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Masella, R. Curcuma Longa. Encyclopedia. Available online: https://encyclopedia.pub/entry/9440 (accessed on 17 November 2024).
Masella R. Curcuma Longa. Encyclopedia. Available at: https://encyclopedia.pub/entry/9440. Accessed November 17, 2024.
Masella, Roberta. "Curcuma Longa" Encyclopedia, https://encyclopedia.pub/entry/9440 (accessed November 17, 2024).
Masella, R. (2021, May 10). Curcuma Longa. In Encyclopedia. https://encyclopedia.pub/entry/9440
Masella, Roberta. "Curcuma Longa." Encyclopedia. Web. 10 May, 2021.
Curcuma Longa
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This entry is adapted from the peer-reviewed paper 10.3390/nu13051519

Due to the global increase in lifespan, the proportion of people showing cognitive impairment is expected to grow exponentially. As target-specific drugs capable of tackling dementia are lagging behind, the focus of preclinical and clinical research has recently shifted towards natural products. Curcumin, one of the best investigated botanical constituents in the biomedical literature, has been receiving increased interest due to its unique molecular structure, which targets inflammatory and antioxidant pathways. These pathways have been shown to be critical for neurodegenerative disorders such as Alzheimer’s disease and more in general for cognitive decline. Despite the substantial preclinical literature on the potential biomedical effects of curcumin, its relatively low bioavailability, poor water solubility and rapid metabolism/excretion have hampered clinical trials, resulting in mixed and inconclusive findings. In this review, we highlight current knowledge on the potential effects of this natural compound on cognition. Furthermore, we focus on new strategies to overcome current limitations in its use and improve its efficacy, with attention also on gender-driven differences.

turmeric aging brain cognition bioavailability oxidative stress inflammation

1. Introduction

Cognitive decline is a highly disabling and prevalent condition in the aging population, greatly affecting physical health and quality of life. Global average life expectancy, as observed in 2019 by the Global Health Observatory (GHO), was estimated to be 73.4 years in the WHO European Region (https://www.who.int/gho/mortality_burden_disease/life_tables/situation_trends_text/en/ accessed on 25 April 2021). In 2050, the number of people over the age of 60 is expected to reach a total of about 2.1 billion (https://www.who.int/ageing/publications/active_ageing/en/ accessed on 25 April 2021). As the ageing population is rapidly growing due to the global increase in life expectancy in westernized life-style countries, the number of people experiencing cognitive impairment is also expected to grow in parallel. Disregarding overt pathologies, the impact of age itself on cognitive abilities is so disruptive and so underestimated that it has been described as “the elephant in the room” [1][2].

The lack of effective pharmacotherapy has led researchers to seek alternative approaches in order to treat or prevent the cognitive decline accompanying ageing. Accumulating evidence suggests that conditions co-occurring in metabolic dysfunctions such as neuroinflammation, oxidative stress (OS), mitochondrial dysfunction or autophagy may all potentially act as triggers for cognitive decline. Indeed, metabolic syndrome (MetS, defined as the presence of three or more of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides (TG) and low serum high-density lipoprotein—HDL), negatively impacts cognitive performance and brain function possibly increasing neuroinflammation, OS and brain lipid metabolism [3]. Insulin resistance (IR, defined as the inability of peripheral target tissues to respond normally to insulin) is a common condition experienced at old age and often associated with obesity. It typically precedes the onset of type 2 diabetes (T2D) by several years and is considered as a risk factor for cognitive decline in both diabetic and non-diabetic populations [4]. In fact, peripheral IR, by decreasing insulin signaling within the brain, may alter its metabolic functions, increasing OS and neuroinflammation, eventually setting the stage for dementia and neurodegeneration. Thus, neuroinflammation, OS and metabolic dysfunctions involve a strict connection between the brain and the overall metabolic regulation that occur in the periphery. Moreover, changes in microbiota composition and dysbiosis, can potentially influence a number of pathological conditions, include MetS, obesity, T2D, heart failure, and cognitive function (see [5] and references therein).

While novel target-specific drugs are currently lacking [6], some epidemiological studies indicate that natural antioxidant agents, such as polyphenols, polyunsaturated n-3 fatty acids or vitamin-rich foods may delay the occurrence of neurodegenerative disorders. Polyphenols, in particular (e.g., curcumin and resveratrol) having pleiotropic protective effects appear ideal to prevent or treat conditions (such as AD) whose origin is multifactorial [7]. A growing body of research suggests that regular consumption of natural products (vegetables, fruits, leaves, roots, seeds, berries etc.) rich in polyphenols might improve health outcomes through different mechanisms boosting the organisms’ antioxidant defenses [8]. Natural compounds represent a major source for the discovery of drug targets and are ever increasingly attracting the interest of the scientific community, with the main aim of validating their efficacy for the prevention and treatment of different conditions, including cognitive decline and metabolic disorders [9]. Notwithstanding the growing interest in this class of compounds, rigorous clinic trials addressing their specific effects are lacking or show biases due to the nutritional status of the subjects, genetic background, gender, treatment duration and dose–response relationship [10]. With regard to this latter point, a major drawback is related to their bioavailability, i.e., the amount of compound (or of its active principles) that reaches systemic circulation due to intestinal endothelium absorption and first-pass metabolism. Thus, the use of natural products and nutraceuticals poses important questions regarding human safety and calls for a better understanding of their therapeutic efficacy as well as their mechanisms of action.

