Oxidative Medicine and Cellular Longevity

Volume 2013 (2013), Article ID 729804, 9 pages

http://dx.doi.org/10.1155/2013/729804

Review Article

Chrononutrition against Oxidative Stress in Aging

M. Garrido, M. P. Terrón, and A. B. Rodríguez

Department of Physiology (Neuroimmunophysiology and Chrononutrition Research Group), Faculty of Science, University of Extremadura, 06006 Badajoz, Spain

Received 10 March 2013; Revised 30 May 2013; Accepted 2 June 2013

Academic Editor: Nilanjana Maulik

Copyright © 2013 M. Garrido et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Free radicals and oxidative stress have been recognized as important factors in the biology of aging and in many age-associated degenerative diseases. Antioxidant systems deteriorate during aging. It is, thus, considered that one way to reduce the rate of aging and the risk of chronic disease is to avoid the formation of free radicals and reduce oxidative stress by strengthening antioxidant defences. Phytochemicals present in fruits, vegetables, grains, and other foodstuffs have been linked to reducing the risk of major oxidative stress-induced diseases. Some dietary components of foods possess biological activities which influence circadian rhythms in humans. Chrononutrition studies have shown that not only the content of food, but also the time of ingestion contributes to the natural functioning of the circadian system. Dietary interventions with antioxidant-enriched foods taking into account the principles of chrononutrition are of particular interest for the elderly since they may help amplify the already powerful benefits of phytochemicals as natural instruments with which to prevent or delay the onset of common age-related diseases.

1. Introduction

Understanding the aging process has gained in importance with people's increasing life expectancy. Chronological age is the strongest predictor of chronic diseases, and the scientific community is searching for protective agents that can contribute to preventing or delaying the onset of many age-related diseases.

The complexity of the holistic systems of which living cells form a part makes it difficult to distinguish between the causes and consequences of aging. Indeed, it is still unknown whether this process derives from a single or multiple causes [1]. Theories of aging are mainly divided into those assuming that aging is genetically encoded and those assuming that it is due to a decline in maintenance mechanisms and exponential accumulation of molecular damage resulting in degeneration and dysfunction at the cellular level [2]. Among the latter theories, the free radical theory of aging (also known as oxidative stress theory) put forward by Harman in 1956 [3] has received extensive support. It posits that the organism's deterioration resulting from increasing longevity is above all a consequence of the persistent accumulation of free radical mediated damage to essential molecules. This accumulation gradually compromises cell and tissue function, and eventually the entire function of the organism itself [4]. Within this theory, some authors argue that aging results from damage caused by free radicals to nuclear DNA, while others argue that it is a result of alterations to, and progressive loss of, mitochondria as a result of the mutilation of their DNA, thus reducing their biological effectiveness [1]. Indeed, mitochondrial DNA lacks polyamines or protective histones and, thus, is more susceptible than nuclear DNA to oxidative damage. Mutations are, therefore, more likely to take place in the mitochondrial genome of differentiated cells [5]. Curiously, healthy elderly individuals can have oxidative stress levels that are similar to those of young adults [6], or at least comparable in terms of antioxidant defences [7]. This suggests that oxidation is not inevitable in aging.

It is commonly argued that aging is not a genetically controlled process but an interaction between environment and genes [8]. Psychological stress and lifestyle factors appear to have an impact on the level of oxidation [9, 10]. Stress has been the most extensively studied negative factor in the brain's vulnerability to aging. In contrast, positive environmental factors such as a healthy diet can lead to improvements in aging [11]. Indeed, it is estimated that a third of all cancer deaths in the United States could be avoided through appropriate dietary modification [12]. Changes in dietary behaviour, such as increased consumption of fruits, vegetables, and grains, are a practical strategy for significantly reducing the incidence of chronic diseases.

Phytochemicals are bioactive nonnutrient compounds present in fruits, vegetables, grains, and other plant foods. They have been linked to reductions in the risk of major oxidative stress-induced diseases [13]. Numerous investigations have shown a strong link between dietary intake of phytochemicals and reduced risk of cancer and cardiovascular disease worldwide. Thus, a prospective study in Finland involving 9959 men and women (ages 15–99 years) found an inverse association between the intake of flavonoids and the incidence of cancer [14]. After a 24-year follow-up, the risk of lung cancer was reduced by 50% in the highest quartile of flavonol intake. As well as flavonoids, other phenylpropanoids, isoprenoids, and indoleamines, particularly the indole melatonin, merit particular attention due to their biological activities [15].

Melatonin is the principal neurohormone secreted at night by the vertebrate pineal gland. It is an important component of the body's internal timekeeping system [16]. In particular, it is a signal of darkness that encodes time of day and length of day information for the brain [17]. A conceptual difficulty in melatonin research is that, while it is a signal of darkness, it has different functional consequences depending on the given species' time of peak activity. In nocturnal species, it is associated with arousal and physical activity. In diurnal species, it is associated with sleep and rest [16].

In diurnal animals, the onset of melatonin secretion is closely associated with the timing of sleep propensity. It also coincides with decreases in core body temperature, alertness, and performance [18]. For this reason, it is believed to play a part in sleep initiation as the trigger for opening the circadian “sleep gate,” thus acting as a sleep regulator [19]. In this respect, the efficacy of melatonin supplementation to combat sleep disorders is well known, especially in the elderly with their marked reduction in melatonin production [16]. This hormone has a broad spectrum of physiological effects [20]. These include, but are not limited to, chronobiological, immunomodulatory, neuroendocrine, and antioxidant activities (Figure 1). All of these may contribute to the observed anti-aging potency of this natural agent [21].

Figure 1: Physiological functions modulated by the indole melatonin.

Related to its antioxidant activities, melatonin acts as a potent antioxidant and free radical scavenger [22–25]. It not only scavenges the especially toxic hydroxyl radicals, but also performs indirect antioxidant actions via its ability to stimulate antioxidative enzymes [26]. Melatonin diminishes free radical formation at the mitochondrial level by reducing the leakage of electrons from the electron transport chain [27]. Increasing the levels of circulating melatonin, either directly by exogenous administration or indirectly by including vegetables rich in this compound in the diet, enhances the individual's antioxidant status [28–31]. It also stimulates a number of antioxidative enzymes which metabolize reactive products to innocuous agents. As well as for diseases in which there is an elevated production of free radicals, this may have implications for aging since production of this pineal indole wanes with increasing age. Indeed, some authors speculate that its loss contributes to the aging process [4].

