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  1. Dear ALL, Today is my 80th birthday. I continue to be in excellent health. Several factors that I think are important for prolonged healthspan and (possibly) lifespan: I've been practicing CR since April, 1996 (so about 23 years). I do vigorous aerobic exercise for half an hour or longer six days a week at my gym (in my case, on the latest Precor elliptical cross trainer with hand motion, at the maximum resistance and a fast speed). I continue to be fully employed at the University of Rochester as a Professor of Mathematics (a position that I've held since 1974): I'm the oldest member of the Math Department. I teach two courses every term (both in the Fall and Spring -- I'm off for the Summers). I enjoy the teaching, and attending seminars and colloquia. Here is a recent health assessment from my Endocrinologist: (Note: The weight is incorrect -- weight was taken after I'd eaten a huge breakfast of 1 pound of raw Nappa cabbage, and 64 ounces of carefully brewed Chinese white tea -- that's always my breakfast): Wittlin, Steven D, MD at 5/7/2019 10:00 AM Status: Signed HPI: Saul Lubkin is a 79 y.o. male who presents for follow up of Osteoporosis. He now takes Forteo. . He denies any pain , fractures, muscle weakness or kidney stones. He continues on low calorie diet. Patient's medications, allergies, past medical, surgical, social and family histories were reviewed and updated as appropriate. ROS: CONSTITUTIONAL: Appetite good, no fevers, night sweats or weight loss HEENT: No double or blurry vision; denies severe headache CV: No chest pain, shortness of breath or peripheral edema RESPIRATORY: No cough, wheezing or dyspnea NEURO: No MS changes, no motor weakness, no sensory changes ENDO: No polyuria or polydipsia PE: BP 110/60 | Pulse 71 | Ht 1.55 m (5' 1.02") | Wt 61.2 kg (135 lb) | BMI 25.49 kg/m² GENERAL APPEARANCE: well developed, well nourished, no acute distress; aware and alert HEENT: PERLA, EOMI, no lid lag, pink conjunctiva ; no proptosis NECK: supple, no thyromegaly, no lymphadenopathy HEART: RRR, normal S1, S2 CHEST: lungs clear to auscultation bilaterally, no spinal tenderness EXTREMITIES: no clubbing, cyanosis, or edema. Pedal pulses 2+ bilaterally. Both feet clean without deformity, callous, ulceration, or fungal infection. NEUROLOGICAL: Alert and oriented x 3. Normal DTRs SKIN: Orange color. ASSESSMENT/PLAN: Forteo. Mr Lubkin will repeat his DXA . He continues to appear hypercarotenemic. Saul and I had a long discussion. As per usual he is on top of recent research in osteoporosis. He wants Forteo, acknowledging that we have no good data on its use for this long, that convention is that he should be using A bisphosphonate, and that he has had a very small decrease in BMD.. RTC one year with DXA
  2. Many of us here are fairly robotic, and eat the same thing day in and day out. Some of us enjoy more diversity and enjoy exploring culinary aspects of foods. Yet for many people browsing this forum, they aren't exactly sure what our meals looks like. Let us share our wonderful food creations with one another! I just enjoyed a delicious lunch. It consisted of the following: Purple sweet potato, chick peas, broccoli, cauliflower, carrots, mushrooms, 1 tsp of olive oil, 1 tbsp of 20-spice mix, garlic, oregano, parsley, cilantro, chili peppers, and 2 oranges for dessert. Ingredients were organic when possible. I also get centenarian status for eating Okinawan sweet potato, right? Calorie total was about 700-800, but I don't watch that closely. I just eat more or less depending on what the scale says each day. Did I mention the food was incredibly delicious? Bon appetit!
  3. CRON is well known to greatly reduce inflammation. For years, I've been measuring CRP and TNF_alpha, which are supposed to be measurements of inflammation. All but once, I've gotten CRP <5, meaning immeasurably low. All but the last two measurements (in 2016 and 2017) were vanishingly small for TNF_alpha as well -- but the last two measurements were surprisingly high. So a major contradiction between CRP (vanishingly small) and TNF_alpha (high) on these last two measurements. Weird. I asked my CR friendly nephrologist. He didn't know; suggested that I check with some of the CRONNies -- I guess he thinks it possible that it might be one of the weird looking numbers that happen with CR. So I'm following his advice. Anybody -- who is knowledgeable in the mechanisms of these proteins -- have any ideas? -- Saul
  4. Hi ALL! I thought I'd share two experiences with you, both of which happened in very different places. On returning to teach my two courses at the University of Rochester, Dept of Mathematics after several Jewish Holidays, a much younger (healthy and overweight) female colleague and friend of mine, who is a differential geometer, said "I hear you're on a special diet". I responded, "That's true." She then hoped to get some information about it. I responded positively -- it won't be easy, but I might try to explain CRON to her -- that's quite complicated, since we all have such different diets. Then, about two days later, while changing into gym clothes in my gym, I was approached by an extremely old person, who looked like a near-death alcoholic, who I didn't recognize; he said "I hear you're on a special diet". Apparently (he seemed to claim) we're about the same age, and he knew me from before. I mentioned "Calorie Restriction". He said "that must be hard to do". I gave him the URL "crsociety.org". I doubt that he'll do anything. I'm 79, exercise vigorously for 1/2 - 1 hr. most days, and continue to be optimistic and cheerful, and enjoy my work at the UR Math Dept. I'm the oldest member of the UR Math Dept, and in excellent shape. I'm an example of how CR, ON and EX helps one to maintain vitality. I was especially impressed that in two hugely different venues, I was asked the same question; I thought I woiuld share with you. -- Saul
