1. Introduction
In the last two centuries, it has been widely accepted that antibiotics and vaccines are among public health’s greatest accomplishments. Thanks to vaccination, most infectious diseases occurring in youth have been eliminated and global child mortality rates have been reduced [
1]. As a result, life expectancy has increased worldwide (~27 years during the last century) with an increasing number of adults aged over 60 years old [
2]. While the human race celebrates rising longevity, societies have had to confront the resulting rise of the burden of age-related global diseases [
3]. It is no secret that from the fifth decade of life, advancing age is associated with an exponential increase in the accumulation of diverse deleterious changes in cells and tissues that are responsible for the occurrence of chronic diseases [
4]. There is now an ongoing challenge to reduce disease burden by extending “healthspan,” thereby providing extra years spent free of chronic age-related issues such as neurodegenerative disease [
5,
6,
7].
Affecting many older and some younger adults (≅50 million worldwide), neurodegenerative diseases (e.g., mild cognitive impairment, Alzheimer’s disease and related dementias) have become a major public health concern and have been identified as a research priority by the World Health Organisation. Unfortunately, after over 200 clinical trials, anti-aging therapies have been effective at keeping sick people alive but have failed to cure age-related neurological disorders [
8]. Due to the lack of causal pharmacological treatments, brain-related “healthspan” interventions are currently directed toward slowing brain aging and cognitive decline through preventive strategies; these interventions aim to convert extra life years to health years [
5,
9].
The etiology of age-associated cognitive decline is complex and multifactorial with cardiovascular alteration, oxidative stress and neuroinflammation considered major risk factors [
10,
11,
12]. The administration of exogenous antioxidants (e.g., polyphenols) has shown promising findings for reducing the majority of aforementioned risk factors [
13,
14,
15,
16,
17,
18,
19]. Additionally, recent reports recognize (poly)phenols as a brain-friendly intervention that may prevent and delay age-associated decline in cognitive function [
20,
21].
These (poly)phenol compounds, such as flavonoids, phenolic acids and tannins, are found in varying concentrations in a range of plant-based food sources (e.g., legumes, fruit, vegetables, herbal extracts, spices, coffee, tea and cocoa), and their effects on human health have drawn considerable attention. Specifically, (poly)phenols have been linked to a number of health benefits including modulation of inflammation [
14,
15], reductions in risk of cardiovascular disease [
13,
15,
18,
22], anticancer effects [
23] and protection against oxidative stress [
16,
17]. Concerning the neuroprotective effects, a recent systematic review (SR) and meta-analysis (MA) examining the effects of (poly)phenol-rich supplementation on age-related cognitive decline suggested polyphenol-rich supplementation may improve some cognitive and brain functions in older adults. However, it failed to provide evidence regarding the neuroprotective and anti-inflammatory effect of (poly)phenol supplementation in aging adults [
20]. Findings from some individual studies, included in this SR, indicate that polyphenol consumption modulates cerebral hemodynamics [
24] and resting regional cerebral blood flow [
25,
26], while simultaneously enhancing psychomotor functions, speed of attention, episodic memory, verbal fluency and overall cognitive performance in older-aged adults [
24,
27,
28]. Other studies in similar populations have reported nonsignificant effects on certain cognitive functions, specifically executive functioning, working memory and verbal memory [
29,
30], or cerebral blood flow response [
31]. Authors of the previous SR and MA concluded the beneficial effect of polyphenols was dependent on ingested dose and bioavailability, suggesting more promising findings may be found in younger populations [
20].
