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 sleepwake 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 inflammation 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 (REFS87,88).
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 18–20months of age is MHCII positive, compared with only less than 3% of MHCII-positive microglia in mice at 3–4months 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).
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 (TABLE2).
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 metalloproteinase9 (MMP9), inducible nitric oxide synthase (iNOS) and IL-1 through miR-204 activation101. The 3 untranslated region (3UTR) 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.