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Found 15 results

  1. AlPater

    Al's CR updates

    The email list system is broken. Posts cannot be searched. Many of the posts do not make it to the messages I receive individually and via the daily mailings. Therefore, I am sending this message, comprised of citations papers that seem to be appropriate to the room of the Forum. I will try to also provide full-text links and a very brief excerpt or within brackets my synopsis of the paper. I apologize for the fact some papers discuss results of studies on the overweight or obese, but feel that some benefits seen in such subjects bears on a continuum of benefits accrued by CR and provide incentive to folks who are overweight or obese. Below are today's papers. Altered consolidation of extinction-like inhibitory learning in genotype-specific dysfunctional coping fostered by chronic stress in mice. Campus P, Maiolati M, Orsini C, Cabib S. Behav Brain Res. 2016 Aug 6. pii: S0166-4328(16)30505-8. doi: 10.1016/j.bbr.2016.08.014. [Epub ahead of print] PMID: 27506654 http://linkinghub.elsevier.com.sci-hub.cc/retrieve/pii/S0166432816305058 These findings support the conclusion that an experience of reduced food availability strain-specifically affects persistence of newly acquired passive coping strategies by altering consolidation of extinction-like inhibitory learning. The interaction of fasting, caloric restriction, and diet-induced obesity with 17β-estradiol on the expression of KNDy neuropeptides and their receptors in the female mouse. Yang JA, Yasrebi A, Snyder M, Roepke TA. Mol Cell Endocrinol. 2016 Aug 6. pii: S0303-7207(16)30298-2. doi: 10.1016/j.mce.2016.08.008. [Epub ahead of print] PMID: 27507595 http://linkinghub.elsevier.com.sci-hub.cc/retrieve/pii/S0303720716302982 [This paper suggests that steroidal environment and energy state negatively regulate KNDy (Kisspeptin/Neurokinin B/Dynorphin) gene which plays an important role in the https://en.wikipedia.org/wiki/Hypothalamic%E2%80%93pituitary%E2%80%93gonadal_axis] Effects of dietary supplementation with EPA and/or α-lipoic acid on adipose tissue transcriptomic profile of healthy overweight/obese women following a hypocaloric diet. Huerta AE, Prieto-Hontoria PL, Fernández-Galilea M, Escoté X, Martínez JA, Moreno-Aliaga MJ. Biofactors. 2016 Aug 10. doi: 10.1002/biof.1317. [Epub ahead of print] PMID: 27507611 http://sci-hub.cc/doi/10.1002/biof.1317 α-lipoic acid, especially in combination with EPA, upregulated the expression of genes associated with lipid catabolism while downregulated genes involved in lipids storage. Association of the TNF-alpha -308 G/A polymorphisms with metabolic responses secondary to a high protein/low carbohydrate versus a standard hypocaloric diet. De Luis DA, Aller R, Izaola O, Romero E. Nutr Hosp. 2016 Jun 30;33(3):267. doi: 10.20960/nh.267. Spanish. PMID: 27513494 [i have no access to this paper's full texts.] Carriers of -308 GG promoter variant of TNF-alpha gene have a better metabolic response than -308 GA obese with a high protein hypocaloric diet.
  2. [Admin Note: This is a series of posts originally on another thread that started on the topic of how cold exposure can have beneficial effects for health and longevity despite increasing calorie expenditure. I debated where to move them, since they seem to fit General Health & Longevity, CR Practice, and CR Science. I finally opted for CR Science, since you'll see if you haven't been reading them already, they bear directly on CR and CR mimetics. If anyone feels strongly this was the wrong choice, I'll be happy to move the thread to another forum. --Dean] Rodney, Whenever I see someone use the word "surely", I figure the writer isn't very sure about, or doesn't