein O3; GR, glucocorticoid receptor; IDH2, isocitrate dehydrogenase 2 (NADP+), mitochondrial; IL-1, interleukin-1; iNOS, inducible nitric oxide synthase; LC3, microtubule-associ-ated protein 1 light chain 3; LPS, lipopolysaccharide; MAO-A, monoamine oxidase type A; MDD, major depression disorder; miR 134, microRNA-134; MMP9, matrix metalloproteinase 9; NF-κB, nuclear factor-κB; NREM, non-rapid eye movement; NSCs, neural stem cells; OX2R, orexin receptor type 2; PGC1α, peroxisome prolifera-tor-activated receptor-γ co-activator 1α; SREBP2, sterol regulatory element-binding protein 2; SCN, suprachiasmatic nucleus; TORC1, target of rapamycin complex 1.

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Box 1 | Role of sirtuins in age-related hearing loss

Old individuals are more susceptible to develop age-related hearing loss175. The mechanism underlying age-related hearing loss involves a functional decline in the auditory system, although the full mechanism has not been elucidated. One reported cause of age-related hearing loss is the loss of hair cells, the inner ear sensory cells in the cochlea that detect sound. This loss is irreversible and accompanied by the degeneration of spinal ganglion neurons in the same region176. The loss of hair cells has been suggested to be caused by oxidative damage induced by reactive oxygen species in the cochlea. Recent studies have demonstrated that sirtuins (SIRTs) have a role in protecting against age-associated hearing loss by reducing reactive oxygen species. Diet restriction, a regimen known to increase sirtuin activity in most tissues, slows or prevents age-related hearing loss in different mouse strains such as CBA/J mice and C57BL/6J mice121,177 by reducing cochlear degeneration and inducing Sirt3 expression in the cochlea121. SIRT3 is required for diet restriction-mediated prevention of age-related cochlear cell death and hearing loss. SIRT3 deacetylases and activates mitochondrial NADPH-dependent isocitrate dehydrogenase 2 and increases NADPH levels in mitochondria, thus resulting in an increased ratio of glutathione and glutathione disulfide and a decreased level of reactive oxygen species122. In addition, treatment of adjudin, an analogue of lonidamine that suppresses nuclear factor-κB (NF-κB) and confers neuroprotection, protects cochlear hair cells against gentamicin ototoxicity, a rare adverse reaction to administration of the antibiotic gentamycin, by increasing Sirt3 expression and suppressing reactive oxygen species production in rat cochlea and in cultured primary cochlear cells178. The role of SIRT1 in age-related hearing loss is currently unresolved, presumably because of experimental variations179–181. Further studies will be necessary to elucidate the roles of other SIRTs in age-related hearing loss.

Furthermore, Sirt1 knockout in microglia elevates the Il1b transcription mediated by hypomethylation of the specific CpG sites on the Il1b proximal promoter102. IL-1β expression promotes heightened microglial activa-tion in aged brain. Similar to the Sirt1-knockout results, LPS administration enhances microglial activation in Sirt2-knockout mice103. In cultured microglial cell lines, knockdown of Sirt2 increases microglial activation induced by several different stimuli through TLR2, TLR3 and TLR4. Hyperacetylated NF-κB p65 subunit is detected in primary microglia from newborn Sirt2-knockout mice. Expression of miR-204 in aged brain is upregulated104, perhaps because of pro-inflammatory factors entering the brain via a compromised BBB. These findings thus indicate that SIRT1 and SIRT2 in microglia may regulate cytokine production via IL-1β to cause microglial priming in the aged brain, thus contributing to the ageing process. Whether sirtuins are involved in BBB permeability and microglial phagocytosis remains unclear.

Some studies demonstrate that sirtuins are impor-tant agents in fighting against neurodegeneration (TABLE 2). SIRT1 activation has neuroprotective effects against age-associated neurological disorders such as Alzheimer disease102,105–108, Parkinson disease109,110, Huntington disease35,36,111–113 and amyotrophic lateral sclerosis (ALS)106,115,116. In contrast to SIRT1, inhibiting SIRT2 is protective in mouse models of Parkinson dis-ease116 and Huntington disease117–119. Overexpression of another sirtuin family member, SIRT3, in rat primary cerebral cortical neurons results in inhibition of mito-chondrial production of reactive oxygen species120. In the inner ear, SIRT3 has a vital role in preventing age-induced hearing loss during calorie restriction121,122 (BOX 1). Conversely, knockdown of Sirt3 in cultured cor-tical neurons increases excitotoxic neuronal death123.

