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 YinandYang1 (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 herebelow
.Compared to young individuals, about 20% of peo-ple at 55years 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 typeA 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 subtype1 (5-HT1) and postsynaptic 5-HT2 are principally involved in the modulation of anxiety59