Do Dietary Blueberries Delay Aging-Induced Cognitive Function?

1 Introduction

Aging is an essential factor in cognitive decline and the development of various neurodegenerative diseases such as Alzheimer's disease and Parkinson’s disease. While the possible physiological and molecular mechanisms of brain aging are debated, a recent study reported that age-disproportionate atrophy (a faster rate of aging than chronological age) of the brain can be a diagnostic marker of neurodegenerative disorders [1]. Therefore, delaying brain aging may be a key approach to reducing the rates of neurodegenerative disorders, particularly as life expectancy worldwide continues to increase.

A healthy diet is one of the five interventions, including physical and cognitive activity, healthy diet, social engagement, and cardiovascular health monitoring that the structured, higher-intensity intervention had a statistically greater benefit on global cognition among older adults at risk of cognitive decline and dementia, the US POINTER randomized clinical trial [2]. Blueberries (Vaccinium corymbosum) are a key component of the study's healthy diet, suggesting that dietary intake of blueberries may help maintain brain health.

Indeed, increasing evidence supports the idea that blueberry intake improves brain function because of its unique nutrient and non-nutrient composition [3]. For instance, the high content of anthocyanins and flavonoids contributes to blueberry's high antioxidant activity and anti-inflammatory capacity, and the high levels of oxidants and inflammation are the major causes of brain aging [4]. However, the results of these anti-brain aging studies using blueberries are not consistent, particularly in animals and humans, which may be result from the different dosages, treatment periods, and cateroies of blueberries, given that there is a big range of the contents of bioactive compounds in blueberry among different types such as wild, low bush, and high bush [5], different forms (fresh, powder and extracts). In this review, we focus on the anti-aging and anti-brain-aging effects and mechanisms of blueberries in cells, animals, and humans. In particular, we pay attention to the different categories of blueberries in all aspects.

2 Brain aging is a complicated process

Brain aging is caused by several interrelated mechanisms that cumulatively damage neuronal function. The primary mechanisms include oxidative stress and mitochondrial dysfunction; neuroinflammation and changes in the immune response; alterations in synaptic plasticity and neurotransmitter imbalance; and protein aggregation and neurodegeneration. As reactive oxygen species (ROS) accumulate in aging cells, neurons experience oxidative damage, leading to mitochondrial dysfunction, reduced energy production, and subsequent effects on neuronal viability and resilience, accelerating functional decline [6]. Aging increases the overactivation of microglial cells, the resident macrophages of the central nervous system, which generate chronic inflammation, disrupt healthy neuronal communication, weaken the blood-brain barrier, and lead to neurodegeneration [7]. Aging also affects synaptic plasticity, reducing brain’s capacity to adapt to new information. Several neurotransmitters, such as dopamine, acetylcholine, and serotonin, are reduced, disrupting their corresponding functions related to memory, motivation, and focus [8]. Aggregation of misfolded proteins, such as beta-amyloid and tau, forms plaques and tangles, and can disrupt neural signaling pathways and damage cells, which are signs of Alzheimer’s and other neurodegenerative diseases [9]. More research studies have found that gut microbiomes are associated with cognitive aging through communication with systemic inflammation [10].

3 Blueberries are an outstanding source of anti-aging bioactive compounds

There are five main types of blueberries grown in the United States: northern highbush, southern highbush, rabbit eye, lowbush, and half-high, according to the genetic background, growth environment, and features of the plant and fruits [11]. Northern highbush (Vaccinium corymbosum) is the most widely cultivated type, growing to 6-7 feet tall and producing high yields. It has good adaptability in colder environments and includes cultivars such as ‘Duke’, Bluecrop’, and ‘Liberty’. Southern highbush (Vaccinium corymbosum hybrids) is a hybrid of northern highbush and other species, growing in low-chill regions such as Florida and California, and is less cold-tolerant. Cultivars such as ‘Emerald’ and ‘Misty’ bloom early, making them susceptible to frost damage. Highbush blueberry cultivars are very different in bioactive compounds and antioxidant capacity, with certain cultivars showing consistently superior phenolic/anthocyanin levels—making them strong candidates for nutritional biofortification [12]. Lowbush blueberries (Vaccinium angustifolium), often referred to as "Wild blueberries," are much smaller in plant size (about 1 foot tall) and produce small, nutrient-dense berries. These are primarily managed wild stands in Maine and Canada and are often used in frozen blueberry products. Half-High blueberries, a cross between lowbush and northern highbush varieties, grow between 2 and 4 feet tall and are well-suited for extremely cold regions. Examples of these cultivars include ‘Northblue’ and ‘Polaris.’ In contrast, rabbiteye blueberries (Vaccinium virgatum), native to the southeastern United States, are tall-growing plants up to 9 feet that require cross-pollination for optimal fruit production. Cultivars such as ‘Powderblue’ and ‘Tifblue’ are commonly grown in warmer climates.

