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All,

 

Al's latest post about new CR paper contained a really interesting new study in rhesus monkeys [1], with potentially troubling implications for men practicing serious CR with (resulting) low testosterone.

 

It was a study of middle-aged (~12 yo) male rhesus monkeys, making it more relevant to us than any of the rodent studies.

 

Half the monkeys were orchidectomized ☹ to put the kibosh on their testosterone level, and the other half were subjected to mock surgery. After two months of recovery on a standard chow diet (15F / 27P / 59C) supplemented with fresh fruits & vegetables, both groups were made pudgy by shifting them for six months to a western style diet (WSD) that has a similar macronutrient profile to the diet many of us eat day-to-day (33F / 17P / 51C). Then, for 4 additional months, they calorie-restricted both groups by putting them back on the standard chow + F&V diet, but giving them only 70% of their individual baseline (pre-surgery) calorie intake (i.e. 30% CR).

 

They intended to model in their rhesus monkeys the life history of men who undergo androgen deprivation therapy (ADT) for treatment of prostate cancer, so see if calorie-restriction could prevent the metabolic syndrome such treatment often induces in men. But while not perfect, the parallels with us CR folks are unmistakable - i.e. chronic CR resulting in the combination of reduced muscle mass and low testosterone.

 

What they found appears to me to be pretty troubling, as I alluded to in the title and introduction.

 

First, two months after the surgery, while still eating the standard, low-fat chow + F&V diet ad libidum, the orchidectomized (O) monkeys (OMs), but not the intact (I) monkeys (IMs) showed a decrease in lean mass. Not too surprising - lean mass drops with low testosterone.

 

During the six-months of western-style diet (WSD), both groups gained fat. No surprise. But unlike the I monkeys, the O monkeys also lost additional lean mass and bone mass during the WSD period. Once again we see the negative effects of low-T on body composition. In short, the OMs became pretty classic examples of hypogonadal middle-aged men - pudgy, with little muscle mass and low testosterone.

 

Now comes the interesting part - what happened as a result of 30% CR?

 

Obviously both groups lost significant (and comparable) amount of fat mass. Both groups also lost lean mass. As a result, after the CR period both groups had returned to their  relatively-lean baseline (pre-surgery) weight. But relatively to baseline, both groups had a higher percent body fat that they started with, and the O monkeys in particular had a lot less lean mass. The O monkeys also exhibited reduced bone mineral density as a result of CR, and effect not seen in the I monkeys. 

 

In short, low testosterone dropped the O monkey's lean mass and bone mass, and CR did nothing to counteract this effect - if anything it exacerbates it. 

 

But is that necessarily such a big deal?

 

Maybe having low testosterone and reduced muscle mass after CR isn't a problem. In fact, without all that metabolically active muscle tissue, a CR practitioner could presumably eat fewer calories, and hence get more of the healthspan and lifespan benefits of CR, since "CR works by reducing Calorie intake -- period" a famous CR proponent once said. But so as to avoid getting myself into hot water yet again, I'll note that even he recognizes the importance of maintaining lean mass and bone mass via exercise while practicing CR...

 

Obviously late-life sarcopenia and frailty is one concern some of us have about sacrificing too much muscle and bone mass to the CR gods. Unfortunately this short-term study didn't investigate the impact of these effects.

 

But what they did find was even more germane to one of the negative side-effect that has been front and center in our discussions lately (discussed in depth here and here), namely impaired glucose tolerance (IGT). 

 

Not surprisingly, glucose tolerance (as measured by an OGTT) got worse in both I and O monkeys after eating the western diet for six months. But then, after 30% CR for four months, the I monkeys'  glucose tolerance improved to the point where it was close to baseline again. In contrast, the poor, skinny, low-testosterone O monkeys, lacking much muscle mass, continued to show impaired glucose tolerance. The authors summarized their result as:

 

CR improved these metabolic parameters [i.e. hyperinsulinemia and insulin resistance - DP] only in intact animals, whereas orchidectomized animals remained glucose-intolerant, despite a significant loss in fat mass.

 

Put another way, CR coupled with low testosterone results in a precipitous drop in muscle mass, which led to impaired glucose tolerance.