Some components of foods possess biological activities which influence circadian rhythms in humans. But also “when” the food is consumed influences the normal functioning of biological rhythms. A central target of current chronobiological research is how nutrients can alleviate or even prevent diseases. In the present review, we shall focus on the potential use of chrononutrition as a novel dietary strategy to counteract the deleterious actions of free radicals and reactive species on physiological systems during aging.

2. Chronobiology: At the Cutting Edge of Health Sciences

We humans are immersed in an environment characterized by repetitive rhythmic cycles [32]. Conditions that are modified by different temporal cycles include organic efficiency, pathologies and the pharmacokinetics, pharmacodynamics, and efficacy of drugs. These cycles also entrain various processes, both physiological (body temperature, hormone and neurotransmitter secretion, and immune, cardiovascular, and digestive functions) and behavioural (sleep/wake cycle, activity/rest periods, digestion and excretion, sensory perception, learning, and memory), to a well-defined rhythm [33]. This phenomenon of rhythmicity extends to all classes of living beings, whether animals or plants, and at all levels of organization (molecules, cells, tissues, and organs).

Chronobiology is the discipline that studies the nature and function of biological rhythms, defined as the recurrence of any event within a biological system at roughly regular intervals [34]. The human body's biological clocks, for example, are controlled by synchronization with signals from the external environment [35].

The entire spectrum of biological rhythms covers an extremely wide range of frequencies [36]. All organisms, however, present circadian rhythms. These are biological processes that have an endogenous, entrainable oscillation of about 24 hours. They affect most of the organism's physiological functions—the sleep/wake cycle, immune function, melatonin secretion, and the production and secretion of numerous neurotransmitters [37, 38]. The internal synchronization provided by circadian clocks may be altered by many factors, one of which is aging. The aging process leads to a situation of chronobiological imbalance that results in shortening the period and reducing the amplitude of the oscillator, loss of the circadian rhythm itself, appearance of an ultradian pattern, and internal desynchronization [39, 40]. During aging, any disturbance or imbalance in the relationship between the circadian and homeostatic systems may lead to the impairment of numerous physiological processes.

Antioxidant systems also deteriorate during aging. Elderly individuals, therefore, become more vulnerable to pathological conditions related to oxidative stress and may require an extra supply of dietary antioxidants to combat free radicals [41]. Previous studies by our research group and by other workers have shown that neuroendocrine and immune disorders due to the aging process may be ameliorated by supplementation with melatonin, serotonin, and/or their precursor, the amino acid tryptophan [42–46]. These are all compounds with powerful antioxidant properties [23, 29, 47]. The administration of tryptophan increases the availability of serotonin in the brain [46, 48]. Melatonin levels are consequently elevated as well [49]. Besides being an antioxidant, melatonin also has oncostatic, immunomodulatory, anti-inflammatory, and chronobiotic properties [50–52]. Given this context, the administration of tryptophan and melatonin in accordance with the needs of elderly subjects may contribute to readjusting any disturbances they have in their circadian rhythms.

Knowledge of the nature and function of biological rhythms is of practical as well as theoretical interest. This is reflected in the growing number of applications of chronobiology published in the recent health sciences literature. One such novel area of research is chronopharmacology. This is focused on the design and evaluation of drug delivery systems that release a bioactive agent at a rhythm matching the biological requirements of the treatment of a given disease [53]. Applying the knowledge of circadian function and regulation to the relevance of disease has enabled a chronobiology-based approach in the timing of administration of conventional drugs in order to synchronize the rhythms in disease activity with the efficacy of a particular drug, thus allowing for its optimal efficacy in the patient. Other recent applications of chronobiology include chronopathology, chronotherapy, and chrononutrition, all aimed at reducing the need for invasive methods in therapeutic interventions, and therefore are of unquestionable importance (Figure 2).

Figure 2: Influence of chronobiology applications on aging and disease.

3. Basis of Chrononutrition: Health Benefits

Our eating schedules are dictated not only by food supply, hunger, and satiety, but also by convenience and social habits and pressures. Feeding behaviour is the first element to consider in an organism's nutritional process. The vast majority of studies have focused on examining the homeostatic regulation of the quantity and quality of food ingested. The hypothalamus is the main neural structure involved. It acts in close correlation with the release of such hormones as cholecystokinin (CCK), leptin, ghrelin, and insulin. Temporal aspects of this regulation have been far less studied [54]. Meal timing can affect many physiological processes. The sleep/wake cycle, core body temperature, performance, alertness, and secretion of many hormones are examples. Since these are functions with a circadian rhythmicity, they deteriorate during aging with the weakening of overt circadian patterns [20]. That meal timing has major effects on the body has led to the conviction that, in choosing food, it is not only convenient to consider its nutritional value, but also its capacity to promote or hinder the normal functioning of the circadian cycle's control systems (Table 1). In humans, alterations have been detected in the overall expression of daily rhythms when food intake is limited to the usual period of rest (i.e., at night), as occurs during Ramadan [54].

Table 1: Examples of antioxidant requirements according to chrononutrition principles.

Which?
Where?
When?

Antioxidants
Vitamins (C and E)
Kiwi (Actinidia chinensis);

broccoli (Brassica oleracea)
Daytime

Carotenoids (lycopene)
Watermelon (Citrullus lanatus);

tomato (Lycopersicon esculentum)
Daytime

Phytoalexin (resveratrol)
Grape (Vitis vinífera);

almond (Prunus amygdalus)
Daytime

Tryptophan
Apple (Malus domestica);

lentil (Lens culinaris)
Daytime/nighttime

Serotonin
Banana (Musa sapientum);

coffee (Coffea arabica)
Daytime/nighttime

Melatonin
Cherry (Prunus avium);

nut (Juglans regia)
Nighttime

Nutrients and phytochemicals play an essential part in the regulation of such circadian functions as sleep. Compared with a control diet high in carbohydrates and low in fat, a very low carbohydrate, fat-rich diet has been found to reduce the proportion of rapid eye movement (REM) sleep recorded by polysomnography. But it also increased the percentage of deep slow-wave (NREM) sleep [55]. While the total amount of carbohydrates may influence the architecture of sleep, it does not affect the duration. However, the evidence on whether carbohydrates positively impact sleep quality is not completely consistent, since consuming carbohydrate meals with high or low glycaemic loads seems not to affect any polysomnographically determined sleep index [55]. On the contrary, some components of the typical human diet, such as vitamin B12, improve alertness and concentration and reduce the daytime sleepiness phase [56]. Since some nutrients can entrain the circadian rhythm, diet design must take meal timing into account as well as the quantity and quality of the foods. In particular, the time of day at which food is consumed directly influences certain metabolic and hormonal factors—glucose, free fatty acids, glucocorticoids, and thyroid hormones, among others [57]. These ideas can be subsumed under the concept of chrononutrition. This concept reflects that it is not only the content of food, but also the time of ingestion and the interactions of its nutritional components which naturally contribute to the proper functioning of the circadian system.

