Thursday, March 31, 2016

New Paleo Study by Freese et al

A paper was recently published in the Journal of Evolution and Health (the journal of the Ancestral Health Society) that looked at the effects of simulating a few aspects of a hunter-gatherer lifestyle for 4 days and 3 nights

This study included 13 participants (7 male, 6 female), all Caucasian.  Average age was 39 (± 8.1).  9 of participants had a BMI between 19.3-25, 4 had a BMI between 25-27.4.  7 exercised for more than 3 hours per week and 1 was a smoker

  • Outdoors: the participants “lived and slept outdoors with no shelter”
  • Diet: the participants received fruits, nuts and tubers to eat for lunch and a Paleo dinner.  “The dietary composition of foods was aimed to reconstruct a paleolithic diet based on the recommendations of Cordain and others”.  The participants consumed 1567 calories per day on average during the study (the participants’ usual calorie intake isn’t reported) with a macronutrient ratio of 24:54:22 (P:F:C) (see table 2 for detailed information on the foods they ate).  (The participants got their water from a “nearby holiday apartment”)
  • Exercise: the participants hiked for 3.42 hours per day and did 2.5 hours of other forms of physical activity (“Other activities associated with nomadic hunting and gathering were: swimming, climbing, lifting and building a fire”)
  • Fasting: the participants had an intermittent fasting period of at least 12 hours per day, as they didn’t eat until noon and did the 4+ hour hike while fasted
  • Sleep: the participants slept an average of 7.9 hours.  That being said the participants probably had also benefited from less night-time light (depending on the moon).  (As this study was done in Germany it could be important to know what season is was and what the weather was like) 

The rationale of the study is that various aspects of our evolutionary mismatch leads to low grade inflammation, which promotes obesity and insulin resistance, and that exercise while fasted may be particularly protective against this.  I have written previously on how inflammation is an attractive mechanism of insulin resistance, but current evidence from RCTs in humans doesn’t support that hypothesis so far (blog).  I like the idea of researching tools to mitigate postprandial inflammation, but I doubt much would change in a fasted blood sample after 4 days

The researchers made many measurements related to the immune system/inflammation, the metabolic syndrome and body composition (see table 4 and 5 for more info).  Significant changes included:

Weight (kg)
RDW (%) (RBC distribution width)
Thrombocytes (nL)
Lymphocytes (%)
Fasting Glucose (mg/dL)
CRP high sensitive (mg/L)
Insulin (uU/mL)

With 1597 calories and all that exercise it’s not surprising that the participants, who appear already quite healthy, lost some weight and reduced their fasting glucose and insulin levels.  Surprisingly high sensitivity CRP increased quite a lot (despite the reduction in glucose and insulin levels) and the authors comment on this saying “We suppose, that living in the wild stimulates the innate immune system as shown by Qing [52] and Park [53] via activation of proinflammatory pathways in order to anticipate evolutionary old danger signals such as bacteria, viruses, insects or predators.”  That makes sense and the high level of exercise may have also contributed

A Meta-Analysis of Low Fat and Carbohydrate Trials for Weight Loss

A meta-analysis was published last December looking at weight loss in low fat diet RCTs lasting at least 1 year [1], where a low fat diet was compared with either.

  • Low carbohydrate diets
  • Higher fat diets
  • The participants’ usual diet 

I have covered most of the low fat vs. low carbohydrate trials they included [2] (I looked at trials with at least 100 participants and lasting at least 1 year).  In the low fat vs. low carbohydrate comparison they also included:

In summary, regardless of whether weight loss was a goal or not:

  • Low carbohydrate > low fat
  • Low fat = higher fat
  • Low fat > usual diet 

Macronutrients and weight loss: These results indicate that the low fat diet only had an advantage when compared to the usual diet and was equal to higher fat diets.  As is pointed out in the discussion, this suggests that dietary fat in these trials isn’t likely to influence weight loss; and that the benefit of the low fat diet compared to the usual diet could be due to an intervention effect (more interaction with the research staff/dieticians, more self-monitoring, etc)

The better performance of the low carbohydrate diet would suggest that replacing carbohydrates with fat aids weight loss efforts, while the results from the low fat vs. higher fat trials would suggest that it wouldn’t make any difference.  The reason here might be because the low carbohydrate diets had a higher protein intake but the higher fat diets did not.  The trials where the low carbohydrate group had a higher protein intake than the low fat group tended to be the ones where the low carbohydrate group outperformed the low fat group [2]

This meta-analysis is timely, considering the recent ‘Paleo’ mouse study, where a low carbohydrate, high fat diet unsurprisingly led to obesity in mice [3].  The senior author has said that "Low-carbohydrate, high-fat diets are becoming more popular, but there is no scientific evidence that these diets work.” [4].  As I mentioned in the post, it’s clear none of the authors have read/acknowledged the results from relevant RCTs that contradict his claim and this can be clearly seen from this meta-analysis: that low carbohydrate, high fat diets work to some degree*  and to a better degree than low fat diets**

* Average weight loss in these trials (low fat, low carb, etc) is generally not very exciting.  So now, as the authors conclude "Additional research is needed to identify optimum intervention strategies for long-term weight loss and weight maintenance, including the need to look beyond variations in macronutrient composition."