have real evidence to support, what they are about to say. I'm guilty of it sometimes myself. People's appetites differ for a lot of reasons, many of them without negative health implications. Genetics is one example that can alter metabolic rate and therefore hunger (remember the ob/ob mice who ate more but didn't live shorter lives). Exercise or exposure to cold (and extra brown fat that cold exposure can create/promote) will increase calorie expenditure without detrimental effects. In fact, perhaps my favorite study of all time (except for the suffering of the animals involved) was the famous "rats with cold feet" study [1] by John Holloszy. Holloszy found that rats who lived their lives standing in a cold puddle of water ate 44% more than normally-housed rats, but nonetheless stayed thin and didn't live any shorter lives than the normally-housed rats. In fact they lived slightly longer and got less cancer. Our friend Josh Mitteldorf did a whole blog post about the hormetic benefits of cold exposure, and how it casts serious doubt (if not debunks) the popular "rate of living" theory of aging. --Dean (who composed this post while pedalling shirtless and wearing just bike shorts on his stationary bike in his 59 degF basement to maximize hormesis... ) -------- [1] J Appl Physiol (1985). 1986 Nov;61(5):1656-60. Longevity of cold-exposed rats: a reevaluation of the "rate-of-living theory". Holloszy JO, Smith EK. It has been postulated that increased energy expenditure results in shortened survival. To test this "rate-of-living theory" we examined the effect of raising energy expenditure by means of cold exposure on the longevity of rats. Male 6-mo-old SPF Long-Evans rats were gradually accustomed to immersion in cool water (23 degrees C). After 3 mo they were standing in the cool water for 4 h/day, 5 days/wk. They were maintained on this program until age 32 mo. The cold exposure resulted in a 44% increase in food intake (P less than 0.001). Despite their greater food intake, the cold-exposed rats' body weights were significantly lower than those of control animals from age 11 to 32 mo. The average age at death of the cold-exposed rats was 968 +/- 141 days compared with 923 +/- 159 days for the controls. The cold exposure appeared to protect against neoplasia, particularly sarcomas; only 24% of the necropsied cold-exposed rats had malignancies compared with 57% for the controls. The results of this study provide no support for the concept that increased energy expenditure decreases longevity. PMID: 3781978 [PubMed - indexed for MEDLINE]
  3. I have embarked upon a quest to lengthen my telomeres. Intermittent Fasting is one technique I am utilizing in my effort. The type of Intermittent Fasting I am practicing is water fasts on Tuesdays and Thursdays. Has anyone had their telomeres measured? Does anyone have any input and/or suggestions regarding my objective?
  4. The strategies are pretty standard but still pretty interesting for anyone who’s looked into ‘biohacking’. The guy is a CEO of a company that does half a billion dollars a year in revenue so he definitely has to be high performing. Funny enough he follows a ketogenic diet, fasts frequently and uses ssri’s for mood improvement. Here’s his whole protocol: https://hackernoon.com/im-32-and-spent-200k-on-biohacking-became-calmer-thinner-extroverted-healthier-happier-2a2e846ae113
  5. Valter Longo's work has been discussed around here quite frequently as of late, particularly his work on the fasting mimicking diet. In typical Rich Roll fashion, he goes long form and tries to gain deep insight into Longo's understanding of nutrition, longevity, and health. Rich says that he considers it one of his most important conversations to date.
  6. Dean Pomerleau