3.1. Clinical Applications of Chrononutrition in Oxidative Stress

Harman's free radical theory of aging posits that oxidized macromolecules accumulate with age, resulting in decreased function and shortened life span [3]. Indeed, reduction of oxidative stress has been found to be associated with prolongation of life expectancy in many organisms [58–60]. Avoiding the formation of free radicals and reducing oxidative stress, thereby strengthening the body's antioxidant defences, can reduce the rate of aging and the risk of age-associated diseases [61]. In this sense, the primary prevention of chronic diseases through dietary modification may be just as effective as the secondary treatments that are commonly employed and less costly [62].

The possibility that mammalian life span could be significantly extended by diet modification was first demonstrated in a rodent study published by McCay and coworkers in 1935. This seminal experiment showed that life span can be extended by diet restriction without malnutrition, as opposed to diet restriction with malnutrition which can have the opposite effect [63]. Not only diet restriction, but also dietary patterns can have important long-term benefits for health. The abundance of bioactive phytochemical compounds provided by the fruits, vegetables, wine, and olive oil that make up the typical Mediterranean dietary pattern has proven to be effective in ameliorating some aging conditions associated with oxidative stress [64]. The tocopherols, carotenoids, and vitamin C present in pigmented and citrus fruits, and in such vegetables as carrots, tomatoes, broccoli, and red peppers, are positively correlated with a lower incidence of coronary heart disease [65]. Olive oil contains ubiquinol and tocotrienols which inhibit low-density lipoprotein (LDL) oxidation and reduce the risk of cancer [66]. Other dietary components, such as vitamin E or specific forms of fatty acids, especially polyunsaturated fatty acids (PUFAs), contribute to the modulation of the immune and inflammatory systems, helping to prevent infectious and inflammatory diseases in the elderly [67]. Finally, in 1997 the most significant phenol in red wine, trans-resveratrol, was shown to prevent carcinogenesis in mice [68]. Since then, this phytochemical has been shown to have various pharmacological properties, namely, antioxidative [69], anti-inflammatory [70], anti-diabetic [71], anti-asthmatic [72], and antalgic [73], observed both in vitro and in vivo [74]. The doses applied in human trials examining specific health benefits of resveratrol range from 5 mg to 5 g, and some have considered additional compounds with putative synergistic effects [75]. A major critical limitation of most of the clinical research on resveratrol has been the lack of trials examining the longer-term health effects of this compound. The examples we have briefly discussed above are just a few of the more than several thousands of bioactive compounds that have been identified in foodstuffs from all over the world [76].

The vast majority of studies on the biological functions of phytochemicals have focused on analysing their antioxidant and/or anti-inflammatory properties. Few of them have taken into account the chrononutritional properties responsible for the effectiveness of such compounds. In humans, the type of food (macronutrient) is a temporally controlled variable. Once the nutrient enters the bloodstream, it may resemble the behaviour of a drug. It is thus subject to the principles of chronopharmacology, the most important of which is that the time of day influences both beneficial and unwanted effects. All the processes involved in nutrition display circadian and ultradian patterns which include rhythms of food intake, gut motility, secretion of digestive juices, absorption of digested foods, production of key metabolic enzymes, and energy expenditure. Consequently, different nutrients tend to be absorbed in different proportions, depending on the time of day [54].

Given their potent antioxidant activity, the tryptophan, serotonin, and/or melatonin content of foodstuffs and foodstuff-type beverages such as almonds, nuts, sweet cherries, apples, corn, beer, and olive oil [77–82] may have major implications for animal and human health. This is particularly the case in combating a variety of disorders and diseases in which there is an elevated production of free radicals [83–85]. The antioxidant effects of these compounds have been demonstrated both in animal models and in humans. In animals, a Jerte Valley cherry-based beverage, rich in tryptophan, serotonin, and melatonin, has proven to be an efficient antioxidant-enriched product. Delgado et al. [86] showed that consumption of this product augmented the circulating levels of both melatonin and serotonin. This augmentation was positively correlated with increases in serum antioxidant capacity in both rats (Rattus norvegicus, a nocturnal animal) and ringdove (Streptopelia risoria, a diurnal animal) and in both young and old age groups. Its consumption also modulated the balance of pro- and anti-inflammatory cytokines, especially in the old animals, by downregulating the levels of proinflammatory cytokines and upregulating those of anti-inflammatory cytokines [87]. The clear importance of this type of finding is that nutritional interventions could delay or even prevent the functional deterioration of the immune system that accompanies aging [88]. The therapeutic properties shown by this cherry-based beverage may be attributed to the high melatonin content of the Jerte Valley cherry, although the involvement of other antioxidants, such as polyphenols, cannot be ruled out.

Given these results with animal models, tests were conducted with humans. It was found that both a diet enriched with Jerte Valley cherries and the ingestion of a Jerte Valley cherry-based nutraceutical product improve the antioxidant status of young, middle-aged, and elderly individuals [31, 89]. Particularly noteworthy was that not only the substantial amount of melatonin, serotonin [78], and tryptophan [80] contained in these Jerte Valley cherries, but also the timing of the meal, were critical to achieving the beneficial effects of these dietary interventions. Since serotonin and melatonin have opposite circadian rhythms, for example, serotonin levels peak during the day while those of melatonin peak at night (Figure 3), the cherries and the cherry-based product were consumed twice a day, once at lunch and once as supper desserts. The lunchtime consumption of cherries or the cherry-based product was designed both to directly increase the diurnal circulating serotonin concentration and to indirectly increase the nocturnal circulating melatonin concentration by enhancing the amount of serotonin available to be converted into melatonin at night [31, 90]. Hence, together with the ingestion of cherries (or the cherry-based product) at supper time, this boosts the total nighttime circulating melatonin levels [31, 91]. These interventions succeeded in improving the subjects' antioxidant status. The likelihood that this was indeed due to increases in the melatonin and serotonin concentrations was confirmed indirectly by determining the urine 6-sulfatoxymelatonin (aMT6-s) and 5-hydroxyindoleacetic acid (5-HIAA) levels. Most importantly, both of these nutritional interventions showed sleep-promoting and mood-enhancing actions in the young, middle-aged, and elderly subjects, which correlated with the increments in melatonin and serotonin levels, respectively [31, 90, 91].