Furthermore, SIRT3 protects against mitochondrial fragmentation and neural cell death in ALS models124. These findings highlight the benefits of manipulating sirtuin activity to suppress age-associated neurological disorders (for a full discussion, see REF. 125). Given that microglia-specific Sirt1-knockout mice display elevated IL-1β production and exhibit exacerbated memory deficits in a neurodegenerative mouse model102, we can infer that SIRT1 affects the crosstalk between neurons and microglia and that its age-induced inactivation may contribute to the pathogenesis of neurodegenerative diseases.

Linking brain ageing and systemic ageingAs described in the previous section, the brain displays a range of crucial pathophysiological changes in its con-stituent cells, structures and functions during the pro-cess of ageing. Its own ageing also affects the functions of peripheral tissues and organs through many hormones and the autonomic nervous system. In particular, the hypothalamus plays a critical part in the production of many hormones and in the regulation of the autonomic nervous system, and it is emerging that age-associated decline in hypothalamic function mediates ageing at a systemic level and ultimately affects longevity.

The hypothalamus controls ageing. It has been shown that unique areas of the brain and specific subpopu-lations of neurons have important roles in the control of systemic ageing and longevity. In Caenorhabditis elegans, two particular neurons in the head, the ASI neurons, can mediate lifespan extension in response to caloric restriction126. Lifespan extension requires the ASI neuron-specific activity of SKN-1, a homologue of the mammalian NRF2 transcription factor, which activates cellular defences against oxidative and xenobiotic stress. Interestingly, the ASI neurons regulate energy metabo-lism in C. elegans and may thus represent a functional analogue of the mammalian hypothalamus. Consistent with this notion, many studies have linked sirtuins with the function of specific neurons or areas of the hypo-thalamus, such as the arcuate, ventromedial, DMH and SCN6,32. Two important recent papers have begun to provide insight into the role of the hypothalamus in the regulation of mammalian ageing and longevity11,127.

One study has demonstrated that both male and female brain-specific Sirt1-overexpressing transgenic mice (BRASTO mice) have extended median and max-imal lifespan11. Associated with this lifespan extension, several physiological traits of BRASTO mice, including physical activity, body temperature, oxygen consump-tion and sleep quality, are maintained during ageing. Particularly, their skeletal muscle maintains a youthful morphology and function of the mitochondria during ageing owing to enhanced sympathetic nervous tone during the dark period. Although the mechanism by which the signal from the hypothalamus is directed spe-cifically to skeletal muscle is still not known, it is conceiv-able that skeletal muscle stimulated by the sympathetic nervous system might induce systemic events that con-tribute to the delay in ageing and lifespan extension. Comparison of two different transgenic lines suggests

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Nature Reviews | Neuroscience

Hypothalamus

Blood vessel

eNAMPT

IL-6

FNDC5

CCL11

FGF21

Blood-derivedmonocyte

Hormones and autonomic nervous system

Skeletal muscle

Liver

Adipose tissue

β2-microglobulin

Sirtuin

NAD+

NMN

NR

that the predominant overexpression of SIRT1 and spe-cific neuronal activation in the DMH and LH underlie the increased longevity effect in BRASTO mice. The enhanced neural activity in the DMH and LH observed in these mice during the dark period also counteracts age-associated physiological decline, operating through the upregulation of orexin receptor type 2 (Ox2r) by SIRT1 and its novel partner NKX2.1, a Nk2 family homeodomain transcription factor. Intriguingly, over-expression of SIRT1 in the DMH of aged wild-type mice is sufficient to ameliorate age-associated decline in phys-ical activity and body temperature to levels equivalent to those of young mice. Therefore, the DMH, and possibly the LH, are likely to be key regions of the hypothalamus that control ageing and longevity in mammals.

The other study demonstrated that inhibition of NF-κB signalling selectively in the mediobasal hypothala-mus (MBH) prolongs lifespan in mice, whereas the activa-tion of NF-κB signalling selectively in the MBH shortens their lifespan127. These findings suggest that attenuation of NF-κB activity in the hypothalamus is crucial to coun-teract ageing and promote mammalian longevity. NF-κB

signalling inhibits the transcription of the gene gonado-tropin-releasing hormone (Gnrh), mediating its age-asso-ciated decline127. Interestingly, intracerebroventricular or subcutaneous administration of GnRH in mice prevents the age-associated decline in neurogenesis in the hypo-thalamus and hippocampus, muscle strength and size, skin thickness, bone mass and tail tendon collagen integ-rity. It seems that microglial NF-κB activation results in the production of TNF, thereby stimulating hypothalamic NF-κB and causing neuroinflammation in hypothalamic neurons. As discussed above, chronic low-grade inflam-mation due to microglial priming plays an important part in the pathogenesis of neuroinflammation. What triggers microglial NF-κB activation in the MBH dur-ing the ageing process needs to be further investigated. Because SIRT1 and SIRT2 function as inhibitors of microglia-mediated inflammation and neurotoxicity, it will be of great interest to examine a potential connection between SIRT1-mediated and NKX2.1-mediated signal-ling in the DMH and LH and NF-κB signalling in the MBH in the control of mammalian ageing.

