Author: Prof John Nolan, Director Nutrition Research Ireland
Introduction: Carotenoids and Cognition
One of the main challenges of our ageing population is to limit the burden of any disability or disease and maximise the quality of life in later years, so that we can continue to function and engage with our environment and its surroundings in a positive way. The Nutrition Research Centre Ireland is a multidisciplinary group studying the role of nutrition and lifestyle for human well-being. Our current research interests include the study of key nutrients for cognitive function and brain health with a major goal of identifying ways to reduce Alzheimer’s disease.
The Ageing Population
By 2030, it is estimated that the world’s older population (i.e., individuals aged above 65 years) will reach 1 billion; and by 2050, it is estimated that they will represent 16.7% (or 1.6 billion) of the total global population (He et al., 2016). This ageing trend is predicted to continue and is driven largely by increases in life expectancy resulting partly from, in improvements in socio-economic status, greater access to healthcare and advances in technology.
While increases in life expectancy are one of humanities greatest achievements, the growing and ageing population presents significant social and economic challenges. Of particular concern is the increasing prevalence of age-related diseases (e.g., cardiovascular disease, age-related macular degeneration and dementia) (U.S. National Institute on Ageing and World Health Organization, 2011) in parallel with the growing population and increases in life expectancy (Figure 1; (Power et al., 2019)). For this reason, emphasis is now being placed on strategies to promote healthy ageing, with the aim of minimising the burden of disability and disease in later life and maximising the quality of life for individuals in their later years.
The Ageing Process
In order to devise strategies for successful ageing, it is important to understand the biology of ageing, the mechanisms that contribute to the ageing process, and the link between ageing and disease.
Ageing is a highly complex and multifactorial pathophysiological process that occurs gradually over time and causes structural and functional alterations within an organism (Kowald and Kirkwood, 1996). Ageing is caused by a continuing and lifelong accumulation of cellular and molecular damage. Throughout our lives, the cells in our body will accurately and reliably replicate themselves between 50 and 70 times (depending on the cell type and the amount of damage it encounters). Once a cell reaches its limit (known as the Hayflick limit) (Hayflick, 1998) it is unable to continue replication and enters apoptosis (programmed cellular death). As more and more cells in our body and brain reach their limit, declines in physical and mental capacity appear (Farley et al., 2011).
There are many biological mechanisms that underlie the ageing process including oxidative damage (i.e., cumulative exposure to unstable molecules, which results in tissue injury and damage of nucleic acids, lipids, carbohydrates and proteins) and inflammation over a prolonged period (i.e., chronic inflammation), which can cause cellular damage. Understanding these mechanisms is challenging as they are influenced by many internal and external factors such as genetics, life events in childhood (e.g., interactions with peers) and adulthood (e.g., new career, parenthood), occurrence of a health conditions (e.g., CVD) and lifestyle habits (e.g., smoking). While ageing is not synonymous with disease, the deterioration in cellular functions increases the risk of disease and disability as the cellular response becomes less efficient.
The brain is the control centre for the human nervous system and is responsible for receiving, processing, interpreting and responding to information sent from within or outside the body.
Cognition refers to the mental process of acquiring information and understanding through thoughts, experiences and the senses. Cognitive abilities can be broadly classified into two groups: crystallized and fluid abilities. Crystallized abilities refer to skills and memories that have been acquired over an individual’s lifetime (e.g., general knowledge, vocabulary). Fluid abilities refer to the capacity to process, manipulate and transform information to complete a task at a point in time (e.g., problem-solving, reasoning).
Cognition can also be divided into specific domains such as memory, perception, language, decision-making, planning and reasoning. Changes in cognition occur as individuals age. Some cognitive domains such as speech, language and procedural memory (e.g., remembering how to play the piano) will remain stable as we age while other domains such as prospective memory (e.g. remembering to perform a specific action in the future) and executive function (e.g. multi-tasking or planning) will decline with increasing age (Murman, 2015).
When initial age-related changes occur, the brain is able to compensate (e.g. using additional brain regions and neural circuitry for computational support) and this enables individuals to continue to function normally. However, as neuronal damage increases (due to internal and external factors e.g. genetics, occurrence of a health condition, lifestyle habits) the brain can no longer compensate for these changes and individuals begin to show subtle cognitive decline (Raz, 2009). This reduces the efficiency and effectiveness of neurons to communicate to one another and leads to signs and symptoms of cognitive decline.