 

Note - the impaired metabolic health of the CR + Low-T monkeys was not a result of either differences in food intake or physical activity between the two groups - "... there was no significant group differences in these parameters under any of the dietary regimens studied."

 

But they did observe an interesting effect of physical activity. At the end of the western diet period (i.e. pre-CR), across the entire population of monkeys, as well as within each group, monkeys that engaged in more physical activity had a lower percent fat mass (and by implication, a higher percent lean muscle mass), and exhibited better glucose metabolism, as illustrated in these two graphs showing % body fat (left) and OGTT glucose area under the curve (right), as a function of how active each of the monkeys was, as measured by a collar-worn accelerometer (Open circles = O monkeys, solid circles = I monkeys):

 

0v2r6Aq.png

 

 

Unfortunately, they don't report correlation between physical activity and glucose metabolism after the CR period. But given the across-the-board drop in lean mass as a result of CR that they observed, it seems likely to me that the observed relationship would still-hold, and perhaps be exaggerated, post-CR.

 

So how do the authors interpret their results? Here are some of the key passages from the discussion section:

 

The present study demonstrates that skeletal muscle loss in testosterone-deficient [non-human primates] correlated with the development of [insulin resistance] and glucose intolerance during the [western style diet] and CR periods.
 
Surprisingly, there was no significant effect of testosterone deficiency on diet-induced change in fat mass, including fat gain during the WSD period and fat loss during the CR period, suggesting that insulin resistance in [low-testosterone androgen deprivation therapy] patients is related to the loss of skeletal muscle, which is the primary anatomical site responsible for glucose disposal.
 
In other words, according to the authors: low-T (with or without CR) → reduced muscle mass → impaired glucose tolerance.

 

Thus, testosterone may play a protective role in male physiology, while its deficiency may increase the susceptibility of males to metabolic syndrome.

 

While this study was really meant to model men who are hypogonadal as a results of android deprivation treatment for prostate cancer, it seems to me to have potentially important implications for CR folks1, many of whom exhibit low-T, low muscle mass, and impaired glucose tolerance.

 

The silver lining may be the observation about physical activity. By staying active (particularly after meals), and eating enough to maintaining muscle mass and avoid getting too skinny, we may be able to mask (if not altogether prevent) the negative effects of impaired glucose tolerance associated with serious CR that many of us have observed. 

 

--Dean

 

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1And Todd A in particular.

 

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[1] Int J Obes (Lond). 2016 Aug 18. doi: 10.1038/ijo.2016.148. [Epub ahead of print]

 

Perpetuating effects of androgen deficiency on insulin-resistance.

 

Cameron JL, Jain R, Rais M, White AE, Beer TM, Kievit P, Winters-Stone K, Messaoudi I, Varlamov O.

Full text: http://sci-hub.cc/10.1038/ijo.2016.148

 

 
Abstract
 
Background/Objectives: Androgen deprivation therapy (ADT) is commonly used for treatment
of prostate cancer, but is associated with side effects such as sarcopenia and insulin resistance.
The role of lifestyle factors such as diet and exercise on insulin sensitivity and body composition
in testosterone-deficient males is poorly understood. The aim of the present study was to
examine the relationships between androgen status, diet, and insulin sensitivity.
Subjects/Methods: Middle-aged (11-12-yo) intact and orchidectomized male rhesus macaques
were maintained for two months on a standard chow diet, and then exposed for six months to a
Western-style, high-fat/calorie-dense diet (WSD) followed by four months of caloric restriction
(CR). Body composition, insulin sensitivity, physical activity, serum cytokine levels, and adipose
biopsies were evaluated before and after each dietary intervention.
 
Results: Both intact and orchidectomized animals gained similar proportions of body fat,
developed visceral and subcutaneous adipocyte hypertrophy, and became insulin resistant in
response to the WSD. CR reduced body fat in both groups, but reversed insulin resistance only
in intact animals. Orchidectomized animals displayed progressive sarcopenia, which persisted
after the switch to CR. Androgen deficiency was associated with increased levels of interleukin-
6 and macrophage-derived chemokine (CCL22), both of which were elevated during CR.
Physical activity levels showed a negative correlation with body fat and insulin sensitivity.
Conclusion: Androgen deficiency exacerbated the negative metabolic side effects of the WSD,
such that CR alone was not sufficient to improve altered insulin sensitivity, suggesting that ADT
patients will require additional interventions to reverse insulin resistance and sarcopenia.
 
