'Survival of the Fittest!' Large-Scale Study Backs Classic Evolutionary Paradigm - Being Unfit Worse Than Smoking | Plus: Fit/Unfit - What are You + What Can You do About it?

Even the difference between having 'below ' vs. 'above average' fitness levels amounts to the same 1.4-fold increase in mortality risk the scientists calculated for smoking cigarettes.

When I first read about the latest study from the Cleveland Clinic and that it would demonstrate that "not working out" was "worse than smoking", I expected that a press-release writer had compared the reduction in mortality risk and physical fitness, which has been observed by a new medium-scale observational study from his employer, to the hazard ratio (HR) other scientists calculated for smoking in a completely different study (or meta-analysis) for publicity reasons.

However, upon closer scrutiny, it turned out that both, the hazard ratio for smoking vs. non-smoking, which is 1.41 (p < 0.001), and the hazard ratio for elite vs. low fitness, which is 5.05 (p < 0.01) and hence 3.6 times higher, were based on analyses of the same dataset - cool!

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When someone claims that being unfit (which is not identical to "not working out", though | see red box for elaborations) is worse than smoking, he is thus not comparing apples to oranges if he quotes Kyle Mandsager's latest study to support this claim.

Figure 1: Risk-Adjusted All-Cause Mortality | Adjusted hazard ratios (HRs) for all-cause mortality compared with low performers in all patients (A) and by sex (B) (P values are for comparisons with low performers | Mandsager 2018).

One could, even go one step further and add that even having coronary artery disease (CAD | adjusted HR 1.29, 95% CI 1.24-1.35; P<0.001) and/or diabetes (adjusted HR 1.40, 95% CI 1.34-1.46; P<0.001) is not as bad as being unfit vs. super fit (adjusted HR 5.04, 95% CI 4.10-6.20; P<0.001).

Moreover, Mandsager found that even small differences in fitness, as well as differences among the fittest 20%, went hand in hand with a practically relevant reduction in mortality risk.

Over the course of the ~8-year period Mandsager et al. monitored their subjects, the researchers did, for example, observe the same 1.4-fold increase in mortality risk for people with 'below' and 'above average' fitness levels as they did for smokers vs. non-smokers.

Table 1: Group classifications by cardiorespiratory fitness used in the study by Mandsager et al. 2018; marked in green is a 30-year-old male with a 'high' fitness level.

How was the subject's fitness assessed? In the study at hand, the fitness of the subjects was quantified according to their estimated VO2Max.

The latter had been determined for all 122 007 patients in different exercise tests (the specific tests were chosen according to the patients' individual health status). Table 1 gives you an overview of the VO2 values in METs (1 MET = 3.5 ml^O2/kg^bodyWeight/min, hence 13.7 METS = 47.95 ml^O2/kg^bodyWeight/min) and the corresponding fitness level.

You want tangible examples? Well, a 30-year-old who will be exhausted after walking (1.7 mph) on a treadmill with an incline that progressed from 0-10% in 3-minute intervals for 9 minutes would fall into the 'low' fitness category. The same 30-year-old would be categorized as 'highly' fit if he managed to stay on the treadmill for 18 minutes, progressing, again in 3-minute intervals, from walking (1.7mph) at 0% incline to running at 4.2 mph at an incline of 16% before he'd be totally exhausted (see infobox "How do you estimate your fitness" for more info). 

And people with a 'below average' fitness level (= having a VO2max  of 8.2 ml/kg/min METs vs. 6.1 ml/kg/min) still had a -52.8% (p < 0.01) reduced hazard of biting the dust than those who found themselves in the lowest fitness category.

Figure 2: Plot of the hazard ratios for being in the 'low' (left) and 'high' (right) fitness versus all other categories (based on Mandsager 2018); note: everything above the red demarcation line at HR = 1.0 indicates that being in the corresponding fitness category vs. 'low' (left) and 'high' (right) is protective, everything below the red line indicates that being in this category is associated w/ a greater mortality hazard compared to having a 'low' or 'high' fitness level, respectively.

In comparison, the -22% reduced mortality hazard the scientists observed, when they compared subjects with 'elite' (VO2Max of 13.8 ml/kg/min METs) vs. 'high' (VO2Max of 11.4 ml/kg/min METs) fitness levels, seems relatively small. The fact that you still see reductions in people's mortality risk in these realms of literally 'extraordinary' performance is, however, quite outstanding and should motivate you not to measure your training success in PRs on the bench, alone. Apropos...

Now, your most important question probably is: Where do I stand 'fitness-wise'?

Well, to answer this question you'd have to do a treadmill maximal exercise test like the one(s) the subjects in the study at hand did. Since, different tests were used - according to what the participants' fitness/health would allow - your best bet here is the so-called "Bruce test".

Table 2: Overview of the speed and grade at which you have to run on the treadmill during the Bruce test (University of British Columbia) - the stages are completed subsequently. Your outcome is calculated based on the cumulative time you spent on the treadmill as VO2 max = 14.8 - (1.379 x T) + (0.451 x T²) - (0.012 x T³). With that being said, you can also use a tool like QxMD to calculate your fitness level. 

The Bruce test, which was designed in 1963 by Robert. A. Bruce, MD, as a noninvasive test to assess patients with suspected heart disease, is also commonly used to estimate the VO2 max in athletes.

Like every other maximal exercise test, the Bruce test requires you to run on a treadmill (tests with cycle ergometers and other 'cardio' equipment are also possible) while the speed and incline of the treadmill, you're running on, is increased in 3-minute intervals (see Table 2). The test ends when you cannot keep up with the pace, any longer. Your age, sex, and the stage you've made it to will then allow you to estimate your VO2Max.

Let's consider an example: Say you are 30 years-old male, did an incremental running test and were exhausted after 16 minutes, when you were running at a speed of 4.2mph at an incline of 16%... a calculator like the one from OxMD would then tell you that your capacity is ~14.64 mL/kg/min METs, which is significantly better than the predicted average for a 30-year old 11.4 mL/kg/min METs.

To actually measure your VO2Max, which was the measure of fitness that was used in the study at hand, you would need a treadmill and a metabolic cart as it is shown in the video, but you can estimate it using just the treadmill.

