The elderly population is characterized by its susceptibility in their cardiovascular system and thus likely to developing cardiovascular diseases as well as related events associated to the aging process (e.g. to psychiatric disorders). The elderly population consumes high amounts of substances containing caffeine. If on one hand the chronic consumption of caffeine-containing substances (in particular coffee) may be beneficial, on the other hand acute consumption might be harmful to the cardiovascular system (e.g. by increased blood pressure). Acute caffeine consumption also promotes other benefits to elderly population such as to increase physical performance and aids in the treatment of symptoms related to psychiatric disorders. A potential substance that could inhibit the acute effects of caffeine on the cardiovascular system is inorganic dietary nitrate. Inorganic dietary nitrate supplementation has been show to be an effective hypertensive substance (through nitric oxide production via the nitrate-nitrite-no pathway) with no apparent adverse effects. The aim of this review was to highlight, with data published in the literature, the effects of caffeine and dietary nitrate, isolated and in association on blood pressure modulation in the elderly population. Whilst they have been studied independently in the elderly, they have only been studied in combination in young healthy adults.

The Aging process promotes anatomic and functional changes in several systems of the organism.¹ The mainly changes that happen in the cardiovascular system are cardiomyocytes hypertrophy with reduction in their number, decrease in the sensitivity of beta adrenergic stimuli, catecholamine’s and maximum cardiac output, arterial wall thickness and increase in the sub endothelial collagen, in the inflammatory markers, in the pulse wave and peripheral vascular resistance.² These changes result in an increase in the blood pressure (BP) in the elderly population, a scenario that might progress to hypertension and other possible complications that might come from it, such as stroke, heart ischemia and arterial diseases among others.³ Those conditions might also be worsened by deleterious nutritional habits.

Caffeine is a fast absorbed stimulant substance with action in the whole body that reaches its peak in 30 to 90 minutes. It has been well established in the literature that the consumption of 3 to 6mg/kg of caffeine is needed to obtain an Ergogenic effect⁴ however; it might increase BP and reduce blood flow.⁵ In young adults, caffeine acute supplementation (200mg) when combined with exercise can decrease (14-22%) myocardial blood flow;^6,7 moreover, 300mg when combined with exercise can lead to a reduction of blood flow and vascular conductance in the arm by ~50% and increase angiotensin II (ANG II) by ~44%.⁸

These caffeine hypertensive effects seem to last several hours after physical exercise.⁹ Blood flow decrease do not seems to occur when individuals are at rest, it is speculated that the hemodynamic effects of caffeine during exercise are due to the fact that caffeine antagonizes the vasodilator effects of physical activity (i.e. it inhibits the adenosine receptors).¹⁰ The afore mentioned data suggests us that when individuals engage in physical activity after caffeine intake, they are exposed to a greater risk of suffering a cardiovascular event (e.g, myocardial ischemia or cardiac arrhythmia) compared to the situation of non-physical activity or physical activity without caffeine intake.¹⁰

Other caffeine effects are analgesic promotion, decrease in pain sensitivity; thermo genesis increase and fatigue delay during physical exercise.⁴ Caffeine has many effects on central nervous system, such as catecholamine release, focus, and mood, state of alert, reaction time and memory improvement.⁴ In particular, these effects make caffeine a powerful cryogenic and treatment aid in several diseases related to aging such as Parkinson and Alzheimer’s diseases, depression, cognitive failure, etc.^11,12

Caffeine can be found in coffee, tea and chocolate among other foods/drinks, with the amount of caffeine being different between them. It is one of the most consumed substances by elderly population and that might be negative to the cardiovascular function when consumed in excess.¹³ More than a habit, caffeine consumption has positive effects on several aspects of the elderly day to day activities,¹⁴ reinforcing this routine. On the other hand, nitrate supplementation is an effective strategy to increase nitric oxide (NO) availability in the body. NO is considered a potent vasodilator and it has influence in different metabolic processes of the body, thus the importance of maintaining adequate levels of this substance in the body. Some of the actions of NO are to regulate BP and blood flow, to influence muscle contractility, cellular respiration process, calcium and glucose metabolism.^15,16

