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  1. 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 ]
  2. In her latest video/podcast Rhonda Patrick interviews Dr Guido Kroemer on one of her pet topucs: autophagy. I've been listenig to the podcast while driving today, it's a really information-dense. Types of signalling, reltionship with mTOR, IGF-1, prolonged fasting and intermittent fasting. The CR society is mentioned and one of the studies on some practitioners (members of this forum?). The study has not been specified.
  3. The more I read the more I come to a more conservative position on this topic Most eye opening is the synopsis here ( sorry, no full text available): https://www.ncbi.nlm.nih.gov/pubmed/26374764 In essence, most of the benefits of fasting arise and reach near maximal levels within the first 12-24 hours of fasting: lower average fasting glucose, lower average fasting insulin, increased insulin sensitivity, lower mean CRP / TNF-alpha / IL-6 inflammation as well as near peak levels of autophagy by the end of each day's fasting cycle That being the case, I don't see how regular 5 day water fasts improve upon this unless they carry additional benefits. For the sake of discussion, let's leave out caloric restriction as a benefit as this can be achieved in either or neither regimen). In other words, if 20/4 intermittent fasting is a (mostly) daily ritual, the cumulative influence of daily spurts of of autophagy may not benefit any more from performing an annual or semi-annual or perhaps even monthly 5-day fast. It appears that longer (e.g. 3-5 day+ fasts) do temporarily do several additional and unique things that daily 20/4 intermittent fasting has not been demonstrated to do: For example, a higher level of ketosis/ ketone bodies during the fast, and upregulation of sirtuin pathways that take several days to activate. This won't be achieved by daily shorter fasts by itself in the absence of overall caloric restriction. However, I do not see evidence these unique changes achieved with and specific to prolonged fasts are in any way lasting once completing such fasts. Thus while the impact of autophagy (something both daily 20/4 fasts and 5 day fasts both have in common) is expected to persist --- ie, once a cell undergoes apoptosiis, or autophagy eliminates defective proteins or damaged nucleic acid, etc --- in contrast, the things unique to 5 day prolonged fasts such as upregulation of sirtuin pathways are short-term and transient phenomenon. Since the benefits that are accrued by and unique to 5-day fasts appear to be proportional to the time in these pathways, even a monthly 5 day fast is still ~ 5/30 or a bit longer to the extent the cascade does not shut off right away. Less so for less frequent 5-day fasts. So it is not clear to me that 5-day fasts, unless performed very frequently add anything to a 20/4 daily time restricted feeding. The advice "if you are healthy perform a 5 day fast twice a year or quarterly if you are healthy" ( paraphrasing Valter Longo) may not apply if you are already performing daily intermittent fasting. What do you think? Do 5-day fasts add anything unique AND clinically significant above and beyond the potentially benefits of shorter daily ( "intermittent") fasts? Does anyone here practice or feel that the data is supportive of doing both? Edited 2/16/17am
  4. All, Over on this thread, Cloud did a helpful translation of a talk (in Italian) by everyone's favorite CR researcher, Luigi Fontana. In his talk, Luigi mentions a new paper [1] he and colleagues published this month in the open access journal Cell Reports (full text). It looks at several important biomarkers in some of us from the CR Society (mean BMI 19.2), as compared with endurance athletes (mean BMI 22.4) and normal weight controls (mean BMI 25.2). The CR group has significantly higher cortisol (15.6 ng/dl) than either the athletes (11.2) or the controls (12.3). The authors suggest this could be a good thing, since it may reduce systemic inflammation, and is consistent with elevated corticosteroids in CRed rodents. They didn't report any comparison of inflammation markers directly, but did show that one marker of inflammation, tumor necrosis factor alpha (TNF-a), was inversely correlated with cortisol levels across all subjects. This suggest to me that the change in TNF-a (or other markers of inflammation) probably wasn't significantly different across groups, or they would have reported it directly. Unfortunately, the rest of the paper only compares the CR group with the controls - they apparently didn't perform muscle biopsies on the athletes. Compared with controls, the CR folks had higher levels of stress-related biomarkers, like several heat shock proteins (HSPs), and markers of upregulated autophagy, "involved in cellular protein quality control and removal of dysfunctional proteins and organelles." Here is their conclusion: These CR-induced hormetic responses may play a key role in preserving protein quality control, preventing age-associated proteotoxicity, and increasing the capacity for degrading dysfunctional proteins and organelles, thereby preserving cell functionality and the capacity to adjust to a changing environment. These vital housekeeping homeostatic processes have been shown to protect against age-associated disease and may be involved in slowing the rate of aging in humans. Luigi & co. seem to be big into the health/longevity benefits of hormesis lately, including CR, intermittent fasting, exercise, and keeping abdominal fat low. See this thread for more on Luigi's current perspective, from Cloud's translated highlights from Luigi's recent talk. --Dean ------------- [1] Cell Reports 14, 1–7 January 26, 2016 http://dx.doi.org/10.1016/j.celrep.2015.12.042 Long-Term Calorie Restriction Enhances Cellular Quality-Control Processes in Human Skeletal Muscle Ling Yang,1,11 Danilo Licastro,2,11 Edda Cava,3,4,11 Nicola Veronese,3,5 Francesco Spelta,3,6 Wanda Rizza,3,7 Beatrice Bertozzi,3 Dennis T. Villareal,3,8 Go¨ khan S. Hotamisligil,1 John O. Holloszy,3 and Luigi Fontana Full text: http://www.cell.com/cell-reports/pdf/S2211-1247(15)01483-7.pdf SUMMARY Calorie restriction (CR) retards aging, acts as a hormetic intervention, and increases serum corticosterone and HSP70 expression in rodents. However, less is known regarding the effects of CR on these factors in humans. Serum cortisol and molecular chaperones and autophagic proteins were measured in the skeletal muscle of subjects on CR diets for 3–15 years and in control volunteers. Serum cortisol was higher in the CR group than in age-matched sedentary and endurance athlete groups (15.6 ± 4.6 ng/dl versus 12.3 ± 3.9 ng/dl and 11.2 ± 2.7 ng/dl, respectively; p % 0.001). HSP70, Grp78, beclin-1, and LC3 mRNA and/or protein levels were higher in the skeletal muscle of the CR group compared to controls. Our data indicate that CR in humans is associated with sustained rises in serum cortisol, reduced inflammation, and increases in key molecular chaperones and autophagic mediators involved in cellular protein quality control and removal of dysfunctional proteins and organelles.
  5. Rhonda Patrick has discussed for some time the use of Sauna to not only enhance athletic performance, but also promote longevity via induction of heat shock proteins. For example, see https://m.youtube.com/watch?v=eWKBsh7YTXQ Basic science and animal models are consistent with at least some population based research: http://www.ncbi.nlm.nih.gov/m/pubmed/25705824/ Have any cronies experimented with a combination of the two? It seems that while seemingly contradictory the mechanisms are actually different hence combining both cold and hot stressors may be workable.
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