Figure 3: Circadian rhythms of melatonin and serotonin. Black lines represent normal circadian patterns of melatonin and serotonin secretion, while grey lines show a disturbed pattern due to aging process.

3.2. Clinical Implications of Chrononutrition in Aging

Aging is a complex process. It is related to circadian rhythm disruption with the resulting sleep disturbances [92] and other physiological and psychological dysfunctions [93]. These include impaired nutrient absorption [94, 95], immunosenescence [96–98], decreased hormone levels [99], and neuronal death [100, 101]. The age-associated disruption in the sleep/wake rhythm has been linked to the conventional decline in melatonin levels in advancing age (Figure 3). It may be corrected by supplementation with melatonin or with foodstuffs rich in melatonin (or in melatonin's precursors). In this respect, Bravo et al. [102] have shown that the consumption of tryptophan-enriched cereals increases aMT6-s and 5-HIAA levels, with the consequent improved mood and sleep quality in elderly subjects. Given the mood-enhancing and wakefulness-promoting properties of serotonin during the daytime, and the sleep-regulating functions of tryptophan, serotonin, and melatonin at night, these cereals were consumed twice a day (at breakfast and supper).

There is clear evidence that aging is associated with elevated basal morning levels of circulating glucocorticoids, such as cortisol [103]. It is commonly believed that altered HPA activity,  for example, increased glucocorticoid activity or decreased brain serotonin concentration, is associated with several age-related pathologies [104]. In this sense, the consumption of the aforementioned Jerte Valley cherry product was effective in diminishing cortisol levels in young, middle-aged, and elderly subjects, the decline being especially more pronounced with advancing age. Increases in plasma tryptophan availability have been shown to enhance positive mood and dampen the cortisol response after an acute exposure to experimental stress. The mechanism is via enhancement of the brain serotonin functions that are involved in the adaptation to stress [105, 106]. Consequently, the tryptophan and serotonin present in the Jerte Valley cherry product may contribute to reducing cortisol levels, particularly in the elderly who are more vulnerable to stress.

It is noteworthy that many studies of the health-promoting effects of the antioxidant-rich fruits and foodstuff-type beverages present in the Mediterranean diet report better outcomes in advanced ages. Thus, González-Flores et al. [107, 108] find that the consumption of both plums (Prunus salicina Lindl. cv. Crimson Globe) and grape juice elevated the aMT6-s levels and the antioxidant capacity determined from the urine in young, middle-aged, and elderly individuals, with the effects being greater with advancing age. Likewise, Garrido et al. [109] reported that the inclusion of lycopene (the most potent in vitro antioxidant of the carotenoids) in a virgin olive oil enhanced the antioxidant effects of its ingestion. Again, the increases in this antioxidant capacity were positively correlated with age. The explanation may be that while energy requirements decrease with advancing age, nutritional requirements increase because of the greater demand for maintenance of the functionality of physiological systems [110].

4. Concluding Remarks

Just as research has provided a solid foundation for the overall relationship between food and health, the links between specific food components and particular health risks are now also being confirmed. This has had a direct impact on the food processing industry which has begun to turn its attention to the development of nutraceutical products. The marketing of the first infant milk formula that took into account the circadian variations of the different components present in breast milk clearly contributed to bringing science and industry together. This artificial infant milk (Blemil Plus®) is a dissociated formula consisting of different nutritional components that promote wakefulness, such as vitamins A, C, E, and B12 (Blemil 1 Plus day; N° WO2006/034955; PCT/EP2005/054516), and others that help to improve the effectiveness and quality of sleep, such as tryptophan, medium-chain triglycerides, and the nucleotides uridine and adenosine, among other constituents (Blemil 1 Plus night; N° WO2006/034955; PCT/EP2005/054516). A ground-breaking clinical study in the field of nutrition was the demonstration that the implementation of these chronobiologically adapted formulas in the diet indeed contributes to consolidating the sleep/wake cycle in the newborn [111].

In general, dietary interventions with antioxidant-enriched foods based on the principles of chrononutrition are particularly relevant for the elderly, since this population commonly experiences progressive deterioration in physiological functions and metabolic processes. The aforementioned tryptophan-enriched cereals and the Jerte Valley cherry product have been shown to have especially beneficial effects on sleep quality and antioxidant status in the elderly. These nutritional strategies may contribute to taking full advantage of the potential benefits of phytochemicals as natural instruments with which to prevent or delay the onset of common age-related diseases.

Most clinical studies conducted in the field of chrononutrition have so far focused their attention on small groups of the population with no marked health problems. Clearly therefore, larger-scale studies are required on priority groups of the population, for example, cancer or obesity patients, to examine the clinical relevance of the supplementation of diets with chronobiotically enriched foodstuffs. Such studies would also help adapt the elaboration of diets and foodstuffs to the needs of specific populations according to age, sex, health goals, lifestyle, and genetic predisposition to certain diseases.

Acknowledgment

This study was supported by the Gobierno de Extremadura (Re: GRU10003).

References

J. Miquel, “Integración de teorías del envejecimiento (parte II),” Revista Española de Geriatría y Gerontología, vol. 41, no. 2, pp. 125–127, 2006.

B. F. Oliveira, J. A. Nogueira-Machado, and M. M. Chaves, “The role of oxidative stress in the aging process,” TheScientificWorldJournal, vol. 10, pp. 1121–1128, 2010.

D. Harman, “Aging: a theory based on free radical and radiation chemistry,” Journal of Gerontology, vol. 11, no. 3, pp. 298–300, 1956.

R. J. Reiter, S. D. Paredes, A. Korkmaz, L. C. Manchester, and D. X. Tan, “Melatonin in relation to the “strong” and “weak” versions of the free radical theory of aging,” Advances in medical sciences, vol. 53, no. 2, pp. 119–129, 2008.

J. Miquel, “Envejecimiento celular y molecular: teorías del envejecimiento,” in Manual de Geriatría, F. Guillén and I. Ruipérez, Eds., pp. 29–42, Salvat, Barcelona, Spain, 3rd edition, 2002.

M. J. Cals, M. Succari, E. Meneguzzer et al., “Markers of oxidative stress in fit, health-conscious elderly people living in the Paris area,” Nutrition, vol. 13, no. 4, pp. 319–326, 1997.