How to estimate your VO2Max / Fitness? When you've done your own Bruce Test at home or at the gym, you don't have to use the formula VO2 max = 14.8 - (1.379 x T) + (0.451 x T²) - (0.012 x T³). You can simply calculate those values using tools like QxMD based on the speed and incline that you were running at, when you had to abort the test... Keep in mind, though, irrespective of the formula or calculator you use, the figure you get is just an estimation of your VO2Max and will never be as accurate as data from a metabolic cart (see video).

In fact, those 14.64 ml/kg/min METs are ~28% better than the prediction for a 30-year old male. And in the study at hand, your imaginary counterpart would find himself in the upper ranks of the "high fitness" group (see Table 1).

There's still room for improvement, though; if you achieved the 'elite' level (VO2Max of >15ml/kg/min METs) you'd have an even lower mortality hazard than those in the 'high fitness' category - a non-significant (p = 0.09) improvement of -19%, as the corresponding sex-specific data from the FT (sex-specific values are not plotted in Figure 3) suggests. By the way, with the same fitness values your likewise imaginary 25-year-old girlfriend would not just already be at the 'elite' level, she would also record a borderline significant -35% (p = 0.06) reduction in all-cause mortality compared to an already fit (female) friend in the 'high' fitness category.

I guess, by now you'll begin to realize that both one's fitness, as well as the reduction in mortality risk one can expect based on the results of the study heavily, depend on various confounding factors, i.e. one's sex, age, comorbidities, etc.

DO not confuse the time you spend exercising with the fitness level you have! If you read the headlines, you will find that several websites chose similar titles like "No Such Thing as Too Much Exercise, Study Finds" - a headline that (falsely) suggests that it's the amount of and hence the time you spend exercising that's at the heart of the reduced mortality hazard in the study under review.

Table 3: Case-control studies presenting life expectancy of (former) athletes compared to that of control subjects (Reimers 2012).

(Un?)fortunately, the time you spend on the treadmill, in the gym or running, walking, and cycling outdoors is at best a proxy, but by no means a valid predictor of your physical fitness. I would bet my favorite pair of gym-shoes (and yes, I love squatting in them) that there's more than one SuppVersity reader who would achieve higher fitness levels - in this context estimated VO2max values - if he/she trained less not more. It would thus be haphazard to increase your training volume beyond your adaptational capacity to reduce your mortality risk - the opposite could happen!

Yes, studies in (former) elite athletes do indeed confirm an increased life expectancy (1-8 years, depending on the study, see Table 3 | Reimers 2012). However, unlike the weekend warriors at your local gym, these athletes have trainers who make sure that they don't out-train their own recovery ability and continuously improve their VO2max (fitness-)levels.

Scientists are well aware of this potentially life-threatening disconnect between actual physical activity and the estimated VO2Max values (~physical fitness). John Higgins, MD, MBA, MPhil, from the Lyndon B. Johnson General Hospital in Houston, for example, warns that the study he was not actively involved cannot account for possible adverse effects of (too) intense training and highlights: "[W]e cannot exclude [...] issues with overtraining or overdoing the exercise to extremes with respect to total weekly volume, and not allowing an appropriate recovery after exercise"(MedPageToday) - if it applies at all, the overtly simplistic mantra "more helps more" does therefore only apply to physical fitness, yet not to the amount of effort you invest in achieving it.

The latter is an important insight, as it can also explain why some of the effects the scientists observed when they compared the 'high' vs. 'elite' fitness group did not reach statistical significance. We've seen that earlier in our example. If you thought that was bizarre, what do you make of the fact that exactly those of whom you'd usually suspect that they'd benefit most, i.e. people with comorbidities such as CAD [=Coronary artery disease], diabetes, hypertension, or hyperlipidemia (i.e. high blood lipids) do not seem to benefit from 'elite' fitness (see Figure 3).

Figure 3: Risk reduction in subjects with elite vs. high fitness status; only full bars represent sign. effects (Mandsager 2018)

That's not just odd, it also conflicts with the titles of the mainstream media coverage of the study at hand. Gizmodo.com, for example, titled: "No Such Thing as Too Much Exercise, Study Finds" (Gizmodo.com) - now obviously that's an unwarranted identification of 'fitness' and 'exercise', but what about the previously quoted title from medpagetoday.com: "Confirmed: Higher Cardiorespiratory Fitness Predicts Lower Mortality"?

What's the Optimal HIIT Protocol for Trained Individuals? 48 x 10s or 8 x 60s for Fitness + Improved Body Composition? Find out!

How do you increase your VO2Max? One of the most recent meta-analyses indicates that similar increases in VO2Max (which is the measure of fitness in the study at hand) "can be achieved in low training doses at higher exercise intensities[, e.g. #HIIT, and] higher training doses of lower intensity [#cardio]" (Scribbans 2016). Obviously, this does not negate that "[w]hen [the] volume of exercise is controlled, higher intensities of exercise are more effective for improving VO2max than lower intensities of exercise in healthy, young adults" (Gormley 2008).

Now this does mean that #HIIT (vs. #cardio) is the more time-efficient exercise modality to increase your fitness (Helgerud 2007), it is yet - and people tend to forget that these days - not the only way of upgrading your fitness from 'above average', where I hope most of you will be now, to 'high'. Both, the tried and proven "steady-state" training (albeit at challenging intensities of 70%-85% for long durations), as well as an intense, fast-paced resistance training, have the potential of increasing one's VOMax significantly (note: for the latter VO2max increases will probably only occur in rather untrained individuals | see Ozaki 2013).

Irrespective of the mode of exercise you use, there's one thing you should keep in mind: The fitness of the subjects in the study at hand was tested only at baseline, it is thus not clear how long you'd have to stay at a given (improved) fitness level to reap the corresponding mortality benefits.

In contrast to the Gizmodo headline, the MedPageToday-title does not imply that "more exercise helps more". It implies that a higher fitness value predicts lower mortality - and that's exactly what the study at hand shows - irrespective of the previously highlighted lack of significance.

Figure 3: Number of subjects classified as having a "low", "below average", "average", "high", and "elite" fitness levels; see Table 1 for what the fitness levels mean in METs (plotted based on Mandsager 2018).

The latter - and I guess you have probably suspected that already - is almost certainly a consequence of (a) the overall small number of participants in the 'elite' group, i.e. N=3570 vs. N~30,000 in all other fitness classes, as well as (b) the generally lower likelihood that someone with 'elite' fitness suffers from diabetes, high blood lipids, or any of the other comorbidities Mandsager et al. investigated separately. And in fact, ...