Blueberries are called “Super fruit” because of the high levels of phytochemicals, bioactive compounds with health benefits, and nutrients. Blueberries contain five types of phytochemicals, including anthocyanins, phenolic acid, flavonoids, tannins, and stilbenes. Anthocyanins are the most abundant phytochemicals (typically 35%–74% of total content), responsible for the fruit’s blue and purple pigments. Major types include malvidin, cyanidin, delphinidin, petunidin, and peonidin. The most common flavonoids include flavanols (such as quercetin, myricetin, and kaempferol) and flavan-3-ols (like catechin and epicatechin). responsible for the deep blue-purple coloration of blueberries, are present in varying amounts across different types. These phytochemicals may exert anti-aging effects via their high antioxidant and anti-inflammatory properties [13]. In addition, blueberries are rich in dietary fiber, vitamins and minerals [14], particularly vitamin C in fresh berries, which supports immune function and skin health. However, the content and list of phytochemicals in blueberry depend on the type, cultivar, growing environment, harvest, as well as the processed forms (fresh, powder, juice or extracts) of blueberry [15-18]. For instance, the total anthocyanin content is 250-400 mg/100g fresh weight (FW), 150-250 mg/100g FW, 100-200 mg/100g FW, 150-300 mg/100g FW, and 200-300 mg/100g FW, in lowbush, northern highbush, southern highbush, rabbiteye, and half-high, respectively [16, 18-20] (See Table 1 for the levels of other major phytochemicals, antioxidant capacity etc. of the five types of blueberries) [21-28]. Another example is that the epicatechin content range is wide across different rabbiteye cultivars: 0 mg/100g FW in Premier, 48 mg/100g FW in Woodard, and 129 mg/100g FW in Briteblue [15]. Therefore, the type, cultivar, processed forms, and growing environment should be noted in reporting blueberry health benefits and their phytochemical contents.

4 Dietary interventions: blueberries and aging

4.1 In vitro studies

Blueberry anthocyanin extracts (BAE) protected retinal pigment epithelial cells against the aging process; 0.1 ug/ml of BAE increased cell viability from 14.6% to 76.9% and reduced senescent cells from 92.5% to 58.2% [29]. Blueberry extract (0.1-0.5 mg/ml) can significantly increase the viability (33-53%) and proliferation rates (30%) of hippocampal human neural progenitor cells and was also able to reverse the decreases in viability and proliferation induced by a cellular stressor by 94-140% and 50-90%, respectively [30]. The serum from mice fed blueberries inhibits senescence pathways in osteoblastic cells [31].

4.2 Animal studies

Dietary intake of blueberry polyphenol extracts (67µg/mL, 200 µg/mL) increased the mean lifespan of Caenorhabditis elegans by 14% and 28%, as well as improved thermotolerance. These blueberry extracts also increased survival time during 16 hours of heat stress at 35 °C by 2.5-fold, but did not protect against oxidative stressors such as hydrogen peroxide or paraquat [32]. These effects may be mediated by regulating stress resistance and metabolic regulation through the CaMKII signaling pathway. Another study also found that blueberry polyphenol extracts extended yeast lifespan by 28% by activating sirtuin-dependent stress-resistance pathways, which play essential roles in regulating aging and cellular homeostasis [33]. In hypertensive rats, blueberry-enriched diet (2% w/w lyophilized, 371-399 mg/day, equivalent to 4.1 g of fresh blueberries) intakes for 6-12 weeks or 12 weeks reduced systolic and mean arterial pressures (20% compared to controls), decreased total ROS production (65%) and superoxide and peroxynitrite (70-80%) and increased catalase activity (30%) in kidney [34]. Another study found that rats fed with uncategorized blueberries (5% w/w of diet) experienced a 22% increase in median lifespan and improved mitochondrial respiratory chain activity, suggesting that blueberries help with age-related metabolic dysfunction and oxidative tissue damage [35].