  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. Dear ALL, I returned home from a five day stay at Kripalu (the Kripalu Center for Yoga and Health, a Yoga resort in the Berkshires in Western Massachusetts). As usual, it was a delightful experience: Yoga every morning and evening, Kripalu Yoga dance every day at noon, and the CR friendly foods available at every buffet meal. One of the talks that I went to was VERY interesting. It was given by the head nutritionist at Kripalu. To my surprise and delight, for the first time, the value of Calorie Restriction was strongly noted and praised. (Alternate day fasting was extolled as well.) Also, it was noted that the SAD diet includes much too much protein. And that the (old) idea of being on a low fat (but high carb) diet was utterly wrong -- it was noted that the obesity epidemic sprouted as this incorrect notion was promoted. The fact that Americans eat far too much protein was also noted -- so a low calorie, low protein, very low carb, high fat diet was identified as being highly desirable . The speaker noted that it was highly desirable for your muscles to be using ketones for fuel rather than glucose -- i.e., to be on a ketotic diet. Also noted: The importance of the gut microbiota -- and, to a lesser extent, of the skin microbiota. The speaker noted, in response to questions, that she didn't use soap when she showered -- wanting to maintain the healthy microbes on her skin. All of this was delightful to hear. The negative (although not very important): As usual, the speaker -- and probably all attendees (except I) -- were strongly opposed to the use of artificial sweeteners (such as aspartame sweetened soda) as well as sugary drinks. Interestingly, the same nonsense was presented by the first speaker at the last CR Conference. The argument against sucralose: It was correctly noted that, although humans cannot metabolize sucralose, undesirable gut microbes that thrive on sugar can, and do, metabolize sucralose -- encouraging their undesirable increase. This is, of course, true. However, of course, it's virtually irrelevant -- since sucralose is (something like) 200 times as sweet as sugar -- so you consume so little sucralose, that the effect on your microbiota is insignificant. The argument presented against aspartame: It is an artificial sweetener, and therefore must not be consumed, since it is not natural. Similarly for neotame. (Of course, this is a religious belief; no argument except concensus of the audience.) Wierdly, even steviosides (the sweet molecule in stevia leaves) was deprocated -- since it is a "refined" substance. I should note that, the nonsense deprocating artificial sweeteners and stevia was not emphasized; it was a response to a question. Aslo, I should note that I personally have simply gone off all sweeteners -- although I sometimes drink diet soda. For example, my morning carefully brewed Chinese white tea is dleiciosly consumed, with no sweetener -- it tastes best without. The only sweet things that I consume is perhaps an apple. Anyway, I'm delighted by the new emphases of the Kripalu nutritionists. -- Saul
  7. 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?
  8. Aubrey remains pretty skeptical of the benefits of CR in humans. http://www.planettechnews.com/interviews/ptn-interviews-dr-aubrey-de-grey-researcher-and-a-thought-leader-in-anti-aging-regenerative-medicine Here is the relevant section from this Q&A article : Q: You comment in your talks that tinkering with metabolism is not a viable approach, because it is too complicated and impossible to modify without causing "more harm than good". However, it seems a number of anti aging companies, focused on drugs and genetic engineering, seem to be pursuing this route. Can you explain this disagreement? Aubrey: Great question. The short answer is that there is one exception to my comment, but it’s an exception that doesn’t seem likely to have much practical significance for humans. The exception is calorie restriction. The drugs and other simple interventions (including genetic ones) that companies are looking at are almost all focused on making the body behave as if it is in a famine. The motivation, of course, is that famine (and these drugs) can greatly postpone aging in short-lived laboratory organisms like mice, rats and (even more so) worms. But it turns out - and for very obvious evolutionary reasons - that this doesn’t work nearly so well in long-lived species as in short-lived ones. The most that I think humans can possibly benefit by that kind of approach is a couple of years.
  9. All, I was wondering if CR has ever been studied in large creatures? It seems that the effects of CR seem to scale down as the size of species goes up. For example, I believe we can double or triple the lifespan of flies and worms, and modestly extend maximum lifespan in larger species like dogs. The evidence for humans is of course murky and the jury is still out on whether maximum lifespan will be effected, or just health span. I'm wondering though if CR has ever been studied in a species physically larger than humans. Perhaps horses? Deer? Cows? Buffalo?
