Surprise: Consuming 1–5 cups of coffee/day was related to lower mortality among never smokers; they forgot to discount/adjust for pack-years of smoking, healthy & unhealthy foods, & added sugar

Dietary research on coffee: Improving adjustment for confounding. David R Thomas, Ian D Hodges. Current Developments in Nutrition, nzz142, December 26 2019. https://doi.org/10.1093/cdn/nzz142

Abstract: Meta-analyses have reported higher levels of coffee consumption to be associated with lower mortality. In contrast, some systematic reviews have linked coffee consumption to increased risks for lung cancer and hypertension. Given these inconsistencies, this narrative review critically evaluated the methods and analyses of cohort studies investigating coffee and mortality. A specific focus was adjustment for confounding related to smoking, healthy and unhealthy foods and alcohol. Assessment of 36 cohort samples showed many did not adequately adjust for smoking. Consuming 1–5 cups of coffee per day was related to lower mortality among never smokers, in studies which adjusted for pack-years of smoking, and studies adjusting for healthy and unhealthy foods. Possible reduced health benefits for coffee with added sugar have not been adequately investigated. Research on coffee and health should report separate analyses for never smokers, adjust for consumption of healthy and unhealthy foods, and for sugar added to coffee.

Keywords: Coffee, diet, methods, confounding variables, covariates, adjustment, smoking, healthy foods, cohort studies, added sugar

[Check also the study after the discussion below]