4.3 Human studies

A randomized, controlled, double-blind, crossover intervention study reported that 12 weeks of anthocyanin (300 mg/day) supplementation improved endothelial function (12–15%) by increasing nitric oxide bioavailability and reducing arterial stiffness [36]. This improvement in endothelial function further enhanced cerebral blood flow and cognitive performance in adults with vascular risk factors [36]. Similarly, a single dose (222mg) of wild blueberry extract significantly reduced systolic and diastolic blood pressure by 5.6 mmHg and 3.2 mmHg, respectively, and attenuated natural cognitive decline compared to placebo in a healthy older adult population (aged 68-75) [37]. Interestingly, topical application of blueberry extract (100 μg/mL)-containing product on skin (twice daily, 12 weeks) increased in skin hydration (20-30%) and reduced oxidative and inflammatory marker levels, such as 4-hydroxynonenal, heme-oxygenase-1 (HO-1), and cyclooxygenase-2 (COX2) (40-50%) in ex vivo human skin explants [38, 39].

5 Brain interventions: blueberries and brain aging

5.1 In vitro studies

The neuroprotective properties of blueberries have been demonstrated in several approaches. First, blueberry extract (0.1-0.5 mg/ml) increased cell viability (33-53%) and proliferation rates (30%) and reversed the cellular stressor-induced decreases in viability (94-140%) and proliferation (50-90%) in human hippocampal neural progenitor cells [30]. Secondly, nonpolar blueberry extract (5 μg/mL) reduced tumor necrosis factor-α-induced (TNF-α) ROS production in human neuroblastoma cells, suggesting blueberries can reduce inflammation-driven oxidative stress in neural aging. [40]. The third study found that Aβ25-35-induced cytotoxicity, including decreased neuron viability and increased levels of lactate dehydrogenase and ROS, was effectively reversed by protocatechuic acid, the primary metabolite of blueberry extract [41]. Blueberry polyphenols may support brain aging by acting on several key pathways at once. By inhibiting enzymes involved in inflammation, neurotransmitter breakdown and amyloid formation, blueberry could also help preserve neuronal function and slow age-related cognitive decline [42].

5.2 Animal studies

Wild blueberries extract (30 or 60 mg/kg body weight) injection (intraperitoneally, i.p.) in male, 3-4-month-old Balb-c mice for 7 days significantly improved learning and memory (a step-through latency time of 228 ± 38 seconds compared to 101 ± 32 seconds in the control group) [43]. Additionally, both dosage groups reduced brain lipid peroxidation products (by 38% or 79%) and increased brain ascorbic acid levels (by 21% or 64%), indicating that blueberry extract increased brain antioxidant levels. The treatments also significantly decreased acetylcholinesterase (AChE) activity, an enzyme that functions as a neurotransmitter and has lower levels associated with a healthy brain, suggesting that the cognitive improvements from blueberry extracts were mediated by increasing antioxidant activity and inhibiting AChE [43]. Aged rats fed with a blueberry-enriched diet (2% by weight for 8 weeks) had improved spatial memory retention for 30% in Morris water maze tests via reduced neuroinflammation, enhanced synaptic plasticity, and increased brain-derived neurotrophic factor signaling in hippocampal regions [44]. Contextual memory improved with both wild bluberry spectrum powder and extract, while untreated aged mice at 18 months declined [45]. Three weeks of 2% (w/w) blueberry supplementation improved spatial working memory in aged rats from 57% to 83% accuracy and was associated with increased hippocampal cAMP response element-binding protein (CREB) phosphorylation and brain-derived neurotrophic factor (BDNF), and providing cognitive benefits to neuroplasticity pathways [46]. A 2% blueberry-enriched diet, with a blend of two varieties decreased post-traumatic stress disorder (PTSD)-like neuroinflammation in rats by reducing hippocampal inflammatory cytokins and microglial activation, indicating anti-inflammatory neuroprotection [47]. Aged rats fed a 2% (w/w) blueberry-supplemented diet for 4 months showed restored object-recognition memory to young rats and had significantly lower nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) protein levels in 4 of 5 brain regions, correlating with better memory performance [48]. A 2% blueberry-supplemented diet resulted in the presence of anthocyanins within the brains of aged rats and was associated with improved memory performance, supporting a direct role of blueberry polyphenols in mechanisms relevant to brain aging [49]. Supplementation of a high-fat diet with 4% freeze-dried blueberry powder in middle-aged mice prevented diet-induced cognitive impairment, resulting in significant improvements in object recognition memory and spatial learning performance, bringing outcomes close to those observed in control diet–fed animals [50].