** While the difference between the low carbohydrate and low fat groups isn’t large, consider that most of the low carbohydrate diet arms were mostly ad libitum while most of the low fat arms included some level of advice to deliberately reduce calorie intake

A paradigm shift: This paper is primarily a meta-analysis looking at weight loss in RCTs of low fat diets, where the main conclusion is that “Findings from our systematic literature review and meta-analysis of RCTs do not support the efficacy of low-fat diet interventions over higher-fat diet interventions of similar intensity for significant, long term, clinically meaningful weight control”.  Some people may see this as a profound loss for the low fat dogma (which is still very prevalent in the media and in public health), particularly as this paper is co-authored by a few big names (David Ludwig, Walter Willett and Frank Hu).  But before you get too surprised, realise that the Harvard School of Public Health hasn’t been promoting a low fat diet for quite a while [5]

Their ideal slightly higher fat diet is one that’s low in saturated fat and high in polyunsaturated fat, where vegetable oils are included on the Harvard healthy eating plate and are recommended to be a major fat source [6].  These kinds of people can influence policy makers and it’s interesting to note that the new 2015 USDA dietary guidelines have removed the restriction on total fat intake but have made ‘oils’ part of their key recommendations and a kind of pseudo food group [7, 8, 9].  This is mainly based on the idea that replacing saturated fat with polyunsaturated fat will reduce the risk of coronary heart disease, however this isn’t supported by adequately controlled RCTs [10, 11].  The new emphasis of vegetable oils, which are ubiquitous and something westerners have no difficulty getting plenty of, may simply just dilute the nutrient density of the diet

Tuesday, March 22, 2016

Diet, Uric Acid and Gout

The conventional advice surrounding diet and gout will recommend that to reduce the consumption of high protein and high purine foods.  On the other hand, people giving advice in alternative health communities may argue against the need reduce protein and purine consumption and then stress the importance of the ‘fructose > uric acid’ mechanism

In a couple of earlier blog posts I looked evidence from clinical trials on how protein and fructose affect uric acid

  • Fructose increases postprandial uric acid, but will only increase fasting uric acid if it increases insulin resistance
  • High protein and purine meals will likely increase postprandial uric acid, but have a modest or no effect on fasting uric acid 

If you deal with the underlying causes (such as insulin resistance (see initial post)) then you no longer have to worry about the triggers (protein, purines, fructose, etc).  This will often deal with other current or future health issues rather than just putting a bandaid on the current problem.  This is particularly important for gout where foods rich in protein, purines or fructose include meat, fish, organ meats, legumes, some vegetables, fruit and chocolate*.  This list includes most whole foods and many of the healthiest things to eat.  Many high purine foods would have been staples in the diet of ancient humans prior to agriculture (grains and dairy) and purines could potentially be a measure of cellularity as as RNA is a major source of purines

But the postprandial effects shouldn’t be discounted** as they could potentially trigger a gout attack in a susceptible person.  Much of the rest of the literature on how diet affects postprandial uric acid is concerned with the postprandial inflammatory response.  (I wrote about this an earlier post on how consumption of most macronutrients leads to postprandial inflammation but several substances in whole foods and exercise have been found to protect against this).  However, the outcomes of these studies are mixed and there are two contradictory narratives.

In healthy overweight middle-aged adults, a high calorie (1416 kcal), moderate protein (51g, 14%) high fat (82g, 52%) and low purine meal increased postprandial triglycerides, inflammation and uric acid levels, whereas other plasma antioxidants (uric acid is an antioxidant) were not affected [1].  A later study using the same meal found this postprandial increase in uric acid to be prevented by antioxidant and polyphenol rich fruit juices [2].  The increase in uric acid is thought to be due to an endogenous antioxidant response to postprandial oxidative stress that can be prevented by ingestion of antioxidant-rich and polyphenol rich fruit juices [1] [2]

