The effects of protein consumption on cognitive function may be partially explained by the interaction of essential amino acids with a number of different growth and neurobiological markers (61) including IGF-1, BDNF and VEGF as well as inflammatory markers and zinc. Each of these will be discussed below.
2.5.1 IGF-1
IGF-1 is important for neurogenesis, proliferation and the transport of amino acids and protein synthesis with circulating levels declining with age (107, 108). However, there is some evidence that dietary protein, particularly animal and soy protein (and protein supplementation), can modulate levels of IGF-1 (308). For instance, one study conducted in 10 healthy volunteers found that refeeding using diets which had
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variable protein dosages but adequate energy (35 kcal energy/kg and 0.2, 0.4 and 1.0 g/kg protein) following 5 days of fasting resulted in significant increases in IGF-1, even at the lowest level of protein (0.31 U/ml increase) (309). A dose response was also observed with a 0.52 U/ml increase for 0.4 g/kg protein and an increase of 1.04 U/ml for 1.0 g/kg protein (309). However, when fed the energy variable diets (and 1.0 g/kg protein), no changes in IGF-1 were observed (309) indicating that there may be an adequate energy intake threshold which must be met before protein begins to have an effect on IGF-1 levels.
Previous research has also shown that IGF-1 can cross the BBB and this suggests that increases in peripheral IGF-1 can influence levels of IGF-1 in the brain (111). Hence, IGF-1 may be one of the mechanisms by which increased dietary protein might improve cognitive function. Currently, there has been little research which has investigated the protein-induced effects of IGF-1 on cognitive function. One cross- sectional study conducted in 1535 men and women with a median age of 74 years reported a trend between the highest tertile of IGF-1 (≥105 ng/ml) and cognitive function (executive function and verbal abilities) (110). Further, a meta-analysis on the effects of IGF-1 on cognitive function in healthy older adults found a significant positive correlation between serum IGF-1 and all measures of cognitive function (effect size of 0.57) (109). Lastly, a 2-week intervention conducted in 60 older adults at risk of malnutrition found that IGF-1 significantly increased following supplementation with a 200ml oral supplement (16 g of protein, 12 g of fat and 60 g of carbohydrate) and changes in IGF-1 were negatively associated with levels of pro- inflammatory markers such as IL-6 and TNF-α, which have been associated with cognitive decline (310). Together these studies suggest that increases in IGF-1 due to dietary protein may be beneficial for cognitive function, although there appears to be no studies which have directly assessed if there is a cause-and-effect relationship.
2.5.2 VEGF
VEGF is thought to play a role in cognitive function due to its main role in angiogenesis and homeostasis of adult vasculature (311). There is also an association between increased levels of VEGF and amyloid plaques in AD (312-314). Although previous research has found that diets low in red and processed meats are attributed to lower rates of certain cancers (312, 314), it is the fat content from these meats which has been associated with the onset of particular cancers (such as colon and
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bowel cancer) (314). Therefore, VEGF and proteins from lean red meats may still be beneficial to health. However, currently there is no research that has been conducted investigating the effects of a protein-enriched diet on VEGF levels or potential benefits including cognitive function.
2.5.3 BDNF
Adequate BDNF levels are important for preventing neuronal death, memory and learning and circulating levels decrease with age (77). There is evidence that peripheral levels of BDNF can be increased by diet, particularly dietary restriction (315-317). In animals, it has been found that intermittent fasting and caloric restriction are beneficial for enhancing and maintaining cognitive functioning through interactions with BDNF levels (315-318). Further, decreases in hippocampal concentrations of BDNF have also been observed in animal models when fed a high saturated fat diet (319), which suggests that higher intakes of saturated fats may be detrimental for cognitive function.
In humans however, there is very limited research on the effects of diet on BDNF and cognitive function. Several studies show similar findings to the animal models with one review on the impact of diet and exercise on brain plasticity and disease reporting that diets high in saturated fats were associated with a decrease in BDNF concentrations (320). Another study on the effects of a high fat/refined sugar diet on brain structure and function also found that BDNF levels decreased after consuming this diet for as little as two months and up to two years (115). Moreover, there is evidence that increasing dietary intake of zinc, which is found in abundance in red meat, may influence BDNF levels (321). While these studies suggest that dietary factors can enhance BDNF concentrations peripherally, there is no research into whether dietary protein can influence cognitive function through an increase in BDNF concentrations.
