A Review of the Impact of Wine Consumption on Health and the Bioactive Compounds

Responsible for Health Effects

Introduction

“Wine” is quite a general category of alcoholic beverages that includes drinks of many
different colors, tastes, aromas, and mouthfeels from all around the world. It can be used as a
reason to gather, a conversation piece, a food enhancer, and a social lubricant. Humans have been
consuming wine for thousands of years, so there must be no significant issue with imbibing
moderate amounts of wine - but are there benefits?

This review is aimed at going over the general positive effects of grape wine as well as
focusing on a few specific compounds that contribute to these claimed benefits. Misinformation
about wine’s health effects often floats around, so there have been many different studies
conducted on animals and humans to determine what exactly in wine can be helpful to the body
and the mind.

Subjective Health Measurements

Before diving into the specific compounds of interest, it is important to understand why
so many studies have been done to determine what could be improving the health of wine
drinkers. Researchers have done extensive studies on the subjective, self-rated health of people
who consume wine as well as other alcohol beverages compared to those who do not drink or
those who drink excessively. While self-rated health may appear to be very vague and not useful
as a true metric of health, it is actually a fairly good predictor of mortality. A study from 1982
tested the hypothesis that self-rated health is a predictor of mortality independent of objective
health status, and they determined that mortality rate for people whose self-rated health was poor
was nearly three times higher than that of people who rated their health as excellent (Mossey and
Shapiro 1982). The results were controlled for objective health status, age, sex, life satisfaction,
and income. Ultimately, self-rated health has been proven to be a relatively effective method for
determining subjects’ true health statuses, making it far simpler for researchers to test the health
of subjects in the experiments that determined the health of wine drinkers.

Oksanen and Kokkonen conducted a random sample of Finnish people aged 18-69 (n = 2591)
and interviewed them regarding psychological distress, self-efficacy, self-perceived health,
uncontrolled drinking, negative events during drinking, hazardous drinking and consumption of
alcohol. Regression models that were adjusted for many different potential confounding
variables such as employment status, education, age, marriage status, and more revealed that
those who only drank wine with meals reported less hazardous drinking, lower psychological
distress, and high subjective well-being, as seen in Table 1 alongside the full results (Oksanen
and Kokkonen 2016).
 Another pair of Finnish researchers used a 1992 questionnaire (n = 6,040) and discovered
that the group of men and women who consumed 1-4 drinks of wine per week had fewer cases of
suboptimal health than those who drank no wine (Poikolainen and Vartiainen 1999). Those who
consumed 10 or more drinks were more likely to have suboptimal health. The researchers
included major lifestyle variables in the list of potential confounders, such as smoking, exercise,
and lack of friends, but the association between wine and health remained significant. However,
the researchers did admit that there could be unknown confounding variables that they did not
adjust for.

A big question arises from papers that only use wine for the beverage of potential benefit:
is it wine in particular that is associated with these benefits, or is it simply alcoholic beverages in
general? Grønbæk et al. investigated this question using a questionnaire (n = 12,039) and
categorized the results into those who had 0, 1-2, 3-5, and 5+ drinks the day before. The groups
were then subcategorized into groups who drank wine, beer, or spirits primarily. Interestingly,
light and moderate wine drinkers (1-5 drinks the day prior) had significantly lower odds for
having suboptimal health at 0.72 (95% confidence interval (CI) 0.56 to 0.92) and 0.65 (95% CI
0.49 to 0.87), respectively, when compared to non-wine drinkers as well as those who primarily
drink spirits (Grønbæk et al. 1999). Additionally, those who prefer to drink beer had an odds
ratio of 1.50 for suboptimal health compared to subjects who consume wine.

Despite these convincing correlations, claims about wine in particular having a significant
positive effect on health are still laden with doubt due to potential confounding variables
despite all of these studies accounting for at least some of them. For example, the
Oksanen and Kokkonen study acknowledged that consumption of wine with meals is associated
with a higher socioeconomic status, but socioeconomic status was not adjusted for in the study
for reasons that were not explained in the paper (Oksanen and Kokkonen 2016). Grønbæk et al.
also adjusted for many factors, like smoking, contact with family, contact with friends, physical
activity intensity, education, chronic diseases, and body mass index, but they did not ask
questions about socioeconomic status despite admitting that it is a potential confounding
variable. Socioeconomic status could easily be one of the largest confounding variables for these
types of studies, as a higher self-perceived socioeconomic status is strongly correlated with better
mental and physical health (Kim and Radoias 2021). A higher socioeconomic status is also
associated with consuming wine with meals (Mortensen et al. 2001), so by the transitive
property, there is clearly an issue with socioeconomic
status as a confounding variable.