Interestingly, several complications such as atherosclerosis, stroke and especially hypertension, are associated with reduced NO bioavailability, or even a deficiency in its production.^17,18 Nitrate is available for consumption in two main forms, as organic nitrate or inorganic nitrate. Inorganic nitrate can be found in several natural sources and it is considered healthy and therefore has no side effects presented so far.¹⁵⁻²⁰ Inorganic nitrate (instead of organic nitrate) has been chosen as the most used option for nitrate supplementation due to its salivary regulation (which prevents NO spurt).²⁰ Inorganic nitrate it is present, mainly, in vegetables, and is encountered in larger concentration in arugula, spinach, lettuce, celery and beetroot.²⁰

The inorganic nitrate pharmacokinetics that results in NO bioavailability starts in the mouth, where anaerobic bacteria (located in the tongue) transforms nitrate in nitrite. After this modification, nitrite arrives in the stomach, where it is converted to NO and is absorbed; it enters the bloodstream and is distributed throughout the body.²¹

Once in its action site, NO stimulates cyclic guano sine monophosphate (cGMP) production which in high concentration reduces calcium entrance in the sarcolemma and reduces calcium release of its storage sites promoting vasodilatation.²² Furthermore, the increase of NO production reduces the Ang II activity in the renal tubules (inhibiting renal vasoconstriction), preventing an increase in systemic BP.²³

NO action peak occurs, on average, between two to three hours after inorganic nitrate consumption.^24,25 Inorganic nitrate consumption may promote a 2.5 to 6.4mmHg decrease in systolic BP and a 0.4 to 3.0mmHg decrease in diastolic BP.²⁶ Inorganic nitrate peak effect on BP occurs 2.5-3 hours following ingestion (coinciding with nitrite plasma levels) and its half-life is between 5 and 8 h.²⁰

Although there are few studies which approach inorganic nitrate supplementation for the elderly population, the results are positive regarding BP control (or its decrease), using dietary sources of nitrate.

Therefore, the aim of this review was to discuss, with data published in the literature, the effects of caffeine and inorganic dietary nitrate, isolated and in association on BP modulation in the elderly population.

A systematic review was conducted by 4 independent researchers on two different electronic data bases. We used articles from 2006-2016, searched on PubMed and EBSCO (Figure 1). Fluxogram search of caffeine and inorganic nitrate combination in elderly blood pressure. The key words used were caffeine (caffeine OR coffee OR 1, 3, 7-trimethylxanthine), nitrate (nitrate OR beet OR beta vulgaris OR lettuce OR spinach), blood pressure (blood pressure OR hypotension OR hypertension), and elderly (elderly OR aged OR aging) combined at least in pairs. References found were all closely examined to ensure adherence of the article to the subject. We included articles with all key words in the title (or in the abstract) which approached the substances combination on BP behavior, in the elderly. Later we also included articles that would approach caffeine or inorganic nitrate alone on BP behavior, in the elderly. We excluded articles that addressed caffeine or inorganic nitrate with other supplements and articles that considered other circumstances instead of BP control (Figure 2). Fluxogram searches of isolated caffeine and inorganic nitrate supplementation in elderly blood pressure.

Figure1 Fluxogram search of caffeine and inorganic nitrate combination in elderly blood pressure.

Figure 2 Fluxogram searches of isolated caffeine and inorganic nitrate supplementation in elderly blood pressure.

When we used all the key words in combination, we retrieved 0 articles from both databases (Figure 1). There seems to be no papers, until now, that analyzed both substances in combination and its effects on BP behavior in the elderly.

The search with the key words caffeine or nitrate alone with blood pressure and elderly was more fruitful, we found 233 articles with caffeine, blood pressure and elderly as key words and 127 articles with nitrate, blood pressure and elderly as key words (and all related terms as described above) that were further processed to the end result of 5 and 9 articles, respectively (Figure 2) a summary of all articles used in the review are presented in (Table 1) (Table 2).

Acute caffeine supplementation might increase BP.³⁴ However; chronic coffee consumption presented conflicting date, while some studies³¹⁻³³ associate chronic coffee consumption with lower risk of CHD development, one study ²⁸ presented adage-related increase in systolic BP and pulse pressure increased at high levels of coffee consumption (Table 2). Of nine studies with inorganic nitrate supplementation, only one study⁴⁵ did not showed decrease in BP after inorganic nitrate supplementation/feeding condition (Table 1).

