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  1. Well, since we've started a thread here on the "General Health and Longevity" forum dedicated to Colon Cancer Prevention, I figured we might as well have one for prostate cancer too, particularly since CR practitioners are overwhelmingly male, and because among US men, prostate cancer is the most common cancer and second leading cancer killer based on CDC Statistics. Plus, there is a new study [1] showing how good my favorite diet (vegan) is for prostate cancer prevention. The study followed ~26,000 men (obviously) who are participating in the famous Adventist Health Study-2, and recruited between 2002 and 2007. It found that men eating a vegan diet were 35% less likely to develop prostate cancer (HR: 0.65; 95% CI: 0.49, 0.85) relative to omnivores during the mean follow-up period of 7.8 year, even after adjusting for age, race, family history of prostate cancer, education, screening for prostate cancer, calorie intake, and BMI. The last is significant because it shows that it wasn't just a result of the vegans being thinner than the omnivores that protected them from prostate cancer. Interestingly, and distinctively from other studies of this population where health benefits relative to omnivores have been observed among all the categories of vegetarians, the benefits observed here for prostate cancer avoidance were entirely restricted to the vegan diet group. Below is the summary table of relative risks for the different diet groups, broken down by race. Looking at data for white men I've highlighted. None of the other vegetarian categories have even a hint of reduction in prostate cancer risk relative to omnivores, not even the pesky pesco-vegetarians - only the vegans: So if you want to avoid the most common form of cancer among men in the US, and the second leading cause of cancer death, go vegan! --Dean -------------- [1] Am J Clin Nutr. 2015 Nov 11. pii: ajcn106450. [Epub ahead of print] Are strict vegetarians protected against prostate cancer? Tantamango-Bartley Y(1), Knutsen SF(2), Knutsen R(2), Jacobsen BK(3), Fan J(2), Beeson WL(2), Sabate J(2), Hadley D(4), Jaceldo-Siegl K(2), Penniecook J(2), Herring P(2), Butler T(2), Bennett H(2), Fraser G(2). BACKGROUND: According to the American Cancer Society, prostate cancer accounts for ∼27% of all incident cancer cases among men and is the second most common (noncutaneous) cancer among men. The relation between diet and prostate cancer is still unclear. Because people do not consume individual foods but rather foods in combination, the assessment of dietary patterns may offer valuable information when determining associations between diet and prostate cancer risk. OBJECTIVE: This study aimed to examine the association between dietary patterns (nonvegetarian, lacto-ovo-vegetarian, pesco-vegetarian, vegan, and semi-vegetarian) and prostate cancer incidence among 26,346 male participants of the Adventist Health Study-2. DESIGN: In this prospective cohort study, cancer cases were identified by matching to cancer registries. Cox proportional hazards regression analysis was performed to estimate HRs by using age as the time variable. RESULTS: In total, 1079 incident prostate cancer cases were identified. Around 8% of the study population reported adherence to the vegan diet. Vegan diets showed a statistically significant protective association with prostate cancer risk (HR: 0.65; 95% CI: 0.49, 0.85). After stratifying by race, the statistically significant association with a vegan diet remained only for the whites (HR: 0.63; 95% CI: 0.46, 0.86), but the multivariate HR for black vegans showed a similar but nonsignificant point estimate (HR: 0.69; 95% CI: 0.41, 1.18). CONCLUSION: Vegan diets may confer a lower risk of prostate cancer. This lower estimated risk is seen in both white and black vegan subjects, although in the latter, the CI is wider and includes the null. © 2016 American Society for Nutrition. PMID: 26561618
  2. https://www.nytimes.com/2018/03/30/business/coffee-cancer-warning.html This is the first I've heard about acrylamide. I'm really not sure how to make sense of this. It must be difficult for judges to try to wrap their heads around the science and make the correct ruling. I'd be interested in seeing some disinterested medical takes on the issue.
  3. From this new article from the BBC: "Across mammals alone, expected lifespan can vary 100-fold, from shrews that live for no longer than 1.5 years to the bowhead whales that can live for more than 200. It is as if, for various reasons, natural selection has somehow pushed certain creatures to evolve their own elixir of life." The writer goes on to talk to scientists studying genes and gene expression in whales, bats and naked mole rats, in hopes of discovering how they live so long, and in particular avoid cancer. The article talks about the possibility of using gene therapy to replicate some of the longevity-promoting genetic changes observed in these long-lived animals in people someday. One of the researchers talks about a study I'd sign up for - comparing bowhead whale gene expression to the gene expression of people practicing CR! It reminds me of the study [1] Luigi Fontana did on our muscle tissue - namely comparing our gene expression to that of CRed rats. Note: This is yet another example of a post that would be fit better on a "Science of Health & Longevity" forum, rather than here on the "CR Science & Theory" forum. How about it Brian/Tim? --Dean ---------------------------- [1] Mercken, E. M., Crosby, S. D., Lamming, D. W., JeBailey, L., Krzysik-Walker, S., Villareal, D. T., Capri, M., Franceschi, C., Zhang, Y., Becker, K., Sabatini, D. M., de Cabo, R. and Fontana, L. (2013), Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger transcription profile. Aging Cell, 12: 645–651. doi: 10.1111/acel.12088. Full Text: http://onlinelibrary.wiley.com/doi/10.1111/acel.12088/full
  4. - Some media articles interviewing an author of the new study and also referencing previous studies showing links between B12 and B6 supplementation and cancer: https://www.sciencedaily.com/releases/2017/08/170822175515.htm https://www.theatlantic.com/health/archive/2017/08/b12-energy/537654/
  5. [Admin Note - This thread started with this post on the "Organ Donation" thread, where Thomas asked about aspirin in the context of kidney donation, where he said: One thing that I didn't know before, and that I would like to learn more about, is that people who donate a kidney can't take aspirin anymore. I wonder why that is. It also gives me pause since aspirin might be pretty beneficial. I don't currently take a baby aspirin, but after watching that interview with Judith Campisi I wonder if it could be useful to suppress low-grade inflammation. Lifelong aspirin supplementation as a means to extending life span. -DP] Thanks Dean. Do you think there is wisdom in regularly (or semi-regularly) taking a baby aspirin to suppress low-grade inflammation? I've just gotten started looking into it, and as usual, I feel like it is hard to keep perspective. As a layperson with limited time I can go down a rabbit hole and end up more confused than when I started. To some degree I feel like I need to rely on the general sense of a larger community of interested laypeople and experts. I'm not quite sure what that is in this case. Aspirin seems promising, but I'm wary of the side effects.
