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  1. All, A while back James posted a link to this very recent review paper by John Speakman [1] in his Weekly CR Research update. I figured now would be a good time to bring it (back) to people's attention, both because having read it I realize it contains some interesting stuff, and more importantly, because it is the research that Speakman is scheduled to talk about at the upcoming CR Conference, according to the conference program. In the paper, Speakman and colleagues review the history of CR, and the dispute that has existed from the beginning and continues to this day over whether the longevity benefits are due to calorie restriction in general or protein restriction (PR) in particular. You can get a sense of how the controversy is ongoing from this recent discussion between Michael and me over a Dr. Greger video about the role of calorie restriction vs. (animal) protein restriction. I won't try to put words in Michael's mouth, but my sense from that discussion was that he and I agreed that keeping protein on the low side (RDA-ish level), sticking mostly to plant proteins, and combining lowish protein with CR is best, because it results in low(ish) IGF-1, which is good for health & longevity. Or put the other way - CR without PR is likely to be less (or in-) effective because IGF-1 remains high if one's diet is replete with (animal) protein, as was demonstrated years ago by Luigi Fontana on a few of us CR humans (PMID 18843793). But apparently Speakman isn't so sure. In fact, in his latest paper [1], he argues that the benefits of CR are overwhelmingly attributable to restricting calories, and that at least in rodents: ncreasing CR (with simultaneous protein restriction: PR) increases lifespan, and that CR with no PR generates an identical effect. He does acknowledge that PR without CR does seem to increase lifespan as well, but to a much lesser extent and through an apparently different pathway than CR. He interprets the data to suggest that isocaloric protein restriction in rodents, i.e. going from a typical diet with 20% protein to a low protein diet with 12% protein, would extend median lifespan by 4.5%. This is a much smaller boost than the 30% median longevity increase typically achieved with 40% CR. It's not just in this review [1] that Speakman criticizes the idea of protein restriction for longevity. In this recent study [2], discussed in detail here, Speakman et al compared short term CR vs. PR (without CR) in mice, and found IGF-1 level dropped with CR but not with PR. But see my discussion of that study for why I didn't consider Speakman's PR results in [2] to be very fair or informative. In short, I remain unconvinced by Speakman's argument that it's almost exclusively CR, independent of PR, that matters for lifespan benefits in rodents. But there were two other points in Speakman's latest paper [1] worth mentioning, and worth discussing with him at the conference. First, he acknowledges that his interpretation of the CR vs. PR literature is most at odds with a recent study by Solon-Biet et al [3], which fed 25 distinct ad lib diets to 25 groups of mice, with each diet group differing in their macronutrient composition. The results of [3] can best be summarized by this handy graphical abstract: In short, [3] found that a low-protein, high-carb diet resulted in the mice actually eating more food but living longer than mice fed a high-protein, low-carb diet. A high (crappy) fat, low-protein diet did even worse. What Speakman says about [3], as well as insect CR studies is really interesting, and potentially relevant for human CR practitioners. Here is an extended quote from the Speakman paper [1], but you can skip it and read my summary below the quote if you're impatient ☺: A possible explanation for the unusual response of the mice studied by Solon-Biet et al. (2014) was the manner in which the restriction was applied, which was exceptional among studies of rodents (Solon-Biet et al. 2014). In all previous studies of CR in rodents, the subject animals are given a ration of food that is lower than the intake of an ad libitum fed control group. Details of the exact protocols vary, in particular when and how frequently the ration is delivered (reviewed in Speakman and Mitchell, 2011) but they all have in common a shortfall in the quantity (i.e. mass) of food eaten, relative to ad libitum fed animals. In contrast, Solon-Biet et al. (2014) generated restriction by diluting the diet with indigestible cellulose. Hence, while the mice ingested fewer calories, they did so while ingesting almost twice as much mass of food (Solon-Biet et al. 2014). This difference may be critical, because a potentially key component of the response to CR is a stimulation of the hunger signalling pathways in the brain (Hambly et al. 2007; 2012; Lusseau et al. 2015). When components of these pathways are knocked out, the response to CR is attenuated (e.g. NPY null mice). Diluting the diet, rather than restricting the amount available, may potentially generate fundamentally different responses in the neuropeptide pathways that link restriction to its beneficial actions with respect to lifespan (Lusseau et al. 