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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  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 -------------  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.
I've suffered from early waking insomnia all my life. Until a few years ago, it was fairly minor, and manageable. But a few years ago, in connection with some other andropause-like changes I went through, I started to wake and not get back to sleep after 4-5 hours of sleep instead of 6-7 (8 hours is optimal for me). I was also losing weight, though I don't think I was eating less. I think I moved into an aged phenotype all at once. (Long story there.) Regardless of the strange changes that took place a few years ago, the early waking, which was always a problem, became worse. I've had my early morning cortisol tested several times over the last few years, and it's always been above the reference range. This is no big surprise for a person on CR: low blood sugar causes an increase in cortisol (which keeps blood sugar from falling "too low"). It's not that I'm tense, it's not that I'm hungry (well, I am, but I always am). I'm just awake. Well, my 2:1 diet plan has yielded some interesting results. The night after Feast Day 2, I sleep beautifully! The night after Feast Day 1, I often sleep fairly well. The night after the fasting day (right now around 700 calories/day), I sleep worse than ever. I wake too early, and can't get back to sleep. I'm happy, non-tense, not really hungry even. Just really awake. So now I'm thinking I might take timed-release zolpidem or something on fasting days before going to bed. But I'm wondering if anyone else has tried any cortisol lowering strategies that have helped with sleep. A lot of supplements that supposedly lower cortisol seem to do so (if they work at all...) by lowering stress. I'm not stressed. Phosphatidylserine blunts the post-exercise cortisol spike, but it’s not clear it would help with low glucose-induced cortisol. Suvorexant might be a better choice than timed-release zolpidem (or one of the other Z-drugs), but I haven't studied the relation between orexin and cortisol enough to know whether it would help me. Any CR folks with early morning insomnia have any strategies they'd like to share?
I'm wondering if anyone has thoughts about the appropriate upper limit for diurnal (morning) serum cortisol in CR. I know it's supposed to be high, but I'm having trouble finding appropriate benchmarks. My concern is -- how high? And are there corresponding biomarkers that one might correlate with cortisol being too high such as glucose? I seem to only find salivary. Also, if anyone has any conversion (salivary --> serum) that might be helpful. Thanks very much!