  6. Dean Pomerleau

    Nuts and Mortality

    Al Pater posted the following prospective study [1] (thanks Al!) on the association between nut intake and mortality amongst a group of 20,000 middle aged Italians. It found that compared with people who didn't consume nuts, people who consumed them more than 8 times per month had about a 50% reduction in all-cause mortality risk during the 4 years of followup, largely due to reduced cancer risk. They found the nut eaters also had lower levels of inflammation. Not surprisingly, nut consumption was more beneficial for those who otherwise didn't adhere to a Mediterranean diet. More evidence that nuts are a very healthy food! --Dean ------------- [1] Br J Nutr. 2015 Sep;114(5):804-11. doi: 10.1017/S0007114515002378. Nut consumption is inversely associated with both cancer and total mortality in a Mediterranean population: prospective results from the Moli-sani study. Bonaccio M(1), Di Castelnuovo A(1), De Curtis A(1), Costanzo S(1), Bracone F(1), Persichillo M(1), Donati MB(1), de Gaetano G(1), Iacoviello L(1). Author information: (1)1Department of Epidemiology and Prevention,IRCCS Istituto Neurologico Mediterraneo,Neuromed,86077 Pozzilli,Isernia,Italy. Nut intake has been associated with reduced inflammatory status and lower risk of CVD and mortality. The aim of this study was to examine the relationship between nut consumption and mortality and the role of inflammation. We conducted a population-based prospective investigation on 19 386 subjects enrolled in the Moli-sani study. Food intake was recorded by the Italian version of the European Project Investigation into Cancer and Nutrition FFQ. C-reactive protein, leucocyte and platelet counts and the neutrophil:lymphocyte ratio were used as biomarkers of low-grade inflammation. Hazard ratios (HR) were calculated using multivariable Cox proportional hazard models. During a median follow-up of 4·3 years, 334 all-cause deaths occurred. As compared with subjects who never ate nuts, rare intake (≤2 times/month) was inversely associated with mortality (multivariable HR=0·68; 95 % CI 0·54, 0·87). At intake ≥8 times/month, a greater protection was observed (HR=0·53; 0·32, 0·90). Nut intake (v. no intake) conveyed a higher protection to individuals poorly adhering to the Mediterranean diet (MD). A significant reduction in cancer deaths (HR=0·64; 95 % CI 0·44, 0·94) was also observed, whereas the impact on CVD deaths was limited to an inverse, but not significant, trend. Biomarkers of low-grade inflammation were reduced in nut consumers but did not account for the association with mortality. In conclusion, nut intake was associated with reduced cancer and total mortality. The protection was stronger in individuals with lower adherence to MD, whereas it was similar in high-risk groups (diabetics, obese, smokers or those with the metabolic syndrome), as compared with low-risk subjects. Inflammation did not explain the observed relationship. PMID: 26313936 [PubMed - in process]
  7. My wife has always preferred her beverages and food really hot, and my new stainless steel travel mug keeps my tea & coffee really hot for a long time. So I did a little searching for the possible dangers of drinking hot beverages. It indeed appears from this meta-analysis [1] that drinking excessively hot beverages or hot (temperature-wise) foods is associated with an increased risk of esophageal cancer. So I've started putting a couple ice cubes in my tea & coffee to quickly cool them a bit from the ~200F temperature I brew at before trying to drink them. --Dean --- [1] Int J Cancer. 2009 Aug 1;125(3):491-524. doi: 10.1002/ijc.24445. High-temperature beverages and foods and esophageal cancer risk--a systematic review. Islami F(1), Boffetta P, Ren JS, Pedoeim L, Khatib D, Kamangar F. Author information: (1)Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran. Coffee, tea and maté may cause esophageal cancer (EC) by causing thermal injury to the esophageal mucosa. If so, the risk of EC attributable to thermal injury could be large in populations in which these beverages are commonly consumed. In addition, these drinks may cause or prevent EC via their chemical constituents. Therefore, a large number of epidemiologic studies have investigated the association of an indicator of amount or temperature of use of these drinks or other hot foods and beverages with risk of EC. We conducted a systematic review of these studies and report the results for amount and temperature of use separately. By searching PubMed and the ISI, we found 59 eligible studies. For coffee and tea, there was little evidence for an association between amount of use and EC risk; however, the majority of studies showed an increased risk of EC associated with higher drinking temperature which was statistically significant in most of them. For maté drinking, the number of studies was limited, but they consistently showed that EC risk increased with both amount consumed and temperature, and these 2 were independent risk factors. For other hot foods and drinks, over half of the studies showed statistically significant increased risks of EC associated with higher temperature of intake. Overall, the available results strongly suggest that high-temperature beverage drinking increases the risk of EC. Future studies will require standardized strategies that allow for combining data and results should be reported by histological subtypes of EC. PMCID: PMC2773211 PMID: 19415743 [PubMed - indexed for MEDLINE]
  8. On the thread about cranberries, Rodney got us talking about prunes, and how they may be good for maintaining bone health via increased IGF-1, which is a double-edged sword. This is pretty well-known among knowledgeable CR practitioners, but I thought it worth highlighting, particularly since I came across this interesting discussion & video on the potential tradeoff between "performance" and longevity with respect to IGF-1. It discusses (and gives citations) for many of the benefits of IGF-1, including muscle repair/preservation as well as long-term cognitive health. Interestingly, it doesn't mention helping maintain bone health as another benefit of the anabolic effects of IGF-1. But on the downside, it talks about increased cancer risk and the widely-observed reduced longevity (in humans and animals) associated with higher levels of IGF-1. Here is the summary paragraph: There you have it. It’s a trade-off when it comes to growth hormone and IGF-1. More of it enhances muscle and neuronal growth while simultaneously preventing atrophy. Less of it will increase the expression of stress resistance genes and extend your lifespan. Which do you prefer, having better muscle and cognitive performance or living longer? Overall, it seems like a good primer for anyone who wants to learn about the pros and cons of the reduced IGF-1 often associated with practicing CR. --Dean
  9. Sthira

    What if I hate garlic & onions?