5.3 Human studies

A randomized, double-blinded, placebo-controlled study evaluated the effects of blueberry supplementation (1.0g/day, 12 weeks, n=23) on cognitive function in older patients with mild cognitive impairment. The results found that blueberry supplementation significantly improved several cognitive domains, including total cognitive aptitude test scores, spatial imagery efficiency, working memory, and recognition memory [51]. A similar study showed that older adults who consumed 1 cup (148 g fresh) of blueberries (50%:50% mixture of rabbiteye and northern highbush blueberry (V. ashei Reade ‘Tifblue’ and V corymbosum Rubel) per day for 12 weeks had a 16% improvement in memory accuracy and an increased activation in brain regions linked to executive function and memory consolidation, such as the prefrontal cortex and hippocampus [52]. A single dose (30g) of freeze-dried wild blueberry supplementation boosted executive function by 8-12% overall in 7-10-year-old children across several varieties of cognitive tasks compared to placebo [53]. A 6-month, double blinded RCT showed that 35g per day of freeze-dried wild blueberry powder significantly improved speed by decreased latency of 65ms on cognitive processing in adults with mild cognitive decline compared with placebo [54]. Healthy older adults consumed 30mL/day concentrated blueberry juice [55] or 444-621mL/day of wild blueberry juice [56] for 12 weeks showed increased resting brain perfusion and greater task-related brain activation and improved working memory compared to placebo. Supplementation with a phenolic-rich rabbiteye blueberry preparation in healthy older adults was associated with measurable improvements in cognitive performance, and these benefits were linked to circulating blueberry-derived phenolic metabolites, suggesting a direct contribution of blueberry bioactive to cognitive function during aging [57].

6 Mechanisms of anti-brain aging effects of blueberries

6.1 Cellular level

It is well known that aging results from cumulative damage to cellular components (DNA, proteins, lipids) by ROS, with mitochondria being both a primary source and a target of ROS. The brain is especially vulnerable due to its high oxygen consumption, lipid-rich content, and limited antioxidant defenses, which can damage neurons and promote inflammation [6, 58]. Blueberry phytochemicals, such as anthocyanins and phenolic acids, can directly scavenge ROS by donating hydrogen atoms or electrons and neutralize superoxide anion, hydroxyl radicals, and hydrogen peroxide. These chemicals also enhance endogenous antioxidant defenses, including superoxide dismutase, catalase, glutathione peroxidase, and heme oxygenase-1. For instance, anthocyanins decreased ROS levels, ROS-producing enzyme, malondialdehyde, and overall antioxidant enzyme expression and activity in HUVECs and HepG2 cells [59]. Polyphenols in wild blueberry (lowbush) extracts have anti-aging effects, partly by fighting ROS formation [60]. Blood biomarker studies show people with higher levels of specific antioxidants and fatty acids have "younger" brain structure and function [61]. On the other hand, increased resistance to oxidative stress contributes to extended lifespan in C. elegans [62].