Dementia is the umbrella term used to describe a collection of neurological disorders that causes deterioration in cognition (e.g. memory, thinking, behaviour and the ability to perform everyday tasks), beyond what is associated with normal ageing. Dementia represents the most significant stage of cognitive decline and is one of the fastest growing age-related diseases, with incidence rates doubling every 6.3 years (on average) from 65 to 95 years of age. Every 20 years this figure is expected to almost double, reaching 75 million by 2030 and 131.5 million by 2050 (Alzheimer’s Disease International, 2018). Dementia is now a trillion-dollar disease worldwide and, worryingly, is expected to increase to a staggering $2 trillion annually by the year 2030.
As a result of the increasing prevalence rates and growing burden on society, emphasis is being placed on strategies to promote healthy aging, with the aim of minimising the burden of disability and disease in later life and maximising the quality of life for individuals in their later years. Given that pharmacological approaches remain elusive, focus is also being placed on preventative strategies to delay the onset and reduce the risk of developing dementia, with particular focus on Alzheimer’s disease, as it is the most common form of dementia.
Nutrition and Cognitive Health
Emerging evidence suggests that healthy lifestyles throughout life may reduce the risk, or delay the onset, of cognitive decline in later life. Indeed, it has been suggested that a third of Alzheimer’s disease cases could be averted by modification of lifestyle (Barnes and Yaffe, 2011). Accumulating evidence suggests that good nutrition (e.g. fruits, vegetables, fish) is important for optimising cognition (Valls-Pedret et al., 2015) and maintenance of cognition (Pelletier et al., 2015), and is also associated with reduced risk of Alzheimer’s disease in later life (Otaegui-Arrazola et al., 2014).
Dietary components known as carotenoids selectively accumulate in the brain where they play important physiological functions and activities. Carotenoids are naturally occurring plant pigments that are ubiquitous throughout nature and synthesised de novo by photosynthetic organisms (plants, algae, cyanobacteria) and some non-photosynthetic organisms (Alcaino et al., 2016). Carotenoids can be classified as carotenes (which are puro hydrocarbons and contain no oxygen) or xanthophylls (which are oxygen derivatives and more polar than carotenes).
Importantly, carotenoids cannot be synthesised de novo by humans and so they must be obtained from the diet, primarily through the leaves of edible plants and dark green, yellow, orange, and red vegetables and fruits. In blood and most tissues, the xanthophyll carotenoids account for just 40% of total carotenoid concentrations, whereas carotenes account for approximately 60% of carotenoids present (Kaplan et al., 1990); in the brain, the xanthophyll carotenoids account for more than 65% of total carotenoids, suggesting preferential uptake of xanthophylls across the blood–brain barrier (i.e. a semi-permeable barrier separating blood from cerebrospinal fluid) and selective accumulation into brain tissue (Craft et al., 2004).
The xanthophyll carotenoid lutein is one of the most concentrated carotenoids in the brain. It is for this reason that the majority of the research to date has studied the role of lutein in cognition (see Figure 2).
Population-based and cross-sectional studies have shown that higher concentrations of carotenoids (measured in blood and via self-report [i.e. questionnaires]) are associated with better cognitive performance in healthy individuals (Feeney et al., 2017, Johnson et al., 2013). Other smaller studies have also observed positive associations between the xanthophyll carotenoids and cognitive domains including memory (Cannavale et al., 2019), executive function (Johnson et al., 2013) and language (Zamroziewicz et al., 2016a). Of interest, studies have shown that carotenoid concentrations are lower in individuals with mild cognitive impairment (Rinaldi et al., 2003) and Alzheimer’s disease (Mullan et al., 2017, Nolan et al., 2014a) when compared to individuals free of cognitive impairment. Additionally, plasma carotenoid concentrations (lutein and β-carotene in particular) correlate inversely and significantly with Alzheimer’s disease severity (Wang et al., 2008).
The carotenoids lutein, zeaxanthin, and meso-zeaxanthin are preferentially concentrated in the central retina (macula lutea, which is part of the central nervous system) where they are collectively referred to as macular pigment. Interestingly, macular pigment levels correlate positively and significantly with brain concentrations of lutein and zeaxanthin (Vishwanathan et al., 2016). Therefore, the measurement of macular pigment can be used as a non-invasive clinical biomarker of brain nutrition and, potentially, cognitive health, given that higher macular pigment levels have been associated with better cognitive performance in both healthy (Ajana et al., 2018, Feeney et al., 2013) and cognitively impaired individuals (Renzi et al., 2014). Higher consumption of green leafy vegetables (rich in the xanthophyll carotenoid lutein) in particular has also been associated with a reduced risk of Alzheimer’s disease and a slower rate of cognitive decline (Loef and Walach, 2012, Morris et al., 2018). Overall, observational evidence suggests that greater carotenoid consumption is associated with better cognitive performance and a reduced risk of cognitive decline.