    Dr. Greger, god bless him, is convincing me of the cancer-fighting benefits of g&o. What would you do if you hated these important vegetables but would like to be in their club? Supplements prob don't work, right so-- ever retrained your taste buds to like stuff you just don't? Also the problem is in my stomach. With garlic and onions I eat them but they seem to sit there inside of me -- stinkily -- for a day or two of uncomfortableness. I even think I may be allergic to them.
  10. AlPater

    Five Years Ago You'd Be Dead

    Ad libitum, indeed. Aubrey would eat it up? Five Years Ago You'd Be Dead Jack Coulehan Ann Intern Med. 2016;164(9):632. doi:10.7326/M16-0330 http://annals.org.sci-hub.cc/article.aspx?articleid=2518315 My doctor rides on the shoulders of magnets and molecules, perched like a Hindu prince on an elephant, secure in believing my malicious invader, fatal then, will now succumb to reason. His confidence predicting the past unnerves me. Should I be overjoyed to learn how accidental my fragile thread's endurance is? These days, he tells me, the tumor is hardly worse than a winter cold, a week of summer insomnia, or a busted sparkplug. I'd like to slip the illusion into my breast pocket and keep it close for ten years.
  11. Hello! I am a woman of reproductive age and am interested in the idea of CR. I am looking for information on how this affects the hormonal profile and function, and whether it causes amenorrhea, and if so, whether this is by default a bad thing. Most of the information on amenorrhea I can find tends to refer to anorexic or overly athletic individuals and classifies this as a non-desirable or pathological occurrence. However, I have read before that having fewer periods and lower levels of female hormones can have a protective effect against cancers. If I go on a CR diet, will I be at risk of losing my periods, and is this dangerous to my health if so? What is the experience of other CR women, and have their been tests or studies on this particular topic? Any help pointing me in the direction of resources on this topic would be greatly appreciated. Thank you!
  12. Al Pater posted [1], a study single-blind clinical trial comparing breast cancer rates among subjects assigned to two version of a Mediterranean diet (one supplemented with EVOO and one supplemented with nuts) or to a "low-fat" control diet. Actually the controls only received advice to reduce dietary fat. They didn't actually comply, since (from supplemental material) the end of trial fat intake as a percentage of total cal: Med-EVOO 41%, Med-Nut 39%, Control Diet 37%. So its really comparing a breast cancer risk between a Mediterranean diet with nuts or EVOO to a standard crappy diet. What they found was that women on either the Med-EVOO diet or the Med-Nut diet had a lower risk of breast cancer, but only the Med-EVOO groups risk reduction (0.32, 95% CI, 0.13-0.79) was statistically significant. The Med-Nut group's risk was 0.59 (95% CI, 0.26-1.35) compared with controls. So once again, a Mediterranean diet is shown to be good for avoiding cancer, this time breast cancer. --Dean ---------- [1] JAMA Intern Med. 2015 Nov 1;175(11):1752-60. doi: 10.1001/jamainternmed.2015.4838. Mediterranean Diet and Invasive Breast Cancer Risk Among Women at High Cardiovascular Risk in the PREDIMED Trial: A Randomized Clinical Trial. Toledo E, Salas-Salvadó J, Donat-Vargas C, Buil-Cosiales P, Estruch R, Ros E, Corella D, Fitó M, Hu FB, Arós F, Gómez-Gracia E, Romaguera D, Ortega-Calvo M, Serra-Majem L, Pintó X, Schröder H, Basora J, Sorlí JV, Bulló M, Serra-Mir M, Martínez-González MA. Full text via sci-hub.io: http://archinte.jamanetwork.com.sci-hub.io/article.aspx?articleid=2434738 Abstract IMPORTANCE: Breast cancer is the leading cause of female cancer burden, and its incidence has increased by more than 20% worldwide since 2008. Some observational studies have suggested that the Mediterranean diet may reduce the risk of breast cancer. OBJECTIVE: To evaluate the effect of 2 interventions with Mediterranean diet vs the advice to follow a low-fat diet (control) on breast cancer incidence. DESIGN, SETTING, AND PARTICIPANTS: The PREDIMED study is a 1:1:1 randomized, single-blind, controlled field trial conducted at primary health care centers in Spain. From 2003 to 2009, 4282 women aged 60 to 80 years and at high cardiovascular disease risk were recruited after invitation by their primary care physicians. INTERVENTIONS: Participants were randomly allocated to a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). MAIN OUTCOMES AND MEASURES: Breast cancer incidence was a prespecified secondary outcome of the trial for women without a prior history of breast cancer (n = 4152). RESULTS: After a median follow-up of 4.8 years, we identified 35 confirmed incident cases of breast cancer. Observed rates (per 1000 person-years) were 1.1 for the Mediterranean diet with extra-virgin olive oil group, 1.8 for the Mediterranean diet with nuts group, and 2.9 for the control group. The multivariable-adjusted hazard ratios vs the control group were 0.32 (95% CI, 0.13-0.79) for the Mediterranean diet with extra-virgin olive oil group and 0.59 (95% CI, 0.26-1.35) for the Mediterranean diet with nuts group. In analyses with yearly cumulative updated dietary exposures, the hazard ratio for each additional 5% of calories from extra-virgin olive oil was 0.72 (95% CI, 0.57-0.90). CONCLUSIONS AND RELEVANCE: This is the first randomized trial finding an effect of a long-term dietary intervention on breast cancer incidence. Our results suggest a beneficial effect of a Mediterranean diet supplemented with extra-virgin olive oil in the primary prevention of breast cancer. These results come from a secondary analysis of a previous trial and are based on few incident cases and, therefore, need to be confirmed in longer-term and larger studies. PMID: 26365989