  10. All, In case you missed it, Al posted a pointer to a new review paper [1] by Luigi that reviews lots of interesting human CR results, including Okinawans, Biosphere II, Minnesota Starvation Study, CALERIE-I and II, and our own CR Society Cohort study. I read through it and didn't see anything particularly new. Pretty much a thorough review of everything we already know about human CR, much of it from his own work. Most of the positive evidence for CR benefits in humans comes from us. Reading between the lines, and looking at the lack of many expected changes, the CALERIE studies were somewhat of a disappointment. For anyone who is steeped in CR science, it probably isn't worth reading, except perhaps as a refresher. But for newcomers to CR, it looks to be a very good introduction. --Dean -------- [1] Ageing Res Rev. 2016 Aug 17. pii: S1568-1637(16)30183-0. doi: 10.1016/j.arr.2016.08.005. [Epub ahead of print] Review. Calorie restriction in humans: An update. Most J, Tosti V, Redman LM, Fontana L. Full text: http://sci-hub.cc/10...arr.2016.08.005 Abstract Calorie restriction (CR), a nutritional intervention of reduced energy intake but with adequate nutrition, has been shown to extend healthspan and lifespan in rodent and primate models. Accumulating data from observational and randomized clinical trials indicate that CR in humans results in some of the same metabolic and molecular adaptations that have been shown to improve health and retard the accumulation of molecular damage in animal models of longevity. In particular, moderate CR in humans ameliorates multiple metabolic and hormonal factors that are implicated in the pathogenesis of type 2 diabetes, cardiovascular diseases, and cancer, the leading causes of morbidity, disability and mortality. In this paper, we will discuss the effects of CR in non-obese humans on these physiological parameters. Special emphasis is committed to recent clinical intervention trials that have investigated the feasibility and effects of CR in young and middle-aged men and women on parameters of energy metabolism and metabolic risk factors of age-associated disease in great detail. Additionally, data from individuals who are either naturally exposed to CR or those who are self-practicing this dietary intervention allows us to speculate on longer-term effects of more severe CR in humans. PMID: 27544442
  11. drewab

    CR: My Story

    Hi All, I've hung out on these forums for a little while now. Long enough that I'm pretty sure I have begun to understand some of its finer content - and important things like why Dean gives Michael a hard time. I'd like to share a little about my story. At 24 years old I was being monitored for cardiovascular problems. My family physician had detected a heart murmur on my annual checkup and I was showing some really strange blood pressure readings (regularly ~155/45). An echocardiogram revealed that I had a bicuspid aortic valve that was leaking quite significantly. This lead to the replacement of my aortic valve via open-heart surgery at 24. Unfortunately post-op I developed acute endocarditis, which become chronic endocarditis. I lived the next 27 months of my life in and out of hospitals visiting IV clinics for antibiotics 3x daily to find this heart infection. I had PICC lines installed, and was administered just about every kind of high-potency anti-biotic you can imagine, and for 27 months straight. I was hospitalized a total of 5 times and was probably close to death at a few points. Closer than I'd like to believe. Needless to say, antibiotics weren't working. So I required open heart surgery for a second time. I was 26 years olds at this point. Trans-esophegeal echocardiograms confirmed a large vegetation on my aortic valve and aorta. This is basically a mass of bacteria, platelets, white blood cells, etc. I had my aortic valve replaced again, along with my aorta. Additionally, arteries were reattached in different locations, so that future heart surgery doesn't have to be invasive - the current gear in my heart is believed to last 10-20 years - hopefully. I've talked to Dr. Essylstyn twice on the phone and he feels next time I need surgery, it will be done through trans-aortic valve implantation. He also said 'no one makes a habit out of sternotomies, they suck.' He's right. They are awful. The second surgery went well. And here is something that Dean and his ethical vegan spirit will like. I was profoundly impacted by this experience for many reasons. One of which was the fact that a cow had to die for me to live. Bovine tissue is used to construct the valve replaced in my heart. When I woke up from the second surgery and had no desire to consume animals ever again. I never had a bite of meat again. I almost immediately went vegan despite having never read a thing about it. (Technically speaking I've consumed animal products maybe once-twice a year when in a pinch, but that's really not significant to the story) I went to my local bookstore and picked up one of the first health books I saw. Which happened to be the Blue Zones. I often wonder what would have happened if I randomly grabbed an Atkins or paleo book. I thank whatever higher power is out there that it was the Blue Zones. That quickly lead to the assimilation of the China Study, Finding Ultra, Prevent and Reverse Heart Disease, The Spectrum, The CR Way, and so on. Pre-heart surgery I was just under 220 pounds, somewhat muscular too and consuming about 400g of protein per day - that is not a typo. After the second procedure I was about 185 pounds. This morning I was 149 pounds. 5.5 years after starting a WFPB vegan, lightly CR'd diet. (See photo attached from today - BMI is 20.7). You can also tell I don't have the perfect CR body, but it's been through a lot. I have a little loose skin, some big scars, and some mild man boobs. But whatever. I'm alive, happy, and contributing a lot to this world each day. In discussion of how I got the bicuspid valve in the first place, my cardiologist has 3 possible explanations: a) I was born with it b) I was hospitalized as an infant with a fever of unknown origin, which may have rheumatic fever c) I was hospitalized as an infant with a fever of unknown origin, which may have endocarditis. Though I will never know for sure, and I suppose there is the possibility it was something else. Here is the amazing thing. I had developed an enlarged heart since it was working so hard to re-pump blood that was flowing backwards through my valve. My heart returned to normal size, something my cardiologist said does not happen. Maybe the surgery was a great success, maybe it was the CR lifestyle, or some combination of the two. I personally think that if I returned to my old ways, my heart would not have shrunk down. The other biomarkers of mine are great. Fasting glucose is 79. BP is 110/60. Total cholesterol is 129. Triglycerides are 29. And so on. Interestingly, the one I have that doesn't add up to CR levels is IGF-1. Which came back at about 280 when I had it tested about a year ago. Anyway - I just had a nice breakfast of wild rice, barley, mango, raisins, flax, cocoa, almond butter, and about 5 oz of arugula. It's awfully cold outside, so it's time to go for a brisk walk in a tank-top and shorts to get some CE with my dog. Thanks for listening folks!