Discussion

Cohort studies provide a crucial source of evidence for investigating the long-term effects of
specific foods and dietary patterns on health. Critical analyses can help improve the quality
of cohort research designs. The focus of this narrative review was to assess the quality of
adjustment for potential confounding in research on coffee. Although this report is based on
a small number of published articles, as far as we are aware, it is the first to systematically
examine the relationship between adequacy of adjustment for smoking and food as
covariates, and the significance of these findings for research on coffee and health
outcomes such as mortality. Evidence from 34 published studies supported the view that
inadequate adjustment for confounding for both smoking and unhealthy foods reduced the
likelihood of finding a significant health protective effect for coffee. The review also noted
that the potentially negative health effects of sugar added to coffee have not been
adequately investigated.
Inadequate adjustment for confounding between coffee consumption and smoking has led to
misleading findings in both cohort studies and meta-analyses, particularly for the association
between coffee and lung cancer and pancreatic cancer. Two meta-analyses reported a
significant association between higher coffee consumption and increased risk of lung cancer
(15, 79). Both these meta-analyses did not assess the effectiveness of adjustment for
smoking in the individual studies included in the meta-analyses. An association has been
reported between coffee consumption and pancreatic cancer, but this association becomes
non-significant among non-smokers and studies which have adjusted for smoking (13). As
noted earlier, the Grosso et al. meta-analysis reported a significant linear inverse trend
between coffee intake and mortality rates among never-smokers (8). The differences
between never and ever smokers were most evident in cancer deaths. Never smokers
showed significantly lower cancer death rates with increasing coffee consumption. In
contrast, among former and current smokers, increasing coffee consumption did not reduce
risks for cancer mortality.
Given the inadequacy of adjustments commonly used for smoking, studies reporting on the
health effects of coffee, and other exposures that may be linked to smoking, should report
relative risks separately for never smokers (5, 80). As some groups show large differences in
smoking rates between men and women, separate analyses by sex should also be reported.
Future studies may also need to include the use of e-cigarettes (vaping).
These findings have implications for other dietary studies making adjustments for smoking
status, where smoking may be associated with other food variables or lifestyle patterns. For
example, an extensive review on risk thresholds for alcohol consumption based on 83
prospective studies, used a binary variable (current smoker versus non-smoker) to adjust for
smoking (81). Adjustment using binary variables is more likely to be linked to misleading
assessments of relative risks, especially where an exposure variable (alcohol) and the
potential confounder (smoking) have a non-linear association. Many published reports which
have used binary covariates to adjust for smoking may have residual confounding resulting
from smoking-associated health risks.
When smoking adjustments are used, authors should report explicitly how the variable or
variables were constructed for smoking adjustment and how these variables were entered
into regression analyses. Only one article included in the current review reported this detail
(52). Another concern is avoiding use of the term ‘non-smokers.’ This term is ambiguous,
and has been used to refer to both ‘never smokers’ and ‘non-current smokers.’ It is better to
use the terms for which the meaning is clear such as; never, former (past, previous) and
current smokers.
Higher levels of coffee intake were commonly associated with consumption of unhealthy
foods in the studies reviewed. Additional evidence for this association is evident in studies
on dietary patterns using factor analysis. Six systematic reviews focussed on food patterns
were found where coffee was reported among the specific foods related to healthy and
unhealthy eating patterns (82-87). From the six reviews, 101 individual studies using factor
analysis were examined. Among the individual studies, 14 reported the association of coffee
with the primary factors. Eleven out of 14 studies reported coffee as loading on factors
commonly labelled as ‘western’ or unhealthy among samples from nine countries. This
‘unhealthy’ pattern consisted of red meat, processed meat, refined grains, alcohol, sweet
foods and coffee (82, 84, 86, 87). These findings are consistent with the importance of
adjusting for food groups. Where potential covariation between coffee and unhealthy foods
has not been adjusted, it is less likely that higher coffee consumption will be associated with
reduced mortality and morbidity.
Current research indicates that added sugar is a risk factor for health problems such as
obesity, cardiovascular disease and diabetes (42, 88, 89). Taking coffee with added sugar,
and flavoured coffees with sugar as a sweetener, are likely to reduce the health benefits of
coffee (90). A literature search for studies investigating the association between coffee and
health outcomes found few which reported the proportion of coffee drinkers who added
sugar and none which reported the amount of sugar added.
The omission of sugar as a potential confounder in research on coffee may be based on the
assumption that sugar intake has negligible health effects. The continued omission of added
sugar is likely to be a legacy from dietary questionnaires constructed prior to 2000, which are
unlikely to have included questions to measure sugar added to coffee. The influential
NHANES question set used for repeated national surveys in the US illustrates this problem.
In NHANES, sugar added to coffee was measured by the following questions;
123 How many cups of coffee, caffeinated or decaffeinated, did you drink? (over the
last 12 months)
Ten response categories were provided from ‘None’ to ‘6 or more cups per day.’
126 How often did you add sugar or honey to your coffee or tea?
Ten response categories were provided from ‘Never’ to ‘6 or more times per day.’
The question on added sugar or honey does not provide a quantity estimate for added sugar
(e.g. teaspoons). Reports on tea and coffee consumption based on the NHANES surveys
have ignored added sugar in the profiles of groups consuming tea or coffee. For example, a
2016 paper reported around 75% of adults in the US drinking coffee in the past 12 months,
and around 49% drank coffee daily (1). No mention was made of the proportion of coffee
drinkers who added sugar.
In contrast, the more recently constructed UK Biobank question set, used in a cohort for
which recruitment started in 2003, does allow for calculation of added sugar (91). This
survey included the following question;
How much sugar did you add to your coffee (per drink)?
Six responses categories were provided, from none to 3+ teaspoons.
One of the few studies which mentioned sugar in coffee was a report on the US NIH-AARP
Diet and Health case-control study of older people (50-71 years at recruitment) (92). Among
242,171 tea and coffee drinkers in the control group, 49% did not add sugar or honey to tea
or coffee, 25% added sugar or honey and 26% added other sweeteners. Those who did not
add sweeteners to tea or coffee had a lower risk for depression than people who added any
type of sweetener (92). A Korean study reported that instant coffee mixes with added sugar
were associated with an increased risk of metabolic syndrome, compared to other types of
coffee (93).
There has been sufficient evidence at least since 2010 to justify the inclusion of added sugar
as a potential confounder in studies of the association between coffee and health outcomes.
In two umbrella reviews on coffee and health, one did not mention sugar at all (6) and the
other mentioned it as a possible limitation of the existing research (5). Given the practice of
ignoring added sugar in studies of coffee and health, nearly all the published findings on
health outcomes from drinking coffee may reflect unadjusted confounding which could
reduce the likelihood of finding health benefits from coffee. Confounding is most likely for
health outcomes where sugar has been reported as a risk factor, such as weight gain,
obesity, metabolic syndrome, diabetes and blood lipids. Confounding with added sugar may
be most likely to occur among people drinking three or more cups of coffee per day and who
add more than 1 teaspoon of sugar per cup. For example, a person drinking 5 cups per day
with 2 teaspoons of sugar per cup would have an added sugar intake of around 50 grams
per day (1 teaspoon ≈ 5 grams) just from their coffee consumption. It is possible that part of
the reduced protective effect of coffee for consumption of 5+ cups/day, which some studies
have reported, may be due to added sugar.
In terms of implications for further research related to the health effects of coffee, there were
several topics for which no research was found. These include studies investigating the
association of coffee consumption with other dietary and lifestyle patterns. A particular
pattern of interest is the use of coffee as a substitute for other beverages such as alcohol or
SSB, especially in social settings. In addition, no studies were found which included selfreporting of reactions to coffee, especially among occasional drinkers of coffee. Some
people may be allergic to coffee or have adverse reactions to caffeine. Research is needed
on the strategies people use to self-manage coffee consumption at comfortable levels. One
RCT, examining the effects of coffee, required participants to drink one litre of coffee every
day for two weeks. Negative reactions (‘palpitations and tremor during the first days of
drinking the cafetière coffee’) were reported as being sufficiently severe for one participant to
drop out of the study. However, as was evident in this report (94), RCT studies are unlikely
to gather information about participants’ reactions to exposures, in this case drinking more
coffee than usual.
For some people, coffee drinking is associated with social contact and social support (95,
96). Studies linking coffee consumption with, for example, reduced risk of depression, may
have confounding due to increased social contact and support being associated with coffee
consumption (97). More research is needed on the social contexts associated with coffee
consumption and the extent to which these contexts may have beneficial effects on health.
A pattern evident among Japanese men, and which may occur in other societies, is that
some people may consume coffee instead of alcohol in settings where both types of drinks
are available. This pattern of substitution does not appear to have been investigated. As
well, changes in coffee consumption over time, and reasons for change, appear not to have
been investigated. Only a few studies have reported consistency of coffee consumption over
a period of several years (72). A pattern needing further research is the extent to which
people take up, or increase, their coffee consumption as a substitute for drinking alcohol or
sugar-sweetened beverages.
Research using self-report measures of coffee consumption should clearly describe the
questions used to measure coffee and should note whether added sugar was measured,
including flavourings which include sugar. No information was found about the various types
of milks added to coffee. For some consumers, milk may be used instead of sweeteners to
reduce the bitterness of coffee and is likely to be a healthier option than sugar.
More reviews are needed to document which research studies on food groups and patterns
have included coffee as a food variable, and which included coffee but did not report it
because it was not associated with outcomes of interest. Research using cohort samples
should assess whether coffee drinking is associated with unhealthy eating patterns and if so,
allow for this association when adjusting for potential confounders.
This review has several limitations. It was restricted to cohort or observational studies.
Cohort studies may have unadjusted confounding which is a limitation for attributing a causal
relationship between exposures and health outcomes. The findings which have been
reported here were dependent on the assumptions made when assessing the quality of
smoking adjustment and adjustment for healthy and unhealthy foods. The assessment of the
quality and levels of significance between coffee consumption and mortality was dependent
on the information reported in each of the 34 articles reviewed. If this information was
inaccurate or incomplete, it could affect the findings reported.