  13. In his latest video (embedded below), everyone's favorite ☺ nutrition expert, Dr. Michael Greger talks about a topic near and dear to my own heart - dietary diversity when it comes to plant foods. He cites several studies including [1] which found different specific fruits and vegetables were protective against the development of cancer in different regions of the colon (i.e. proximal vs. distal). Study [2] found variety of fruits & vegetables consumed (independent of quantity) was associated with reduced risk of lung cancer in smokers. But study [3] was perhaps the most interesting. Researchers followed 7000 people for 11 years to see how their reported (via 7-day food diary) dietary quantity and variety of fruits and vegetables correlated with the development of type 2 diabetes (T2D). They found eating more quantity of F&V was associated with a 21% reduced risk of subsequent T2D. But eating a greater variety of F&V trumped the benefits of quantity - being associated with a 39% reduction in subsequent risk of T2D. Every different kind of F&V a person ate per week was associated with a 4% reduction in T2D. Since I eat almost 50 different F&Vs at every meal, I should have low enough risk to protect both me and anyone standing nearby☺. Dr. G. points to the fact that the body appears to have receptors specifically (and perhaps serendipitously?) tuned to bind with specific phytochemicals in different fruits & vegetables, as an explanation for why eating a greater variety of F&V conveys health benefits. He doesn't mention the other important motivation in my book for eating a wide variety of fruits, vegetables, and other healthy plant foods. Namely, you minimize the risk of detrimental effects from eating too much of any one of them, be it a result of pesticides, contaminants, or unknown anti-nutrients. --Dean -------------- [1] J Am Diet Assoc. 2011 Oct;111(10):1479-90. doi: 10.1016/j.jada.2011.07.008. Fruit and vegetable consumption and the risk of proximal colon, distal colon, and rectal cancers in a case-control study in Western Australia. Annema N(1), Heyworth JS, McNaughton SA, Iacopetta B, Fritschi L. Author information: (1)Western Australian Institute for Medical Research, Australia. Comment in J Am Diet Assoc. 2011 Oct;111(10):1476-8. J Am Diet Assoc. 2011 Oct;111(10):1472-5. J Acad Nutr Diet. 2012 May;112(5):610; author reply 610-1. BACKGROUND: Fruits and vegetables (F/V) have been examined extensively in nutrition research in relation to colorectal cancer (CRC). However, their protective effect is subject to debate, possibly because of different effects on different subsites of the large bowel. OBJECTIVE: To determine whether any association between F/V consumption and risk of CRC differed by subsite of the bowel (proximal colon, distal colon, and rectum). DESIGN: The Western Australian Bowel Health Study is a population-based, case-control study conducted between June 2005 and August 2007. Complete food frequency questionnaire data were analysed from 834 CRC cases and 939 controls. Logistic regression analysis was used to estimate the effects of quartiles of F/V intake on risk of CRC at different subsites. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for CRC overall and for the three separate subsites. RESULTS: Risk of proximal colon cancer and rectal cancer was not associated with intakes of total F/V, total vegetable, or total fruit. Brassica vegetable intake was inversely related with proximal colon cancer (Q4 vs Q1 OR 0.62; 95% CI 0.41 to 0.93). For distal colon cancer, significant negative trends were seen for total F/V, and total vegetable intake. Distal colon cancer risk was significantly decreased for intake of dark yellow vegetables (Q4 vs Q1 OR 0.61; 95% CI 0.41 to 0.92) and apples (Q4 vs Q1 OR 0.51; 95% CI 0.34 to 0.77). An increased risk for CRC was found to be associated with intake of fruit juice (Q4 vs Q1 OR 1.74; 95% CI 1.24 to 2.45). CONCLUSIONS: Our results suggest that different F/V may confer different risks for cancer of the proximal colon, distal colon, or rectum. Future studies might consider taking into account the location of the tumor when examining the relation between F/V consumption and risk of CRC. Copyright © 2011 American Dietetic Association. Published by Elsevier Inc. All rights reserved. PMID: 21963014 --------- [2] Cancer Epidemiol Biomarkers Prev. 2010 Sep;19(9):2278-86. doi: 10.1158/1055-9965.EPI-10-0489. Epub 2010 Aug 31. Variety in fruit and vegetable consumption and the risk of lung cancer in the European prospective investigation into cancer and nutrition. Büchner FL(1), Bueno-de-Mesquita HB, Ros MM, Overvad K, Dahm CC, Hansen L, Tjønneland A, Clavel-Chapelon F, Boutron-Ruault MC, Touillaud M, Kaaks R, Rohrmann S, Boeing H, Nöthlings U, Trichopoulou A, Zylis D, Dilis V, Palli D, Sieri S, Vineis P, Tumino R, Panico S, Peeters PH, van Gils CH, Lund E, Gram IT, Braaten T, Sánchez MJ, Agudo A, Larrañaga N, Ardanaz E, Navarro C, Argüelles MV, Manjer J, Wirfält E, Hallmans G, Rasmuson T, Key TJ, Khaw KT, Wareham N, Slimani N, Vergnaud AC, Xun WW, Kiemeney LA, Riboli E. Author information: (1)National Institute ofPublicHealth and the Environment, Bilthoven, The Netherlands. frederike.buchner@rivm.nl BACKGROUND: We investigated whether a varied consumption of vegetables and fruits is associated with lower lung cancer risk in the European Prospective Investigation into Cancer and Nutrition study. METHODS: After a mean follow-up of 8.7 years, 1,613 of 452,187 participants with complete information were diagnosed with lung cancer. Diet diversity scores (DDS) were used to quantify the variety in fruit and vegetable consumption. Multivariable proportional hazards models were used to assess the associations between DDS and lung cancer risk. All models were adjusted for smoking behavior and the total consumption of fruit and vegetables. RESULTS: With increasing variety in vegetable subgroups, risk of lung cancer decreases [hazard ratios (HR), 0.77; 95% confidence interval (CI), 0.64-0.94 highest versus lowest quartile; P trend = 0.02]. This inverse association is restricted to current smokers (HR, 0.73; 