2015). For example, the patterns of response in gut hormones that regulate satiation and satiety, and direct vagal afferents that respond to gut distension, are likely to be very different in mice that are underfed, compared to those that voluntarily overeat a diluted diet. Indeed, the fact the animals fed the diluted diet do not completely compensate for the caloric deficit, in the presence of excess food, suggests that hunger signalling pathways are down- rather than up-regulated. Basically what Speakman is saying is that the unusual results in Solon-Biet et al [3] (i.e. PR is more important than CR) may have to do with the "hunger hypothesis" - namely that CR may only work if the organism experiences hunger, and the metabolic processes that are associated with hunger. In particular [3] used "calorie dilution" to achieve "voluntary" CR in the mice while allowing them ad lib access to food. Specifically, in [3] the so-called CR group was given ad lib access to their food, but their food was diluted with cellulose so that the mice ended up feeling full but eating fewer calories than the other groups, who were eating the same (or less) volume of food, but with more calories because it was a more calorie-dense diet. In short, Speakman's interpretation of [3] seems to be that CR may only work if you're hungry. Something we should definitely ask him about at the conference! The other, related, point Speakman makes is the following. When CR studies restrict both calories and volume of food, the CR rodents gobble up their food very quickly - within a short time after food gets dumped into their trough. Such feeding is typically done once per day during the week, but can sometimes happen once in three days since researchers often feed rodents on Friday, and then not again until Monday. This results in intermittent fasting (IF) for the rodents, in addition to CR, and this IF might have it's own benefits. Here is another longish quote from Speakman [1]: One potential factor that potentially compromises the interpretation of the caloric restriction studies that involve giving the animals less food to eat is that in some protocols the animals may not only be restricted but may also be intermittently fasted (IF) (Simpson et al. 2015). IF, sometimes called ‘every other day feeding’ protocols involve the deliberate withholding of all food supply for periods in excess of 24h. It has been shown that such protocols may result in lifespan extension even in the absence of any decrease in overall food intake (Carlson and Hoelzel, 1946; Goodrick et al 1983; Ansom et al 2005). In some CR protocols there may be an inadvertent exposure to IF because the animals are fed a large ration on Fridays (3x the normal size) but not refed until Monday. Potentially then the animals may eat all the food on the first day and then be exposed to fasting until the next feed on Monday. The CR protocol would then be confounded by an IF exposure. While researchers like Speakman may consider the conflation of CR & IF as compromising the interpretation of CR experiments (and hence unfortunate), many of us consider the combination of CR & IF a good thing if it helps us maximize health and longevity. So it will be worth asking Speakman about his perspective on CR vs IF at the conference as well. In summary - Speakman is a real smart cookie. His recent research comparing CR & PR, along with the other studies I've referenced above and in the other related threads, are well worth reviewing so we can dialog intelligently with him at the conference. In addition, Speakman and colleagues have done very interesting work on the influence of metabolic rate on rodent lifespan, and specifically, the benefits of cold exposure, as I discussed here - which I'm also looking forward to talking with him about as well. Hope to see you at the conference - it promises to be fun and educational! --Dean --------- [1] Exp Gerontol. 2016 Mar 19. pii: S0531-5565(16)30069-9. doi: 10.1016/j.exger.2016.03.011. [Epub ahead of print] Calories or protein? The effect of dietary restriction on lifespan in rodents is explained by calories alone. Speakman JR(1), Mitchell SE(2), Mazidi M(3). Full text: http://sci-hub.cc/10.1016/j.exger.2016.03.011 Almost exactly 100years ago Osborne and colleagues demonstrated that restricting the food intake of a small number of female rats extended their lifespan. In the 1930s experiments on the impact of diet on lifespan were extended by Slonaker, and subsequently McCay. Slonaker concluded that there was a strong impact of protein intake on lifespan, while McCay concluded that calories are the main factor causing differences in lifespan when animals are restricted (Calorie restriction or CR). Hence from the very beginning the question of whether food restriction acts on lifespan via reduced calorie intake or reduced protein intake was disputed. Subsequent work supported the idea that calories were the dominant factor. More recently, however, this role has again been questioned, particularly in studies of insects. Here we review the data regarding previous studies of protein and calorie restriction in rodents. We show that increasing CR (with simultaneous protein restriction: PR) increases lifespan, and