  12. Here is a new 20min video interview of Aubrey de Grey on Youtube in which he covers some interesting topics, including: The self-experimentation Liz Parrish from Bioviva has done to modify expression of genes telomerase & for preventing sarcopenia. Aubrey says there some evidence these modifications could be beneficial. But both have their potential downsides as well (e.g. cancer for telomerase). He admires Parrish for her boldness, and for bringing the possibility of genetic manipulation in humans for health / longevity to the public debate. But he worries that it will be very difficult to identify any measureable benefits that might result from these interventions, since Parrish is young and healthy The newly FDA-approved study of metaformin as a potential anti-aging drug. He is skeptical of CR mimetics like metaformin, due to his skepticism that CR will have much longevity benefit in long-lived species. He applauds the effort to study aging as a disease that can be treated, as this study attempts. CRISPR-cas9 gene editing technology He sees lots of potential for this technology to facilitate the kind of health / longevity interventions his SENS Foundation is investigating He doesn't see a lot of benefits/advantages (yet) for using the other recently publicized DNA technology, DNA_Origami, for drug delivery relative to other drug delivery methods. --Dean
  13. I came across this gem - a cross sectional/correlational study on being a father and T levels. The reason I think it's important is that Tanzanian hunter gatherers are known to eat 100-150g of fibre daily, something many of us here do. In addition they have a low BMI and low energy intake. http://rspb.royalsocietypublishing.org/content/276/1655/347 I'm typing this from my phone so my response has to be limited, but here were some points I picked up on: -their T in general is far lower than Americans - 150 pmol vs Americans being 250-400pmol (I'm not familiar with this unit and google didn't help) -caring for offspring closely lowered AM T by 30% and PM T by 50% (same trend not seen in America) -more closely caring for children lowered T more, while distance parenting didn't -fidelity lowered T -T didn't vary by age in these groups, suggesting you can maintain some T as you age Maybe this is why some CR practitioners like Paul McGlothin are able to maintain youthful T levels. Thoughts?
  14. Wow. Safety of two-year caloric restriction in non-obese healthy individuals. Romashkan SV, Das SK, Villareal DT, Ravussin E, Redman LM, Rochon J, Bhapkar M, Kraus WE; CALERIE Study Group. Oncotarget. 2016 Mar 15. doi: 10.18632/oncotarget.8093. [Epub ahead of print] PMID: 26992237 Free Article http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=8093&path%5B%5D=23850 file:///C:/Documents%20and%20Settings/user/My%20Documents/Downloads/8093-123150-2-PB.pdf Abstract BACKGROUND: The extent to which sustained caloric restriction (CR) in healthy non-obese adults is safe has not been previously investigated. OBJECTIVE: Assess the safety and tolerability of sustained two-year CR intervention in healthy, non-obese adults. DESIGN: A multi-center, randomized controlled trial. Participants were randomized using a 2:1 allocation in favor of 25% CR vs. Ad-Libitum intake (AL). Adverse and serious adverse events (AE, SAE), safety laboratory tests, and other safety parameters were closely monitored. RESULTS: Three participants were withdrawn from the CR intervention because of the safety concerns. No deaths and one SAE was reported by participants in the CR group. Although the difference in AE between AL and CR groups was not significant, within the CR group, the incidence of nervous system (p = 0.02), musculoskeletal (p = 0.02) and reproductive system (p = 0.002) disorders was significantly higher in the normal-weight than in the overweight participants. At months 12 and 24, bone mineral densities at the lumbar spine, total hip, and femoral neck of participants in the CR group were significantly lower than in those in the AL group. CONCLUSIONS: Two-years of CR at levels achieved in CALERIE was safe and well tolerated. Close monitoring for excessive bone loss and anemia is important. KEYWORDS: Gerotarget; calorie restriction; dietary energy restriction; humans; safety
  15. drewab

    Is CR for me?

    Hi All, I'm trying to decide if CR is really a good fit for me. Without revealing too much, here is what I can say. I've been following a WFPB for nearly 5 years. By default a plant-based diet (vegan) diet is a form of CR, but not quite all the way to what many people here practice. I seem to oscillate right of the cusp of authentic CR. Many biomarkers are close, but may sway back and forth. Here is some of my info: -31, male, BMI = 20.7, (always between 20-21) -5"11, 143-150 pounds, depending on time of year, fitness, etc. -Low body temperature (usually 35.8ish) -BP fluctuates between being super good, and just good (i.e.. 100/60 up to 120/80). This seems to tell me I'm right on the cusp of CR. -I exercise a decent amount. Covering 15000-20000 footsteps daily, along with weight training 2x weekly, daily meditation and yoga. -Extremely low or immeasurable markers of inflammation (PSA, CRP, homocysteine, low-ish WBC) -Cortisol sometimes creeps up, sometimes not -I recently had my IGF-1 tested and was really surprised it came back at 280! But I may have messed up the test results by binging on some dates the night before. -The reason for WFPB/CR is that I was experiencing some major health crisis at the time, which had been ongoing for a long, long time. Here is a sample of what I ate yesterday, for about 2500 calories: (anything less for calories, and my weight has been dropping) a. Oats, chia, cocoa, spinach/chard/kale, banana, cherries b. Lentils, spring mix, banana, 1/2 avocado c. Barley, bell pepper, onion, green beans, broccoli, cauliflower, blackberries, 1/2 avocado My biggest conundrum is the issue of testosterone. I had it tested pre-WFPB and it came back at 9 (range 10-28 and my weight at that time was about 175 pounds). Since then it's been all over the place. It's been as low as 2 and as high as 15, and I've had it tested maybe 6 times. My concern is that if I really get serious about CR, I will decimate my already 'iffy' levels of testosterone. Now, I'm married, have kids, and don't need to be chasing around anyone, but it seems like I might not be the best fit for CR. Or maybe I'm right in the range of CR/not CR'd given that my T levels and some other tests have varied so much. Thoughts? Am I a good candidate for CR?