95% CI, 0.57-0.93 highest versus lowest quartile; P trend = 0.03). In continuous analyses, in current smokers, lower risks were observed for squamous cell carcinomas with more variety in fruit and vegetable products combined (HR/two products, 0.88; 95% CI, 0.82-0.95), vegetable subgroups (HR/subgroup, 0.88; 95% CI, 0.79-0.97), vegetable products (HR/two products, 0.87; 95% CI, 0.79-0.96), and fruit products (HR/two products, 0.84; 95% CI, 0.72-0.97). CONCLUSION: Variety in vegetable consumption was inversely associated with lung cancer risk among current smokers. Risk of squamous cell carcinomas was reduced with increasing variety in fruit and/or vegetable consumption, which was mainly driven by the effect in current smokers. IMPACT: Independent from quantity of consumption, variety in fruit and vegetable consumption may decrease lung cancer risk. ©2010 AACR. PMID: 20807832 ------------- [3] Diabetes Care. 2012 Jun;35(6):1293-300. doi: 10.2337/dc11-2388. Epub 2012 Apr 3. A prospective study of the association between quantity and variety of fruit and vegetable intake and incident type 2 diabetes. Cooper AJ(1), Sharp SJ, Lentjes MA, Luben RN, Khaw KT, Wareham NJ, Forouhi NG. Author information: (1)MRCEpidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, U.K. OBJECTIVE: The association between quantity of fruit and vegetable (F&V) intake and risk of type 2 diabetes (T2D) is not clear, and the relationship with variety of intake is unknown. The current study examined the association of both quantity and variety of F&V intake and risk of T2D. RESEARCH DESIGN AND METHODS: We examined the 11-year incidence of T2D in relation to quantity and variety of fruit, vegetables, and combined F&V intake in a case-cohort study of 3,704 participants (n = 653 diabetes cases) nested within the European Prospective Investigation into Cancer and Nutrition-Norfolk study, who completed 7-day prospective food diaries. Variety of intake was derived from the total number of different items consumed in a 1-week period. Multivariable, Prentice-weighted Cox regression was used to estimate hazard ratios (HRs) and 95% CIs. RESULTS: A greater quantity of combined F&V intake was associated with 21% lower hazard of T2D (HR 0.79 [95% CI 0.62-1.00]) comparing extreme tertiles, in adjusted analyses including variety. Separately, quantity of vegetable intake (0.76 [0.60-0.97]), but not fruit, was inversely associated with T2D in adjusted analysis. Greater variety in fruit (0.70 [0.53-0.91]), vegetable (0.77 [0.61-0.98]), and combined F&V (0.61 [0.48-0.78]) intake was associated with a lower hazard of T2D, independent of known confounders and quantity of intake comparing extreme tertiles. CONCLUSIONS: These findings suggest that a diet characterized by a greater quantity of vegetables and a greater variety of both F&V intake is associated with a reduced risk of T2D. PMCID: PMC3357245 PMID: 22474042
  14. All, It has been thought that CR lifespan benefits are likely to linearly increase with degree of CR, up to very severe CR, based on rodent data like the famous Weindruch study [2], data from which is highlighted on the CR Society home page, and reproduced in this graph: As you can see, compared with ad-lib fed mice, 25% CR provided some benefits. But severe CR, where mice ate 55% or even 65% less food than the AL group, lived much longer than the 25% restricted group. And note that this benefit was seen across the board. No sign of early mortality in the severely restricted mice - the survival curves for the 55% & 65% CR mice are completely to the right of the 25% CR mice survival curve, which in turn is completely right of the AL mice survival curve. From this it looks like the more CR the better. But the recent NIA/Wisconsin monkey data doesn't look so cut and dried. In fact, one plausible interpretation of the NIA monkey results (as we've discussed elsewhere, e.g. here), is that if eating a healthy diet, restricting calories beyond that required to avoid obesity doesn't provide additional longevity benefits. So how much CR is required to garner the benefits? Perhaps this new rodent study [1] sheds some light on the topic, as far as rodent studies can be extrapolated to humans (more on that below). What they did was restrict the calories of a common strain of rats (F344 - all male) in two groups - 10% and 40% restriction relative to AL-fed controls. Then they let them all live out their natural lifespan to see how longevity and causes of death compared between the 3 groups (AL, CR25, CR40). Here are the two important graphs and the most important table from the paper, illustrating the main lifespan results, image originally from this analysis of the study on crvitality.com, red annotations are mine. As you can see from the survival curves and Table 1, both the CR10 and CR40 groups had mean longevity that was significantly longer than the AL group, but they did not significantly differ from each other, at 796 days for AL, 918 days for CR10 and 947 days for CR40. One way to look at this result is that on average, restricting enough to avoid obesity (i.e. CR10), resulted in a 15% increase in mean lifespan. Bumping it up to severe restriction (CR40) bought the rats an additional (non-significant) 4% of mean lifespan relative to obesity-avoiding 10% CR (15% vs. 19% increased lifespan, respectively). That seems like a pretty modest (if any - given its non-significance) lifespan gain for a lot more severe restriction. On the other hand, the longest lived 10% of the CR40 rats did indeed significantly outlive the CR10 rats, as can be seen from both the graph on the left above, and from the longevity table. Quantitatively, the longest lived 10% of the CR10 rats enjoyed a 37% longer life than the average AL rat, while the longest lived 10% of the CR40 rats enjoyed a 54% longer life than the average AL rat, a gain of 17% in lifespan from CR10 to CR40. That sounds pretty good, as long as you are one of the lucky, few longest-lived CR40 rats. From the survival graph, it looks like