    Longo Patents Intermittent Fasting

    Sorry everyone. It appears Valter Longo has patented intermittent fasting. So you all gotta pay up. Seriously. Pretty crazy. Here is the abstract from the patent, which was just granted last month: Methods and diets for lowering glucose and/or IGF-1 levels US 9237761 B2 ABSTRACT A method of improving longevity and/or alleviating a symptom of aging or preventing age related diseases is provided. The method includes a step in which the subject's average and type of daily protein intake, IGF-I, and IGFBP1 levels, and risk factors for overall mortality, cancer and diabetes are determined. With respect to protein consumption, the relative amounts of protein calories from animal and plant sources are determined. A periodic normal calorie or low calorie but low protein fasting mimicking diet with frequencies of every 2 weeks to 2 months is provided to the subject if the subject's average daily protein intake level and type and/or IGF-I levels, and/or IGFBP1 levels is identified as being greater or lower than a predetermined cutoff intake/level and if the subject is younger than a predetermined age. The method is also shown to alleviate symptoms of chemotoxicity. I'm no patent attorney, but it would seem like there should be sufficient "prior art" to invalidate this patent. --Dean
  7. drewab

    Fasting - The Movie

    I'm sure this movie will be of interest to many CR members. I just watched it and thought it was an interesting film that included the pros/cons of fasting. The movie talks about many different forms of fasting (IF, TRF, multi-day water fasts, juice fasts, etc.). It includes appearances from many big names including Valter Longo, Alan Goldhammer, and many more. Before I muddy the waters and give my thoughts, I would be curious as to what others think. The cost to rent it is relatively inexpensive. The movie can be viewed here: http://fastingmovie.com/
  8. BrianMDelaney

    FMD vs. "inverted FMD"

    Hi everyone, Many people have been asking, both here and elsewhere, about the safety and efficacy of various time-restricted eating schemes. This is of particular interest to me since, for reasons that are irrelevant to most here (an unusual constellation of health challenges), I have been finding conventional CR (=the same, low energy intake per day) unworkable. Before I continue, I should emphasize that the best bet for health and longevity, based on the science we have (which is limited), is indeed conventional CR. But for those who want to try time-restricted eating, I'm wondering about the relative merits of two approaches, and I'd appreciate feedback. I've been thinking this through mostly on my own, and find myself unable to reach a conclusion. Experimental evidence is so limited, I think it's more helpful to reflect a bit on mechanisms, or even evolution. (More helpful doesn't mean very helpful, though....) Type 1: Longo/FMD. The evidence for benefit in both lab animals and humans is limited, but is at least somewhat compelling. It seems unlikely that there's any antiaging benefit per se, beyond that which would have obtained with the same overall ("longish-period averaged") reduction in calories. Type 2: "Inverted FMD". If the Longo approach involves having non-CR signaling patterns (high mTOR, IGF1, insulin, etc.) be the norm, with a sudden several-day period of CR signaling patterns being the exception, "inverted FMD" would be CR, perhaps somewhat mild, as the norm, with a several-day, or week-long period of "feast" signaling. (Credit where credit is due: James Clement is the one who suggested this pattern of eating as possibly better than the Longo pattern.) Type 1 vs. Type 2. Type 2 seems to me to be more like the pattern of eating under which we evolved – scarcity as the norm, with the occasional feast when the tribe came upon a bunch of food – but that doesn't say much about its benefits, though it might suggest that the body would be more adapted to it. Hm.... what we really need is more science on this. Does anyone here know Longo? I've emailed him a couple times and not gotten a response. A small trial comparing the two approaches could be helpful (though only slightly of course, since the main interest of many here is effect on mortality, for which we still don't have great biomarkers). Brian
  9. Sthira