T. Kostka, J. Drai, S. E. Berthouze, J.-R. Lacour, and M. Bonnefoy, “Physical activity, aerobic capacity and selected markers of oxidative stress and the anti-oxidant defence system in healthy active elderly men,” Clinical Physiology, vol. 20, no. 3, pp. 185–190, 2000.

N. A. Bishop, T. Lu, and B. A. Yankner, “Neural mechanisms of ageing and cognitive decline,” Nature, vol. 464, no. 7288, pp. 529–535, 2010.

Y. Gidron, K. Russ, H. Tissarchondou, and J. Warner, “The relation between psychological factors and DNA-damage: a critical review,” Biological Psychology, vol. 72, no. 3, pp. 291–304, 2006.

P. Møller, H. Wallin, and L. E. Knudsen, “Oxidative stress associated with exercise, psychological stress and life-style factors,” Chemico-Biological Interactions, vol. 102, no. 1, pp. 17–36, 1996.

P. Garrido, “Aging and stress: past hypotheses, present approaches and perspectives,” Aging and Disease, vol. 2, no. 1, pp. 80–90, 2011.

N. Khan, F. Afaq, and H. Mukhtar, “Cancer chemoprevention through dietary antioxidants: progress and promise,” Antioxidants and Redox Signaling, vol. 10, no. 3, pp. 475–510, 2008.

R. H. Liu, “Health benefits of fruit and vegetables are from additive and synergistic combinations of phytochemicals,” American Journal of Clinical Nutrition, vol. 78, no. 3, pp. 517S–520S, 2003.

P. Knekt, R. Järvinen, R. Seppänen, et al., “Dietary flavonoids and the risk of lung cancer and other malignant neoplasms,” American Journal of Epidemiology, vol. 146, no. 3, pp. 223–230, 1997.

D. González-Gómez, M. Lozano, M. F. Fernández-León, M. J. Bernalte, M. C. Ayuso, and A. B. Rodríguez, “Sweet cherry phytochemicals: identification and characterization by HPLC-DAD/ESI-MS in six sweet-cherry cultivars grown in Valle del Jerte (Spain),” Journal of Food Composition and Analysis, vol. 23, no. 6, pp. 533–539, 2010.

S. R. Pandi-Perumal, I. Trakht, V. Srinivasan et al., “Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways,” Progress in Neurobiology, vol. 85, no. 3, pp. 335–353, 2008.

S. R. Pandi-Perumal, V. Srinivasan, G. J. M. Maestroni, D. P. Cardinali, B. Poeggeler, and R. Hardeland, “Melatonin: nature's most versatile biological signal?” FEBS Journal, vol. 273, no. 13, pp. 2813–2838, 2006.

J. Arendt, “Melatonin and human rhythms,” Chronobiology International, vol. 23, no. 1-2, pp. 21–37, 2006.

N. Zisapel, “Sleep and sleep disturbances: biological basis and clinical implications,” Cellular and Molecular Life Sciences, vol. 64, no. 10, pp. 1174–1186, 2007.

M. Karasek, “Melatonin, human aging, and age-related diseases,” Experimental Gerontology, vol. 39, no. 11-12, pp. 1723–1729, 2004.

B. Poeggeler, “Melatonin, aging, and age-related diseases: perspectives for prevention, intervention, and therapy,” Endocrine, vol. 27, no. 2, pp. 201–212, 2005.

M. P. Terrón, S. D. Paredes, C. Barriga, E. Ortega, and A. B. Rodríguez, “Comparative study of the heterophil phagocytic function in young and old ring doves (Streptopelia risoria) and its relationship with melatonin levels,” Journal of Comparative Physiology B, vol. 174, no. 5, pp. 421–427, 2004.

S. D. Paredes, M. P. Terrón, A. M. Marchena et al., “Effect of exogenous melatonin on viability, ingestion capacity, and free-radical scavenging in heterophils from young and old ringdoves (Streptopelia risoria),” Molecular and Cellular Biochemistry, vol. 304, no. 1-2, pp. 305–314, 2007.

S. D. Paredes, I. Bejarano, M. P. Terrón, C. Barriga, R. J. Reiter, and A. B. Rodríguez, “Melatonin and tryptophan counteract lipid peroxidation and modulate superoxide dismutase activity in ringdove heterophils in vivo. Effect of antigen-induced activation and age,” Age, vol. 31, no. 3, pp. 179–188, 2009.

R. J. Reiter, L. C. Manchester, and D.-X. Tan, “Neurotoxins: free radical mechanisms and melatonin protection,” Current Neuropharmacology, vol. 8, no. 3, pp. 194–210, 2010.

C. Rodríguez, J. C. Mayo, R. M. Sainz, et al., “Regulation of antioxidant enzymes: a significant role for melatonin,” Journal of Pineal Research, vol. 36, no. 1, pp. 1–9, 2004.

R. J. Reiter, S. D. Paredes, A. Korkmaz, M. J. Jou, and D. X. Tan, “Melatonin combats molecular terrorism at the mitochondrial level,” Interdisciplinary Toxicology, vol. 1, no. 2, pp. 137–149, 2008.

R. J. Reiter, L. C. Manchester, and D.-X. Tan, “Melatonin in walnuts: influence on levels of melatonin and total antioxidant capacity of blood,” Nutrition, vol. 21, no. 9, pp. 920–924, 2005.

S. D. Paredes, M. P. Terrón, J. Cubero et al., “Tryptophan increases nocturnal rest and affects melatonin and serotonin serum levels in old ringdove,” Physiology and Behavior, vol. 90, no. 4, pp. 576–582, 2007.

M. Garrido, J. Espino, D. González-Gómez, et al., “A nutraceutical product based on Jerte Valley cherries improves sleep and augments the antioxidant status in humans,” The European e-Journal of Clinical Nutrition and Metabolism, vol. 4, no. 6, pp. e321–e323, 2009.

M. Garrido, S. D. Paredes, J. Cubero et al., “Jerte valley cherry-enriched diets improve nocturnal rest and increase 6-sulfatoxymelatonin and total antioxidant capacity in the urine of middle-aged and elderly humans,” Journals of Gerontology A, vol. 65, no. 9, pp. 909–914, 2010.

A. Córdova-Castañeda and J. L. Esquinca-Ramos, “Cronobiología. Ritmos biológicos,” in Psiquiatría-3 Programa de Actualización Continua en Psiquiatría, Intersistemas, Hidalgo, México, 2001.