Key words: androgen deprivation therapy, hypogonadal, Western-style diet, obesity,
sarcopenia.
 
Abbreviations: ADT, androgen-deprivation therapy, CR, caloric restriction; NHP,
nonhuman primate; SM, skeletal muscle; SC, subcutaneous; VIS, visceral; WAT, white adipose
tissue; WSD, Western-style diet.
 

 

PMID: 27534842

 

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A very interesting study, Dean —thanks for calling it out and the work of summarizing it, and Al for posting it in the first place.
 
I wish, obviously, that they had used a different design, based on or including groups that were not rendered obese after orchidectomy (either having been made obese before surgery or being lean to begin with). This is obviously a quite diffeent situation than CR, where the drop in T occurs after CR and concomitant weight loss, as a metabolically-regulated state, and alongside other diet-related metabolic shifts rather than in isolation. But it's still good data to look at
 

They intended to model in their rhesus monkeys the life history of men who undergo androgen deprivation therapy (ADT) for treatment of prostate cancer, so see if calorie-restriction could prevent the metabolic syndrome such treatment often induces in men. But while not perfect, the parallels with us CR folks are unmistakable - i.e. chronic CR resulting in the combination of reduced muscle mass and low testosterone.


Even for that, this seems like a poor design, unless there is a known tendency for men to suddenly take up residence at one of the remaining Krispy Kremes immediately after ADT. There is certainly no lack of overweight and obese PC patients. Do the authors give any kind of rationale for this design?
 

so as to avoid getting myself into hot water yet again, I'll note that even [Michael] recognizes the importance of maintaining lean mass and bone mass via exercise while practicing CR...


Oh, you poor, persecuted dear.
 

what happened as a result of 30% CR?
 
Obviously both groups lost significant (and comparable) amount of fat mass. Both groups also lost lean mass. As a result, after the CR period both groups had returned to their  relatively-lean baseline (pre-surgery) weight. But relatively to baseline, both groups had a higher percent body fat that they started with, and the O monkeys in particular had a lot less lean mass. The O monkeys also exhibited reduced bone mineral density as a result of CR, and effect not seen in the I monkeys. ...

Not surprisingly, glucose tolerance (as measured by an OGTT) got worse in both I[ntact] and O[rchidectomized] monkeys after eating the western diet for six months. But then, after 30% CR for four months, the I monkeys'  glucose tolerance improved to the point where it was close to baseline again. In contrast, the poor, skinny, low-testosterone O monkeys, lacking much muscle mass, continued to show impaired glucose tolerance. The authors summarized their result as:
 

CR improved these metabolic parameters [i.e. hyperinsulinemia and insulin resistance - DP] only in intact animals, whereas orchidectomized animals remained glucose-intolerant, despite a significant loss in fat mass.

 


Did they actually look at the effects of diet alone on T? Obesity lowers free T, and weight normalization tends to restore it; CR per se obviously lowers T, but of course this isn't proper CR, and I can't for the life of me find any data on T in the UWisc obesity-avoidance "CR" study.
 

Put another way, CR coupled with low testosterone results in a precipitous drop in muscle mass, which led to impaired glucose tolerance.