We searched for a combination of all key words with no success, both databases retrieved zero (0) results. It seems that the idea of studying caffeine (in order to improve performance during physical exercise) and inorganic nitrate (to prevent BP to increase in an excessive manner) combined is an idea for future studies. However, we could find some studies that might be useful for us to speculate how these substances behave, used separately, and how they affect the elderly BP. There is no literature consensus about the effects of caffeine consumption on BP increase. Turley et al.²⁷ report that BP increase can happen from the consumption of approximately 5mg/kg of caffeine.

When we look to it from the elderly point of view, it seems that caffeine consumption is acutely associated with an increase in BP and pulse pressure related to increasing age. That is especially true for overweight and over 70 years subjects.²⁸ In contrast, some authors have shown that long-term coffee consumption may be beneficial in cardiovascular and metabolic functions.^29,30

However, it seems that chronic caffeine consumption (in the coffee form) seems to be associated with lower cardiovascular disease risk and metabolic syndrome,^31,32 although Uiterwaal et al.³³ found an association with hypertension risk and abstinence of coffee consumption. Farragut et al.³⁴ demonstrate that acutely caffeine supplementation (250mg) increased BP independently of age, gender or hormonal status, even in caffeine chronic consumers (i.e., 80mg/day). These effects can be attributed to two factors.

The first one is the vasoconstriction which occurs due to an increase in angiotensin II (ANG II) production and noradrenalin release.¹⁰Adenosine has an antagonist effect to caffeine, promoting inhibitory effects in the organism. As both these substances compete for the same receptors (situated in brain and blood vessels) the consumption of sufficient amounts of caffeine can prevent the receptors of being stimulated by adenosine. Also, one of the adenosine functions is the inhibition of neurotransmitters release, such as noradrenalin. Because caffeine acts directly in adenosine receptors it ends up facilitating this neurotransmitters release.^35,36 The second one is the vasoconstriction, which happens due to both the block of cyclic guano sine monophosphate (cGMP) and the decrease in adenosine action. The cGMP activity stimulates calcium reabsorption, when it is inhibited it causes the endothelium cells to be hyperpolarized, due to high concentration of calcium in cellular cytosol. Thus, endothelium cells become unable to relax and to promote vasodilatation.¹⁰

Together these data indicate that it seems to occur a hormesis phenomenon on BPdueto chronic caffeine consumption, as well as it occurs with physical exercise.³⁷ Recent human¹⁵⁻³⁸ and animal²³⁻³⁹ evidences show that acute inorganic nitrate ingestion promotes vasodilatation and consequently decreases BP in both normotensive and hypertensive conditions, as well as it might prevent kidney injuries in these conditions.³⁹ A meta-analysis study by Servo et al.²⁶ (including both young and elderly population) showed that inorganic nitrate supplementation decreased arterial BP in an average of -4.4mmHg, meanwhile diastolic BP decreased -1.1mmHg and this alterations are associated with a daily dose of inorganic nitrate ingestion.

Specifically in the elderly, Kapil et al.⁴⁰ found significant BP decreases with 4 weeks of beetroot juice consumption (with ~6.4mmol of nitrate) on hypertensive patients (18-65 years). Another study with elderly people (average 62 years) reported that concentrated beetroot juice (for 4-weeks, with 6.4mmol of nitrate) reduced significantly daily BP Jaja A et al.⁴¹ In healthy men and women (38-69 years), Liu et al.⁴² showed a lower systolic BP, pulse pressure and increased large artery compliance, after an acute meal rich in inorganic nitrate (220 mg). In addition, a double-blind, randomized, crossover study composed by 3 days with either nitrate-rich concentrated (∼9.6 mmol/day) beetroot juice also showed a decrease in both diastolic and systolic BP, in elderly (60-70 yr).⁴³

In a study with mice ⁴⁴ it has been showed that inorganic nitrate supplementation (8 to 10 wk) improves several aspects of metabolic syndrome (such as insulin sensitivity, hypertension and endothelial dysfunction). This study is important, because endothelial dysfunction is commonly present in hypertensive elderly patients. Interestingly, in T2DM (type 2 diabetes mellitus) elderly patients, Gilchrist et al.⁴⁵ did not observed any change in both diastolic and systolic BP after 2 week of beetroot juice supplementation (with 7.5 moles of nitrate per day) neither improvements in endothelial function or insulin sensitivity Chang J et al.⁴⁶ Further research is needed, because evaluated patients who were making drug use (to control co morbidities associated to T2DM), which might affect vascular function and them the response to inorganic nitrate. Gilchrist et al. assessed neither plasma nitrite nor NO, this is necessary because NO response to inorganic nitrate supplementation varies widely between health and unhealthy elderly Lundberg JO et al.⁴⁷