    Fasting

    So I fasted for a few hundred days back in 2014, and I got good at it and it felt good. Like I was doing something good for body and spirit. I started with shortie day fasts, nothing consistent, then kept up the practice and increased to longer fasts -- 3, 4, 5, 7, and I did one 10-day fast. Then I lost interest. This year I've returned to fasting -- inspired by Valter Longo, I suppose, but also this guy with an awesome last name. He seems pretty solid:
  10. An argument against prolonged fasting (>24 hours): In their book “the perfect health diet” by Paul Jaminet Ph.D. and Shou-Ching Jaminet Ph.D., the authors note that “Long fasts do not upregulate autophagy more than short fasts do. In mice, autophagy peaks within the first twenty-four hours of a fast and then drops back to normal levels within forty-eight hours of fasting.” While this is in mice, since they published their work similar findings have come out in humans too. Further, they note that “Although long fasts do not upregulate autophagy, they do lead to a more exaggerated drop in autophagy upon resumption of feeding. Mice starved for forty-eight hours experience complete suppression of autophagy when feeding is resumed. [1] In rats starved for five days, autophagy is completely eliminated throughout the first day of refeeding and takes several more days to return to normal. [2] Regarding this delay in resumption of autophagy, they cite “a study of famine victims who had lost 25 percent of body weight during a famine and then were given unlimited food found that only 4.9 percent had detectable infections when refeeding began, but 29.1 percent had overt infections two weeks later. […] the infections that flared up were all intracellular infections—the kind that are fought by autophagy.” [3].Those authors, who saw increased malaria following fasting, concluded “Severe undernutrition can suppress certain infections, mostly those due to intracellular pathogens and especially P. falciparum. Refeeding reactivates suppressed infection and can increase vulnerability to certain new infections especially of viral origin. Based on this, they argue that, “with autophagy suppressed [ by prolonged fasts ] pathogens are free to multiply,” and therefore: “in order to maximize immunity, we want our fasts to be shorter than twenty-four hours. Such short fasts are long enough to induce the highest rates of autophagy—thus maximizing immunity. Longer fasts would not increase autophagy, but would increase the period of immune suppression after the fast ends. Long fasts make infections worse, not better.” They did endorse shorter fasts [4] in the 16-24 hour range, citing the work in alternate day fasts. They also noted a couple of healthy population that practice some version of least partial intermittent fasting, Orthodox Christians following a Mediterranean diet [5] and the Kitavans, [6] “who are noted for their absence of disease […] where the “main and only cooked meal is at sunset, after the gardening has been completed, and generally consists of yams, taro, and occasionally fish, wild fowl, pork, or sea fowl eggs. During the day mangoes, breadfruit, bananas, and green coconuts and their milk may be eaten while working.” [5] We should probably acknowledge here that besides not quite practicing complete intermittent fasting, these populations may be healthy for other reasons. But I think their basic point here is that we have pretty good empirical data on safety of practicing a lifetime of shorter <24 hour fasts in real populations. In contrast, we have less empirical data for the long-term health impact - including any cumulative metabolic damage from the hypothetical proliferation of intracellular parasitic and opportunistic infection -- of practicing lifelong regular prolonged complete fasts >24 hours. Has delayed resumption of autophagy with prolonged fasts been raised as a concern here in the past? Interested in thoughts and perspectives on their arguments for keeping fasts <24 hours. References* * Link to their book via Amazon provided above, repaginated references obtained from http://perfecthealthdiet.com/notes/#Ch40 [1] Mortimore GE et al. Quantitative correlation between proteolysis and macro- and microautophagy in mouse hepatocytes during starvation and refeeding. Proceedings of the National Academy of Sciences of the United States of America 1983 Apr;80(8):2179–83, http://pmid.us/6340116. [2] Pfeifer U, Bertling J. A morphometric study of the inhibition of autophagic degradation during restorative growth of liver cells in rats re-fed after starvation. Virchows Archive B: Cell Pathology 1977 Jun 24;24(2):109–20, http://pmid.us/407706. [3] Murray MJ et al. Infections during severe primary undernutrition and subsequent refeeding: paradoxical findings. Australian and New Zealand Journal of Medicine 1995 Oct;25(5):507–11, http://pmid.us/8588773. [4] Carlson AJ, Hoelzel F. Apparent prolongation of the life span of rats by intermittent fasting. Journal of Nutrition 1946 Mar;31:363–75, http://pmid.us/21021020. Hat tip to Mark Sisson: The myriad benefits of intermittent fasting, February 16, 2011, www.marksdailyapple.com/health-benefits-of-intermittent-fasting/. [5] Sarri KO et al. Greek Orthodox fasting rituals: a hidden characteristic of the Mediterranean diet of Crete. British Journal of Nutrition 2004 Aug;92(2):277–84, http://pmid.us/15333159. Trepanowski JF, Bloomer RJ. The impact of religious fasting on human health. Nutrition Journal 2010 Nov 22;9:57, http://pmid.us/21092212. [6] Malone MJ. Society—Trobriands, http://lucy.ukc.ac.uk/ethnoatlas/hmar/cult_dir/culture.7877 [link does not work but is the citation provided at http://perfecthealthdiet.com/notes/#Ch40 ]
  11. Thomas G