R. Refinetti, Circadian Physiology, CRC Press, 2006.

J. A. Madrid, “An introduction to chronobiology,” in Chronobiology and Obesity, M. Garaulet and J. M. Ordovás, Eds., pp. 11–28, Springer Science, New York, NY, USA, 2013.

J. A. Madrid, “Los relojes de la vida. Una introducción a la cronobiología,” in Crobiobiología Básica y Clínica, J. A. Madrid and M. A. Rol de Lama, Eds., pp. 39–81, Editec@red, Madrid, Spain, 2006.

E. Haus and M. Smolensky, “Biological clocks and shift work: circadian dysregulation and potential long-term effects,” Cancer Causes and Control, vol. 17, no. 4, pp. 489–500, 2006.

C. Barriga Ibars, J. A. Madrid, M. P. Terrón et al., “The pineal gland: functional connection between melatonin and immune system in birds,” Biogenic Amines, vol. 18, no. 3-6, pp. 147–176, 2004.

C. J. Morris, D. Aeschbach, and F. A. J. L. Scheer, “Circadian system, sleep and endocrinology,” Molecular and Cellular Endocrinology, vol. 349, no. 1, pp. 91–104, 2012.

E. M. Gibson, W. P. Williams III, and L. J. Kriegsfeld, “Aging in the circadian system: considerations for health, disease prevention and longevity,” Experimental Gerontology, vol. 44, no. 1-2, pp. 51–56, 2009.

O. Froy, “Circadian rhythms, aging, and life Span in mammals,” Physiology, vol. 26, no. 4, pp. 225–235, 2011.

A. G. Ma, S. Ge, M. Zhang et al., “Antioxidant micronutrients improve intrinsic and UV-induced apoptosis of human lymphocytes particularly in elderly people,” Journal of Nutrition, Health and Aging, vol. 15, no. 10, pp. 912–917, 2011.

A. B. Rodríguez Moratinos, M. P. Terrón, J. Durán, E. Ortega, and C. Barriga, “Physiological concentrations of melatonin and corticosterone affect phagocytosis and oxidative metabolism of ring dove heterophils,” Journal of Pineal Research, vol. 31, no. 1, pp. 31–38, 2001.

M. P. Terron, J. Cubero, J. M. Marchena, C. Barriga, and A. B. Rodriguez, “Melatonin and aging: in vitro effect of young and mature ring dove physiological concentrations of melatonin on the phagocytic function of heterophils from old ring dove,” Experimental Gerontology, vol. 37, no. 2-3, pp. 421–426, 2002.

I.-Y. Yoon, D. F. Kripke, J. A. Elliott, S. D. Youngstedt, K. M. Rex, and R. L. Hauger, “Age-related changes of circadian rhythms and sleep-wake cycles,” Journal of the American Geriatrics Society, vol. 51, no. 8, pp. 1085–1091, 2003.

S. D. Paredes, A. M. Marchena, I. Bejarano et al., “Melatonin and tryptophan affect the activity-rest rhythm, core and peripheral temperatures, and interleukin levels in the ringdove: changes with age,” Journals of Gerontology A, vol. 64, no. 3, pp. 340–350, 2009.

S. D. Paredes, C. Barriga, R. J. Reiter, and A. B. Rodríguez, “Assessment of the potential role of tryptophan as the precursor of serotonin and melatonin for the aged sleep-wake cycle and immune function: Streptopelia risoria as a model,” International Journal of Tryptophan Research, vol. 2, no. 1, pp. 23–36, 2009.

S. D. Paredes, M. P. Terrón, A. M. Marchena et al., “Tryptophan modulates cell viability, phagocytosis and oxidative metabolism in old ringdoves,” Basic and Clinical Pharmacology and Toxicology, vol. 101, no. 1, pp. 56–62, 2007.

S. S. Mateos, C. L. Sánchez, S. D. Paredes, C. Barriga, and A. B. Rodríguez, “Circadian levels of serotonin in plasma and brain after oral administration of tryptophan in rats,” Basic and Clinical Pharmacology and Toxicology, vol. 104, no. 1, pp. 52–59, 2009.

S. Sánchez, C. L. Sánchez, S. D. Paredes, A. B. Rodríguez, and C. Barriga, “The effect of tryptophan administration on the circadian rhythms of melatonin in plasma and pineal gland of rats,” Journal of Applied Biomedicine, vol. 6, no. 4, pp. 177–186, 2008.

R. Hardeland, “Melatonin: signaling mechanisms of a pleiotropic agent,” BioFactors, vol. 35, no. 2, pp. 183–192, 2009.

R. Hardeland, D. P. Cardinali, V. Srinivasan, D. W. Spence, G. M. Brown, and S. R. Pandi-Perumal, “Melatonin-a pleiotropic, orchestrating regulator molecule,” Progress in Neurobiology, vol. 93, no. 3, pp. 350–384, 2011.

F. Radogna, M. Diederich, and L. Ghibelli, “Melatonin: a pleiotropic molecule regulating inflammation,” Biochemical Pharmacology, vol. 80, no. 12, pp. 1844–1852, 2010.

B.-B. C. Youan, “Chronopharmaceutics: gimmick or clinically relevant approach to drug delivery?” Journal of Controlled Release, vol. 98, no. 3, pp. 337–353, 2004.

A. López, M. A. Rol de Lama, and J. A. Madrid, “Ritmos biológicos en la nutrición y metabolismo,” in Cronobiología Básica Y Clínica, J. A. Madrid and M. A. Rol de Lama, Eds., pp. 513–553, Editec@red, Madrid, Spain, 2006.

A. Afaghi, H. O'Connor, and C. M. Chow, “Acute effects of the very low carbohydrate diet on sleep indices,” Nutritional Neuroscience, vol. 11, no. 4, pp. 146–154, 2008.

G. Mayer, M. Kröger, and K. Meier-Ewert, “Effects of vitamin B12 on performance and circadian rhythm in normal subjects,” Neuropsychopharmacology, vol. 15, no. 5, pp. 456–464, 1996.

C. Escobar, C. Cailotto, M. Angeles-Castellanos, R. S. Delgado, and R. M. Buijs, “Peripheral oscillators: the driving force for food-anticipatory activity,” European Journal of Neuroscience, vol. 30, no. 9, pp. 1665–1675, 2009.

K. L. Quick, S. S. Ali, R. Arch, C. Xiong, D. Wozniak, and L. L. Dugan, “A carboxyfullerene SOD mimetic improves cognition and extends the lifespan of mice,” Neurobiology of Aging, vol. 29, no. 1, pp. 117–128, 2008.