Chronic inflammation is now recognized as a central driver of brain aging, accelerating cognitive decline and increasing the risk for neurodegenerative diseases. It is not just a consequence of aging but an active contributor to the pathological process [63]. There are four possible mechanisms: 1) Chronic activation of the brain's immune cells (microglia & astrocytes) leads to excessive release of toxic inflammatory chemicals; 2) Inflammation and oxidative stress form a vicious cycle; 3) Inflammatory chemicals can damage blood vessels and the brain's white matter; 4) Dysfunctional immune cells fail to properly clear toxic protein aggregates like amyloid-β and tau, hallmarks of Alzheimer's disease. The anti-inflammatory effects of blueberries worked through all four approaches [13]. For example, a 2% blueberry diet decreased microglial activation and astrogliosis in intraocular hippocampal grafts to middle-aged rats [64]. Blueberries exert antioxidant effects by directly scavenging ROS, increasing SOD activity, and decreasing ROS production [59, 60, 65], as aforementioned. Blueberry extract neutralizes amyloid Aβ25-35-induced cytotoxicity [28] and reduces amyloid formation [42]. Wild blueberry extract significantly improved vascular function and attenuated natural cognitive decline compared to placebo in a healthy older adult population [37].

6.2 Molecular level

Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a vital role in the balance of oxidants/antioxidants and in chronic inflammation, and its expression and activity are attenuated with aging. Blueberries can increase the mRNA levels of Nrf2 and the translocation to the nucleus of Nrf2, regulate its downstream molecules HO-1, NQO1, SOD, and finally mitigate oxidative stress and chronic inflammation in diabetic rats [66], human vascular endothelial cells [67], and aging rats [68]. The molecular antioxidant effects of rabbiteye blueberry anthocyanins are consistent with activation of the NRF2–ARE signaling pathway, leading to enhanced expression of endogenous antioxidant enzymes and reduced oxidative damage [69].

Fig (1). Possible mechanisms of blueberries delay brain aging

The mitogen-activated protein kinase (MAPK) pathway plays essential roles in regulating chronic inflammation, redox signaling, apoptosis, and stress responses. Under oxidative stress, aberrant activation of MAPKs, such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38, leads to cellular dysfunction and tissue injury [18, 52, 70, 71]. Blueberry extracts reversed amyloid-β (Aβ42, 25 µM) or lipopolysaccharide-induced ROS by downregulating MAPK phosphorylation in primary hippocampal neuronal cells [72]. Furthermore, blueberries strengthen cellular antioxidant capacity through MAPK-Nrf2 cross-talk in human aortic endothelial cells [25].

NF-kB pathway is a major driver of neuroinflammation and oxidative stress. The anti-inflammatory effects of blueberries may be mediated by inhibiting NF-κB activity [49], preventing IκB-α degradation and blocking NF-κB translocation to the nucleus [50], and inhibiting NF-κB expression [73]. The suppression of NF-κB reduces inflammatory markers (TNF-α, IL-6), exerts neuroprotective effects, and contributes to healthier brain aging.

Heat shock proteins (HSPs), such as HSP-12, HSP-16, and HSP-70, typically increase in expression as C. elegans ages [74]. It is widely used to dissect conserved mechanisms of aging because its stress-response and proteostasis pathways are evolutionarily preserved. Wild blueberries extract blocked the age-related increase in HSP mRNA levels and extended lifespan in C. elegans [32]. In rats, a 10-week blueberry diet completely restored the brain's HSP-70 response to stress in old rats, matching levels seen in young rats and enhancing learning and memory [35].

Telomere biology is a central mechanism in aging, linking telomere length to age-related diseases and mortality. Telomeres are protective DNA-protein complexes at chromosome ends composed of repetitive DNA sequences and sheltering proteins. After incomplete replication, the resulting DNA progressively shortens with each cell division due to lagging-strand DNA synthesis. Telomeric DNA can accelerate attrition after ROS damage due to its high susceptibility. Short telomeres trigger DNA damage responses such as p53/p16 activation, leading to irreversible cell-cycle arrest [21]. Polyphenols from blueberries delay telomere shortening and upregulate telomerase activity via sirtuin 1(SIRT1) activation and the mechanistic target of rapamycin (mTOR) pathway, thereby elongating telomeres and delaying cellular senescence [75].