Curcumin, one of the best investigated botanical constituents in the biomedical literature, has been receiving increased interest due to its unique molecular structure, which targets inflammatory and antioxidant pathways, and its potential to improve healthspan [11][12][13][14][15]. The genus Curcuma includes approximately 80 species and is regarded as one of the largest genera of the Zingiberaceae family [16]. Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a lipophilic polyphenol active extract deriving from the rhizome of Curcuma Longa. Curcumin (and curcuminoid analogs such as demethoxycurcumin and bisdemethoxycurcumin) provides the characteristic bright yellowish/golden pigment of turmeric widely used in traditional Indian and Chinese medicine from thousands of years because of a number of beneficial effects on human health [17][18]. Today curcumin is used all over the world as a supplement, spice and food additive. It is considered a safe compound suitable for daily dietary use by the United States Food and Drug Administration (FDA), the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the European Food Safety Authority (EFSA) who have indicated 0–3 mg/kg as an acceptable daily intake (https://www.fda.gov/food/generally-recognized-safe-gras/gras-notice-inventory accessed on 25 April 2021) [19]. Many of its medical uses have been mechanistically validated in in vitro and in vivo preclinical studies (more than 3000 investigations, see [20]) mainly focusing on its antioxidant and anti-inflammatory properties. In recent years, the positive effects of curcumin have been observed in several chronic diseases ranging from cardiovascular, gastrointestinal, neurological disorders and diabetes to several types of cancer [21][22][23][24]. The consumption of curcumin has been associated with a global improvement in the glycemic and lipid profile in patients with MetS [25]. In addition, amelioration in cognitive function in animal models has been widely documented due to its action on structure and functionality of neuronal membranes [26][27]. Despite this evidence it is worth mentioning that curcumin is characterized by poor stability, a feature resulting in an overall low oral absorption, though, once in the blood stream, curcumin appears to be stable and able to reach target tissues [28]. However, as far as the brain is concerned, its application raises the critical issue of its ability to cross the blood–brain barrier (BBB), an issue deserving further investigation [29].

2. Curcumin, Oxidative Stress and Inflammation

The neuropathological features of the brain affected by dementia suggest that the oxidative and inflammatory burden plays a role in the progression of pathological signs by reducing brain plasticity, thus, being an important risk factor for cognitive disability [30]. To this regard, metabolic dysfunctions that are often associated with OS and inflammation, may greatly accelerate the onset and worsen the progression of cognitive functions by promoting brain ageing and reducing healthspan [31].

Neuroinflammatory processes are a main feature of neurodegenerative disorders in which microglia and astrocytes are over-activated, resulting in increased production of pro-inflammatory cytokines. Moreover, deficiencies in the anti-inflammatory response may also contribute to neuroinflammation. More specifically, the activated neuroglia by increasing both NF-κB, COX2 and iNOS levels may induce, in turn, the release of pro-inflammatory cytokines, such as IL-6, IL-1α and TNF-β. This pervasive inflammatory condition results in an overall increase in the OS burden leading to neuronal toxicity and the subsequent cognitive deficits characterizing neurodegenerative diseases. Numerous studies have indicated that curcumin is an effective antioxidant both in vivo and in vitro [9]. Curcumin treatment could attenuate cell apoptosis, decrease the level of lipid peroxidation, and increase the activity of various antioxidant enzymes including superoxide dismutase (MnSOD) and glutathione (GSH) [32], thus helping to break the vicious cycle sustaining neuroinflammation and containing the progression of neurodegenerative diseases [33]. The underlying mechanism is possibly associated with the function of NFE2-related factor-2 (Nrf2), a transcription factor promoting the upregulation of antioxidant defenses [33].

As far as apoptosis is concerned, many mechanisms have been proposed. Xi-Xun Du and colleagues indicated that curcumin’s property of iron chelation and reduction may underlie its anti-apoptotic effects [34]. Chen and co-workers reported that curcumin may exert its cytoprotective effects against neurotoxic agents via its antiapoptotic and antioxidant properties through the Bcl-2–mitochondrion–ROS–inducible nitric oxide synthase pathway [35]. Moreover, Yu and colleagues reported that the inhibition of JNK pathway and the activation of caspase-3 cleavage might prevent neuronal death [36]. Indeed, the anti-inflammatory and antioxidant properties of curcumin are strictly related to its action on apoptotic pathways and on neuronal death. In fact, pro-inflammatory cytokines are not only involved in the so-called neuroinflammaging but may also trigger the apoptotic process. Likewise, excessive OS may directly lead to mitochondrial swelling and apoptosis. Thus, inflammation and apoptosis are related in a vicious cycle leading to neuronal death [37].

