Dementia is a progressive, incurable neurodegenerative disease leading to significant alterations of brain structure and function, resulting in cognitive decline, physical impairment, and changes in behaviour [1, 2]. Worldwide, more than 50 million people had dementia in 2020 and this figure is predicted to increase three-fold by 2050 [2, 3]. Cases are not distributed equally across the globe with most (> 60%) cases living in low- and middle-income countries where resources, research and policy focused on dementia is scarce [2, 4, 5]. The increasing number of older adults aged 65 years and over represents one of the major drivers of the growing number of dementia cases globally and the large proportion of dementia cases are expected to occur in very old individuals (≥ 80 years) [3, 5, 6].

Dementia has a multifactorial pathogenesis, and is linked to a plethora of modifiable and non-modifiable risk factors including for example increased age, female gender, genetics (e.g., Apolipoprotein e4 allele status), nutrition (poor diet), lifestyle (e.g., smoking, physical activity), socioeconomic status (e.g., deprivation), low education, and poor cardio-metabolic health status (e.g., hypertension, diabetes and obesity) [7]. With no cure, the maintenance of a healthy physical and cognitive trajectory across the life course is an international public health priority to reduce the projected number of dementia cases impacting not only the individual, but also society.

Numerous observational and experimental studies have investigated the links between nutrition and the brain health ranging from testing associations and effects of dietary patterns (i.e., Mediterranean Diet, Dietary Approach to Stop Hypertension (DASH) Diet, to single foods (i.e., green leafy vegetables, oily fish) and nutrients (i.e., minerals, vitamins, phytochemicals) provided alone or in combination [8,9,10]. Caloric restriction (CR) and, more recently, an increased dietary nitrate consumption have been linked independently with several health benefits including anti-ageing effects and improvements of brain health and cognitive performance [8,9,10]. Some of the key biological mechanisms underpinning the benefits of CR and dietary nitrate on brain physiology involve the modulation of oxidative stress [11,12,13], inflammation [14], mitochondrial function [11, 12], insulin [15, 16], and nitric oxide signalling and autophagy [17,18,19]. This opinion paper provides a brief overview of key nutritional factors that may influence brain health, and it proposes a physiological rationale for the synergistic effects of combined CR and dietary nitrate interventions on brain health as an effective strategy for dementia risk reduction and prevention.

Ageing, obesity and vascular dysfunction: the dementia risk triad

Ageing is linked to a progressive decline of vascular, metabolic, and neurocognitive functions [20]. Some of the mechanisms underpinning these functional declines include reduced metabolic efficiency, decreased anti-inflammatory responses, elevated production of reactive oxygen species (ROS), and declined nitric oxide (NO) production [1, 21,22,23,24]. A progressive loss of synaptic connectivity, neuronal plasticity and accumulation of aberrant native proteins (Beta-Amyloid, Tau-Protein, Lewy-Bodies) are key features of the ageing process [22]. In most individuals, these changes do not result in clinical manifestation of cognitive impairment or dementia [22]. However, if functional and structural damages become more extensive and overcome compensatory mechanisms, cognitive dysfunction may accelerate and lead to the onset of clinical dementia [22]. For a detailed review of pathogenetic hallmarks of ageing and dementia risk, see Hou et al. [20].

Obesity is causally linked to various chronic conditions including diabetes, hypertension, coronary heart disease, and cancer [25, 26]. Obesity has also been associated with an accelerated cognitive decline across the life course including impairments in global cognition, logical memory, delayed recall, and verbal fluency [25]. Mid-life obesity is a key risk factor for the onset of late-life dementia [25,26,27]. Obesity also showed an increased risk of atrophy in grey and white matter regions (frontal, temporal and occipital cortices, thalamus, hippocampus, and midbrain) and is linked to a reduction of regional blood flow in the pre-frontal cortex [26]. Excess adiposity has been linked to a decreased whole-body NO production and endothelial dysfunction (could be a result of a reduction in NOS activity [28]), which may affect neuro-vascular coupling, blood-brain barrier (BBB) permeability and reduced cerebral blood flow (CBF) [25, 27]. Obesity-related vascular dysfunction significantly impacts brain function and increases the risk across the various dementia sub-types as cerebrovascular dysfunction represents a common pathogenetic feature [1, 24]. A reduction of nitric oxide (NO) bioavailability has been linked to hypertension and cerebral hypoperfusion, which are closely linked to the occurrence of major events in the brain such as cerebral ischemia and stroke [24, 29, 30].

Nutrition and brain health

Maintaining brain functions requires an optimal supply of energy and nutrients. The brain is an energy-demanding organ (20% of the total body energy production), heavily relying on the oxidative metabolism of carbohydrates and fat [31, 32]. Glucose and ketone bodies are the primary sources of energy for the brain to drive ATP production, preserve neuronal and glial cellular integrity and ensure the efficiency of neurotransmission [33]. Polyunsaturated fatty acids (omega-3), vitamins B (1, 6, 9, and 12), D, E, and C, minerals (iron, copper, calcium, and zinc), and other nutrients with antioxidant properties (i.e., polyphenols, dietary nitrates) may have a crucial role in the preservation of cerebrovascular and cognitive functions by regulating synaptic transmission, membrane fluidity, endothelial function, and neurotransmitter and signal-transduction pathways [8,9,10].