Recent reports identify young people as the most attractive targets for interventions to extend healthspan [
32]. Because their organs are not yet damaged, it is theoretically possible to reduce the onset of age-related diseases and cognitive decline by applying anti-aging interventions to people while they are still young and healthy [
33]. These reports suggest preventive interventions in older adults seem to be focused on the wrong end of the lifespan, which may mitigate possible beneficial effects of the tested intervention [
32,
34]. Yet, most human anti-aging research, including randomized trials of polyphenol interventions, examine older adults, most of them suffering from chronic disease [
20,
35]. As a result, very little is known about the effect of polyphenol interventions on brain-related aging processes in healthy young humans. Additionally, the few available studies in this field demonstrate controversial findings; some of them indicate improved brain function following acute and/or chronic ingestion of polyphenol-rich supplementation [
36,
37,
38,
39,
40], while other findings fail to prove beneficial effects on cognitive function and brain structures of young and middle-aged adults [
41,
42,
43].
Taken together, it seems that there are a current gap in knowledge with a lack of consensus regarding the neuroprotective effect of polyphenol intervention in healthy young individuals. Therefore, the present study aimed to systematically review the literature and conduct a MA of all trials investigating the acute and chronic effects of (poly)phenol-rich supplementation on cognitive functions and brain health in young and middle-aged healthy adults.
4. Discussion
The present SR and MA is the first to examine the effects of acute and chronic (poly)phenol-rich supplementation on cognitive and brain parameters in young and middle-aged adults. Data regarding changes in a variety of cognitive functions and brain parameters following an acute and/or chronic consumption of (poly)phenol-rich supplementation were extracted from the reviewed trials. However, only a few items were sufficiently comparable and were included in the MA (i.e., SRT, RVIP, SS-7s, MF and BDNF). The pooled analysis of the acute and/or chronic administrations (4 weeks) of (poly)phenol-rich supplementation suggests a beneficial effect on the majority of the assessed cognitive functions including SRT, SS-7s and MF with faster SRT, higher correct numbers during SS-7s and lower MF compared to placebo condition. Particularly, the data of the forest plots are significantly skewed towards an effect from acute compared to chronic polyphenol intervention. For the SS-7s cognitive test, a significant effect was observed for the acute administration of 500mg trans-resveratrol [
36], 272 mg flavonoids [
37], and 250 mg catechin [
49] or resveratrol [
48]. However, no significant effects were observed for the chronic administration (4 weeks) of similar catechin [
49] and trans-resveratrol [
36] doses. Similarly, a significant beneficial effect on MF was observed for the acute administration of 250 mg polyphenols [
48,
49]. However, this effect was blinded during the chronic administration of the same dose [
49]. Moreover, the two effective (poly)phenols doses (300 mg of phenolic contents [
51] or 4 g of matcha tea [
39]) on SRT were isolated only to acute administration. These results indicate a beneficial effect of an acute (poly)phenol-rich supplementation on the majority of the assessed cognitive functions and suggest an acute dose of 250 mg (poly)phenols is sufficient to generate an immediate improvement in SS-7s and MF, while a higher dose is needed to observe a significant effect on SRT. Similarly, a chronic dose of 250–500 mg (poly)phenol showed no significant effect on cognitive functions [
36,
49]; it seems that higher doses (>500 mg/day) and/or higher bioavailability of phenolic contents are needed during chronic interventions to improve cognitive functions.
In agreement with these findings, some of the included studies in the MA have reported that an acute ingestion of 250–300 mg of cocoa flavanols improved visual search efficiency and aspects of cognitive performance during a highly demanding task and reduced reaction time and participants’ self-reported mental fatigue [
40,
49]. Similarly, in response to an acute dose of 4 g matcha tea or 200 mL of purple grape juice, Dietz et al. [
39] and Haskell-Ramsay et al. [
51] demonstrated a significant improvement in tasks measuring basic attention abilities and psychomotor speed. Besides, the improvement of these specific cognitive functions and findings from other individual studies confirm the beneficial effect of both acute and chronic consumption of (poly)phenol-rich supplementation on further cognitive performances and showed improved performance on the digit symbol substitution test at 2 h following an acute consumption of 500 mL of citrus juice containing 70.5 mg flavonoids [
38]. Regarding chronic (poly) phenol-rich supplementation, only one study showed a significant improvement on multiple cognitive functions including short- and long-term memory, mental flexibility, planning and letter fluency [
41] following 10 weeks of a daily dose of 100 mL of isoflavone with high phenolic bioavailability (≈43%).