Furthermore, issues arise with the selection of

subjects and the definition of “an abstainer” in these
studies. More specifically, some studies may consider
abstainers to be those who have never consumed
alcohol, while more often than not the studies consider
those who started but quit at some point to also be
abstainers. Liang and Chikritzhs strayed from the
traditional method of computing the relative risk by
doing “intention-to-treat” analysis where former
drinkers and those with an unknown drinking status
were treated as drinkers whose level of consumption
was unknown. When both were compared with
lifelong abstainers to address selection bias, nearly all
of the protective effect of light drinking disappeared
and most of the protective effect of moderate drinking
was gone (Liang and Chikritzhs 2013), as seen in
Figure 1. However, these groups of drinkers were not
stratified into each type of drink (wine, beer, spirits,
etc.), so it is unclear whether or not the effects of the
intention-to-treat analysis would be as significant on
those who drink light or moderate amounts of wine. A
study using this analysis for wine drinkers versus beer
and spirit drinkers would give a more definitive
answer on the perceived health effects of wine.

Objective Health Measurements

While it is certainly useful to observe wine’s potential effects on overall health, there may
be relatively unnoticed benefits of wine consumption that are more particular to one metabolic
process or organ function. Many studies have been conducted on more specific aspects of health
that wine may improve.
Serum Uric Acid
 Serum uric acid levels that are elevated beyond normal levels can cause new renal
diseases in humans, making it a notable topic to cover (Tada et al. 2021). Alcohol consumption
has been noted to increase the serum uric acid to creatinine ratio in subjects, which is strongly
associated with a higher risk of metabolic syndrome (n = 9,104) (Moriyama 2019). However, this
study did not distinguish between types of alcohol. Choi and Curhan’s 2004 study (n = 14,809)
did, however, and showed that beer and liquor increased serum uric acid by 0.46 mg/dl (95% CI
0.32 to 0.60) and 0.29 mg/dl (95% CI 0.14 to 0.45) per serving per day respectively with
P-values for both being below 0.01. For wine, there was no association between increasing
servings and serum uric acid values (0.04 mg/dl; 95% CI -0.20 to 0.11; P-value of 0.6) (Choi and
Curhan 2004).

Stibůrková et al. performed a similar study, although they used drinks per day instead of
observing changes by increasing servings (n = 589). After testing wine and beer separately, the
results that were cleared of confounding variables were in agreement with Choi and Curhan,
showing that beer consumption increased serum uric acid and wine did not alter it. So, while
there is not necessarily a direct benefit from consuming wine as it relates to serum uric acid
levels, it shows that if people are going to consume an alcoholic beverage, wine is the safest on
average for maintaining constant serum uric acid concentrations.

Coronary Heart Disease

Grape wine has been thoroughly examined for its effects on coronary heart disease
because it is known to have many different antioxidants present in the grapes before and after
fermentation. Polyphenols, a large group of compounds containing phenolic acids, lignans,
stilbenes, and flavonoids, are
the antioxidants present in
wine. Antioxidants are
incredibly important for
heart health as they prevent
free radicals from oxidizing
low-density lipoprotein
cholesterol (LDLs). LDLs
can pass through endothelial
cells and into the tissue
where they can be oxidized
by free radicals, causing
endothelial damage.
Additionally, monocytes will
enter the tissue and turn into
macrophages to clean up
oxidized LDLs. These
macrophages can consume
smooth muscle cells that
have been stripped, causing
fat buildup and, finally, atherosclerotic plaques that can clog arteries. The whole process is
shown in Figure 2. Given that this process can be stopped from the very beginning by
antioxidants - and that heart diseases are the leading cause of death in the United States
(https://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm) - lots of attention has inevitably
fallen on antioxidants in wine for being the potential explanation for the higher self-reported
health claims. For clarity, this is referring to red wines as opposed to white wines which are
relatively very low in polyphenols..