  16. I, and a number of other CR practitioners I know, eat what most people would consider a very monotonous diet - eating (virtually) the same thing nearly every day. And usually not what most people would consider the tastiest of foods either, since most people's palates find the tastiest foods to be those that are generally not very health (e.g. cakes, pies, cookies, pizza, chips, etc.), and thus we tend to limit them or avoid them altogether. As a result, my wife and family have often wondered how I can stand to eat the same thing every day, and I've wondered it too. Why do I look forward to eating, and specifically the taste of, my same-old (one) meal every day? This new study [1] (press release) posted by Al Pater to the CR email list (thanks Al!) may provide a clue. Some caution is on order in extrapolating to humans the results of [1], since it was conducted in isolated slices of neurons from the brains of rats. But it is interesting nonetheless for what it suggests about the reward value of food, particularly for animals (and maybe people) subjected to calorie restriction. So here goes... In the main part of the study, they had three groups of rats, labelled FR (food restricted), AL (ad lib) and OB (obese rats, fed three different diets: AL rats had free access to standard rat chow. [FR] rats received 40–50% of AL intake of standard rat chow daily until body weight was reduced by 20%, after which food was titrated to maintain this weight. OB rats had free access to rat chow and chocolate Ensure, a highly palatable liquid with moderately high fat and sugar Not surprisingly, by the end of the four week diet intervention, the OB rats were fat, and the FR rats were thin and had a much lower level of circulating serum insulin than either AL or OB rats. They then isolated slices from parts of the striatum of the brains of the rats in the three groups. The striatum is known to be part of the mammalian reward system, and is the primary brain area associated with the neurotransmitter dopamine, the release of which is known to be associated with all types of reward, including food reward, not to mention the reward from drugs like cocaine. Slices from the FR rats were exposed to insulin, since insulin level in the brain have been previously shown to influence dopamine release. But the previous results were ambiguous - insulin has previously appeared to increase both dopamine release and dopamine reuptake, so it hasn't been clear whether increased insulin in the brain (e.g. after eating a meal with glucose) would result in a net increase or decrease in dopamine signalling, particularly in the reward center (striatum). What these researchers found was quite unambiguous. In slices from the FR rats' striatum, dopamine release was extremely sensitive to insulin level - in fact 10x more sensitive than the AL rats. In other words, it took very little insulin for the FR rats' striatum to release lots of dopamine. In contrast, the obese (OB) rats showed just the opposite. Their tendency to release dopamine was a lot less sensitive to insulin than AL, and especially FR rats brain slices. Here is the relevant graph from the full text of the paper: It shows the amount of dopamine released (y-axis) in response to various levels of infused insulin (x-axis) in three different parts of the striatum, for the FR (blue) and OB (maroon) rats. What you can see is that in all three areas, it took nearly two orders of magnitude more insulin to trigger the same amount of dopamine release in the OB rats as the FR rats (e.g. 10-30 nM for OB vs 0.3 nM for FR). Put another way - at low levels of insulin (e.g. 0.3 or 1.0 nM), the FR rats brains were releasing a substantial amount of dopamine, significantly more than AL controls, while the OB rats weren't releasing any dopamine (i.e. 0% of AL controls). In short, CR rats (and maybe humans) appear to get a lot more "bang for their buck" from food - i.e. a greater feeling of reward (via increased dopamine) from a given amount of food/glucose/insulin ingested. So perhaps this could explain in part why CR practitioners find their modest diets (modest both in terms of calories and palatability) to continue to be rewarding - we're getting a big dopamine release relatively to 'normal' people because of the increased sensitivity of our brain's reward center to insulin. Regarding palatability, the researchers in [1] went a step further, using a different set of rats (obviously, since the first set was dead ). In this second part of the experiment, they investigated the effect of blocking insulin action in the reward center of behaving rats on the development of food preferences. Specifically, they gave rats two glucose sweetened beverages, with different flavorings added to make them distinguishable, but both still quite palatable. They gave rats each of the two drinks, but alternating them from one day to the next. Whenever the rats received one of them, they paired it with an injection of an insulin-blocking agent to their striatum, to prevent the insulin spike following consumption of the drink from triggering a rewarding dopamine release. With the other beverage, they didn't block insulin, and therefore didn't block the rewarding release of dopamine that resulted from consuming the second beverage. As you might predict by now, when the rats were given free access to the two beverages after this conditioning, the rats preferred the beverage where insulin hadn't been blocked, presumably because they'd developed a taste preference for that flavor as a result of its consistent pairing with dopamine release in the striatum. Extrapolating to human CR practitioners - this might explain why we find our simple, monotonous diet so palatable. Specifically, our brains release a lot of dopamine in response to the insulin spike when we eat, so the taste of our monotonous diet becomes associated with the "good feeling" produced by dopamine, in a way not so different from the positive sensation produced by cocaine, which blocks dopamine reuptake at synapses in the striatum, thereby effectively increasing dopamine signalling. In summary, this study appears to suggest (assuming these rat results can be extrapolated to humans) that one's palate (i.e. food preferences) really does change, as many people have reported, as a result of eating a calorie-restricted, healthy, but not-especially-tasty diet for an extended period of time, and that this change is mediated by insulin signaling, insulin sensitivity, and dopamine release in the brain's reward center. --Dean ------------ [1] Nat Commun. 