A recent meta-analysis Larsen FJ et al.⁴⁸ evaluated data of beetroot juice supplementation effect on 24-hr ABPM (ambulatory blood pressure monitoring) in older subjects, it was concluded that nitrite concentrations, followed by inorganic nitrate ingestion, works as a potential factor influencing the association between inorganic nitrate and vascular responses. So, oral micro biota, gastric redo environment, oxygen tension and pH in the peripheral circulation or reeducates enzymes efficiency (factors that influence the conversion of inorganic nitrate to nitrite)need to be investigated in the elderly using inorganic nitrate supplementation to control BP levels Kenjale AA et al.⁴⁹

In a study with mousse and rats Lane et al.⁵⁰ it was verified that caffeine consumption inhibits NO synthesis (blocking NO syntheses) inducing cerebral artery constriction. Despite these opposite actions NO production from inorganic nitrate supplementation is an independent pathway of NO syntheses,⁴⁷ i.e., acts as a "backup" (preventing NO decrease) if a deficiency in the NO production occurs. Interestingly, caffeine with NO availability works as a protective combination during ethanol induced cerebral artery constriction.⁴⁶ Analyzing these two substances from the literature results we can assume that acute inorganic nitrate or inorganic nitrate rich meals consumption can decrease BP enough to modulate caffeine’s impact on the elderly BP Siervo M et al.⁵¹ Table 3 shows that inorganic nitrate vascular effects are contrary to those promoted by caffeine consumption. In young subjects, inorganic nitrate consumption has been show to improve mitochondrial efficiency⁴⁸ which is related to its cryogenic potential. This results also true to elderly subjects.⁴³⁻⁴⁹ These data indicates cryogenic potential (beyond cardiovascular health) of this substance to the elderly population.^52,53

Few studies can be found in the literature related to caffeine and inorganic nitrate association. These studies had the primary objective to verify caffeine-nitrate association effects in exercise performance and none of them used elderly subjects. Glaister et al.²⁵ offered a 7.3mmol of inorganic nitrate and 5mg/kg of caffeine to well-trained cyclists and observed an increase on their performance. However, due to caffeine group and caffeine plus inorganic nitrate group results similarity, the authors assigned this increase exclusively due to caffeine action. Lane et al.⁵⁰ conducted a study with cyclists, but with a different dosage. In this study, they offered a single dosage of 8.4 mmol of inorganic nitrate and two dosages of 1.5mg/kg of caffeine, totalizing 3mg/kg of caffeine. Similarly to the study of Glister et al.²⁵ the results between caffeine group and caffeine plus nitrate group were similar, so the authors concluded that inorganic nitrate has no cryogenic effects when associated with caffeine. Handizlik & Gleeson²¹ on the other hand, presented benefits from caffeine/nitrate association. In their study, they offered 8mmol of inorganic nitrate and 5mg/kg of caffeine to well-trained cyclists and the results were positive. VO₂ significantly increased in the caffeine-nitrate group, compared to both substances, when consumed isolated.

These results present a general idea from caffeine and nitrate associated effects, although the extrapolation of these results to the elderly population has to be done carefully since the mentioned studies were proposed to investigate only performance in young individuals. Caffeine is a well-known cryogenic substance and a potential substance to help in the treatment of several diseases related to aging. On the other hand, elderly usually have high BP and acute caffeine ingestion might increase it even more (mainly during the physical exercise), whereas inorganic nitrate consumption might be a helpful tool (working concomitantly) to maintain the cryogenic properties of caffeine and improve exercise performance for the elderly without the side effects on BP.

We can conclude that acute caffeine ingestion promotes BP increase in the elderly; however, chronic consumption seems to promote benefic adaptations on BP. On the other hand acute inorganic nitrate ingestion promotes BP decreases in this population. Although adult studies analyzing caffeine, inorganic nitrate and exercise suggest a potential healthy synergic association especially to the elderly, new studies are needed to verify this suggestion.

These new studies should investigate further its effects on cardiovascular health and physical fitness with special attention to the amount and nature (meal, capsules, and drinks) of the substances consumed and to the metabolic situations (at rest or during exercise) where they are used.

None.

Author declares there is no conflict of interest in publishing the article.

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