    Fasting and Fainting

    In 2017 I've decided to try to do quarterly five day water-only fasts. I did my first one on Jan 2-6. Because of some upcoming travel in April I'm doing my second one now. I'm on the last day of a five day water-only fast. I usually take my blood pressure every day. For the first three days of this fast my blood pressure was pretty normal for me lately, about 120ish over 70ish. But yesterday my blood pressure was 100/65. I thought the reading might be a fluke so I took it a few more times and got the same result. Even later in the day it was still in that same range. Yesterday I felt dizzy when I stand up too quickly, but I've took things slowly during the day. Last night I couldn't sleep. I felt wide awake, restless, and my back hurt. At around 2:30 a.m. I got up to use the bathroom. I don't remember falling but the next thing I knew I was on the floor holding my hip and in a little pain. I fainted and hit my stomach on the corner of a table and the top of a chair, and my hip has a nice bruise. My chin and jaw hurt a little too (I must have hit my chin on the floor). I've never fainted before and I'm concerned. My wife quickly googled fasting and fainting and found info on dehydration. During my fast in Jan. I was trying to drink as much water as Cron-o-meter says I should. I think that was a mistake. I had to drink an abnormally large amount of water. I guess that is because I'm not getting any water from the foods I normally eat. But the last two days of the fast in Jan. I felt very odd, and basically treated them as sick days. I would have broken the fast if I felt that way early on, but since I was so close to being finished I just stuck it out in bed. Looking up info online I saw stuff about drinking too much water on a fast diluting electrolytes. I don't know much about that but I figured that must be why I didn't feel well. So for this current fast I have only been drinking when I feel thirsty and stopping when I feel quenched. I haven't been logging every drink, but I seem to be drinking plenty and I have to go to the bathroom frequently. Indeed it was the need to go to the bathroom that got me up at 2:30 a.m. when I fainted. The info my wife found said I should drink some lemon juice in water and some brine from a pickle jar. I really didn't like the idea of breaking the fast with brine. I did drink one glass of lemon juice and water. So I guess technically I broke my water-only fast. I'm considering breaking the fast for real and eating some food. I feel fine at the moment and I guess I would prefer to finish the fast for primarily psychological reasons. Rationally I am committed to doing what is best for my health, whether that is fasting or breaking a fast. But it still feels a bit like giving up, laziness, or quitting if I break the fast earlier than I had planned, even if I have a good reason. We are psycho-somatic creatures and I think this psychological element is worth tending to as well as the somatic element. I would appreciate any advice about how to make this decision (I only have about 12 hours left to go anyway). But mainly I'm more concerned that I've tried relatively moderate length water-only fasts twice now and have had issues both times. Many people are able to fast for much MUCH longer without any issues at all.
  12. Hi all, I have enjoyed consuming content on this forum. Thank you to all members who actively post. Please know that many lurk in the background and benefit from the exchange of knowledge. I am about to embark on my first FMD using the Prolon box. I have previously completed water only fasts. I will compare FMD changes in biomarkers to those of other fasting interventions (water, self-hacked FMD, etc.) I was planning to track the enclosed at onset and immediately post FMD, any suggestions on others? IGF FBS Ketones hs-CRP ESR Homocysteine CBC --- Microbial load (uBiome) Organic Acids Test (Great Plains, urine)
  13. drewab