2015 Oct 27;6:8543. doi: 10.1038/ncomms9543. Insulin enhances striatal dopamine release by activating cholinergic interneurons and thereby signals reward. Stouffer MA(1,)(2), Woods CA(3), Patel JC(2), Lee CR(2), Witkovsky P(4), Bao L(1,)(2), Machold RP(5), Jones KT(6), de Vaca SC(6), Reith ME(6,)(7), Carr KD(6,)(7), Rice ME(1,)(2). Free full text: http://www.nature.com/ncomms/2015/151027/ncomms9543/full/ncomms9543.html Press release: http://www.eurekalert.org/pub_releases/2015-10/nlmc-nrf102215.php Insulin activates insulin receptors (InsRs) in the hypothalamus to signal satiety after a meal. However, the rising incidence of obesity, which results in chronically elevated insulin levels, implies that insulin may also act in brain centres that regulate motivation and reward. We report here that insulin can amplify action potential-dependent dopamine (DA) release in the nucleus accumbens (NAc) and caudate-putamen through an indirect mechanism that involves striatal cholinergic interneurons that express InsRs. Furthermore, two different chronic diet manipulations in rats, food restriction (FR) and an obesogenic (OB) diet, oppositely alter the sensitivity of striatal DA release to insulin, with enhanced responsiveness in FR, but loss of responsiveness in OB. Behavioural studies show that intact insulin levels in the NAc shell are necessary for acquisition of preference for the flavour of a paired glucose solution. Together, these data imply that striatal insulin signalling enhances DA release to influence food choices. PMCID: PMC4624275 PMID: 26503322
  17. All, There is an interesting new review paper [1] on the relative effectiveness and potential synergy between dietary / calorie restriction and 'dietary balance' - i.e. optimized nutrition without reduced calories. Here are the passages from the free full text that I found most interesting, for those without the time to read it all: In rodents, increasing the P[rotein] : C[arbohydrate] ratio affects longevity without being influenced by total calorie intake, ultimately leading to an increased mTOR activation. The longest lifespan extension was achieved by a low protein / high carbohydrate diet, which the authors believe to result from low mTOR activation and low insulin levels. Inhibition of mTOR, a proaging pathway, by manipulating the ratio of macronutrients is believed to extend longevity in rodents [14]. As described above, mTOR and IGF-1 signalling by amino acids and the effect of low protein diets on longevity regulation suggest further investigation into how dietary balance affects aging. Also in primates, DR composition has a major impact in results regarding lifespan extension, supporting the notion that balance of nutrients in the diet might be more important in healthy lifespan extension than dietary restriction. Two studies, one from the Wisconsin National Primate Research Centre (WNPRC) and another from the National Institute on Aging (NIA) presented different results when subjecting rhesus monkeys to 30% CR regimen. The WNPRC study reported a decreased mortality in the CR group in comparison to the control group with a 50% lower incidence of diabetes, cancer, and cardiovascular diseases [17, 86]. On the other hand, the NIA study did not find significant differences between CR and control groups, although supporting the beneficial impact of CR on healthspan [87]. The major differences between these two studies were the dietary regimens and the protein and carbohydrate sources used in each study. In the WNPRC study, the protein source used was lactalbumin and the carbohydrate source derived from corn, starch, and 28.5% sucrose, whereas, in the NIA study, the protein source used derived from wheat, corn, soybean, fish, and alfalfa meal, and the carbohydrate source derived from ground wheat and corn with 3.9% sucrose [81]. The differences in results from the two studies could be attributed to the variations in food ingredients and possibly to the protein source; one derived from animal and the other derived from plant sources that have been previously described to affect aging [81, 88]. In humans, very recent cohort studies suggest a correlation between age-related diseases and high protein diets from animal sources. Based on the US national survey of health and nutrition, NHANES III database, a recent article reports that the 50-to-65 age group with high protein intake had a 75% increase in overall mortality and a fourfold increased risk of cancer mortality in comparison to individuals with low protein intake, which was attenuated or abolished when protein intake was derived from plants. Interestingly, in individuals over 65 years, the high protein intake was reported to reduce cancer and overall mortality. These results were confirmed in mice, proving that protein absorption is affected by aging. The study also confirms the correlation between higher IGF-1 levels with more dietary protein and the incidence and progression of both melanoma and breast cancer [15]. Likewise, a Swedish cohort reported that low carbohydrate high protein diets are associated with increased risk of cardiovascular diseases [89]. Michael may disagree, but the evidence, including the primate studies, seem to be shifting the scientific consensus towards the perspective that it isn't just about "calories, calories, calories" when it comes to health (which has been known for a long time) but also when it comes to longevity. --Dean ----------- [1] Oxid Med Cell Longev. 2016;2016:4010357. doi: 10.1155/2016/4010357. Epub 2015 Nov 23. Dietary Restriction and Nutrient Balance in Aging. Santos J(1), Leitão-Correia F(1), Sousa MJ(2), Leão C(1). Free Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4670908/ Dietary regimens that favour reduced calorie intake delay aging and age-associated diseases. New evidences revealed that nutritional balance of dietary components without food restriction increases lifespan. Particular nutrients as several nitrogen sources, proteins, amino acid, and ammonium are implicated in life and healthspan regulation in different model organisms from yeast to mammals. Aging and dietary restriction interact through partially overlapping mechanisms in the activation of the conserved nutrient-signalling pathways, mainly the insulin/insulin-like growth factor (IIS) and the Target Of Rapamycin (TOR). The specific nutrients of dietary regimens, their balance, and how they interact with different genes and pathways are currently being uncovered. Taking into account that dietary regimes can largely influence overall human health and changes in risk factors such as cholesterol level and blood pressure, these new findings are of great importance to fully comprehend the interplay between diet and humans health. PMCID: PMC4670908 PMID: 26682004