it was only the top ~20% of CR40 rats that enjoyed any longevity benefits relative to the CR10 rats, and it looks like this was almost (but perhaps not quite) fully counterbalanced by the bottom 20% of the CR40 rats dying before the CR10 rats (see red annotations on graph above for places where CR40 had an advantage and a disadvantage for lifespan relative to CR10). The Gompertz graph on the right above shows that rate of aging in the CR40 group appeared to be slowed relative to the other two groups, which didn't appear to differ from each other. In short, if you're lucky (and the rat data in [1] translates to humans - see below), this data suggests that going for severe CR might gain you an extra ~14 years relative to obesity avoiding mild CR. But if you're unlucky, severe CR might kill you off early by almost an equivalent amount. If you are average (mean or median), you can expect to do about the same in terms of lifespan with either mild CR (i.e. enough to avoid obesity) or severe CR. But wait a minute - one thing Michael always cautions about is the need to make sure the animal husbandry in a study is good, and the strain being used isn't one of those f**cked up ones that dies early, or is particularly fragile and therefore not a good candidate for CR research. From [3] (and from memory), it is apparent that the F344 strain of rats is one that is commonly used in CR research. Below is the mortality curves for F344 rats fed AL or 40% CR diets from [3]. The mortality curve for the AL-M (ad lib fed male) group looks about the same in [3] as in study we've been looking at [1], with median lifespan around 800 days and max around 1000 days. But if anything the 40% CR group of F344 (male) rats looks better in [1] than in [3] below - where (eyeballing it) the median lifespan looks to be around 900 days (vs. nearly 1000 in [1]) and max is around 1150 days (vs. 1400 in [1]). Note also that unlike in the mortality curves above from [1], the mortality curve for the 40% CR rats from [3] spends time below the AL curve from around 400 to 600 days (see red annotations below), representing early mortality in the CR rats, likely due to the stress of severe CR. So it doesn't look like there was any problem with strain or husbandry in [1] that might invalidate its results. In fact, based on the results of [3], it would seem that [1] may be overestimating the (max) longevity upside of severe CR, and underestimating the early mortality risk of severe CR, making severe CR in [1] seem like a better deal relative to a milder, obesity-avoiding level of CR that it actually may be. Unfortunately 10% CR wasn't tested in [3] - only AL and CR40. The author's of [1] seemed surprised by the modest benefits of severe CR40 relative to mild, obesity-avoiding CR10, saying: The data from this study clearly demonstrate that a 10% restriction of food significantly increases the lifespan of male F344 rats and, surprisingly, that the increase in lifespan is comparable to what was observed for rats that were restricted 40%. These data were surprising because of the general view that increasing the level of DR up to 40% would result in a continuous increase in lifespan, as reported by Weindruch et al.[2] for female C3B10RF1 mice in which a significant increase (over 20%) in the mean survival occurred between approximately 25% and 55% DR. ... These data in combination with the data from Duffy et al.,[4] which reported that feeding rats 10% and 25% DR was as effective as 40% DR in reducing the early mortality of male Sprague–Dawley rats, demonstrate that the lifespan of certain strains of rats and mice does not increase linearly up to 40% DR. Most of the extension of lifespan appears to be achieved by levels of DR much lower than 40% DR. But what about translatability of such rodent data to humans? - a topic currently under discussion over on this thread, where just last night Michael said: So how good a model of human aging is the natural aging of these critters? Not very good it seems to me, if this study is typical of rodent causes of death (which I think it is), based on this table from the full text: As you can see from the table above, like most rodents, a clear majority died from various forms of cancer, with leukemia being by far the most common single cause. As we all know (and which is graphically illustrated here) cardiovascular disease in its various forms is the #1 killer of humans (at least in the US and other developed nations) - cancer only accounts for 23% of human death. Further, leukemia is only the 6th most common cancer killer in people, accounts for only 5% of all cancer deaths and only ~1% of all causes of death in the US. Based on this cause-of-death mismatch, these leukemia-prone rats, and cancer-prone rodents in general, don't seem like a very good model of the "diseases of aging" that kill people. As a corollary, the fact that CR40 significantly reduced leukemia deaths relative to CR10 in [1] seems unlikely to "move the bar" for human longevity, even if these results would translate directly to people. So the takeaway message from this one seems to be that even CR rodent results, which have always been the best data we have to support large additional lifespan benefits of 'serious' CR relative to simply avoiding obesity, may be open to question both in terms of the magnitude of the benefit, and their translatability to humans. Michael, if I'm missing something I'm sure I'll hear from you. --Dean ------- [1] Ann N Y Acad Sci. 2015 Dec 22. doi: 10.1111/nyas.12982. [Epub ahead of print] Significant life extension by ten percent dietary restriction. Richardson A(1,)(2), Austad SN(3), Ikeno Y(4), Unnikrishnan A(1), McCarter RJ(5). Free full text: http://onlinelibrary.wiley.com/doi/10.1111/nyas.12982/epdf Although it is well documented that dietary restriction (DR) increases the life span of rodents and other animals, this increase is observed at relatively high levels of DR, in which rodents are typically fed 40% less than that consumed by rodents fed