"[t]he prevalence of associated comorbidities decreased significantly with increasing performance [and what's interesting] with the exception of hyperlipidemia, which was present in 31.6% (1128 of 3570) of elite performers and only 25.1% (7323 of 29 181) of low performers (P < .001)" (Mandsager 2018). 

If you take another look at the striped bars, which represent non-significant differences, in Figure 3, you will find that these bars refer to the same groups, the scientists mentioned in the quote: subjects with CAD, diabetes, high blood lipids, and normal blood pressure values, i.e. those people who were under-represented in the elite fitness group. Accordingly, the lack of statistical significance doesn't really come as a surprise... and if that's not motivating enough: the 'elite' vs. 'high' fitness advantage for the whole group was 22% and statistically significant (p = 0.02).

If you are too lazy to upgrade and maintain your fitness level, you may be interested in my article and interview about "The Vampire Approach to Longevity" from April 2018, an article + SHR interview in which I discuss the use of literally 'young blood' injections for life-extension purposes | read more

Bottom line: "Survival of the fittest", that's a phrase that you would usually expect to read in a biology textbook, not in a study about human health and longevity... but wait: humans are animals and in the animal kingdom it's the fittest who survive - against that background, let me ask you: Is it really surprising that being 'super fit' vs. 'unfit' increases your all-cause mortality risk by a factor 5x, and hence 3.6-fold more than smoking in the same cohort of N = 122,007 patients of the Cleveland Clinic who were screened for their cardiorespiratory fitness?

You can probably answer this allegedly populist question on your own and would thus like to point out that the mere size of the study is not a sufficient predictor of the validity, relevance, and explanatory power.

In this regard, the authors highlight the following: "The degree to which high CRF [cardiorespiratory fitness] preselects patients with lower mortality vs causes a reduction in mortality is not discernible from our study" (Mandsager 2018). 

Or, as I would phrase it: Since we're dealing with a retrospective observational study, we are not allowed to infer a causal relationship between the subjects' fitness levels and their mortality risk. What we can do, however, is to call the existence of a causal link a "reasonable assumption" - an assumption of which we know that it is unlikely to be either challenged or confirmed in an 8-10-year longitudinal, large-scale, randomized clinical trial in subjects that were not chosen, because they were advised to participate in an exercise test at the Cleveland Clinic. Why's that? Well such a trial would cost millions of research dollars and face a good dozen of severe obstacles ranging from ethical issues to very practical questions such as: "How do I ensure minimal dropouts and the maintenance of the initial fitness level?" | Comment!

References:

• Gormley, Shannan E., et al. "Effect of intensity of aerobic training on V˙ O2max." Medicine & Science in Sports & Exercise 40.7 (2008): 1336-1343.
• Helgerud, Jan, et al. "Aerobic high-intensity intervals improve V˙ O2max more than moderate training." Medicine & Science in Sports & Exercise 39.4 (2007): 665-671.
• Mandsager K, Harb S, Cremer P, Phelan D, Nissen SE, Jaber W. "Association of Cardiorespiratory Fitness With Long-term Mortality Among Adults Undergoing Exercise Treadmill Testing." JAMA Network Open. 1.6 (2018):e183605. doi:10.1001/jamanetworkopen.2018.3605
• Ozaki, Hayao, et al. "Resistance training induced increase in VO 2 max in young and older subjects." European Review of Aging and Physical Activity 10.2 (2013): 107.
• Reimers, Carl D., G. Knapp, and Anne Kerstin Reimers. "Does physical activity increase life expectancy? A review of the literature." Journal of aging research 2012 (2012).
• Scribbans, Trisha D., et al. "The effect of training intensity on VO2max in young healthy adults: A meta-regression and meta-analysis." International journal of exercise science 9.2 (2016): 230.

If the Androgen Receptor Response to Training Determines Your Gainz, the Question is: How Can You Optimize 'ur AR Density? Training-, Diet-, and Supplement-Effects Reviewed

Your androgen receptor status may not just determine how much muscle you gain - the data from Morton et al. seems to suggest that it even determines if you make visible muscle gains, at all.

Unless you've missed following the SuppVersity on Facebook, yet, you will remember my recent, highly popular post which previewed the results of a recent study from the McMaster University in Ontario. Meanwhile, the full-text of the study has been published and it highlights what I pointed out before: It supports previous research, which showed that neither the acute increase in intramuscular free testosterone, nor dihydrotestosterone, or 5α-reductase predicts the muscle gains of resistance-trained men.

More importantly, however, it has the potential to shift the interest in post-exercise changes of testosterone, IGF1, GH & co. to the androgen receptors or rather how they (and maybe other receptors, like the IGF-1 receptor) respond to resistant exercise.

Read more about studies involving TRT/HRT & co on suppversity.com:

What to expect from normalizing Testosterone

Testosterone Gel Augments 'ur Gainz

PWO T-Increases Don't Determine Your Gainz

The Hormonal + Other Underpin-nings of Gainz

Impressive 12% T-Boost (+20% IGF1) W/ Tribulus

T +/- Exercise to Rejuvenate Old Muscle?!

As previously discussed, Morton et al. examined if there's a link between circulating hormones, intramuscular hormones, and intramuscular hormone-related variables in resistance-trained men before and after 12 weeks of RET. The study results speak for themselves:

"Unlike intramuscular free testosterone, dihydrotestosterone, or 5α-reductase, there was a linear relationship between androgen receptor content and change in LBM (P < 0.01), type 1 CSA (P < 0.05), and type 2 CSA (P < 0.01) both pre- and post-intervention. [Thus indicating that] intramuscular androgen receptor content, but neither circulating nor intramuscular hormones (or the enzymes regulating their intramuscular production), influence skeletal muscle hypertrophy following RET in previously trained young men" (Morton 2018). 

This result becomes particularly obvious if you take a look at the type-I & -II muscle fiber and lean body mass gains of the AR high vs. AR low responders. Effectivel, Morton et al. didn't just find that those with the highest- (HIR; n = 10) androgen receptor (AR) response made the greatest gains, it even suggests that those with a suboptimal AR response don't see any gains, at all.

Figure 1: When they stratify the 20 subjects according to their androgen receptor response to training, Morton et al. found that one group saw great, the other almost no gains and thus shed a whole new light on the previously known, but often ignored correlation between AR density and skeletal muscle hypertrophy (Morton 2018).

