The field of nutraceuticals has gained momentum since its inception in 1998 by De Felice as the population expresses increasing interest in self‐managing their risk of disease. The pharmaceutical industry has benefitted greatly from nature, and indeed, approximately a third of FDA‐approved drugs over the past 20 years are based on natural products or their derivatives (Thomford et al., 2018). Therefore, it stands to reason that we can yet harvest many more therapeutic entities from nature and that indeed supplementation and enrichment of nutritional agents in their natural form will have benefits. From a regulatory standpoint, however, this is a risk‐management minefield, with a plethora of marketed products containing highly variable source material (Andrew & Izzo, 2017; Colalto, 2018). Clinicians feel ill‐informed and reluctant to make recommendations without a reputable body of evidence. To put this in perspective, the chemical composition of plants reflects the region of planting, climate conditions and season of harvesting, plant species and cohabiting organisms amongst others. While it can be argued that the pharmaceutical pipeline for new drug products reaching clinic is excessively long in achieving patient benefit, this is necessitated through careful attention to safety. Even in this painstakingly regulated setting, we still see examples of catastrophic toxicity at the clinical trial stage (Tranter, Peters, Boyce, & Warrington, 2013), which bring into question the more relaxed attitudes to governance in the nutraceutical field.

Food products for nutritional purposes are not regulated in the same manner as licensed medicines and, even when sold as supplements, do not undergo the same scrutiny (Andrew & Izzo, 2017). The public tend to believe that natural products are safe, with certain sub‐groups of the population being highly motivated to explore dietary possibilities to improve their health, for example, cancer sufferers, the elderly and athletes (Gahche, Bailey, Potischman, & Dwyer, 2017; Garthe & Maughan, 2018; Viscuse et al., 2017). To fully realise the potential of these agents, it is insightful to consider the active components of the food products and with this information develop notional “therapeutic indices” for these products or use them as the launchpad for drug development.

The BJP Themed Edition 2017 focussing on the value of nutraceutical research contains a series of in‐depth articles and a comprehensive editorial (Andrew & Izzo, 2017), reviewing the active ingredients of a wide variety of nutritional agents proposed to promote health benefits. The spectrum of responsive diseases ranged from the cardiovascular, gut, inflammatory and global ageing. The edition highlighted the difficulties in comparing research studies and product profiles noting that there was still a lack of high‐quality randomised studies in the field. These deficiencies constrain our abilities to carry out systematic reviews. With a rapidly changing landscape, here we revisit the field in 2020. We are seeing an upsurge in new herbal products emerging from Traditional Chinese Medicine as reviewed by Nicolussi, Drewe, Butterweck and Meyer Zu Schwabedissen (2020). While several nutraceuticals such as St John's Wort have been known to cause drug interactions for some years, our understanding of how this comes about has vastly increased, and Nicolussi et al. (2020) provide a contemporary overview of the field. Newer nutraceuticals are gaining favour but often are less well understood, and Williamson, Liu and Izzo (2020) visit five newcomers, the active components of Nigella seeds, Astaxanthin Cannabidiol, Ginseng, and Monk fruit.

A large section in this edition is devoted to un‐picking the benefits of the Mediterranean diet and the “French Paradox,” whereby moderate consumption of red wine, in the presence of fruits and vegetables, olive oil, some cheese and limited red meat is robustly associated with longevity and lower levels of all‐cause mortality including heart disease, type 2 diabetes, cancer and cognitive dysfunction. The review by Schwingshackl, Morze and Hoffmann (2020) explores components within the Mediterranean diet thought most likely to endow benefits, providing informative schematics of the potential networks of biochemical changes underpinning the effects. The main challenge in this setting has been to define appropriate comparator diets. However, several larger trials have now been conducted. Studies of further diets such as the Paleolithic diet and FODMAP (Fermentable Oligo‐, Di‐, Mono‐saccharides And Polyols) diet share similar caveats.