While that is one way to summarize this finding, and I absolutely do not discount it, they're not looking at CR, but normalizing body weight after weight gain itself preceded by orchidectomy in one group; they're looking at energy "restriction" in the context of pre-existing complete androgen deprivation (and concomitant effects on estrogen); and there hasn't been any data from what you've posted (and I'm hoping this is just an oversight that you can correct) to actually link the IGT to muscle mass per se, or its interactions with orchidectomy. Did they track that?
 

they did observe an interesting effect of physical activity. At the end of the western diet period (i.e. pre-CR), across the entire population of monkeys, as well as within each group, monkeys that engaged in more physical activity had a lower percent fat mass (and by implication, a higher percent lean muscle mass), and exhibited better glucose metabolism


Well, if "monkeys that engaged in more physical activity had a lower percent fat mass ... exhibited better glucose metabolism", how if at all did they disentangle the effects of fat from muscle on glucose tolerance? If after the weight-normalization period "both groups lost significant (and comparable) amount of fat mass ... [and]  had returned to their  relatively-lean baseline (pre-surgery) weight. But relatively to baseline, both groups had a higher percent body fat that they started with, and the O monkeys in particular had a lot less lean mass" then ipso facto the O monkeys also had either a higher fat mass, or at the absolute minimum a higher % body fat, yes?

 

And did they look at abdominal/visceral adipose in particular?
 

Unfortunately, they don't report correlation between physical activity and glucose metabolism after the CR period. But given the across-the-board drop in lean mass as a result of CR that they observed, it seems likely to me that the observed relationship would still-hold, and perhaps be exaggerated, post-CR.


That is, again, a really unfortunate oversight.
 

So how do the authors interpret their results? Here are some of the key passages from the discussion section:
 

The present study demonstrates that skeletal muscle loss in testosterone-deficient [non-human primates] correlated with the development of [insulin resistance] and glucose intolerance during the [western style diet] and CR periods.

 

Surprisingly, there was no significant effect of testosterone deficiency on diet-induced change in fat mass, including fat gain during the WSD period and fat loss during the CR period, suggesting that insulin resistance in [low-testosterone androgen deprivation therapy] patients is related to the loss of skeletal muscle, which is the primary anatomical site responsible for glucose disposal.

 
 That seems like a moderate jump for ADT (unless ADT also leads to a rise in fat mass), and a much larger (tho' not giant) leap for low T resulting from CR in intact, normal weight people without pre-existing metabolic and endocrine disorders.

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An interesting study indeed. It makes me wonder about the following. How low are T levels of monkeys that have been orchidectomized? Are they comparable to people practicing CR? If they have undergone an orchidectomy, wouldn't they have absolutely obliterated T level, even way past CR levels? 

 

Those practicing CR often seem to have T levels in the 200-300 range, which is definitely at the bottom or outside of the reference range. But what about men who undergo radical castration? I bet their T levels are far lower than that since almost all of a man's testosterone is produced in the testicles (~95% according to an endocrinologist I saw).  The remaining 5% is produced in the adrenal glands.  

 

Something else that popped into my head is this: women tend to enjoy greater longevity than men yet have massively lower testosterone and significantly less muscle mass. Do they do worse on an oral glucose test? I wonder if a women's testosterone level is similar to that of someone who has undergone an orchidectomy.

 

As someone with T levels that average about 300, I am greatly interested in all things T related. I find it to be quite frustrating. 

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Some of these tips might help someone trying to raise their T level, also adequate sun and vitamin D have been shown to be related to T.  Dr. Gregger talked about T in some interview video I was watching recently (it wasn't one of his own videos) where he mentioned some interesting studies about sex boosting T (but only when there is another person involved, haha) and that it's easy to observe a boost in T based on how quickly your facial hair grows out.

 

"Something else that popped into my head is this: women tend to enjoy greater longevity than men yet have massively lower testosterone and significantly less muscle mass. Do they do worse on an oral glucose test?"

 

Women also have more BAT than men, but I'm not sure how much of a factor that may be in their life expectancy or OGT.

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Hey Gordo,

 

Anecdotally, vitamin D supplements don't seem to make a difference in my libido (I take 2000 i.u. in winter), and in summer I get out in the sunshine daily, perhaps for about 30 minutes wearing only shorts.  The sun does seem to make a positive impact on both my T levels and libido, whereas supplements do not. I'm not sure if the sun is stimulating T production, nitric oxide, or some combination of the two. 

 

The only reading I have ever had in the 400's was in the middle of June last year. when I was getting lots of sun and lifting weights more. I wish I could lift heavier weights and more frequently as it seems to be a reliable way to increase T, particularly free T.  However, after having open-heart surgery twice (see here for info on that), I develop chest pain 12-48 hours post intense exercise, that only lasts for minutes, but is very intense and scary.  Things like HIIT, cross fit, heavy weights, or intense tempo runs/road races can cause it. 