D.-F. Dai, L. F. Santana, M. Vermulst et al., “Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging,” Circulation, vol. 119, no. 21, pp. 2789–2797, 2009.

A. Shibamura, T. Ikeda, and Y. Nishikawa, “A method for oral administration of hydrophilic substances to Caenorhabditis elegans: effects of oral supplementation with antioxidants on the nematode lifespan,” Mechanisms of Ageing and Development, vol. 130, no. 9, pp. 652–655, 2009.

M. Meydani, “Nutrition interventions in aging and age-associated disease,” Annals of the New York Academy of Sciences, vol. 928, pp. 226–235, 2001.

R. H. Liu, “Health benefits of phytochemicals in whole fruits,” in Nutritional Health: Strategies For Disease Prevention, N. J. Temple, T. Wilson, and D. R. Jacobs, Eds., pp. 293–310, Springer Science, New York, NY, USA, 2012.

C. M. McCay, M. F. Crowel, and L. A. Maynard, “The effect of retarded growth upon the length of the life span and upon ultimate body size,” Journal of Nutrition, vol. 10, no. 1, pp. 63–79, 1935.

M. O. Hadziabdić, V. Bozikov, E. Pavić, and Z. Romić, “The antioxidative protecting role of the Mediterranean diet,” Collegium Antropologicum, vol. 36, no. 4, pp. 1427–1434, 2012.

F. Visioli and C. Galli, “The role of antioxidants in the Mediterranean diet,” Lipids, vol. 36, pp. S49–S52, 2001.

C. K. B. Ferrari, “Functional foods, herbs and nutraceuticals: towards biochemical mechanisms of healthy aging,” Biogerontology, vol. 5, no. 5, pp. 275–289, 2004.

D. Wu, M. Meydani, S. N. Han, L. S. Leka, and S. N. Meydani, “Effect of dietary supplementation with fish oil in combination with different levels of vitamin E on immune response in healthy elderly human subjects,” The FASEB Journal, vol. 14, p. A238, 2000.

M. Jang, L. Cai, G. O. Udeani et al., “Cancer chemopreventive activity of resveratrol, a natural product derived from grapes,” Science, vol. 275, no. 5297, pp. 218–220, 1997.

H. Zhao, Q. Niu, X. Li, et al., “Long-term resveratrol consumption protects ovariectomized rats chronically treated with D-galactose from developing memory decline without effects on the uterus,” Brain Research, vol. 1467, pp. 67–80, 2012.

F. Busch, A. Mobasheri, P. Shayan, et al., “Resveratrol modulates interleukin-1β-induced phosphatidylinositol 3-kinase and nuclear factor κB signaling pathways in human tenocytes,” The Journal of Biological Chemistry, vol. 287, no. 45, pp. 38050–38063, 2012.

M. Ramar, B. Manikandan, T. Raman, et al., “Protective effect of ferulic acid and resveratrol against alloxan-induced diabetes in mice,” European Journal of Pharmacology, vol. 690, no. 1–3, pp. 226–235, 2012.

T. Ichikawa, R. Hayashi, K. Suzuki, et al., “Sirtuin 1 activator SRT1720 suppresses inflammation in an ovalbumin-induced mouse model of asthma,” Respirology, vol. 18, no. 2, pp. 332–339, 2013.

M. Falchi, A. Berteli, R. Galazo, P. Viganò, and B. Dib, “Central antalgic activity of resveratrol,” Archives Italiennes de Biologie, vol. 148, no. 4, pp. 389–396, 2010.

R. E. Wu, W. C. Huang, C. C. Liao, et al., “Resveratrol protects against physical fatigue and improves exercise performance in mice,” Molecules, vol. 18, no. 4, pp. 4689–4702, 2013.

J. M. Smoliga, J. A. Baur, and H. A. Hausenblas, “Resveratrol and health—a comprehensive review of human clinical trials,” Molecular Nutrition and Food Research, vol. 55, no. 8, pp. 1129–1141, 2011.

C. Alasalvar and F. Shahidi, “Composition, phytochemicals, and beneficial health effects of dried fruits: an overview,” in Dried Fruits: Phytochemicals and Health Effects, C. Alasalvar and F. Shahidi, Eds., pp. 1–19, Blackwell Publishing, Oxford, UK, 2013.

S. D. Paredes, A. Korkmaz, L. C. Manchester, D.-X. Tan, and R. J. Reiter, “Phytomelatonin: a review,” Journal of Experimental Botany, vol. 60, no. 1, pp. 57–69, 2009.

D. González-Gómez, M. Lozano, M. F. Fernández-León, et al., “Detection and quantification of melatonin and serotonin in eight Sweet Cherry cultivars (Prunus avium L.),” European Food Research and Technology, vol. 229, no. 2, pp. 223–229, 2009.

M. D. Maldonado, H. Moreno, and J. R. Calvo, “Melatonin present in beer contributes to increase the levels of melatonin and antioxidant capacity of the human serum,” Clinical Nutrition, vol. 28, no. 2, pp. 188–191, 2009.

J. Cubero, F. Toribio, M. Garrido et al., “Assays of the amino acid tryptophan in cherries by HPLC-fluorescence,” Food Analytical Methods, vol. 3, no. 1, pp. 36–39, 2010.

A. Ramakrishna, P. Giridhar, and G. A. Ravishankar, “Phytoserotonin: a review,” Plant Signaling and Behavior, vol. 6, no. 6, pp. 800–809, 2011.

USDA National Nutrient Database for Standard Reference, 2012, http://ndb.nal.usda.gov/

D. M. Richard, M. A. Dawes, C. W. Mathias, A. Acheson, N. Hill-Kapturczak, and D. M. Dougherty, “L-tryptophan: basic metabolic functions, behavioral research and therapeutic indications,” International Journal of Tryptophan Research, vol. 2, no. 1, pp. 45–60, 2009.

R. Piga, Y. Naito, S. Kokura, O. Handa, and T. Yoshikawa, “Protective effect of serotonin derivatives on glucose-induced damage in PC12 rat pheochromocytoma cells,” British Journal of Nutrition, vol. 103, no. 1, pp. 25–31, 2010.

R. J. Reiter, D. X. Tan, L. Fuentes-Broto, et al., “Melatonin salvages neural tissue from ischemia/reperfusion injury,” The Open Neuroendocrinology Journal, vol. 3, pp. 112–120, 2010.