that CR with no PR generates an identical effect. None of the residual variation in the impact of CR (with PR) on lifespan could be traced to variation in macronutrient content of the diet. Other studies show that low protein content in the diet does increase median lifespan, but the effect is smaller than the CR effect. We conclude that CR is a valid phenomenon in rodents that cannot be explained by changes in protein intake, but that there is a separate phenomenon linking protein intake to lifespan, which acts over a different range of protein intakes than is typical in CR studies. This suggests there may be a fundamental difference in the responses of insects and rodents to CR. This may be traced to differences in the physiology of these groups, or reflect a major methodological difference between 'restriction' studies performed on rodents and insects. We suggest that studies where the diet is supplied ad libitum, but diluted with inert components, should perhaps be called dietary or caloric dilution, rather than dietary or caloric restriction, to distinguish these potentially important methodological differences. Copyright © 2016 Elsevier Inc. All rights reserved. PMID: 27006163 --------- [2] Oncotarget. 2015 Sep 15;6(27):23213-37. The effects of graded levels of calorie restriction: II. Impact of short term calorie and protein restriction on circulating hormone levels, glucose homeostasis and oxidative stress in male C57BL/6 mice. Mitchell SE(1), Delville C(1), Konstantopedos P(1), Hurst J(2), Derous D(1), Green C(1), Chen L(3), Han JJ(4), Wang Y(5), Promislow DE(6), Lusseau D(1), Douglas A(1), Speakman JR(1,)(5). Author information: (1)Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, UK. (2)Mammalian Behaviour & Evolution Group, Institute of Integrative Biology, University of Liverpool, Liverpool, UK. (3)Key Laboratory of Systems Biology, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, China. (4)Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. (5)State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Chaoyang, Beijing, China. (6)Department of Pathology and Department of Biology, University of Washington, Seattle, USA. Limiting food intake attenuates many of the deleterious effects of aging, impacting upon healthspan and leading to an increased lifespan. Whether it is the overall restriction of calories (calorie restriction: CR) or the incidental reduction in macronutrients such as protein (protein restriction: PR) that mediate these effects is unclear. The impact of 3 month CR or PR, (10 to 40%), on C57BL/6 mice was compared to controls fed ad libitum. Reductions in circulating leptin, tumor necrosis factor-α and insulin-like growth factor-1 (IGF-1) were relative to the level of CR and individually associated with morphological changes but remained unchanged following PR. Glucose tolerance and insulin sensitivity were improved following CR but not affected by PR. There was no indication that CR had an effect on oxidative damage, however CR lowered antioxidant activity. No biomarkers of oxidative stress were altered by PR. CR significantly reduced levels of major urinary proteins suggesting lowered investment in reproduction. Results here support the idea that reduced adipokine levels, improved insulin/IGF-1 signaling and reduced reproductive investment play important roles in the beneficial effects of CR while, in the short-term, attenuation of oxidative damage is not applicable. None of the positive effects were replicated with PR. PMCID: PMC4695113 PMID: 26061745 ------- [3] Cell Metab. 2014 Mar 4;19(3):418-30. doi: 10.1016/j.cmet.2014.02.009. The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice. Solon-Biet SM(1), McMahon AC(2), Ballard JW(3), Ruohonen K(4), Wu LE(5), Cogger VC(2), Warren A(2), Huang X(2), Pichaud N(3), Melvin RG(6), Gokarn R(7), Khalil M(8), Turner N(9), Cooney GJ(9), Sinclair DA(10), Raubenheimer D(11), Le Couteur DG(12), Simpson SJ(13). Free full text: http://www.cell.com/cell-metabolism/abstract/S1550-4131(14)00065-5 Comment in Science. 2014 Mar 7;343(6175):1068. The fundamental questions of what represents a macronutritionally balanced diet and how this maintains health and longevity remain unanswered. Here, the Geometric Framework, a state-space nutritional modeling method, was used to measure interactive effects of dietary energy, protein, fat, and carbohydrate on food intake, cardiometabolic phenotype, and longevity in mice fed one of 25 diets ad libitum. Food intake was regulated primarily by protein and carbohydrate content. Longevity and health were optimized when protein was replaced with carbohydrate to limit compensatory feeding for protein and suppress protein intake. These consequences are associated with hepatic mammalian target of rapamycin (mTOR) activation and mitochondrial function and, in turn, related to circulating branched-chain amino acids and glucose. Calorie restriction achieved by high-protein diets or dietary dilution had no beneficial effects on lifespan. The results suggest that longevity can be extended in ad libitum-fed animals by manipulating the ratio of macronutrients to inhibit mTOR activation. Copyright © 2014 Elsevier Inc. All rights reserved. PMID: 24606899