Schwingshackl et al. (2020) introduce the discussion of the therapeutic benefits of resveratrol, a phytoalexin from the polyphenol grouping found in red wine, which has achieved particular interest and where the depth of research is greater (Durazzo et al., 2019). This agent is explored in more detail in another article of this themed issue (Cheng et al., 2020). The global “healthy ageing” and “exercise mimic” profile of its activity is in large part attributed activation of SIRTUIN 1 with downstream consequences AMPK activation, itself a master regulator of metabolism. Man, Xia, Daiber and Li (2020) explore this mechanism further in relation to interactions of polyphenols and circadian clock genes. Resveratrol is an example of a nutraceutical which has been extensively investigated in clinical trials (Tabeshpour, Mehri, Shaebani Behbahani & Hosseinzadeh, 2018), and the authors cite a 2012 clinical trial showing that its consumption in red wine lowers blood glucose and improves lipid profile. However, it is important to balance the healthcare message given the known long‐term adverse effects of alcohol (Collaborators, 2018), and the use of a purified product may be more desirable. Resveratrol's actions in improving memory performance are also explored by Howes, Perry, Vasquez‐Londono and Perry (2020) in this themed issue. Visioli, Davalos, Lopez de Las Hazas, Crespo and Tome‐Carneiro (2020) dissect the beneficial actions of extra virgin olive oil (EVOO). Polyphenols are thought responsible for the cardioprotective effect of EVOO, despite being a minor component. It is the presence of polyphenols that define EVOO from olive oil. However, EVOO by its luxury nature is bespoke to its producer and thus hard to standardise: The composition of polyphenols is highly dependent on climate, cultivar and production, before even considering challenges of aligning chemical analysis. However, polyphenol fractions recovered during production offer opportunities for products with a more chemical definition (Visioli et al., 2020). These contain hydroxytyrosol and oleocanthal, the former discussed in detail. Hydroxytyrosol is currently the only polyphenol backed by a health claim to lower lipid oxidation by the European Food Standards Agency (EFSA), but to date, a specific receptor has not been identified and a variety of biochemical pathways of action were proposed, including interactions with SIRTUIN 1—the field is moving away from believing that the effects are solely underpinned by anti‐oxidant properties. Enough safety data have been collated to allow hydroxytyrosol to gain novel food status by EFSA. The effects of EVOO to modify the methylome in breast cancers is also explored by Donovan, Wren, Cenker, Selmin and Romagnolo (2020). The theme of polyphenols is continued by Man et al. (2020) in the context of the microbiota where the metagenomic effects of nutraceuticals are an emerging field. Schwingshackl et al. introduce how resveratrol promotes a more “metabolically healthy” microbiome over 4 weeks. Given that there are concerns about explaining the systemic effects of polyphenols on the basis of their low bioavailability, this discrepancy may be explained by the fact that the beneficial actions may actually not require absorption. Differences in the microbiota across races however again make clinical trials hard to interpret and lead to inconsistencies in findings (Schwingshackl et al., 2020). The article by Quigley (2020) thoughtfully evaluates research studies on the microbiota, highlighting the difficulties of defining a “standard” microbiome signature for health and that data are derived from faecal sampling which will not reflect sub‐regions of the gut. Quigley (2020) contrast prebiotics and probiotics. Prebiotics are digested by the microbiota, favouring the growth of sub‐populations, a clear example being colonisation of the infant gut encouraged through oligosaccharides in human milk. This is a further area which is an allowed health claim by EFSA, for example, for native chicory inulin promoting stool frequency (https://www.efsa.europa.eu/en/efsajournal/pub/3951). The field of probiotics is less robustly investigated. These products contain live micro‐organisms intended to have health benefits to the host.

Cai, Folkerts, Folkerts, Maurer and Braber (2020) specifically explore the health effects of dietary fibre on the microbiota further. Dietary fibre can protect the intestinal barrier function through modulation of cell junctions, the glycocalyx and also the local immune responses (Cai et al., 2020). Its consumption promotes healthy commensal microbiota and defends against infection with pathogenic species. An emerging series of receptors are showing specificity for interacting with fibre including toll like receptors and those with carbohydrate recognition domains, such as lectin. However, a large part of the beneficial effects of fibre arises through the generation of short‐chain fatty acids (acetate, propionate and butyrate) and microbial products of digestion (Cai et al., 2020). These interact largely through GPCRs, but PPARs and more recently the aryl hydrocarbon receptor have been shown to play a role.

Schwingshackl et al. (2020) introduce the field of nutrigenomics in relation to the Mediterranean diet, whereby nutritional agents can affect the genome of the host through a variety of mechanisms, including epigenetics and generation of long non‐coding RNAs. The topic is reinforced in other two review articles of this themed issue (Beetch et al., 2020; Donovan et al., 2020). Epigenetic changes wrought by environmental exposure and inflammation may underpin the global burden of chronic disease. The ability of dietary anti‐oxidants to remodel DNA methylation, vital in the efficiency of gene expression and associated with chronic disease, opens new doors to regulate the ageing process. A number of nutraceutical compounds are discussed in relation to their ability to reverse aberrant methylation patterns associated with chronic disease. The specific example of dietary fat and changes in DNA methylation in breast cancer is explored in detail by Donovan et al. (2020). While a case can be made for changes in methylation with respect to dietary fats, clinical studies are yet sparse with many confounding factors, such as weight changes.

Of particular interest in ageing, Howes et al. (2020) reviews a wide range of phytochemicals believed to improve cognitive performance and again here resveratrol features, improving memory performance. Nutraceuticals have the capacity to protect and aid neurogenesis, for example, trigonelline, a pyridine alkaloid in coffee, but it is as yet not clear whether the effect will be beneficial in the Alzheimer's population or more so in protecting at the early stages of ageing. Finally, a review article highlighted the mechanisms of plant‐derived compounds, both herbal extracts and pure compounds, which have the potential, on the basis of preclinical studies, to attenuate resistance against cancer chemotherapy and possibly to exert chemopreventive effects (Lin et al., 2020).

The compendium of articles is united in their belief in the value of nutraceuticals for promoting health but also firmly assert the need for long‐term clinical studies conducted with rigour. In many areas, evidence generated preclinically or in cell‐based studies has been extrapolated to man but not rigorously tested in that setting. While understanding the activities of individual components is attractive, we should not forget that these agents come from sources where multiple chemicals co‐exist and indeed it may be the co‐consumption of a panel of agents where the benefits lie. Dietary chemicals may not exert their benefits in isolation. However, the nutraceutical field is advancing and still furnishing the medical communities with its riches in 2020.