J. Delgado, M. P. Terrón, M. Garrido et al., “A cherry nutraceutical modulates melatonin, serotonin, corticosterone, and total antioxidant capacity levels: effect on ageing and chronotype,” Journal of Applied Biomedicine, vol. 10, no. 2, pp. 109–117, 2011.

J. Delgado, M. del Pilar Terrón, M. Garrido et al., “Jerte Valley cherry-based product modulates serum inflammatory markers in rats and ringdoves,” Journal of Applied Biomedicine, vol. 10, no. 1, pp. 41–50, 2012.

J. Han and R. J. Ulevitch, “Limiting inflammatory responses during activation of innate immunity,” Nature Immunology, vol. 6, no. 12, pp. 1198–1205, 2005.

M. Garrido, D. González-Gómez, M. Lozano, et al., “Characterization and trials of a Jerte Valley cherry product as a natural antioxidant-enriched supplement,” Italian Journal of Food Science, vol. 25, no. 1, pp. 90–97, 2013.

M. Garrido, J. Espino, D. González-Gómez, et al., “The consumption of a Jerte Valley cherry product in humans enhances mood, and increases 5-hydroxyindoleacetic acid but reduces cortisol levels in urine,” Experimental Gerontology, vol. 47, no. 8, pp. 573–580, 2012.

M. Garrido, D. González-Gómez, M. Lozano, et al., “A Jerte Valley cherry product provides beneficial effects on sleep quality. Influence on aging,” The Journal of Nutrition Health and Aging, vol. 17, no. 6, pp. 553–560, 2013.

Y.-L. Huang, R.-Y. Liu, Q.-S. Wang, E. J. W. Van Someren, H. Xu, and J.-N. Zhou, “Age-associated difference in circadian sleep-wake and rest-activity rhythms,” Physiology and Behavior, vol. 76, no. 4-5, pp. 597–603, 2002.

A. R. Barnard and P. M. Nolan, “When clocks go bad: neurobehavioural consequences of disrupted circadian timing,” PLoS Genetics, vol. 4, no. 5, Article ID e1000040, 2008.

T. Woudstra and A. B. R. Thomson, “Nutrient absorption and intestinal adaptation with ageing,” Bailliere's Best Practice and Research in Clinical Gastroenterology, vol. 16, no. 1, pp. 1–15, 2002.

J. Meier and A. Sturm, “The intestinal epithelial barrier: does it become impaired with age?” Digestive Diseases, vol. 27, no. 3, pp. 240–245, 2009.

E. Ortega, J. J. Garcia, and M. De La Fuente, “Ageing modulates some aspects of the non-specific immune response of murine macrophages and lymphocytes,” Experimental Physiology, vol. 85, no. 5, pp. 519–525, 2000.

H. J. Hutt, P. Bennerscheidt, B. Thiel, and M. Arand, “Immunosenescence and vaccinations in the elderly,” Medizinische Klinik, vol. 105, no. 11, pp. 802–807, 2010.

E. S. Cannizzo, C. C. Clement, R. Sahu, C. Follo, and L. Santambrogio, “Oxidative stress, inflamm-aging and immunosenescence,” Journal of Proteomics, vol. 74, no. 11, pp. 2313–2323, 2011.

E. Ferrari and F. Magri, “Role of neuroendocrine pathways in cognitive decline during aging,” Ageing Research Reviews, vol. 7, no. 3, pp. 225–233, 2008.

G. A. Qureshi and S. H. Parvez, Oxidative Stress and Neurodegenerative Disorders, Elsevier, Oxford, UK, 2007.

S. K. Shankar, “Biology of aging brain,” Indian Journal of Pathology and Microbiology, vol. 53, no. 4, pp. 595–604, 2010.

R. Bravo, S. Matito, J. Cubero, et al., “Tryptophan-enriched cereal intake improves nocturnal sleep , melatonin, serotonin, and total antioxidant capacity levels and mood in elderly Humans,” Age, 2012.

C. Wrosch, G. E. Miller, S. Lupien, and J. C. Pruessner, “Diurnal cortisol secretion and 2-year changes in older adults' acute physical symptoms: the moderating roles of negative affect and sleep,” Health Psychology, vol. 27, no. 6, pp. 685–693, 2008.

G. Aguilera, “HPA axis responsiveness to stress: implications for healthy aging,” Experimental Gerontology, vol. 46, no. 2-3, pp. 90–95, 2011.

C. R. Markus, B. Olivier, G. E. M. Panhuysen et al., “The bovine protein α-lactalbumin increases the plasma ratio of tryptophan to the other large neutral amino acids, and in vulnerable subjects raises brain serotonin activity, reduces cortisol concentration, and improves mood under stress,” American Journal of Clinical Nutrition, vol. 71, no. 6, pp. 1536–1544, 2000.

C. Firk and C. R. Markus, “Mood and cortisol responses following tryptophan-rich hydrolyzed protein and acute stress in healthy subjects with high and low cognitive reactivity to depression,” Clinical Nutrition, vol. 28, no. 3, pp. 266–271, 2009.

D. González-Flores, B. Velardo, M. Garrido et al., “Ingestion of japanese plums (Prunus salicina Lindl. cv. Crimsonglobe) increases the urinary 6-sulfatoxymelatonin and total antioxidant capacity levels in young, middle-aged and elderly humans: nutritional and functional characterization of their content,” Journal of Food and Nutrition Research, vol. 50, no. 4, pp. 229–236, 2011.

D. González-Flores, E. Gamero, M. Garrido et al., “Urinary 6-sulfatoxymelatonin and total antioxidant capacity increase after the intake of a grape juice cv. Tempranillo stabilized with HHP,” Food and Function, vol. 3, no. 1, pp. 34–39, 2012.

M. Garrido, D. González-Flores, A. M. Marchena, et al., “A lycopene-enriched virgin olive oil enhances antioxidant status in humans,” Journal of the Science of Food and Agriculture, vol. 93, no. 8, pp. 1820–1826, 2013.

C. N. Martyn, D. J. P. Barker, and C. Osmond, “Mothers' pelvic size, fetal growth, and death from stroke and coronary heart disease in men in the UK,” The Lancet, vol. 348, no. 9037, pp. 1264–1268, 1996.

J. Cubero, D. Narciso, P. Terrón et al., “Chrononutrition applied to formula milks to consolidate infants' sleep/wake cycle,” Neuroendocrinology Letters, vol. 28, no. 4, pp. 360–366, 2007.