It should thus be obvious why the question from the headline is relevant for anyone busting his ass in the gym - the question "How do you make sure you're one of the guys in the 'high responders' group?" My review of the literature can give you some pointers:

• Resistance training is probably the best-proven modulator of AR density - It may sound too good to be true, but many of you may probably already be following the best proven "androgen receptor density"-program there is: heavy, high(er) volume resistance training. Based on the results of previous studies that show how androgens can increase the AR density in myonuclei and satellite cells (Ferrando 2002; Kadi 1999; Syms 1985; Gregory 2001), in vitro, many researchers seem to believe that the temporary exposure to exercise-induced increases in testosterone was the causative factor here.
  
  Personally, I don't consider this explanation to be true. If we assume that it's the transient increase in testosterone, the latter should also be a determinant of muscle gains - a significant number of studies does yet show that this is not the case.
  

  

  Figure 2: Changes in skeletal muscle androgen receptor content (mean ± sem) due to the heavy resistance exercise bout (5 × 10RM leg presses) in younger (n = 5 | 28 ± 3 yrs) and older men (n = 8 | 70 ± 2 yrs) before and after the 12-month experimental heavy resistance training period (Ahtiainen 2015) - on a side note: The study confirms the initially postulated correlation between correlated changes in fCSA and lean body mass.

  Furthermore, one would expect the positive effects to occur relatively soon after the workouts. The reality of scientific studies such as Ahtiainen et al. (2015 | see Figure 2), however, shows that this is not the case - at least not for young men such as the subjects in Morton's study.
  
  

  

  Figure 3: Protein expression of androgen receptor (B) in the skeletal muscle of male and female rats altered by acute exercise. Samples from male (n = 8) and female (n = 8) control rats and from male (n = 8) and female (n = 8) exercised rats (analyzed by immunoblotting | Aizawa 2010).

  For older men, the results look significantly different, but a significant increase in AR density wasn't observed for them either - no wonder in view of the statistical 'power' of this N=8 mini-study. In conjunction with a 2010 study by Aizawa et al. which found pronounced increases in AR density female, but no effect on ARs in male rodents (see Figure 3), and very similar effects in humans (Vingren 2009 | slight decreases and marginal increases in AR in trained men and women, respectively, immediately post and 70 minutes after the workout), one can still speculate that both, age and sex matter when it comes to (a) the AR response and (b) its downstream effects on skeletal muscle hypertrophy, which is - I don't have to tell you that - significantly less pronounced in women and elderly vs. young men.
  
  So, sex and age matter, but they cannot be the only factors to explain the heterogeneity of pertinent studies; and, more importantly, both are irrelevant for the Morton study, which is at the heart of this whole discussion.
  
  The first of two additional confounders that come to mind is the training volume. Vingren et al., who failed to record significant increases in AR density, for example, used a low-volume approach consisting of 8–10 repetitions of #squats at ∼50% of the subjects' estimated 1-RM followed by another set of 2–5 repetitions at ∼85% of the estimated 1-RM.

Check out my research update on BFR and compression garments from October 2018 | go ahead, read it!

Volume = stress, BFR = stress:  I think, at this point, it is worth mentioning that 'artificially' increasing the metabolic stress (an increase that usually comes with increases in volume) via #bloodFlowRestriction (BFR) seems to have a beneficial effect on your androgen receptor, as well. In their 2011 study, Loenecke et al. found that "the acute and chronic testosterone response to blood flow restricted exercise appears to be minimal when examining the current literature".

In view of the significant gains the authors observed that was odd - even though we know that the acute T-response is not a determinant of your gainz - accordingly, the scientists speculate that an increase in androgen receptor density following blood flow restricted exercise may explain why the same amount of testosterone can, when combined with BFR, produce increased gains - and you know what? In view of the way BFR seems to work and the overlap to high-volume training, this is not even totally unlikely.

• 

  Figure 4: People who do high volume training seem to indeed see greater benefits - at least that's what the small-scale study by Spiering et al. (2009) suggests. Bodybuilders who combine high volume training with periodic steroid abuse may even potentiate this effect - no wonder they're getting so big ;-) The chronic (ab-)use of androgens, on the other hand, seems to reduce the effects and will have the AR density return to baseline.

  A similarly low volume was used by Spiering et al. in the control group of their 2009 study, in which a standardized (low volume) knee extension workout was performed either on its own or after doing an upper-body workout (bench press, bench row, and seated overhead press at 4 sets of 10RM), which was specifically "designed to increase circulating T" (Spiering 2009).
  
  I have to say, though, that I personally doubt that the benefits are a consequence of the testosterone response to the upper body workout. If you asked me, I would venture the educated guess that it is rather a mere consequence of the increase in exercise volume and/or the total muscle mass that's involved in the workout.
  
  The volume hypothesis would obviously imply that the changes in androgen receptor density in the immediate and prolonged post-workout period increase with training volume - at least as long as the latter remains within "sane" limits.
  
  And even though I cannot prove the accuracy of this theory, it is corroborated by research from Willoughby & Taylor (2004). They tested the effects of 3x lower-body resistance exercise bouts, each separated by 48 h - all with a high volume of 3x10 on the squat, leg press, and leg extension exercise.
  
  Increases in AR density were observed in Willoughby & Taylor 2004 after only one workout (see Figure 5, sampling point 2), and the effects got significant (compared to control) after the 2nd and 3rd workout (see Figure 5, sampling point 3).
  

  

  Figure 6: Quantitative representation of the means (± SD) for the content of AR mRNA normalized to GAPDH. Numbers 1–4 indicate the four muscle sampling points (1 = immediately before exercise bout 1; 2 = 48 h after exercise bout 1 and immediately before exercise bout 2; 3 = 48 h after exercise bout 2 and immediately before exercise bout 3; 4 = 48 h after exercise bout 3; † sign. different from corresponding preexercise value; ‡ sign. dif. from CON; * sign. Group × Test interaction (P < 0.05 | Willoughby 2004).

  Moreover, the Willoughby study confirms that this increase goes hand in hand with increases in myofibrillar protein (P = 0.002) - with, and that's interesting, significantly greater increases in myofibrillar protein content 48 h after the third exercise bout (muscle sampling point 4) compared with sampling points 1, 2, and 3.
  
  Training at a high enough volume and with sufficient time for the androgen receptor rebound to occur (possibly after 24h, certainly after 48h) is #1 on the list of things that you can do to conserve and maximize your AR levels.
  