ad libitum. It is generally assumed that lower levels of DR will have a lesser impact on life span; however, there are very little published data on the effect of low levels of DR on life span. In this study, we show that 10% DR increased life span to almost the same extent as 40% DR. While both 10% and 40% DR resulted in similar changes in non-neoplastic lesions, 10% DR had no significant effect on the incidence of neoplasia (except for pituitary adenoma), and 40% DR resulted in a significant reduction (40%) in neoplasia. These data clearly demonstrate that the life span of F344 rats does not increase linearly with the level of DR; rather, even a low level of DR can substantially affect life span. This rodent study has important translational implications because it suggests that a modest reduction in calories might have significant health benefits for humans. PMID: 26695614 --------- [2] Weindruch R, et al. (1986). "The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake." Journal of Nutrition, April, 116(4), pages 641-54. --------- [3] J Gerontol A Biol Sci Med Sci. 1999 Nov;54(11):B492-501. Growth curves and survival characteristics of the animals used in the Biomarkers of Aging Program. Turturro A(1), Witt WW, Lewis S, Hass BS, Lipman RD, Hart RW. PMID: 10619312 The collaborative Interagency Agreement between the National Center for Toxicological Research (NCTR) and the National Institute on Aging (NIA) was aimed at identifying and validating a panel of biomarkers of aging in rodents in order to rapidly test the efficacy and safety of interventions designed to slow aging. Another aim was to provide a basis for developing biomarkers of aging in humans, using the assumption that biomarkers that were useful across different genotypes and species were sensitive to fundamental processes that would extrapolate to humans. Caloric restriction (CR), the only intervention that consistently extends both mean and maximal life span in a variety of species, was used to provide a model with extended life span. C57BI/6NNia, DBA/2JNia, B6D2F1, and B6C3F1 mice and Brown Norway (BN/RijNia), Fischer (F344/NNia) and Fischer x Brown Norway hybrid (F344 x BN F1) rats were bred and maintained on study. NCTR generated data from over 60,000 individually housed animals of the seven different genotypes and both sexes, approximately half ad libitum (AL) fed, the remainder CR. Approximately half the animals were shipped to offsite NIA investigators internationally, with the majority of the remainder maintained at NCTR until they died. The collaboration supplied a choice of healthy, long-lived rodent models to investigators, while allowing for the development of some of the most definitive information on life span, food consumption, and growth characteristics in these genotypes under diverse feeding paradigms. ------------ [4] Duffy, P.H., J.E. Seng, S.M. Lewis, et al. 2001. The effects of different levels of dietary restriction on aging and survival in the Sprague–Dawley rat: implications for chronic studies. Aging Clin. Exp. Res. 13: 263–272.
  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
  16. There is a really interesting new meta-analysis [1] in this week's issue of The Lancet on the association between height and health/longevity. Here is a popular press article on the study, with the title Big And Tall: Nutritious Meals May Make Us Taller But They Could Also Increase Our Cancer Risk. The researchers looked at 121 epidemiological studies of over a million people that assessed the association of height with health and lifespan. The heart of the paper are these two graphs: showing how in both men and women, being taller reduces risk of coronary heart disease, but increases risk of cancer. Here is a graphical representation of the over/undernutrition-based mechanisms the authors postulate to explain the observations: The link to cancer via higher insulin in people who eat a lot (and hence grow taller) is familiar. What was a bit surprising was their suggestion that increased levels of grow factors like IGF-1 in taller people may actually improve insulin sensitivity and hence reduce diabetes and cardiovascular disease. --Dean ------------- [1] The Lancet Diabetes & Endocrinology Available online 28 January 2016 DOI: http://dx.doi.org/10.1016/S2213-8587(15)00474-X| Divergent associations of height with cardiometabolic disease and cancer: epidemiology, pathophysiology, and global implications Norbert Stefan, MD, Hans-Ulrich Häring, MD, Frank B Hu, MD, Dr Matthias B Schulze, DrPHcorrespondenceemail Full text: http://dx.doi.org.sci-hub.io/10.1016/S2213-8587(15)00474-X Summary Among chronic non-communicable diseases, cardiometabolic diseases and cancer are the most important causes of morbidity and mortality worldwide. Although high BMI and waist circumference, as estimates of total and abdominal fat mass, are now accepted as predictors of the increasing incidence of these diseases, adult height, which also predicts mortality, has been neglected. Interestingly, increasing evidence suggests that height is associated with lower cardiometabolic risk, but higher cancer risk, associations supported by mendelian randomisation studies. Understanding the complex epidemiology, biology, and pathophysiology related to height, and its association with cardiometabolic diseases and cancer, is becoming even more important because average adult height has increased substantially in many countries during recent generations. Among the mechanisms driving the increase in height and linking height with cardiometabolic diseases and cancer are insulin and insulin-like growth factor signalling pathways. These pathways are thought to be activated by overnutrition, especially increased intake of milk, dairy products, and other animal proteins during different stages of child development. Limiting overnutrition during pregnancy, early childhood, and puberty would avoid not only obesity, but also accelerated growth in children—and thus might reduce risk of cancer in adulthood.