2.5.4 Zinc
It has been suggested that the associations between protein intake and cognitive performance may be related to the role of zinc (42). High concentrations of zinc are found in the synaptic vesicles of neurons and this is thought to play a role in releasing neurotransmitters, myelination and motor development (300). As such,
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reduced concentrations of neuronal zinc have been implicated in the formation of amyloid plaques common in AD (62).
There is evidence to suggest that the effects of zinc may be due to interactions with IGF-1 and neurobiological markers such as BDNF and VEGF. As zinc is able to pass through the BBB, circulating levels of zinc may be indicative of levels of neuronal zinc which could be used to predict cognitive function through its effects on neurobiological markers (321). Figure 2.7 shows the potential relationship between zinc and cognitive function.
Figure 2.7. Relationship between zinc, IGF-1, BDNF, VEGF and cognitive function. Adapted from Szewcyk et al. (2011) (321).
Zinc has been associated with cell proliferation and IGF-1 (322). IGF-1 along with insulin has been shown to affect cellular zinc metabolism (322). Zinc deficiency on the other hand, has been found to reduce levels of IGF-1 suggesting that zinc may influence cognitive function via an indirect effect (297).
Research suggests that the hippocampus is more sensitive to zinc than the cortex (321) and it has been found that zinc deficiency in the hippocampus may impair cognitive function by decreasing levels of BDNF (323) although excessive zinc supplementation can have an unfavourable effect on BDNF (323). However, there is
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evidence that contradicts this which demonstrates that total brain concentrations of zinc may not be easily influenced by serum zinc concentrations despite hippocampal concentrations being sensitive to serum levels (323). Perhaps this is due to the interaction of zinc with IGF-1 and BDNF which are highly prevalent in the hippocampus, although further research is needed to confirm this. In addition, zinc along with copper, has also been found to increase VEGF levels (78) although these findings have not been applied in the context of cognitive function.
In summary, there is evidence that zinc has the ability to pass through the BBB and interact with IGF-1 and neurobiological markers, however it is unclear whether the ingestion of lean red meat or dietary protein enhances these effects. Further research into bioavailable zinc concentration obtained through dietary intake and its relationship with cognitive function is needed.
2.5.5 Inflammation
Chronic inflammation is characterised by elevated concentrations of inflammatory markers systemically which can lead to an increased risk for many diseases (178). Ageing is associated with prolonged inflammation and evidence suggests that this can have a detrimental effect on cognitive health (175). However, it has been suggested that inflammation may be able to be controlled or reduced through diet and particular nutrients. For instance, a recent review of observational and intervention studies on nutrition and inflammation in older adults found that there is an anti- inflammatory effect for n3-PUFA intake, but not for vitamin D or whey protein supplements (324). In contrast, one study using data from the Whitehall II cohort study found that a dietary pattern reminiscent of a Western-style diet (red meat, processed foods and a lower intake of wholegrains) was associated with elevated levels of IL-6 and accelerated cognitive decline (325). However, increases in inflammation due to Western-style diet may be attributed to an increased intake of saturated fats and a lower intake of foods rich in anti-oxidants. There is some evidence which suggests that animal protein may not have any negative effect on inflammation and by extension, cognitive decline when saturated fats are removed. An 8-week study in 60 men and women aged over 20 years in which participants were randomised to either maintain their normal diet or partially replace energy from carbohydrate foods with 200 g/d of lean red meat however, found that increased lean red meat intake does not increase inflammation or markers of oxidative stress (58).
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While there is certainly evidence that diet can modulate inflammation and some evidence suggesting that protein and lean red meat does not have a negative effect on inflammation, it has also been suggested that the effects of dietary protein to maintain availability of amino acids and modulate inflammation may be influenced by other lifestyle factors such as exercise (240). This will be discussed further in the next section.