  Why's that interesting? Because this increase was observed in the biopsy in which you'd measure the effects of the most elevated AR levels after the 2nd workout (~60% over baseline | see Figure 5, again). A correlation analysis that would support a direct relationship between AR increases and gains wasn't conducted, though.

Figure 5: Biopsy timing may make all the difference - If measured 48h after exercise the AR density is significantly increased with either concentric or eccentric contractions .- without significant effects of the contraction mode, by the way (Bamman 2011).

The time-point at which the biopsies were taken in the various previously cited studies alone could explain the hetergoenous results. If we compare design and result of the study by Willoughby & Taylor to Ratamess' 2005 study, the first and only study that compared higher vs. low volume training (6x10 squats vs. 1x10 squats), the assumption that it's all about volume becomes highly questionable. After all, Ratamess and his colleagues from University of Connecticut didn't observe any beneficial effects of an increase in training volume - in fact, the higher volume squat program (10 sets vs. 1 set) actually produced a significant decrease in androgen receptor expression 1h after the workout, while the single set program left the AR density unchanged (Ratamess 2005).

Obviously, this doesn't mean that the AR levels of the subjects of Ratamess' study were not increased to a similar extent as it was observed by Willoughby & Taylor and confirmed by Bamman et al. (see Figure 5 & 6) who both took muscle biopsies 48h post workout - and that's also what Kvorning et al. imply in their 2006 paper when the authors refer to the timing "of the [muscle] biopsies" as a potential explanation for the "divergent results" of studies in this field.

• What we shouldn't forget, here, is that the inconspicuous "after" refers to 48h after the workout in the context of the Willoughby study. It should thus be obvious that the timing of the muscle biopsies is at least a 2nd and potentially even more important confounder that may explain the heterogeneous results of the previously cited studies (see red box above), because, as Vingren et al. point out the "current paradigm says that there's a "stabilization followed by a reduction and then a rebound in the acute AR response" in response resistance exercise.
  
  If this paradigm describes the time-course of the AR response correctly and time is in fact 'of the essence', this has profound implications for your workout programming, sa well. A 24h-48h delay in the AR response does, after all, seem to favor a medium vs. high training frequency with at least 24h of rest between two bouts of high volume resistance training over classic bro-splits, where you train on a daily basis.

While we are waiting for more research to answer the (still) open question about the interaction of volume, recovery times, and the androgen receptor response to resistance training, let's briefly take a look at the little we know about the potential benefits of dietary and supplementary interventions.

• 

  Figure 7: In Kraemer 2006, twenty-one days of LCLT supplementation (2g/day) significantly (P < 0.05) increased pre-exercise vastus lateralis AR content compared with PL. When RE was followed by water intake, AR content increased compared with PRE for PL only. Feeding following RE significantly increased AR content compared with pre-RE values for both LCLT and PL trials.

  Yes, l-carnitine tartrate seems to increase AR density - but is it the only supplement? Before we answer the question, let's briefly revisit the often-cited 2006 study by Kraemer et al. in which the researchers complemented results from a 2003 study which revealed that #LCLT will improve the "number of intact [hormonal] receptors" and thus increase the potential of "hormonal interactions" (Kraemer 2003). The more-recent cross-over study was conducted in ten resistance-trained men (mean+/-SD: age, 22+/-1 yr; mass, 86.3+/-15.3 kg; height, 181+/-11 cm) supplemented with 4g LCLT (equivalent to 2 g of L-carnitine per day) or placebo (PL) for 21 d.
  
  L-carnitine l-tartrate (and only the l-tartrate) form is #2 on the list of proven promoters of exercise-induced AR expression and probably the only one you're not already using to your advantage.
  
  What you'll rarely hear about the study's results, though, is that the benefits were contingent on the consumption of a #postWorkout nutritional supplement containing 8 kcal/kg body mass from 56% carbohydrate, 16% protein, and 28% fat.

A remark on anabolic steroids and their effects on AR density: If you think about high volume training, you probably think about bodybuilders. Needless to say that, for them, the effects of doing plenty of sets and reps often are potentiated by anabolic steroids, of which in vivo studies have shown that they will upregulate the AR content acutely.  Bros should be warned, though, because studies have shown that the steroids lose this effect over time and - when they've been used for weeks or months - the AR density returns to baseline (Ferrando 2002). The use of steroids in shorter cycles (as it obviously is common practice in the real world), on the other hand, has been observed to provide sustained increases in the androgen receptor content of male skeletal muscle (Kadi 1999) - as usual, the effects in females are unknown.

• In fact, the post-workout nutrient provision, alone, had beneficial effects on the androgen-receptor levels the scientists detected in the muscle biopsies they took from their subjects 48h after the last workout (see Figure 7).
  
  Adequate post-workout nutrition is thus #3 on the list and probably something you're already doing to conserve and maximize your AR levels.
  
  In that, it may be that incorporating creatine into this post-workout stack could have (as of yet unproven) extra benefits. How's that? Well, hypothetically, #creatine could exert some of its hypertrophy effects (partially) by an effect on the androgen receptor. Insane idea? Yeah, I admit I cannot prove it, but you will certainly all remember the "creatine increases DHT"-study (Van der Merwe 2009) that resurfaces once a year among a (then) panicking group of fitness enthusiasts. With DHT being four times more biologically potent than testosterone as an androgen receptor activator and its local production from testosterone via 5α-reductase being increased in response to resistance training alongside the androgen receptor content in the previously cited study by Aizawa, et al. (2010 | see Figure in original study), I don't think it's impossible that an interaction exists - if for nothing else in form of a second-order effect due to a creatine-induced increase in training volume.

Figure 8: While the provision of soy and whey did affect the change in skeletal muscle androgen receptor content, only the time effect, i.e. the effect of 12 wks of resistance training was statistically signif. in a recent study from the Auburn Univ. (Haun 2018).

Before anyone asks: 'No, soy protein doesn't negatively affect your androgen receptor density.' While the rumors that it will reduce testosterone are die hard, the evidence that it doesn't affect testosterone and - as of late - also its receptor is increasing. Only recently, Haun et al. (2018) published a study that acquits regular (not specialty = extra high isoflavone) soy protein of ruining your virility.