Feedback from peripheral tissuesGiven that brain regions, such as the hypothalamus, send efferent signals to peripheral tissues, it is conceivable that the peripheral tissues also send afferent signals back to the brain, comprising a feedback loop. In fact, a number of hormones and circulating factors that modulate dif-ferent functions of the brain have been identified from parabiosis and other studies. In this section, we sum-marize such afferent signals that potentially modulate the brain function and affect the process of ageing and longevity (FIG. 3).

White adipose tissue — NAD+ synthesis. White adipose tissue (WAT) can play an important part in ageing, exem-plified by the finding that WAT-specific knockout of the insulin receptor extends murine lifespan128. Although the mechanism of this lifespan extension remains unknown, it is clear that adipose tissue influences systemic physi-ological states as an endocrine organ. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme that catalyses NAD+ biosynthesis from nicotina-mide in mammals129. NAMPT has two isoforms: intra-cellular NAMPT (iNAMPT) and extracellular NAMPT (eNAMPT; also known as PBEF or visfatin)130. A recent study has demonstrated that eNAMPT is secreted from WAT through SIRT1-mediated deacetylation of iNAMPT131. Remarkably, mice with adipose tissue-spe-cific Nampt knockout display significant reduction in cir-culating eNAMPT, hypothalamic NAD+, SIRT1 activity and physical activity131. Furthermore, administration of a NAMPT-neutralizing antibody decreases hypothalamic NAD+ levels. Conversely, mice with adipose tissue-specific Nampt knockin show increases in hypothalamic NAD+, SIRT1 activity, neural activity and physical activity in response to fasting. Indeed, Ox2r expression regulated by hypothalamic SIRT1-mediated and NKX2.1-mediated signalling is upregulated and downregulated in mice with these adipose tissue-specific Nampt knockin and Nampt knockout, respectively131. Therefore, eNAMPT secreted

Figure 3 | Communication between the brain and peripheral tissues. The brain sends signals to peripheral tissues such as adipose tissue, liver and skeletal muscle through hormones and the autonomic nervous system. Nicotinamide phosphoribosyl-transferase (NAMPT), which is the rate-limiting enzyme in mammalian NAD+ biosynthesis, is secreted from adipose tissue as an extracellular form (eNAMPT) into the blood circulation. It has been suggested that the NAD+ intermediate nicotinamide mononucleotide (NMN) is produced via eNAMPT present in the blood and that NMN affects brain function. NMN is used in the brain for generating NAD+, resulting in sirtuin activation. Another NAD+ precursor, nicotinamide riboside (NR), also affects brain function, according to pharmacological studies. The mediator fibroblast growth factor 21 (FGF21) is secreted from adipose tissue, liver and skeletal muscle, and interleukin-6 (IL-6) and fibronectin type III domain-containing protein 5 (FNDC5; the precursor of irisin) are secreted from skeletal muscle. FGF21, IL-6 and FNDC5 enter the circulation and affect brain function. Finally, it has been reported that other circulating factors such as C-C motif chemokine 11 (CCL11), blood-derived monocytes and β2-microglobulin can affect brain function.

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from adipose tissue has an important role in remotely reg-ulating hypothalamic NAD+ biosynthesis and function, implicating a crucial endocrine role of adipose tissue in ageing and longevity control in mammals. It will be of great interest to examine whether the activity of cir-culating eNAMPT is reduced during ageing. eNAMPT also affects other brain regions, and it has been reported that eNAMPT conveys neuroprotection against ischae-mia-induced or ischaemia–reperfusion-induced neuronal injuries132–135.