    Sleep thought of the day

    There are many factors, which act as stressors on the body, and seem to contribute to improved health outcomes. Some of these include: Exercise Fasting Cold exposure Caloric restriction Heat exposure Particular foods that exert hormetic effects (ie. cruciferous vegetables) Some of the above are not without their controversies, but it's interesting that mild sleep deprivation (a mild stressor) doesn't elicit a hormetic effect. Or perhaps it does? Has anyone else had this curious thought before and unpacked it a little?
  14. 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
  15. All, I personally don't do extended fasts except on rare occasions (like my last colonoscopy, when I had to go 5 days without food to clear out my colon for imaging). But I do eat in a limited time window, and fast for most of the day and night, both for convenience, and because I believe it to be healthy for a number of reasons (reduced glucose / insulin exposure, increased autophagy, etc). It looks like we can add 'reducing breast cancer recurrence' to the list of benefits of an extended overnight fast, according to a new study [1] in this month's issue of JAMA (popular press story). In a study of 2400 breast cancer survivors, researchers found that waiting more than 13 hours between her last meal or snack in the evening and her first meal in the morning resulted in a 36% reduction in a woman's risk of breast cancer recurrence relative to fasting for less than 13 hours. The women who fasted longer had better markers of glucose control (HbA1C) and increased sleep duration. The researchers think these benefits may have been at least partly responsible for the reduction in breast cancer recurrence. --Dean ------------ [1] JAMA Oncol. 2016 Mar 31. doi: 10.1001/jamaoncol.2016.0164. [Epub ahead of print] Prolonged Nightly Fasting and Breast Cancer Prognosis. Marinac CR(1), Nelson SH(2), Breen CI(3), Hartman SJ(4), Natarajan L(4), Pierce JP(4), Flatt SW(3), Sears DD(5), Patterson RE(4). Free full text: http://oncology.jamanetwork.com/article.aspx?articleid=2506710 Importance: Rodent studies demonstrate that prolonged fasting during the sleep phase positively influences carcinogenesis and metabolic processes that are putatively associated with risk and prognosis of breast cancer. To our knowledge, no studies in humans have examined nightly fasting duration and cancer outcomes. Objective: To investigate whether duration of nightly fasting predicted recurrence and mortality among women with early-stage breast cancer and, if so, whether it was associated with risk factors for poor outcomes, including glucoregulation (hemoglobin A1c), chronic inflammation (C-reactive protein), obesity, and sleep. Design, Setting, and Participants: Data were collected from 2413 women with breast cancer but without diabetes mellitus who were aged 27 to 70 years at diagnosis and participated in the prospective Women's Healthy Eating and Living study between March 1, 1995, and May 3, 2007. Data analysis was conducted from May 18 to October 5, 2015. Exposures: Nightly fasting duration was estimated from 24-hour dietary recalls collected at baseline, year 1, and year 4. Main Outcomes and Measures: Clinical outcomes were invasive breast cancer recurrence and new primary breast tumors during a mean of 7.3 years of study follow-up as well as death from breast cancer or any cause during a mean of 11.4 years of surveillance. Baseline sleep duration was self-reported, and archived blood samples were used to assess concentrations of hemoglobin A1c and C-reactive protein. Results: The cohort of 2413 women (mean [sD] age, 52.4 [8.9] years) reported a mean (SD) fasting duration of 12.5 (1.7) hours per night. In repeated-measures Cox proportional hazards regression models, fasting less than 13 hours per night (lower 2 tertiles of nightly fasting distribution) was associated with an increase in the risk of breast cancer recurrence compared with fasting 13 or more hours per night (hazard ratio, 1.36; 95% CI, 1.05-1.76). Nightly fasting less than 13 hours was not associated with a statistically significant higher risk of breast cancer mortality (hazard ratio, 1.21; 95% CI, 0.91-1.60) or a statistically significant higher risk of all-cause mortality (hazard ratio, 1.22; 95% CI, 0.95-1.56). In multivariable linear regression models, each 2-hour increase in the nightly fasting duration was associated with significantly lower hemoglobin A1c levels (β = -0.37; 95% CI, -0.72 to -0.01) and a longer duration of nighttime sleep (β = 0.20; 95% CI, 0.14-0.26). Conclusions and Relevance: Prolonging the length of the nightly fasting interval may be a simple, nonpharmacologic strategy for reducing the risk of breast cancer recurrence. Improvements in glucoregulation and sleep may be mechanisms linking nightly fasting with breast cancer prognosis. PMID: 27032109
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