7 Current issues and future studies

While increasing studies have demonstrated the anti-brain-aging effects of blueberries via the aforementioned mechanisms, the results of these studies are inconsistent, even controversial, which results from these limitations/issues: 1) only one type of blueberries was applied. Given that there are five major types of blueberries (northern highbush, southern highbush, rabbiteye, low/wild bush, and half-high) in North America, each type has different levels of phytochemicals, antioxidant capacity, etc. (Table 1), which are the primary molecules exerting an anti-brain aging effect. As shown in Table 2, wild bush is most applied type (7 out of 20), followed by rabbiteye (4 out of 20); 6 articles did not specify which type of blueberry; and 2 articles used a blend of highbush and rabbiteye. Therefore, it is worth comparing the anti-brain effects among these types of blueberries. 2) Different forms and dosages of blueberries were used: fresh, freeze-dried powder, whole phenolic extracts, and pure anthocyanins and phenolic acids. For instance, 1 cup (148 g fresh) of blueberries (50%:50% mixture of blueberry cultivars V. ashei Reade ‘Tifblue’ and V corymbosum Rubel) per day was consumed by older adults for 12 weeks and resulted in a 16% improvement in memory accuracy [52]. For freeze-dried powder, 15g/day wild blueberry powder in children [53], but 24 g/day rabbiteye blueberries in older adults [53] were used in cognition studies. Wild blueberry extract (30-69mg/kg) has significantly improved cognitive performance [43]. It is hard to know whether these blueberries contain the same or similar amounts of phytochemicals as in these studies. Therefore, a similar number of primary phytochemicals should be used in future studies, regardless of the form of blueberries. 3) Only a single dose was tested in most studies, especially in animal and human studies For example, only 1g/day of blueberry extracts in elder patient [51], 2% blueberry extract powder diet weight in rats [35] 15g/day wild blueberry freeze-dried powder in children [36], but 24 g/day rabbiteye blueberries freeze-dried powder in older adults [53], there is no comparison with lower or higher dosages on the protective effects, even these studies reported anti-brain aging effects. 4) There is a big range of intervention periods in different studies. For instance, Wild blueberry extract (30-69mg/kg) on cognitive performance was only for 7 days, even though the results were significant [43]. 1 cup (148 g) of fresh blueberries per day was consumed by older adults for 12 weeks, resulting in a 16% improvement in memory accuracy [52]. Aged rats fed with a blueberry-enriched diet (2% by weight for 8 weeks) had improved spatial memory retention for 30% in Morris water maze tests [44]. In summary, all these factors, such as type, form, dosage, and intervention period, should be considered in future anti-brain-aging studies, given that neurodegenerative processes and aging occur gradually over time and that phytochemical levels vary among different types of blueberries.

List of Abbreviations

AChE, acetylcholinesterase; BAE, Blueberry anthocyanin extracts; BDNF, phosphorylation and brain-derived neurotrophic factor; COX2, cyclooxygenase-2; CREB, cAMP response element-binding protein; ERK, extracellular signal-regulated kinase; FW, fresh weight; HO-1, heme-oxygenase-1; HSPs, heat shock proteins; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B; Nrf-2, Nuclear factor erythroid 2-related factor 2; PTSD, post-traumatic stress disorder; ROS, reactive oxygen species; SIRT1, sirtuin 1; mTOR, mechanistic target of rapamycin; TNF-α, tumor necrosis factor-α.

Funding

This work was funded by the National Science Foundation (grant number 2200536) to Hongwei Si.

Conflict of Interest

The authors declare no conflicts of interest.

Acknowledgements

Hongwei Si: Conceptualization, writing, review & editing, funding acquisition, and project administration; Yang Zhang: writing—original draft preparation and data collection. All authors have read and agreed to the published version of the manuscript.

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