Given that NAMPT produces NMN from nicotinamide and 5ʹ-phosphoribosyl-pyrophosphate, NMN itself might have some important functions as a circulating signalling molecule. Indeed, it has been reported that plasma levels of NMN decrease with age136, and administration of NMN to aged mice ameliorates age-associated reduction in glu-cose-stimulated insulin secretion136, skeletal muscle mito-chondrial function137, NSC pool51 and arterial function138. It has recently been demonstrated that long-term admin-istration of NMN mitigates age-associated physiological decline in mice139. NMN also ameliorates disease condi-tions, including type 2 diabetes induced by high-fat diet or age140, brain damage in a cerebral ischaemia–reperfusion mouse model141, and cognitive impairment and amyloid deposition in Alzheimer disease model rodents142,143. In addition, administration of nicotinamide riboside (NR), which is phosphorylated by nicotinamide riboside kinases to yield NMN, improves oxidative metabolism in skeletal muscle and brown adipose tissue144, attenuates cognitive deterioration in an Alzheimer disease mouse model145 and induces activation of the mitochondrial unfolded protein response and synthesis of prohibitin proteins in mitochondria, rejuvenating muscle adult stem cells in aged mice146. Therefore, it is likely that these NAD+ intermediates play a critical part in the regulation of mammalian ageing and longevity, potentially through their effects on NAD+ biosynthesis and sirtuin activity in the hypothalamus and other key tissues and organs.

Other circulating factors. Over the past 10 years, stud-ies using parabiosis have accelerated the identification of circulating factors that influence tissue ageing (TABLE 3). Parabiosis is a 150-year-old surgical technique that con-nects the vasculature of two living animals147, allowing them to share blood circulation. Circulating hormones or factors transferred from young to old individuals (het-erochronic parabiosis) ameliorate age-associated dys-functions in the brain such as adult neurogenesis148,149, cognition148,149, regeneration150 and angiogenesis150. In addition, young monocytes and/or macrophages facil-itate differentiation of oligodendrocyte precursor cells and remyelination by augmenting the clearance of inhib-itory myelin debris in the injured brain150. By contrast, circulatory factors that rise with ageing can impair the young brain. For example, plasma levels of chemokine C-C motif chemokine 11 (CCL11; also known as eotaxin) rise with age in mice and humans. Systemic injection of CCL11 impairs adult neurogenesis and cognitive func-tion in young mice148. Similarly, blood levels of β2-mi-croglobulin are elevated in ageing mice and humans, and systemic injection or local injection of this molecule into

the hippocampus impairs hippocampal-dependent cog-nitive function and neurogenesis in young mice149. The implication from such parabiosis studies is that brain ageing could be modifiable by targeting factors from the periphery in addition to targeting factors within the brain.

Several factors secreted from peripheral tissues have been identified that are candidates to ameliorate age-associated pathophysiologies in the brain. Fibroblast growth factor 21 (FGF21) is known as a hepatokine, myokine and adipokine151. Overexpression of FGF21 in mice promotes lifespan extension152, possibly via reduced activity of the insulin– insulin-like growth fac-tor 1 (IGF1) signalling pathway153. The central effects of FGF21 are mediated through a receptor complex con-sisting of the FGF receptor and its co-receptor β-klotho, a transmembrane protein expressed in the brain154–156. Overexpression of FGF21 suppresses wheel-running activity156 and terminates the oestrous cycles by sup-pressing the vasopressin–kisspeptin signalling cascade in the SCN, thereby inhibiting the pro-oestrus surge of lutenizing hormone155. Moreover, in a model of ageing involving chronic d-galactose administration, which causes neuronal damage by inducing oxidative stress, sys-temic administration of FGF21 protects the brain from injury by attenuating oxidative stress damage and decreas-ing advanced glycation end products157. These results sug-gest that circulating FGF21 protects SCN neurons — and the brain generally — against age-associated pathophysi-ological changes during ageing152. Growth differentiation factor 11 (GDF11), a secreted growth factor from mature neurons, was found to be present in the blood from young mice and could act as a rejuvenating factor for the brains of aged animals158. Indeed, daily injection of GDF11 enhances vascular remodelling and neurogenesis in old (22 month) mice158. Other reports confirmed these ini-tial results, although they showed that the reagents used to detect GDF11 also detected a related protein, GDF8 (REFS 159,160). We look forward to additional studies to further clarify the role of GDF11 in ageing.