  18. Dean Pomerleau

    Genetics of Obesity

    There is an new study on the link between genetics and obesity reported on in this popular press article: http://www.huffingtonpost.com/entry/obesity-gene-discovery-could-forever-change-weight-loss_55d4f994e4b0ab468d9fc0f4 Study [1] is the (rather technical) abstract for the paper associated with the story. I'll do my best to summarize the background and the findings of this study, which I found really interesting. First a little background. It has been known for a while that a particular gene on chromosome 16 named FTO has many (over 200) SNPs (single nucleotide polymorphisms - i.e. common variations in particular base pairs along this gene), several of which appear to be associated with obesity. Here are two older studies [2][3] that address this linkage. Study [2] focused on SNP rs9939609. It found that people who carry one (or especially two) copies of the 'obese' allele ('A') for this SNP were significantly more likely to be obese than those who carry the 'lean' variant ('T'). Study [3] found the same thing for three other FTO SNPs, rs1421085, rs17817449 and rs8043757. It found that people with the 'obese' variants for these three SNPs ('C', 'G' and 'T', respectively) were about 2.5 times more likely to be obese than those who had the lean variants for these three SNPs ('T', 'T', 'A', respectively). The newest study [1], focused on the first of the three SNPs from [3], namely SNP rs1421085, and did something really cool and cutting edge. They took fat cells from mice and humans and used the recently-developed CRISPR gene editing technique to change this particular SNP from the 'obese' variant ('C') to the 'lean' variant ('T'), and then observed what happened to the cells. What they found was that the fat cells converted from being thermogenically active, 'beige' fat cells (i.e. like brown fat cells) to 'white' fat cells that are much more efficient at storing fat, rather than burning it. This can be spun as a nice mechanistic story to explain why at least this SNP is associated with obesity. People who have 'C' for rs1421085 produce more white fat cells, making them more efficient at storing fat - i.e. they have a more 'thrifty' genotype and will therefore (presumably) store more fat for a given calorie intake. Now comes the interesting citizen science part. Data on all four of obesity-related SNPs mentioned above are available to subscribers of 23andMe. Simply log in, then go to this page: https://www.23andme.com/you/explorer/gene/?gene_name=FTO to get a list of all 200+ SNPs from the FTO gene that 23andMe sequences, and search on the page for these four SNPs. Here are my results: rs9939609 TT (lean variant = T) rs1421085 TT (lean variant = T) rs17817449 TT (lean variant = T) rs8043757 AA (lean variant = A) As you can see, I've inherited two copies (one from each of my parents) of the 'lean' allele for each of these four SNPs. So it is no wonder that unintended weight gain has never been an problem for me - at least according to these SNPs I have the antithesis of the 'thrifty genotype'. I'm curious what other CRONies who are also subscribers to 23andMe have for these SNPs, and whether they consider themselves to have a 'thrifty genotype' (easily gain weight) or not. I also wonder whether long-term success on a CR lifestyle is in any way correlated with the values for these SNPs. There is some indication [4] that some of the FTO SNPs (including rs9939609) have an effect on energy intake and preference for energy dense (i.e. high fat) foods, and from [2] we saw that people with the 'obese' allele for rs9939609 and who eat a high-fat, low-carb diet have a higher BMI, which could discourage people trying to practice CR in order to lose weight. Conversely, having a 'thrifty genotype' might make it easier to maintain a low calorie intake without becoming terribly skinny, which can sometimes result in social pressure to eat more to avoid looking like a concentration camp victim. :) Anyway, I've probably grossly oversimplified the science, but I found it fascinating and would be interested to hear what other 23andMe subscribers have for these alleles. --Dean ------------------------------- [1] N Engl J Med. 2015 Aug 19. [Epub ahead of print] FTO Obesity Variant Circuitry and Adipocyte Browning in Humans. Claussnitzer M(1), Dankel SN, Kim KH, Quon G, Meuleman W, Haugen C, Glunk V, Sousa IS, Beaudry JL, Puviindran V, Abdennur NA, Liu J, Svensson PA, Hsu YH, Drucker DJ, Mellgren G, Hui CC, Hauner H, Kellis M. Background Genomewide association studies can be used to identify disease-relevant genomic regions, but interpretation of the data is challenging. The FTO region harbors the strongest genetic association with obesity, yet the mechanistic basis of this association remains elusive. Methods We examined epigenomic data, allelic activity, motif conservation, regulator expression, and gene coexpression patterns, with the aim of dissecting the regulatory circuitry and mechanistic basis of the association between the FTO region and obesity. We validated our predictions with the use of directed perturbations in samples from patients and from mice and with endogenous CRISPR-Cas9 genome editing in samples from patients. Results Our data indicate that the FTO allele associated with obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner. The rs1421085 T-to-C single-nucleotide variant disrupts a conserved motif for the ARID5B repressor, which leads to derepression of a potent preadipocyte enhancer and a doubling of IRX3 and IRX5 expression during early adipocyte differentiation. This results in a cell-autonomous developmental shift from energy-dissipating beige (brite) adipocytes to energy-storing white adipocytes, with a reduction in mitochondrial thermogenesis by a factor of 5, as well as an increase in lipid storage. Inhibition of Irx3 in adipose tissue in mice reduced body weight and increased energy dissipation without a change in physical activity or appetite. Knockdown of IRX3 or IRX5 in primary adipocytes from participants with the risk allele restored thermogenesis, increasing it by a factor of 7, and overexpression of these genes had the opposite effect in adipocytes from nonrisk-allele carriers. Repair of the ARID5B motif by CRISPR-Cas9 editing of rs1421085 in primary adipocytes from a patient with the risk allele restored IRX3 and IRX5 