Whereas other studies have found that dietary fat has the opposite effect in slightly or non-significantly lowering uric acid.  One study found that 60g of fat (12g SFA, 35.35g MUFA, 12.75g PUFA) slightly but significantly decreased uric acid by from 288 to 278 umol/L and that this correlated with oxidative stress [3].  Another study found heated or unheated olive oil or safflower oil non-significantly reduced uric acid [4].  The explanation here is that postprandial oxidative stress from the increase in postprandial triglycerides lowers endogenous antioxidants such as uric acid, and that a set point for plasma uric acid increases in response to postprandial oxidative stress [3]

Regardless of whether postprandial inflammation increases or decreases uric acid it’s probably a good idea to reduce it (via fruits and vegetables, other whole foods, exercise, etc) as this inflammation alone may contribute to triggering a gout attack

* Dairy and coffee are rich in protein and purines respectively but both are strongly inversely associated with the incidence of gout in observational studies, while fruit and purine rich vegetables aren’t significantly associated with the incidence of gout.  This might be due to other components of these foods lowering uric acid [5]

** “Since the acute effects of fructose to raise blood pressure occur during the ingestion of fructose (and are likely mediated by uric acid), it is not surprising that the authors did not show an effect on blood pressure; indeed, a similarly designed study would conclude that glucose-rich diets do not increase insulin levels.” [6]

That’s probably it for gout.  I’ll leave you with few other resources:

  • A draft chapter on gout not included in Good Calories, Bad Calories (thanks Zooko for the link)
  • An open access Cochrane meta-analysis on dietary supplements for gout [7]
  •’s page on for uric acid [8]

Thursday, March 10, 2016

Does Protein Increase Uric Acid?

In an earlier blog post I looked at the evidenced from clinical trials of whether fructose increases uric acid (blog).  In this post I want to do the same for protein (see table below).  The proposed mechanism here is more obvious – uric acid is a breakdown product of amino acid (and purine) metabolism: so higher protein intake would increase uric acid production, which is thought to lead to higher uric acid

Outcome of high protein group
With kidney stones
High vs. low animal protein
2 weeks
13% increase in urea, no change in uric acid
Healthy adults
200g/d red meat vs. whole grains
3 weeks
10% increase in uric acid
Type 2 diabetes
30% vs. 15% protein
5 weeks
Increase in GH, IGF-1 and urinary cortisol.  No change in uric acid, calcium excretion or thyroid hormones
Middle-aged healthy men
160g/d beef vs. 26g/d beef
6 weeks
No difference in uric acid.  Greater increase in triglycerides
Overweight adults (90% women)
32:28:41 vs. 15:21:66
6 weeks
Greater satiety.  No significant differences (including uric acid), except higher urinary nitrogen, calcium and uric acid)
Healthy adults
29:54:17 vs. 15:36:48
2 weeks
Lower triglycerides, higher 25(OH)D, no difference in uric acid, more acidic urine
Healthy young women
High vs. low acidic amino acid and purine diets
5 days
Non-significant increase in uric acid (~5%)
Postmenopausal women (aged 50 or over)
30g/d of dairy protein (+15g/d protein vs. baseline)
4 weeks
No change in uric acid or urea
Fairly healthy, mostly overweight adults (aged between 35-71)
27:26:47 vs. 16:26:59
(high protein from gluten, fibre held constant)
1 month
Decrease in triglycerides and uric acid.  Increase in urea and urea clearance
Type 2 diabetes
LoBAG30 diet (30:40:30) vs. 15:30:55
6 days
No change in plasma uric acid or cortisol.  Increase in urinary cortisol, sodium, nitrogen, uric acid but no change in pH.  Increase in glucagon

Most of the studies found that a higher protein diet lead to either no change or a modest increase (~10%) in fasting uric acid levels.  The few studies that measured it found high protein diets consistently increased uric acid excretion (higher urine uric acid).  This negative feedback system maintains normal uric acid levels in response to the greater uric acid production from higher protein diets

I struggled to find any studies in humans looking at whether higher protein diets increase postprandial uric acid.  However, I did find a study compared the postprandial uric acid response of haddock, liver and soybeans to look at how different purines affect postprandial uric acid, while keeping total protein and total purines constant [11].  The study concluded that hypoxanthine and adenine disproportionately increased postprandial uric acid, although I don’t think you could say this definitely as there were other differences in the meal and may be other differences in the components of those foods that could influence the postprandial uric acid response.  What you can see from those graphs is that uric acid levels would return to normal a couple to several hours after high protein and purine consumption and so wouldn’t really affect fasting uric acid levels as the trials have shown, but  the postprandial increase in uric acid may be a concern for people with gout or high uric acid levels

* Higher urine uric acid is a factor in the development of uric acid kidney stones.  Uric acid kidney stones account for about 10% of all kidney stones and other factors in their development include low urine pH (diet can influence this and insulin resistance also lowers urine pH (everything seems to come back to insulin resistance)) and low urine volume [12]