Recently, several studies have highlighted the role of inflammatory pathways mediated by the inflammasome in neurodegenerative diseases. In particular, the NOD-like receptor pyrin domain-containing-3 (NLRP3) has been suggested to play a pathogenic role in several neuroinflammatory diseases, including AD [38]. In vitro and in vivo studies have shown that Aβ peptide activates NLRP3 inflammasome in microglial cells. Furthermore, in a mouse model of AD, NLRP3 knockout (KO) mice were protected from impaired spatial memory performance and showed a decrease in the Aβ plaque load [39], similar results were obtained when a specific NLRP3 inhibitor was administered to mice [40]. This evidence points to the inflammasome as a potential therapeutic target for AD treatment [41]. Notably, recent evidence shows that curcumin, by modulating the activity of NLRP3 inflammasome, could be beneficial in reducing neuroinflammation and/or neurodegeneration in different neurological disorders, such as major depression, brain ischemia, AD and epilepsy [13][42][43].

OS is a condition characterizing aerobic biological systems, the major portion of ROS being generated as a by-product of the electron transport chain operating in the mitochondria [44]. As already mentioned, OS is a condition strongly associated to inflammation that may act both as (con)cause and effect of pathological conditions affecting brain ageing; however, a growing body of evidence suggests that ROS are not only responsible for oxidative damage to cells and macromolecules but they may also play a role as mediators in specific signaling cascades. Hydrogen peroxide (H2O2) in particular has been identified as a ROS able to affect the ageing process by specifically mediating insulin signaling and promoting fat accumulation, ultimately affecting the ageing process [45]. Worth to notice, the master regulator of this process is the p66Shc gerontogene, which, by acting within the mitochondrion, increases the generation of H2O2, amplifying insulin signaling [46][47][48]. Interestingly, deletion of p66Shc gene in mice resulted in the decreased formation of mitochondrial H2O2 [48], a feature that has been associated with reduced fat accumulation as well as decreased incidence of metabolic and cardiovascular pathologies [46][49]. Moreover, p66Shc KO mice were characterized by elevated resistance to OS, delayed brain ageing and improved overall healthspan, all features associated with increased brain and behavioral plasticity. In fact, the brain of p66Shc KO mice was characterized by reduced levels of inflammation and OS and increased levels of the neurotrophin brain-derived neurotrophic factor (BDNF); in addition, these mice showed decreased emotionality and improved cognitive function [50][51][52].

Lifestyles have the potential to modulate healthspan during ageing. For example, physical exercise and diet, as well as the consumption of nutraceutical compounds (including curcumin), may greatly contribute to reducing neuroinflammaging by targeting brain pathways related to OS and inflammation (see below, next paragraph). Physical exercise in elderly women has been shown to improve metabolic functions and this was paralleled by a decrease in the peripheral levels of p66Shc gene [53][54]. Very recently, a role for curcumin was also reported in the modulation of the p66Shc gene as its was able to downregulate the expression levels of this gene in peripheral blood mononuclear cells (PBMC), improving diabetic nephropathy in a rat model [55]. These data overall suggest that p66Shc might be exploited as a suitable biomarker of curcumin efficacy to counteract the ageing-related burden and to improve overall healthspan.

3. Conclusions

In this entry, we have touched upon a number of critical issues that should be taken into account when designing preclinical and clinical studies aimed at assessing curcumin efficacy on cognitive functions. Among these, one important factor that clearly needs to be tackled in the future has to do with increasing its bioavailability as well as controlling the impact of nutritional status/diet and lifestyle on curcumin’s effects. Diet is also likely to influence microbiota status, thus, controlling for nutritional status will be crucial for effective future studies.

Another important point relates to the need to assess the effects of this natural compound on both males and females, both in preclinical and clinical studies. As dementia and AD show a much greater prevalence in the female population, it is imperative to address this issue by targeting both sexes/genders [56].

Moreover, given the overlap between the mechanisms of action of many compounds (see, e.g., curcumin and resveratrol), it will be important to target multiple molecular pathways to maximize the effects. Traditional medicines mostly use mixtures of phytochemicals, rather than individual compounds, which suggests the need to examine, with rigorous clinical trials, the role of plant mixtures on brain health [9][57].

Ultimately, in order to assess the effects of natural compounds, such as curcuma, we need to refine our ability to measure health (and the lack of) in a life-long perspective and to characterize the conditions for the transition from health to disease [58][46][59].

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Subjects: Nutrition & Dietetics
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Roberta Masella
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Update Date: 10 May 2021
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