 

The best explanation for the type of chest pain I experience is Prinzmetal's angina. It's different than the chest pain experience by those with plaque in their arteries. Aortic dissection also may be something I have to be aware of. 

 

I also saw the clip Dr. Greger had on testosterone. It's link is here. Having more intercourse is an appealing option, but it's an easier sell for me than my wife!  

 

Most people my age grow thicker beards, more quickly than I. 

Edited by drewab

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Michael, Drew and Gordo,

 

Thanks for the thoughtful replies and additions to the conversation! I'll try to address a few comments / questions. 

 

First off, I agree with both Michael and Drew that this design is far from optimal when it comes to probing the metabolic effects of CR-induced low testosterone in men. It is indeed unfortunate that they snipped the cajones off the monkeys before1 both the western diet feeding, and before the CR to reduce the weight gain. Plus, while these monkeys were seriously CRed wrt calories (living on 70% of baseline for four months), but this didn't result in them getting particularly skinny, only bringing them back to around baseline after plumping up on six months of a western diet. So again, different from our (quite skinny) phenotype. Plus you are right Drew, the T-level in the orchidectomized monkeys is likely to be significantly lower than even the most severe CR folks.

 

Now some specific points / questions. Michael wrote:

Even for that [purpose - i.e. modeling prostate cancer patients treated with Androgen Deprivation Therapy (ADT) - DP], this seems like a poor design, unless there is a known tendency for men to suddenly take up residence at one of the remaining Krispy Kremes immediately after ADT. There is certainly no lack of overweight and obese PC patients. Do the authors give any kind of rationale for this design?

 

Here is the motivation the authors give in the introduction to the full text, which makes their design seem pretty reasonable to me for what they were trying to elucidate. In short, there does appear to be evidence that ADT results in metabolic impairment (with or without Krispy Kremes ☺), and it is (or was) an open question whether calorie restriction would prevent (or exacerbate) these post-ADT metabolic dysfunctions:

 

Of the approximately two million men annually diagnosed with prostate cancer in the United States, one third receive androgen deprivation therapy (ADT) in combination with other therapies 1, 2. Because ADT improves outcomes for high-risk patients treated with radiation therapy for localized disease, and is also a common treatment for patients with increasing prostate-specific antigen levels after local treatment without metastatic disease 3 , side effects of this therapy constitute a significant social and clinical issue. Adverse effects of ADT include metabolic changes such as obesity 4-6 , insulin resistance 7-9 , and diabetes 1, 10, all of which constitute independent risk factors for increased mortality rates in men 11. Obesity and hyperinsulinemia are also associated with a higher risk of prostate cancer-specific mortality, and may promote the development of a more aggressive form of prostate cancer 12 . Cardiovascular disease, which is linked to obesity, has been recognized as the second most common cause of mortality in men with prostate cancer 13 .

 

These factors contribute to the high risk/benefit ratio of ADT, which makes lifestyle modifications essential for survival of prostate cancer patients. Currently, there is a paucity of studies that have explicitly investigated physiologic outcomes of diet in hypogonadal men.

 

Of course, as pointed out above, we CR men go hypogonadal after restricting calories for a while, not before, as in this experimental design. So these monkeys clearly aren't a perfect parallel with us. But alas, as with the primate CR studies, beggars can't be choosers when it comes to CR-related studies in non-human primates...

 

Michael went on:

Did they actually look at the effects of diet alone on T? Obesity lowers free T, and weight normalization tends to restore it; CR per se obviously lowers T, but of course this isn't proper CR, and I can't for the life of me find any data on T in the UWisc obesity-avoidance "CR" study.

 

Disappointingly, it doesn't look like they did any measurements of T in either the orchidectomized or intact monkeys at any point in the study. It wasn't reported in the text or any of the figures, and there does not appear to be any supplemental material. Plus in the methods section they talk about measuring a lot of blood parameters, but T isn't one of them. That is unfortunate, obviously. But it goes without saying that the T level of the orchidectomized monkeys was vastly lower than that of the intact monkeys throughout the study. The obviousness of that fact is probably why the authors didn't even bother to measure it. But it is a disappointing omission from our perspective.