Perhaps the most famous - or infamous, for some - polyphenol is resveratrol. It has been a
popular reference for many media outlets that tout the beneficial effects of consuming wine
because of the misinformed connection that “resveratrol is an antioxidant; resveratrol is in wine;
therefore, drinking wine is good for you.” Resveratrol is produced by grapevines in response to
fungal infections and other stresses throughout the vine as well as in the skins of the grapes
(Sacks and Jeffery 2016). Xiang et al. researched the health effects of resveratrol as well as other
polyphenols present in red wine in terms of their ability to scavenge
1,1-diphenyl-2-picrylhydrazyl (DPPH) in free radical form and superoxide radicals in vitro. The
results showed that there was no significant difference in free radical scavenging capacity for the
control red wines and red wines with 10-fold resveratrol added; overall, less than 5% of the
antioxidant activity of red wine can be attributed to resveratrol (Xiang et al. 2014). The study
ultimately showed that gallic acid was actually the most active antioxidant by a significant
margin, as shown in Table 2.
 Gallic acid is not found in grapes, but it is formed in
wine by the hydrolysis of gallate esters that are present in
condensed and hydrolyzable tannins (Sacks and Jeffery 2016).
Once they have been consumed as a part of the wine, they
scavenge free radicals mainly through two mechanisms:
hydrogen atom transfer and single electron transfer
(López-Martínez et al. 2015). In the hydrogen atom transfer
mechanism - which is characterized by the homolytic bond
dissociation enthalpy of OH groups - a hydrogen atom is simply
transferred to a free radical (Đorović et al. 2014). The single
electron transfer mechanism starts with the gallic acid molecule
losing an electron to form a radical cation, and the radical cation
is then deprotonated (Đorović et al. 2014).

In one study, caffeic acid was found to

be the
most effective antioxidant (Abu-Amsha et al.
1996).
This study was done by diluting wines and
testing
their antioxidant capabilities on metal
ion-dependent
and metal ion-independent oxidation of isolated
LDLs in serum. Frankel and Kanner conducted a
similar study and produced very similar results
(Frankel and Kanner 1993).

There have been full, extensive reviews done

on the potential cardiovascular benefits of consuming red wine in particular for its polyphenol
antioxidants. Weaver et al. concluded that 84% of human studies and 100% of animal studies
showed significant improvements in systolic blood pressure overall from red wine polyphenols,
although there were no significant effects on diastolic blood pressure of flow-mediated dilation
of the brachial artery (Weaver et al. 2021). Ditano-Vázquez et al. did a very similar review,
although it was more for general cardiovascular health. The conclusion was that low to moderate
red wine intake shows improvements in cardiovascular health (Ditano-Vázquez et al. 2019).
 While these reviews contain thorough summaries of hundreds of useful studies, most of them
are in vitro and therefore do not contain definitive evidence that the antioxidant properties of
wines can truly be effective in vivo, although they may be a good guide for potential in vivo
studies (Visioli et al. 2020). However, it has been shown that polyphenols are extremely weak
direct antioxidants when the experiment is performed in vivo. The polyphenols’ bioavailability
is typically so low that they are not available in large enough concentrations cannot seem to
scavenge free radicals; even if they are present in moderate amounts, they do not seem to
scavenge free radicals nearly at the same rate as for in vitro experiments due to kinetic reasons
(Visioli et al. 2020).

There are not only quality issues for in vitro and in vivo studies; problems also stem from
the animal studies, such as those cited in Weaver et al. These animal studies often use extremely
high concentrations of grape polyphenols that could never be achieved in humans unless several
grams of the extracts were ingested (Visioli et al. 2020). Polyphenol concentrations must be
diluted significantly in order to achieve any sort of comparable data, but that is not done in many
of these studies.

Conclusion

Many millions of dollars and hours of time have gone into researching the potential
health benefits that can come from wine, but based on the current research, it is clear that higher
quality and more focused experiments must be conducted in order to determine the true health
benefits of wine if there are any. In this review, we explored the effects of wine consumption on
self-reported physical and mental health, and the data seemed to show a strong correlation to
moderate wine consumption and good health. However, it is extremely difficult to account for
every confounding factor, and many studies did not even include socioeconomic status as a
potential confounding variable despite its strong association with good health and wine
consumption. We then delved into the effects of wine on two physiological aspects: serum uric
acid and heart function. Wine was shown to have no detrimental effects on serum uric acid, and
many studies have claimed that red wine consumption may improve health through quenching of
free radicals that oxidize LDLs. Despite these claims, many of the studies have glaring issues -
mainly incomparability with human systems.

When it comes to recommendations for wine drinkers, the useful outcome of this review
is that these studies did not show a detrimental effect of wine consumption on these
physiological systems as long as it is consumed in moderation. While there still may be no
proven benefits, it may be comforting for consumers to know that there are no major negatives of
moderate wine consumption based on these studies.

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