What Haun et al found, though, is that training increases the androgen receptor density of previously untrained, college-aged men (n = 47, 20 ± 1 yrs) that resistance trained for 12 weeks significantly - with greater increases in the soy vs. whey protein group -  non-significantly greater that is.

• That's too hypothetical for you? Well, in that case, you will like #4 on the list. Although technically not a supplement, people take it for non-medical reasons, anyway: #T3, i.e. iodothyronine, the "active" thyroid hormone which has been found to directly stimulate the expression of androgen receptors in skeletal muscle (Clement 2002). 
• 
  
• Keeping your thyroid chugging along nicely (in particularly the levels of T3) is #4 on the list and, hopefully, a thing that you're already doing to conserve and maximize your AR levels.
  
  Now, I don't recommend using a prescription drug for off-label purposes (also because using too much will - irrespective of increases in AR density - put you at risk of hyperthyroid muscle catabolism). What I do recommend, though is to keep in mind that (over-)training and undereating can trigger a rapid decline in thyroid function and hence T3 levels (see my 2013 article on "self-induced hypothyroidism") - hence, the interaction with T3 makes adequate recovery and nutritional fuelling even more important for those of you who want to maximize their androgen receptor levels.

"That's not much, I am not already doing!" I know that the previous list is not exactly exciting, but if anything, I could add avoid #Nicotine and #alcohol (Basiri 2016) and #castration (Suzuki 1997) to the list of at least decently proven AR expression modulators. Both nicotine and alcohol have been observed to reduce the AR density, ... in rodents and both outside of skeletal muscle, though.

Hence, high(er) volume training, adequate recovery, nutrition, and l-carnitine l-tartrate (yielding 2g of carnitine per day) have - as of today - to be considered the only "proven" promoters of AR density.

Figure 9: Intramuscular (A) free testosterone concentration, (B) dihydrotestosterone concentration, and (C) 5α-reductase expression, didn't differ between AR high and low responders and neither of these hormonal parameters had any effect on the gains of the 20 subjects in Morton's 2018 study..

With creatine making the "potentially beneficial" criteria only hypothetically, this makes l-carnitine l-tartrate (LCLT) the only OTC supplement on the list (note: there's no evidence that other forms of carnitine will do the same and sine LCLT is ~50% tartrate you have to take 4g/d to get the effective dose of 2g carnitine). I have to warn you, though: I doubt that the downstream effects the LCLT-induced increase in AR density (which is relatively small | see Figure 7) on your gains are going to be visible - unless, you have been retired for years if not decades, because all studies showing actual increases in lean mass with carnitine have been conducted in the elderly (Piston 2003; Malaguarnera 2007).

So what does that all mean? Well, if you want to see the often-marketed steroid-like gains, everybody is chasing, you will probably have to wait for a gene-drug that changes both, the baseline expression and exercise-induced increase of androgen receptors on your muscle tissue.

In the meantime, you can console yourself with the realization that in all the excitement about the results of the initially quoted study by Robert Morton, many seem to have forgotten that the scientists found nothing but a correlation between the AR response and increases in muscle size.

Practically speaking, this means: Even if this gene-drug already existed and effectively doubled your AR levels, it's (a) unlikely to double your gains and (b) not even guaranteed to have a significant effect on your gains, at all - and the researchers who emphasize that their data on the "androgen receptor correlation [is] an inflated estimate due to the choice of measuring only higher and lower responders to our training protocol" (Morton 2018) make it quite clear that this estimate was meant to "illustrate the difference in RET-induced muscle hypertrophy and investigate the influence of circulating and intramuscular hormone-variables on two distinct groups" (Morton 2018). In conjunction with other methodological limitations, which are likewise discussed in great detail in the corresponding section of the FT (read it), this 'illustrative' nature of the results leaves ample room for future studies to (a) confirm or refute the 'AR hypothesis of muscle gains' and to (b) quantify the interaction between AR expression and gainz  | Comment!

References:

• Ahtiainen, Juha P., et al. "Effects of resistance training on testosterone metabolism in younger and older men." Experimental gerontology 69 (2015): 148-158.
• Aizawa, Katsuji, et al. "Acute exercise activates local bioactive androgen metabolism in skeletal muscle." Steroids 75.3 (2010): 219-223.
• Bamman, Marcas M., et al. "Mechanical load increases muscle IGF-I and androgen receptor mRNA concentrations in humans." American journal of physiology-endocrinology and metabolism 280.3 (2001): E383-E390.
• Basiri, Mohsen, et al. "Immunohistochemistry study on androgen and estrogen receptors of rat seminal vesicle submitted to simultaneous alcohol-nicotine treatment." Cell Journal (Yakhteh) 18.3 (2016): 458.
• Clément, Karine, et al. "In vivo regulation of human skeletal muscle gene expression by thyroid hormone." Genome research 12.2 (2002): 281-291.
• Deschenes, Michael R., et al. "Endurance and resistance exercise induce muscle fiber type specific responses in androgen binding capacity." The Journal of steroid biochemistry and molecular biology 50.3-4 (1994): 175-179.
• Ferrando, Arny A., et al. "Testosterone administration to older men improves muscle function: molecular and physiological mechanisms." American Journal of Physiology-Endocrinology and Metabolism 282.3 (2002): E601-E607.
• Gregory, Christopher W., et al. "Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen." Cancer research 61.7 (2001): 2892-2898.
• Haun, Cody T., et al. "Soy protein supplementation is not androgenic or estrogenic in college-aged men when combined with resistance exercise training." Scientific reports 8.1 (2018): 11151.
• Kadi, Fawzi, et al. "Effects of anabolic steroids on the muscle cells of strength-trained athletes." Medicine and science in sports and exercise 31.11 (1999): 1528-1534.
• Kraemer, William J., et al. "The effects of L-carnitine L-tartrate supplementation on hormonal responses to resistance exercise and recovery." The Journal of Strength & Conditioning Research 17.3 (2003): 455-462.
• Kraemer, William J., and Nicholas A. Ratamess. "Hormonal responses and adaptations to resistance exercise and training." Sports medicine 35.4 (2005): 339-361.
• Kraemer, William J., et al. "Androgenic responses to resistance exercise: effects of feeding and L-carnitine." Medicine & Science in Sports & Exercise 38.7 (2006): 1288-1296.
• Kvorning, Thue, et al. "Suppression of testosterone does not blunt mRNA expression of myoD, myogenin, IGF, myostatin or androgen receptor post strength training in humans." The Journal of physiology 578.2 (2007): 579-593.
• Loenneke, J. P., et al. "Acute and chronic testosterone response to blood flow restricted exercise." Hormone and metabolic research 43.10 (2011): 669-673.
• Malaguarnera, Mariano, et al. "l-Carnitine treatment reduces severity of physical and mental fatigue and increases cognitive functions in centenarians: a randomized and controlled clinical trial–." The American journal of clinical nutrition 86.6 (2007): 1738-1744.
• Pistone, Giovanni, et al. "Levocarnitine administration in elderly subjects with rapid muscle fatigue." Drugs & aging 20.10 (2003): 761-767.
• Ratamess, Nicholas A., et al. "Androgen receptor content following heavy resistance exercise in men." The Journal of steroid biochemistry and molecular biology 93.1 (2005): 35-42.
• Spiering, Barry A., et al. "Elevated endogenous testosterone concentrations potentiate muscle androgen receptor responses to resistance exercise." The Journal of steroid biochemistry and molecular biology 114.3-5 (2009): 195-199.
• Syms, A. J., et al. "Mechanism of androgen-receptor augmentation. Analysis of receptor synthesis and degradation by the density-shift technique." Journal of Biological Chemistry 260.1 (1985): 455-461.
• Van der Merwe, Johann, Naomi E. Brooks, and Kathryn H. Myburgh. "Three weeks of creatine monohydrate supplementation affects dihydrotestosterone to testosterone ratio in college-aged rugby players." Clinical Journal of Sport Medicine 19.5 (2009): 399-404.
• Venkataraman, P., et al. "Effects of Vitamin Supplementation on PCB (Aroclor 1254)‐Induced Changes in Ventral Prostatic Androgen and Estrogen Receptors." Endocrine research 30.3 (2004): 469-480.
• Vingren, Jakob L., et al. "Effect of resistance exercise on muscle steroid receptor protein content in strength-trained men and women." Steroids 74.13-14 (2009): 1033-1039.
• Willoughby, Darryn S., and Lemuel Taylor. "Effects of sequential bouts of resistance exercise on androgen receptor expression." Medicine and science in sports and exercise 36.9 (2004): 1499-1506.