 

Next Michael wrote:

...there hasn't been any data from what you've posted (and I'm hoping this is just an oversight that you can correct) to actually link the IGT to muscle mass per se, or its interactions with orchidectomy. Did they track that?...

 

Hmmm.... I'm not sure what you mean by "actually link the IGT to muscle mass per se". The two graphs I posted is probably the most direct evidence they derived from their data. They showed that % body fat dropped (and presumably, lean mass went up, at least percentage-wise) with increased physical activity level and that increased physical activity level (in both groups) was correlated with better glucose metabolism. So lower % body fat (and greater % lean mass), correlated with better glucose metabolism in both groups of monkeys. Here is the passage from the discussion section that is relevant to your question, putting these results in the context of other evidence:

 

The main metabolic side effects of ADT in prostate cancer patients include the development of obesity 4-6, 23 and insulin resistance 7-9 . Low free testosterone concentrations were also observed in obese diabetic and obese nondiabetic pubertal and post-pubertal males, with the former displaying a significantly higher prevalence of subnormal testosterone levels 24, 25 . Recent studies demonstrated that males with type 2 diabetes and hypogonadism have additional insulin resistance, while testosterone treatment resulted in its reversal with an improvement in insulin signal transduction 26 . Additionally, testosterone therapy can help achieve more sustained fat mass loss and improve lean mass and insulin sensitivity in hypogonadal men 26, 27, which is consistent with the present report (Figure 1E, 2 and 3). Thus, testosterone may play a protective role in male physiology, while its deficiency may increase the susceptibility of males to metabolic syndrome.

 

So it doesn't sound like there is necessarily a "smoking gun" that implicates the reduction in lean muscle mass (as opposed to the gain in fat mass) resulting from low testosterone as the definitive cause of the observed impaired glucose tolerance. It really would have been nice if they'd done sensitivity analysis across the groups to see how the three important parameters, testosterone level, lean muscle mass, and glucose metabolism correlated with each other.

 

Similarly, Michael wrote:

Well, if "monkeys that engaged in more physical activity had a lower percent fat mass ... exhibited better glucose metabolism", how if at all did they disentangle the effects of fat from muscle on glucose tolerance?

 

Very astute question Michael, and obviously related to the previous one about muscle mass and IGT. The reason the authors point to loss of lean mass, rather than gain of fat mass, as the likely cause of the IGT in the orchidectomized monkeys may be the following observation coupled with the two more graphs I've included below. First, the observation (my emphasis):

 

Two months after surgery, while still eating the chow diet, orchidectomized but not intact animals showed a decrease in lean mass (Figure 1E). Fat mass and bone mineral content (BMC) remained stable in both experimental groups.

 

And the two relevant graphs illustrating the results of the OGTT at various time points in the two groups (white bars = orchidectomized monkeys, black bars = intact monkeys) :

 

QRWFLCR.png

 

Look at the two red arrows I've added. They represent the area-under-the-curve (AUC) for glucose and insulin after a glucose challenge (OGTT) in the relatively-lean orchidectomized monkeys two months after surgery, during which time they were eating a reasonably healthy diet. That was before they started eating the obesogenic western diet. As mentioned in the text snippet above, the orchidectomized monkeys fat mass remained stable during this 2-month period, but they lost lean mass, presumably as a result of low-T. As you can see from the red arrows, between baseline and 2-months post-surgery, the orchidectomized monkey's post-challenge glucose levels went up, while their insulin release went down. This seems hauntingly reminiscent of the metabolic response many CR men have observed. Namely, losing lean mass on a (reasonably) healthy CR diet concomitant with worse postprandial glucose levels and impaired response to an OGTT, apparently resulting from a reduced (early) insulin response...

