Sirtuins are important agents in fighting against neurodegeneration May 19, 2017

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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 important agents in fighting against neurodegeneration.

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 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 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.

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