Growing evidence suggests that myokines may also modulate the process of ageing at a systemic level. Indeed, in skeletal muscle, reduced mTOR complex 1 (mTORC1) signalling resulted in enhanced activity of eukaryotic translation initiation factor 4E-binding pro-tein 1 (4EBP1, a key downstream effector of mTORC1), which in turn increased FGF21 secretion and mediated the protection against age-induced and diet-induced insulin resistance and metabolic rate decline through-out the body161. IL-6 is a cytokine produced by immune cells, vascular endothelial cells, adipocytes and skeletal muscle. A significant amount of IL-6 is produced and released from skeletal muscle after exercise162. IL-6 can cross the BBB163 via saturable transporter systems163, and, in the elderly, elevated levels are linked to poor cognitive function, higher risk of age-associated dis-eases, physical disability and higher mortality164. Finally, it has recently been reported that, in mice, intravenous injection of the presumed hormone fibronectin type III domain-containing protein 5 (FNDC5), the precursor of irisin, leads to a significant increase in Bdnf expres-sion in the hippocampus165. However, direct application

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of irisin to cultured hippocampal neurons does not increase Bdnf expression, suggesting that FNDC5 might have another cleavage product (other than irisin) that can induce Bdnf expression166.

Other candidates. The identification of circulating mol-ecules that have an impact on brain function and its ageing would be not only a clinically useful biomarker of ageing but also a putative preventive and therapeu-tic target for age-associated dysfunctions and diseases. Other promising circulating factors include circulating microRNAs and endothelial progenitor cells, the levels of which decline with age167–171. Further investigation on these circulating molecules will enrich our knowledge on the inter-tissue communications between the brain and peripheral tissues and organs in the systemic regulation of ageing and longevity in mammals.

Future directionsOver the past 20 years, there has been tremendous pro-gress in understanding the mechanisms of ageing and

longevity. Nonetheless, the complexity of ageing as a bio-logical phenomenon is still a big challenge. An emerg-ing approach to understand the tremendous biological complexity of the ageing process at any level of physi-ological hierarchy is to systematically analyse a wealth of ‘omics’ data, including genomics, transcriptomics, epigenomics, proteomics and metabolomics, and clin-ical data from different clinical trials throughout the world172–174. Such a big data-driven integrative approach will help to identify crucial brain pathways that govern mammalian ageing. We hope to address the following important questions to better understand the systemic regulation of mammalian ageing and longevity: what are the primary mechanisms that deteriorate in brain func-tion to affect the ageing process? What are the crucial feedback loops between the brain and peripheral tissues that govern ageing? What therapeutic interventions can counteract the effects of ageing on these feedback loops? A perspective that considers the brain at the centre of ageing seems to be warranted and may speed progress in answering these questions.

Table 3 | Circulating factors and hormones influence tissue ageing

Circulating factor Origin Level in old animals (versus young animals)

Target organ Physiological effects Refs

WNT or WNT-like molecules

Unknown Elevated Muscle ↑ Myogenic-to-fibrogenic conversion 187

CCL11 Unknown Elevated Brain ↓ Adult neurogenesis and cognitive function

148

Blood-derived monocytes Unknown Unknown* Brain ↑ Remyelination 150

β2-microglobulin Unknown Elevated Brain ↓ Adult neurogenesis and cognitive function

149

FGF21 Muscle, liver and adipose tissue

Reduced Hypothalamus ↓ Female fertility 155

Hypothalamus ↑ Physical activity 156

Brain ↑ Neuroprotection 157

Adipose tissue ↑ Protection against age-induced and diet-induced insulin resistance and metabolic rate decline

161

IL-6 Muscle Elevated Brain ↓ Cognitive function 163,164

FNDC5–Irisin Muscle Unknown Hippocampus ↑ Bdnf expression 165,166

eNAMPT Adipose tissue Unknown Brain ↑ Neuroprotection 132–135

Hypothalamus ↑ Physical activity 131

NMN Unknown Reduced Pancreas ↑ Glucose-stimulated insulin secretion 136

Skeletal muscle ↑ Mitochondrial function 137

Hippocampus ↑ NSC pool 51

Vascular ↑ Arterial function 138

Brain ↑ Cognitive function in Alzheimer disease model rats

142,143

↓ APP levels in Alzheimer disease model mice

143

NR Unknown Unknown Brain ↑ Cognitive function in Alzheimer disease model mice

145

Muscle ↑ Oxidative metabolism 144*There are some data that suggest that enhancing remyelinating activity requires youthful monocytes and other factors. APP, β-amyloid precursor; Bdnf, brain-derived neurotrophic factor; CCL11, C-C motif chemokine 11; eNAMPT, extracellular nicotinamide phosphoribosyltransferase; FGF21, fibroblast growth factor 21; FNDC5, fibronectin type III domain-containing protein 5; IL-6, interleukin-6; NMN, nicotinamide mononucleotide; NR, nicotinamide riboside; NSC, neural stem cell.

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