 

As for your specific question (fat gain vs. muscle loss as IGT culprit), the fact that during this early 2-month window post-surgery the O monkeys lost lean mass but didn't gain fat mass, and nevertheless saw a worsening of glucose clearance in response to an OGTT, may have been one reason why they interpret their data as implicating loss of lean mass rather than gain of fat mass as the likely cause of the observed IGT.

 

Admittedly, this is a bit tenuous. Perhaps more directly, here is addition evidence the authors put forth implicating loss of muscle rather than gain of fat in the IGT causal chain:

 

Taken together, diet-induced obesity induced fasting hyperinsulinemia and insulin resistance in both groups of animals. However, CR improved these metabolic parameters only in intact animals, whereas orchidectomized animals remained glucose-intolerant, despite a significant loss in fat mass (Figure 1C-D).

 

In other words, despite losing most of the fat mass they gained while on the western diet as a result of CR, the orchidectomized monkeys remained glucose intolerant. In contrast, during CR the intact monkeys retained their lean muscle mass better than the orchidectomized monkeys, and had more lean mass before they were started on CR. As a result, during the CR period the intact monkeys shed a similar amount of fat as the orchidectomized monkeys, but with more lean mass, the intact monkeys were able to overcome their glucose intolerance, unlike the orchidectomized monkeys.

 

Or so that seems to be the interpretation the authors are putting forth, as far as I can tell.

 

Next Michael wrote:

And did they look at abdominal/visceral adipose in particular?

 

Interesting you should ask. They didn't quantify the relative amount of visceral vs. subcutaneous fat. But they did look at several interesting things about the fat tissue which I didn't mention in my original summary, in the interest of keeping this (relatively) simple and focused on glucose metabolism. First they looked at white adipose tissue cell size, using biopsies of both visceral and subcutaneous fat. Not surprisingly, fat cell size ballooned up during the western diet, and had returned back close to baseline after after the CR period, without much difference in cell size at any time point between the two groups of monkeys. So nothing to see here.

 

Where they did find interesting differences in the two groups was in serum inflammatory cytokines, likely produced in, as well as influential on, adipose tissue. At each of the important time points in the study, they measured circulating levels of a variety of inflammatory markers. The significant results they found are illustrated in the two graphs below:

 

RKA4Tm9.png

 

As you can see, the levels of two important pro-inflammatory cytokines, namely interleukin-6 (IL-6) and macrophage-derived chemokine (MDC, also known as CCL22) remained pretty stable throughout the experiment in the intact monkeys (black bars). But they both went up dramatically and almost immediately (i.e. before the obesogenic western diet period) in the low-T, orchidectomized monkeys. CR did not appear to help bring down these inflammatory markers, and if anything may have in fact increased IL-6 (although the error bar is wide...). They basically conclude from this that testosterone deficiency alone may trigger chronic elevation of these inflammatory markers, particularly MDC.

 

One more loose end - Drew wrote:

 

...women tend to enjoy greater longevity than men yet have massively lower testosterone and significantly less muscle mass. Do they do worse on an oral glucose test? I wonder if a women's testosterone level is similar to that of someone who has undergone an orchidectomy.

 

There are so many differences in hormones and metabolism between men and women that trying to correlate any differences in glucose tolerance to differing levels of testosterone between men and women seems extremely dubious.

 

In closing, I share some of Michael's skepticism regarding the authors' interpretation of their finding - in particular their blaming of the IGT on loss of muscle mass (rather than a gain of fat mass, or a combination of the two) resulting from low-T in the orchidectomized monkeys. It's also clear that the parallel between these low-T orchidectomized monkeys and men practicing CR is far from perfect.

 

Nevertheless, I find it pretty suggestive that orchidectomized monkeys, men who've undergone treatment to intentionally reduce their testosterone (to treat their prostate cancer) and some men practicing serious CR share similar characteristics, including:

  • Low testosterone
  • Reduced muscle mass
  • Impaired glucose tolerance

These parallels suggests to me that these authors may be onto something when they postulate a causal link between the three factors - i.e. low-T → low muscle mass → impaired glucose metabolism.

 

--Dean

 

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1It goes without saying that I also think it unfortunate they snipped the cajones off the monkeys at all, but that is a topic for another thread if anyone wants to pick it up there...

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