The exact mechanism behind the beneficial action of short-term (poly)phenol supplementation in relation to cognition is yet to be conclusively determined. However, a number of potential direct and indirect mechanisms have been proposed to explain the beneficial effects of phenolic compounds on brain function [
64,
65]. These mechanisms include:
- (i)
interaction with gut microbiota [
66] which is known to impact (poly)phenol absorption [
67,
68],
- (ii)
modulation of neuroinflammation [
69] and glucoregulation [
70] with previous studies have demonstrated that impaired glucose tolerance is associated with poorer cognition [
71], improved cerebrovascular function (e.g., CBF, [
72]),
- (iii)
and increased spine density and neurogenesis, particularly in the hippocampus [
73].
Given the multifunctional nature of (poly)phenol effects, it was recently suggested that that all of these mechanisms have a role to play and are also interrelated [
40,
51] with endothelial nitric oxide (NO) representing a key molecule in this relationship [
74].
Because NO has multiple biological functions, previous studies have reported that the physiological beneficial effects of (poly)phenol likely depend in part on its ability to: promote NO synthesis, contribute to flow-mediated dilation [
75], and enhance nitric oxide synthase (NOS) activity as well as NO bioavailability (through limiting NO scavenging by ROS [
76]). Particularly, enhanced cognition due to (poly)phenol consumption is widely reported to be caused by two main effects: NO synthesis and vasodilation and neurotransmission [
40,
77]. Indeed, by stimulating the guanylate cyclase, NO systems mediate vasodilation in blood vessels including cerebral arteries [
78], which results in increased CBF parameters. Consistent findings from several individual studies, including those in the present SR, confirm enhanced cognitive performance in healthy young adults is accompanied by an increase in CBF or cerebral blood oxygenation following the consumption of 250 or 500 mg of trans-resveratrol [
36,
46,
48] or high flavanol cocoa drink [
45,
50]. Similarly, consumption of 500-mL citrus juice containing 70.5 mg flavonoids increases regional perfusion in the anterior cingulate cortex and central opercular cortex of the left parietal lobe at 2 h post consumption compared to the control drink [
38]. As the anterior cingulate cortex is involved in attention and executive function modulation [
79], the confirmed cognitive improvement (e.g., SRT) following (poly)phenol ingestion may be related to the ability of its components to activate NO synthesis responsible for vasodilation and increased activity in this region. However, because vasodilation is not the only relevant biological role of NO, it cannot be assumed that increasing regional perfusion is solely responsible for improved cognitive performance. Independent of its CBF effects, via the activation of NO synthesis, (poly)phenols also influence neuronal signaling pathways [
77], as NO acts as a neurotransmitter [
80]. This offers an alternative explanation of the enhanced cognition following (poly)phenol consumption. Taken together, it is likely that the positive effect of (poly)phenols on brain health is mainly due to two principal effects of the activated NO synthesis pathways: vasodilation and neurotransmission. Nevertheless, because our MA showed that rich (poly)phenol supplementation enhances the majority (SRT, SS-7s and MF), but not all, of cognitive functions (i.e., no effect on RVIP), it appears that the modulations of cognitive functions in response to polyphenol supplementation are more related to neurotransmission rather than vasodilation [
40]. Indeed, if increased vasodilation and CBF are the causal factors, then beneficial effects of (poly)phenols should appear in all cognitive functions and should not be dependent on the type of cognitive process measured, which was not the case in our MA (pooled data for RVIP revealed a non-significant effect).
Regarding the effect of (poly)phenol supplementation on neuroplasticity biomarkers, while individual studies failed to show significant improvement following the consumption of 900 mg cocoa flavanol [
50], 160mg rich-flavonoid Ginkgo biloba [
42] or 250 mg rich-catechin green tea extract [
43], pooled analyses suggest a significant effect on BDNF with higher values compared to placebo condition.