Unhealthy dietary patterns, sedentary lifestyle, social isolation, low educational attainment, smoking, and alcohol addiction are common risk factors for cardiovascular disease and cognitive impairment [2, 21]. In the last decade, greater emphasis has been given to multi-dimensional approaches to dementia prevention, including testing the effects of healthy dietary patterns and providing multiple sources of protective nutrients [34,35,36,37,38]. The Mediterranean diet (MED) and Dietary Approaches to Stop Hypertension (DASH) are examples of dietary patterns, which have been linked to a reduction in cardiovascular and dementia risk in observational and intervention studies [34, 35]. Morris et al. have amalgamated the key features of the two dietary patterns to propose the MIND diet (MED + DASH), which essentially promotes a high consumption of plant-based products (similar to the MED, but with a particular emphasis on increasing the intake of berries and green leafy vegetables) to reduce dementia risk [37]. These dietary patterns emphasize the consumption of fruits, vegetables, whole grains, nuts, seeds, and healthy fats. [37, 39, 40] and encourage a controlled energy intake to match or reduce levels below an individual’s energy requirements (CR). They are rich in protective nutrients including fibre, mono- and poly-unsaturated fatty acids, vitamins, antioxidants, and other nutrients such as polyphenols or dietary nitrate that can positively influence vascular, metabolic, and cognitive functions [30, 41,42,43,44,45,46,47,48,49]. Dietary nitrate may represent a crucial health-enhancing element within plant-based dietary regimens [50, 51]. Hord et al. [52] conducted an estimation indicating that the DASH diet has the potential to deliver as much as 1200 mg/day of dietary nitrate. This is in comparison to the typical daily intake of approximately 110 mg/day found in the general population [53]. In randomized clinical trials, a common dosage of dietary nitrate involves supplementation of around 600 mg/day, achievable through the consumption of two bottles of concentrated high-nitrate beetroot juice [51]. CR strategies and dietary nitrate may therefore represent potential effective nutritional strategies to prevent both endothelial and cognitive dysfunction, thus, reducing the risk of dementia.

Caloric restriction Current evidence

CR aims to reduce the daily caloric intake without causing malnutrition to enhance physical and mental health [54]. CR has been linked to an increase in lifespan across various species and a decrease in age-related morbidity and mortality including rodents, primates, and humans [21, 54,55,56,57,58,59,60,61,62]. In addition, CR enhances the neuro-inflammatory responses [14] and lowers the occurrence of oxidative damage by improving mitochondrial efficiency [11, 63, 64], with a reduction of white matter loss [62], improved cerebral blood flow [21, 56] in several brain regions [11, 64], and enhanced cognitive function [14]. Although much of the evidence for a salutary effect of CR is derived from animal model studies, some human investigations have also identified promising effects of CR on markers of cardiometabolic/brain health.

Forty-nine healthy overweight and obese older adults were randomised to a three-month CR intervention which significantly improved memory, insulin, glucose, and C Reactive Protein compared to high PUFA and a control diet [15]. Nevertheless, not all CR studies have reported beneficial effects [65,66,67]. This could be related to the heterogeneous methods employed, including differences in the CR protocol (e.g., different caloric intake and intervention duration) and study cohort (e.g., animal, and human populations with different ages, sex, and health status). For example, a 6-month randomised trial tested the interactive effects of CR and exercise in forty-eight participants but no significant improvement in cognition was found [67]. In young rats, a two-month CR intervention had an adverse effect on the brain, decreasing neurogenesis and spatial learning assessed using the Morris water maze [68]. On the other hand, a more extended CR intervention (ten months) with older mice showed an improvement in spatial learning [69]. The characteristics of some of the key studies, identified by a non-systematic search of human randomised clinical trials (RCTs) on PubMed, that have investigated the effects of CR on brain health (cognitive function and CBF) are reported in Table 1.

Table 1 Key studies investigating the effects of caloric restriction on brain health in humans Key molecular mechanisms

The main molecular pathways linking CR to the improvement of endothelial and cognitive functions involve sirtuins (SIRT; proteins family), protein kinase B (Akt), AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), autophagy and NO [17]. Sirtuins could be upregulated by various stressors such as energy reduction (CR); when activated and overexpressed, sirtuin catalyses NAD-dependent deacetylase, which has been found to be associated with longevity [58, 59]. In addition, SIRT1 could act as an antioxidant that influences several protein regulations (such as p53, Ku/Bax and FOXO) to resist the stress-induced damage, reduce apoptosis and protect neurons [58, 70]. Additionally, SIRT1 is involved in various metabolic pathways linked to adiposity (PPARγ downregulation), insulin, glucose, and lipid metabolism (PGC-1α and LXRα deacetylation, and UCP2 expression) [58, 70]. Sirtuins have a significant role in enhancing NO bioavailability by activating endothelial nitric oxide synthase (eNOS), directly or indirectly, through the activation of the AMPK pathway [29, 71, 72]. CR-induced Akt phosphorylation through the insulin-PI3K-Akt signalling pathway is important for cell growth and resilience, and synaptogenesis [73], which could enhance vascular [71] and cognitive [74] functions. The activation of AMPK, SIRT1, and Akt during CR plays a crucial role in regulating endothelial function via the Ca2+/calmodulin-dependent kinase II (CaMKII) stimulation, which upregulates eNOS and leads to an increased NO synthesis [75]. CR stimulates autophagy [