repression, activated browning expression programs, and restored thermogenesis, increasing it by a factor of 7. Conclusions Our results point to a pathway for adipocyte thermogenesis regulation involving ARID5B, rs1421085, IRX3, and IRX5, which, when manipulated, had pronounced pro-obesity and anti-obesity effects. (Funded by the German Research Center for Environmental Health and others.). PMID: 26287746 --------------- [2] Br J Nutr. 2012 Nov 28;108(10):1859-65. doi: 10.1017/S0007114511007410. Epub 2012 Jan 23. Association of the fat mass and obesity-associated (FTO) gene variant (rs9939609) with dietary intake in the Finnish Diabetes Prevention Study. Lappalainen T(1), Lindström J, Paananen J, Eriksson JG, Karhunen L, Tuomilehto J, Uusitupa M. A cluster of variants in the fat mass and obesity-associated (FTO) gene are associated with the common form of obesity. Well-documented dietary data are required for identifying how the genetic risk can be modified by dietary factors. The objective of the present study was to investigate the associations between the FTO risk allele (rs9939609) and dietary intake, and to evaluate how dietary intake affects the association between FTO and BMI in the Finnish Diabetes Prevention Study during a mean follow-up of 3·2 years. A total of 479 (BMI >25 kg/m2) men and women were genotyped for rs9939609. The participants completed a 3 d food record at baseline and before every annual study visit. The average intakes at baseline and during the years 1, 2 and 3 were calculated. At baseline, the FTO variant rs9939609 was not associated with the mean values of total energy intake, macronutrients or fibre. At baseline, a higher BMI by the FTO risk genotype was detected especially in those who reported a diet high in fat with mean BMI of 30·6 (sd 4·1), 31·3 (sd 4·6) and 34·5 (sd 6·2) kg/m2 for TT, TA and AA carriers, respectively (P =0·005). Higher BMI was also observed in those who had a diet low in carbohydrates (P =0·028) and fibre (P =0·015). However, in the analyses adjusted for total energy intake, age and sex, significant interactions between FTO and dietary intakes were not found. These findings suggest that the association between the FTO genotype and obesity is influenced by the components of dietary intake, and the current dietary recommendations are particularly beneficial for those who are genetically susceptible for obesity. PMID: 22265018 ----------------------- [3] Gene. 2015 Mar 1;558(1):75-81. doi: 10.1016/j.gene.2014.12.050. Epub 2014 Dec 24. Common variations in the FTO gene and obesity in Thais: a family-based study. Chuenta W(1), Phonrat B(2), Tungtrongchitr A(3), Limwongse C(4), Chongviriyaphan N(5), Santiprabhob J(6), Tungtrongchitr R(7). Several studies have revealed the association between single nucleotide polymorphisms (SNPs) in the first intron of fat mass and obesity-associated (FTO) gene and obesity. To date, more than 100 SNPs in the FTO gene have been identified in various populations. Nevertheless, this association has not yet been confirmed in Thai populations. The aim of this study was to investigate whether FTO variants are associated with obesity in Thais. We analyzed ten variants in the FTO gene (rs9939609, rs9926289, rs8050136, rs9930501, rs9930506, rs9940646, rs9940128, rs1421085, rs17817449, and rs8043757) in 12 families (83 persons); composed of 12 proband cases and 71 associated family members. All participants were genotyped using polymerase chain reaction (PCR) method and DNA sequencing assay. We found significant associations between three SNPs located in the first intron of FTO gene (rs1421085, rs17817449, and rs8043757) and obesity. The odds ratios were 2.82 (95% CI, 1.16-6.90, p=0.02) for rs1421085 and rs17817449, and 3.15 (95% CI, 1.28-7.76, p=0.01) for rs8043757. Strong linkage disequilibrium among ten SNPs was observed (D'>0.8). Haplotype analysis (combination of rs1421085 (T/C), rs17817449 (T/G), and rs8043757 (A/T)) showed that the CGT haplotype is associated with an increased risk of obesity (OR, 2.42; 95% CI, 1.18-4.97; p=0.018) when compared to the reference haplotype (TTA). The SNPs rs1421085, rs17817449 and rs8043757 in the first intron of the FTO gene are associated with increasing risk of obesity in Thais. Copyright © 2014 Elsevier B.V. All rights reserved. PMID: 25542809 [PubMed - indexed for MEDLINE] ------------------ [4] N Engl J Med. 2008 Dec 11;359(24):2558-66. doi: 10.1056/NEJMoa0803839. An obesity-associated FTO gene variant and increased energy intake in children. Cecil JE(1), Tavendale R, Watt P, Hetherington MM, Palmer CN. Author information: (1)Bute Medical School, University of St Andrews, St Andrews, United Kingdom. Comment in N Engl J Med. 2009 Apr 9;360(15):1571-2; author reply 1572. N Engl J Med. 2008 Dec 11;359(24):2603-4. BACKGROUND: Variation in the fat mass and obesity-associated (FTO) gene has provided the most robust associations with common obesity to date. However, the role of FTO variants in modulating specific components of energy balance is unknown. METHODS: We studied 2726 Scottish children, 4 to 10 years of age, who underwent genotyping for FTO variant rs9939609 and were measured for height and weight. A subsample of 97 children was examined for possible association of the FTO variant with adiposity, energy expenditure, and food intake. RESULTS: In the total study group and the subsample, the A allele of rs9939609 was associated with increased weight (P=0.003 and P=0.049, respectively) and body-mass index (P=0.003 and P=0.03, respectively). In the intensively phenotyped subsample, the A allele was also associated with increased fat mass (P=0.01) but not with lean mass. Although total and resting energy expenditures were increased in children with the A allele (P=0.009 and P=0.03, respectively), resting energy expenditure was identical to that predicted for the age and weight of the child, indicating that there is no defect in metabolic adaptation to obesity in persons bearing the risk-associated allele. The A allele was associated with increased energy intake (P=0.006) independently of body weight. In contrast, the weight of food ingested by children who had the allele was similar to that in children who did not have the allele (P=0.82). CONCLUSIONS: The FTO variant that confers a predisposition to obesity does not appear to be involved in the regulation of energy expenditure but may have a role in the control of food intake and food choice, suggesting a link to a hyperphagic phenotype or a preference for energy-dense foods. 2008 Massachusetts Medical Society PMID: 19073975