Recent interventional studies in healthy individuals have observed improvements in various domains of cognition following carotenoid supplementation. These include episodic memory (Power et al., 2018), attention (Hammond et al., 2017) and processing speed (Bovier and Hammond, 2015). To date, no improvements in cognition have been observed among patients with Alzheimer’s disease following carotenoid supplementation alone (Nolan et al., 2015), suggesting that early intervention is likely to be important. Of interest, however, improvements in memory, sight and mood of patients with Alzheimer’s disease were reported by their caregivers following supplementation with xanthophyll carotenoids in combination with omega-3 fatty acids in comparison to patients supplemented with a carotenoid-only formulation (Nolan et al., 2018). This pilot work demonstrated a superior xanthophyll response in blood in the presence of omega-3 fatty acids.
re-MIND (Memory Intervention with Nutrition for Dementia) a recently concluded 2-year nutritional interventional trial, built on this important discovery with the goal of exploring the effects of carotenoids and omega-3 fatty acid supplementation on the natural progression of the mild-to-moderate stage of Alzheimer’s disease. Significant improvements in antioxidant and anti-inflammatory nutrients (omega-3 fatty acids and carotenoids) were observed for the active intervention group compared to placebo. The trial also demonstrated changes in quality of life with carers reporting improvements in memory, mood, and day-to-day activities for the patients on the active intervention compared to placebo. (The formula tested in the re-MIND trial is now commercially available as ReMind™)
Neuro-protective Properties of Carotenoids
The exact mechanisms underlying the relationship between carotenoids and cognitive health and function have not yet been fully elucidated. Carotenoids are premised to be neuro-protective because of their chemical composition and localisation within biological membranes, thus bestowing antioxidant and anti-inflammatory properties at their storage locations. These properties can help mitigate the processes involved in neurodegeneration; namely, oxidative stress and inflammation (Mohammadzadeh et al., 2017). Despite accounting for just 2% of total body weight, the adult human brain consumes a fifth of the body’s total oxygen intake to fuel its billions of neurons and trillions of synapses. Owing to its high oxygen demand and high amounts of poly-unsaturated fatty acids, the brain is particularly vulnerable to oxidative damage. In addition, the integrity of the blood-brain-barrier is also reduced as individuals age. This results in the brain having a higher susceptibility to oxidative damage. Because of their conjugated double-bond structure, carotenoids are efficient scavengers of reactive oxygen species (namely singlet oxygen and peroxyl radicals), primarily through direct energy transfer (i.e. a process known as physical quenching). They can also neutralise reactive oxygen species via electron acceptance, electron donation, or hydrogen abstraction or acceptance (Bouayed and Bohn, 2012, Kaulmann and Bohn, 2014).
Because of their lipid solubility, carotenoids are incorporated into lipid membranes where they can interact with plasma, mitochondria, and nucleus membranes within cells. As a result, carotenoids can reduce the susceptibility of cellular membranes and lipoproteins to oxidative damage through free-radical scavenging (Bouayed and Bohn, 2012). Carotenoids can also affect the structural and dynamic properties of membranes (e.g. thickness, permeability) (Gruszecki and Strzalka, 2005). It has also been shown that the xanthophylls L and Z can positively impact neural efficiency, whereby individuals with higher levels of these xanthophyll carotenoids required less brain power to complete the same tasks as individuals with lower levels of these carotenoids (Bovier and Hammond, 2015, Lindbergh et al., 2016). Finally, evidence also suggests that the anti-inflammatory properties of carotenoids can play a positive role in neurological disorders. These include modulation of inflammatory cells and pro-inflammatory enzymes, downregulation of pro-inflammatory molecule production, and attenuation of inflammatory gene expression (Guest and Grant, 2016). For example, it is posited that carotenoids can influence the immune properties of microglia, which in turn can inhibit the production of pro-inflammatory molecules such as cytokines.
In conclusion, given that pharmacological approaches remain elusive, focus is being placed on preventative strategies to delay the onset and reduce the risk of developing dementia. Given that xanthophyll carotenoids selectively accumulate in brain tissue and given their ability to attenuate the mechanisms involved in the pathogenesis of Alzheimer’s disease (namely oxidative stress and neuro-inflammation), it is likely that they play a significant neuro-protective role by maintaining and optimising cognition and reducing the risk of cognitive decline.
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