Circulating eNAMPT and NAD+ is reduced during ageing

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It will be of great interest to examine whether the activity of circulating 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 injuries.Given that NAMPT produces NMN from nicotinamide and 5-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 age, and administration of NMN to aged mice ameliorates age-associated reduction in glucose-stimulated insulin secretion136, skeletal muscle mito-chondrial function, NSC pool and arterial function.

It has recently been demonstrated that long-term admin-istration of NMN mitigates age-associated physiological decline in mice(139). NMN also ameliorates disease condi-tions, including type2 diabetes induced by high-fat diet or age(140), brain damage in a cerebral ischaemia–reperfusion mouse model, and cognitive impairment and amyloid deposition in Alzheimer disease model rodents.

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 tissue, attenuates cognitive deterioration in an Alzheimer disease mouse model and induces activation of the mitochondrial unfolded protein response and synthesis of prohibitin proteins in mitochondria, rejuvenating muscle adult stem cells in aged mice(146).

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 .

Circulating hormones or factors transferred from young to old individuals (het-erochronic parabiosis) ameliorate age-associated dys-functions in the brain such as adult neurogenesis(148,149) cognition(148,149) regeneration(150) and angiogenesis.

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 brain(150). 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 mice(148).

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 mice(149).

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 adipokine(151).

Overexpression of FGF21 in mice promotes lifespan extension(152), possibly via reduced activity of the insulin– insulin-like growth fac-tor1 (IGF1) signaling pathwa3. 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 brain(154156).

Overexpression of FGF21 suppresses wheel-running activity(156) and terminates the oestrous cycles by sup-pressing the vasopressin–kisspeptin signalling cascade in the SCN, thereby inhibiting the pro-oestrus surge of lutenizing hormone(155).

Moreover, in a model of ageing involving chronic -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 ageing(152).

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 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.