MCTs and High Protein - One Will Turn You into a Metabolic Furnace, the Other Will Just Burn Money - #ShortNews 10/18

It's about time for some nutrition science news.

For today's installment of the #ShortNews, I've picked two hitherto unpublished studies the main results of which have been presented recently as part of the Proceedings of the Nutrition Society Summer Meeting. The studies by Carr et al. and Maher et al. deal with the metabolic effects of two dietary nutrients you'll all be familiar with: protein and medium-chain triglycerides aka MCTs.

Learn more about building muscle and strength while losing fat with www.suppversity.com

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Study Indicates Cut the Volume Make the Gains!

With both of them being conducted in healthy, normal-weight individuals and the use of sophisticated measuring equipment (eg. metabolic chamber in Carr et al.) and/or additional 'cardio' exercise, respectively, both small-scale studies are - in my humble opinion - worth looking at, even in their current pre-publication stage.

• Hunger ↘, satiety ↗, and 24h energy expenditure ↗ by 4.5% after high protein feeding (Carr 2018) - As a SuppVersity reader the sentence "[d]iets that are high in protein have the ability to keep an individual feeling fuller for longer and therefore have the possibility of reducing food intake" will be one you've read in this or a slightly modified version before.
  
  And yes, there's plenty of evidence to show that the manipulation of dietary protein intakes can help people shed weight, avoid weight gain, and significantly improve glucose management and body composition. Studies like the one at hand, i.e. randomized controlled trials in which the authors actually measure the effects of a high vs. normal protein diet on whole body energy expenditure, hunger, and satiety in a cohort of healthy, normal weight participants for more than just the post-prandial phase (here 36h) are yet pretty rare.
  

  

  Figure 1: The high protein diet (green line) was significantly more satiating than it's "energy-balanced" (how's 50% carbs energy balanced? But alas...) iso-caloric cousin the macro composition of which I had to guesstimate because the scientists only reveal that it had "an extra 30 % of energy as protein" (Karr 2018)

  With a study size of N=8 (5 female, 3 male), the trial K.Carr et al. conducted at the NIHR/Clinical Research Facility in Cambridge, isn't exactly what you'd hope for when it comes to 'optimal' statistical power. Still, the objective 36hr measurements of energy expenditure (EE), and subjective hunger and satiety levels (assessed by visual analog scales, hence subjective), Carr and colleagues assessed on two separate occasions in response to (a) a high protein (HP) and (b) energy balanced (EB) diet [macros see Figure 1, right] is one of the better studies on the acute effects of high protein intake - mostly, because the researchers used a metabolic chamber. Unlike the food questionnaires and scales of other studies, this technical device allowed them to assess the subjects' energy expenditure very precisely by the means of whole-body room indirect calorimetry... and the results the authors present in their paper speak for themselves:

  "The VAS measurements demonstrated that on average hunger was significantly less during the HP visit compared to the EB visit and satiety was significantly greater during the HP visit compared to the EB visit (P < 0.0001). Figure 1 presents results from VAS for satiety across the two interventions. Total EE for the HP visits were significantly higher compared to the EB visits (6.07 ± 3.58 kJ/min vs 5.81 ± 3.42 kJ/min, P < 0.0001)" (Carr 2018 | my emphasis).

  With the increased satiety and the concomitant +4.5% relative increase in energy expenditure the scientists measured in response to the HP diet, Carr et al. are right to point out that "[their] study [...] may have implications for future weight loss strategies" (Carr 2018). You shouldn't make the mistake to believe that the latter, i.e. the small thermogenic effect that amounts to 89.48kcal/day, alone, was enough to sustain long-term weight loss.
• MCTs are in fact gasoline for your metabolic fire (Maher 2018) - Just like Carr's previously discussed high-protein study, Maher's latest experiment that involved twelve healthy, normal-weight males (27 ± 11.43 years, BMI: 23.76 ± 2.85 kg/m²) didn't yield revolutionarily new results. It does, however, investigate a question that's probably relevant for many of you:
  
  What happens to a wanna-be or actual athlete like yourself, if you consume plenty of MCTs as part of your habitual diet? Will that shut down your appetite and turn you into a fat burning machine, as some MCT vendors promise?
  