It is well documented that enhanced cognitive functions are related to an increase in serum BDNF levels in the brain stimulating synaptic plasticity and neurogenesis [
81] and that BDNF plays an important role in learning and memory functions [
82]. The pooled findings of the present MA support these reports and show that the significant beneficial effect of (poly)phenol supplementation on BDNF was accompanied by improved cognitive function including SS-7s, MF and SRT.
Previous reports also indicate that: (i) natural catechin polyphenol can be associated with an increased expression of BDNF and higher cognitive function [
83]; (ii) green tea polyphenols can boost the neuritogenic activity BDNF through the activation of NADPH-oxidase pathway [
84]; and (iii) flavonoids, at low nanomolar concentrations, also induce synaptic plasticity [
85] via modulation of receptor function, gene expression and interaction with signaling pathways [
86]. The present MA supports the majority of these findings and pooling the findings related to the effect of different polyphenol supplementation [
42,
43,
50] indicate an increase in BDNF levels compared to placebo.
Particularly, the forest plots reveal (i) a significant effect of an acute dose of 900mg cocoa flavanol [
50], (ii) a significant effect of a chronic (6 weeks) daily dose of ≈40 mg flavonoid with ≈30% phenolic bioavailability [
42] and (iii) a non-significant effect of a chronic (6 weeks) daily dose of 400 mg catechin with ≈18% phenolic bioavailability [
43]. These results indicate that data related to chronic (poly)phenol interventions are skewed towards a beneficial effect on BDNF from higher phenolic bioavailability components. These findings support a recent suggestion [
20] indicating that health effects of (poly)phenols on brain plasticity are closely associated with their bioavailability. Indeed, (poly)phenol components with high bioavailability can cross the blood–brain barrier [
87] and interact with the cellular cascade resulting in upregulation of brain BDNF gene or protein expression [
88].
A recent SR and MA conducted by our research team and addressing cognition and brain function in the elderly population failed to provide evidence regarding the beneficial effect of acute and/or chronic rich (poly)phenol supplementation on executive function, brain plasticity and inflammatory markers [
20]. By showing a significant beneficial effect of similar supplementation on brain plasticity biomarkers (i.e., acute and chronic interventions) and on different cognitive functions (i.e., specifically acute intervention) in young and middle- aged adults, the present paper supports the recent theory identifying young people as the most attractive targets for intervention to extend healthspan [
32]. Indeed, because their brain’s organs are not yet damaged, it seems possible that anti-aging interventions targeting young and healthy people will better prevent onset of age-related diseases and cognitive decline [
33]. However, since chronic studies in young and middle-aged adults are quite short (the majority are between 4 and 10 weeks) when compared with older-adult studies (the majority are 12 weeks with some lasting up to 6 months), further meta-analysis and meta-regression (pooling the results of the different age groups and accounting for the intervention period) are warranted to confirm this theory.
The strengths of the present study include a comprehensive coverage of the current literature via the utilization of a wide range of key words (related to cognition and brain) searched through two scholarly databases, the focus on randomized controlled trials which are the gold standard to confirm the effects of nutritional interventions on cognitive decline, maintenance or improvement [
89], and the high methodological quality (8.8) of the included studies.
However, despite its novelty, the present study is limited by (i) the relatively small sample sizes of the individual studies, which used a large variety of cognitive task batteries, imaging techniques, and brain health biomarkers, resulting in a relatively low number of included studies in the MA, (ii) the evidence of publication bias present in the mental fatigue domain, and (iii) the significant amount of heterogeneity present in all fields of the research domain; especially those related to the employed study design. Indeed, since some cognitive domains (e.g., processing speed, memory) are particularly receptive to practice effects, results must be interpreted with caution when findings from different study designs (e.g., parallel group, counterbalanced design) are pooled. Further high-quality investigations in the field are warranted.