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Check also Caffeine extends life span, improves healthspan, and delays age-associated pathology in Caenorhabditis elegans. George L Sutphin, Emma Bishop, Melana E Yanos, Richard M Moller & Matt Kaeberlein. Longevity & Healthspan volume 1, December 1 2012. https://longevityandhealthspan.biomedcentral.com/articles/10.1186/2046-2395-1-9. This is very important because: .1 makes clearer this may be shared with other species; .2 makes more difficult that the root cause is more healthy people drinking coffee, and easier that the coffee is what is beneficial; .3 there are less confounders (no tobacco, no sugar, & diet can be optimized).

Abstract
Background: The longevity of an organism is influenced by both genetic and environmental factors. With respect to genetic factors, a significant effort is being made to identify pharmacological agents that extend life span by targeting pathways with a defined role in the aging process. On the environmental side, the molecular mechanisms responsible for the positive influence of interventions such as dietary restriction are being explored. The environment experienced by humans in modern societies already contains countless compounds that may influence longevity. Understanding the role played by common compounds that substantially affect the aging process will be critical for predicting and interpreting the outcome of introducing new interventions. Caffeine is the most widely used psychoactive drug worldwide. Prior studies in flies, worms, and mice indicate that caffeine may positively impact age-associated neurodegenerative pathology, such as that observed in Alzheimer’s disease.

Results: Here we report that caffeine is capable of extending life span and improving healthspan in Caenorhabditis elegans, a finding that is in agreement with a recently published screen looking for FDA-approved compounds capable of extending worm life span. Life span extension using caffeine displays epistatic interaction with two known longevity interventions: dietary restriction and reduced insulin signaling. Caffeine treatment also delays pathology in a nematode model of polyglutamine disease.

Conclusions: The identification of caffeine as a relevant factor in aging and healthspan in worms, combined with prior work in both humans and rodents linking caffeine consumption to reduced risk of age-associated disease, suggests that caffeine may target conserved longevity pathways. Further, it may be important to consider caffeine consumption when developing clinical interventions, particularly those designed to mimic dietary restriction or modulate insulin/IGF-1-like signaling. The positive impact of caffeine on a worm model of polyglutamine disease suggests that chronic caffeine consumption may generally enhance resistance to proteotoxic stress and may be relevant to assessing risk and developing treatments for human diseases like Alzheimer’s and Huntington’s disease. Future work addressing the relevant targets of caffeine in models of aging and healthspan will help to clarify the underlying mechanisms and potentially identify new molecular targets for disease intervention.