  Well, we do know from previous research that medium chain triglycerides (MCT) increase energy expenditure (Ogawa 2007; Clegg 2013), and increase satiety and suppress food intake (Kinella 1985; Rolls 1988; Van Wymelbeke 1998).

Coconut oil contains max. 50% MCT: Coconut oil is not a good source of MCT. As discussed at length in my recent "coconut oil for health"-review coconut oil contains "only" 45-53% MCTs. It is thus not surprising that studies such as Kinsella et al. 2017 show consistently that the physiological effects of pure medium-chain triglycerides and coconut oil differ.

• 

  Figure 2: Exercise doesn't "just make you hungry" as some people who also claim that insulin was the sole reason we're fat want you to believe - check out the data from Schubert's 2013 meta-analysis.

  The effects of exercise on appetite regulation are equivocal, though. The only thing we can tell for sure is that acute exercise does lead to energy deficits (Schubert 2013) - this means, energy compensations take time and usually won't occur after a single bout of physical activity. If you review the most important results of Schubert's 2013 meta-analysis (see Figure 2), though, you will see that the majority of studies demonstrate beneficial effects on the subjects' energy balance, i.e. the induction of an energy deficit - in many cases a very significant one.
  
  As Maher et al. point out, "[t]hese effects are achieved through separate mechanisms, and thus there is potential for the combination of MCT and exercise to yield increased satiety" (Maher 2018).
  
  The aim of the study at hand was thus to elucidate the effects of MCT, exercise, or a combination of the two on subjective appetite sensations, energy intake and overall energy balance to answer the previously rised question about the "fat burning machine"... OK, that's not literally part of the outcome measures, but I guess you'll get what I mean.
  All subjects completed four trials in random order. After a 24 h standardisation period and a 12 h fast, participants consumed ...
  • a porridge breakfast which contained 165 kcal of either vegetable oil or MCT oil - followed by either sitting around for 4h or cycling for 1h at 65 % V̇O2peak after having sat around for 3h,
  • a multi-item buffet lunch ad libitum to satiation, after which they completed diet diaries for the rest of the day.
  Expired air samples (for calculation of energy expenditure) and subjective ratings of appetite, on visual analogue scales (VAS), were taken every 30 min only for the initial 4 hours. The analyses of these data showed no effect of either lipid or exercise condition on energy intake at the ad libitum meal (Control-Rest 6278.4 ± 1758.62 kJ; Control-Exercise 6785.2 ± 1370.5 kJ; MCT-Rest 6077.1 ± 1853.5 kJ; MCT-Exercise 6794.4 ± 2030.3 kJ; P ≥ 0.05). There were also no differences for the appetite and satiety VAS scores (all P ≥ 0.05) and no effect on ratings of nausea (P ≥ 0.05).
  

  

  Figure 3: This is probably how MCT producers will display the EE in kcal - minus the arrows with the calorie equivalent, obviously. The latter do, after all, reveal that the benefits are irrelevantly small (Maher 2018)

  What Maher et al. did observe, however, were significant main effects for breakfast (P = 0.031) and exercise condition (P < 0.001) on total energy expenditure. With the subjects who had the MCT breakfast having a significantly greater energy expenditure compared to the control, and - quite obvious - the exercise trials leading to greater energy expenditure than the resting trials (Control-Rest 198.2 ± 138.2 kJ; Control-Exercise 3045.8 ± 606.2 kJ; MCT-Rest 211.1 ± 186.6 kJ; MCT-Exercise 3272.4 ± 763.2 kJ).
  
  If we also take into consideration that the +7.4% "gasoline effect" of MCTs amounts to an increase in energy expenditure of only 54kcal (let's not even talk about the 3kcal increase in the sedentary condition), you will have to agree that it's very unlikely that you'll see weight loss wonders from simply upping your MCT intake - exercise to and fro. That's not the least because a cumulative effect, as it could have existed, or an additional effect of MCTs and/or exercise on energy intake did not exist.

Protein supplements are not necessary to get up to 45% of your energy from protein, but if you choose to eat chicken, cheese, meat, dairy & co, you should know these 8 Simple Rules to Minimize PROTOX! 

So what does this tell us? There's no magic 'nutritional bullet' that will make the fat on your abs melt away ... speaking of fat on your abs: This is one of the reasons I decided to discuss the two studies. They deal with normal-weight adults without metabolic derangement. People who may be unhappy with the aesthetics of their body. For them, and we know that from many previous studies,  different metabolic rules apply compared to those for whom fat loss is essential for survival (eg.morbidly obese type II diabetics, etc.) - rules you could summarize as one rule of thumb: Eat more protein (up to 45% of your energy intake) and don't trust the marketing claims of MCT producers, sellers, and social media celebrities that are pimpin' them | Comment!

References: 

• Carr, K., et al. “Hunger, Satiety and Energy Expenditure after High Protein Feeding.” Proceedings of the Nutrition Society, vol. 77, no. OCE4, 2018, p. E157., doi:10.1017/S0029665118001635.
• Clegg, Miriam E., Mana Golsorkhi, and C. Jeya Henry. "Combined medium-chain triglyceride and chilli feeding increases diet-induced thermogenesis in normal-weight humans." European journal of nutrition 52.6 (2013): 1579-1585.
• Kinsella, R., T. Maher, and M. E. Clegg. "Coconut oil has less satiating properties than medium chain triglyceride oil." Physiology & behavior 179 (2017): 422-426.
• Maher, T.J., et al. “The Effect of Triglyceride Chain Length Combined with Exercise on Appetite, Satiety and Energy Balance.” Proceedings of the Nutrition Society, vol. 77, no. OCE4, 2018, p. E156., doi:10.1017/S0029665118001623.
• Ogawa, Akiko, et al. "Dietary medium-and long-chain triacylglycerols accelerate diet-induced thermogenesis in humans." Journal of Oleo Science 56.6 (2007): 283-287.
• Rolls, Barbara J., et al. "Food intake in dieters and nondieters after a liquid meal containing medium-chain triglycerides." The American journal of clinical nutrition 48.1 (1988): 66-71.
• Schubert, Matthew M., et al. "Acute exercise and subsequent energy intake. A meta-analysis." Appetite 63 (2013): 92-104.
• Van Wymelbeke, Virginie, et al. "Influence of medium-chain and long-chain triacylglycerols on the control of food intake in men." The American journal of clinical nutrition 68.2 (1998): 226-234.