  17. All, Testosterone (T) and other sex hormone levels have always been a topic of interest and concern to CR practitioners. Some men (like me) report dramatically reduced T levels, down to levels not typically seen in any men except the very elderly. Others seem to maintain their T at fairly normal levels for their age. So which is better? On the one hand, low testosterone has sometimes been considered a CR "badge of courage" (among men anyway) - indicating one is practicing serious CR, and a positive reflection of the body trading off fecundity for upregulation of maintenance & repair functions (similar to low IGF-1). Women live longer than men across cultures, which some attribute to differences in T level, and eunuchs have been found to live longer, by as much as 15-20 years [2]! On the other hand, low T often (but not always) has a dramatic effect on libido, and one's overall aggressive drive to succeed / accomplish things. On the health side, negative health outcomes are frequently associated with hypogonadism (low T) in men, including bone health issues [4], sarcopenia [4], cognitive decline [5], and an increased risk of cardiovascular disease. Regarding the latter, some studies (e.g. see [3] for review) have found T supplementation in hypogonadal men reduces cardiovascular disease risk, but the effect may be limited to obese men with metabolic syndrome, or may result from pharmaceutical industry bias in T supplementation trials [6]. Interestingly, this meta-analysis [6] found that in trials not sponsored by Big Pharma, CVD risk was increased among men receiving supplemental T (OR 2.06, 95% CI 1.34 to 3.17). So overall, the relationship between the low T that many serious male CR practitioners exhibit and our long-term health & longevity remains an open question. Moreover, hypogonadism in the general population is typically associated with obesity and metabolic syndrome, obviously a very different etiology than hypogonadism in CR practitioners, making the picture even more muddled... So I reacted with interest, but also some trepidation, when I saw Al Pater post this new study [1] (thanks Al!), on the association of T and other sex hormones with all-cause, cancer and cardiovascular mortality in men. So let's dive in. First off, this was not a supplementation trial - they measured the natural levels of T, Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH), Sex Hormone Binding Globulin (SHBG), free testosterone (FT), and estradiol (E) and in 5300 men of all ages and followed them for an average of 18.5 years to see how many died, from what causes, and how their deaths were associated with these sex hormones. Here are some interesting statistics at baseline, from the free full text Table 1 (see below): As expected, T and FT was lower in older men, whereas LH, FSH, and SHBG increased. Interestingly, smokers had higher T, FT, LH, FSH, E and SHBG than non-smokers at baseline. Exercise, and particular "competitive sport" participation, was associated with increased T, FT, and lower LH. Could be reverse causality - people with high T are more aggressive and therefore more likely to be attracted to competitive sports... Overweight and obese men had dramatically lower T and FT at baseline - which will be important later. Here is the baseline data for sex hormones by demographics for anyone interested in the details (click to enlarge): Now the interesting part - the mortality results (some of which comes from the text of the supplemental material). First for cancer mortality: There was a between-quartile trend towards increased cancer mortality with higher T, but the differences was only really significant in smokers in the highest quartile of T (OR 1.53, 95%CI: 1.14 – 2.08). In non-smokers, T and FT had virtually no impact on cancer mortality. But there was a pretty strong trend towards more cancer with higher levels of LH and FSH. Keep an eye on LH in particular, it will be important later... And now, CVD mortality: Men with total testosterone levels in the highest quartile had a reduced risk of CVD mortality compared to men in the lowest quartile (HR 0.72, 95% CI: 0.53– 0.98). The same relationship held for FT. It is looking bad for us hypogonadal CRers... But this increased CVD risk with low T (and FT) was in the fully-adjusted model, which included factoring out BMI from the analysis (recall overweight/obese men had dramatically lower T and FT at baseline). In a model that adjusted for waist circumference instead of BMI, and especially in a model that adjusted for # of markers of metabolic syndrome, the increased risk of CVD with lower T and FT dropped dramatically to the point of no longer being significant between the highest and lowest quintiles of T = (OR 0.66, 95%CI: 0.38-1.16). In other words, to first approximations, if you ignore low T and FT resulting from (or associated with) metabolic syndrome, the association between low T (and FT) and increased CVD goes away... And now, the all-important All-cause mortality: There was no significant differences in all-cause mortality across age-standardized quartiles of T (OR 1.01, 95%CI: 0.87-1.18) - to some degree higher cancer risk and lower CVD risk with higher T offset each other, so all-cause mortality was a wash with higher T. The same lack of significant mortality effect was seen for inter-quartile comparison of FT (OR 0.87, 95%CI: 0.75-1.00), but when the trend from lowest to highest quartile of FT was considered, lower FT was associated with increased all-cause mortality (p for trend < 0.02). Again, looking (somewhat) bad for hypogonadal CRers... An increased all-cause mortality was seen for men in the highest (vs. lowest) quartiles of LH and estradiol, (HR 1.32, 95% CI: 1.14 –1.53) and (HR 1.23, 95% CI: 1.06 –1.43), respectively. If you are confused by now, perhaps this graphical depiction of the major study findings for all-cause and CVD mortality (with my color highlights) will help (click to enlarge): As you can see, if we focus on all-cause mortality, higher SHBG, higher LH, and lower FT are associated with increased risk. So what the heck does all this mean?!?! Here is my take on it, basically paraphrasing the authors' discussion / speculation. Obesity, and especially metabolic syndrome, are associated with increased mortality risk, and reduced T and FT levels. It may therefore be that low T (& FT) is a marker for impaired androgen signalling in men with metabolic syndrome - i.e. their sex-hormone signalling is messed up, just like some of their other pathways (e.g. insulin signalling) are messed up by all the fat they are carrying. As a result, their LH is elevated - i.e. the "captain" is asking (via increased LH) the "engine room" (i.e. Leydig cells) to produce more T, but the Leydig cells aren't up to the task perhaps because they are gummed up with fat, so T remains low despite elevated LH calling for more. This could be similar in some respects to diabetes, in which insulin doesn't work to clear glucose because of fat so the body calls for the pancreas to produce more, and eventually the beta cells in the pancreas give up the ghost and can't make enough insulin to clear blood glucose. So what does this mean for CR practitioners? In us, T is low on purpose from the body's perspective (if I may speak teleologically) - as indicated by our low LH levels (my bloodwork shows my LH to always be near or below the low end of the RR since starting CR). In other words, rather than T being low because the body can't/won't make it (as is the case in guys with metabolic syndrome), our T is low because our body doesn't need or want it. Again it is perhaps a story similar to IGF-1 and insulin. We (hopefully) have low fasting insulin not because our beta cells are messed up and can't make it (like in late-stage diabetes resulting from metabolic syndrome), but because our bodies don't need/want much insulin - we've got enough insulin to clear the modest amount of glucose we have to process, especially since our insulin sensitivity remains high. So in short, our low T and low FT may reflect an entirely different, (hopefully) healthier state to be in than having low T and FT as a result of metabolic syndrome. But then again, that might be just wishful thinking. In particular, our low T and FT may be "intentional" on the part of our body and it may not be good for us in the long run. In other words, our bodies may be hunkering down to survive the (self-induced) famine by lowering T and FT, but in the process sacrificing "non-critical" systems like muscle mass, bone health, and cognitive function - systems that apparently benefit downstream from higher levels of testosterone. It seems it could go either way. But in any case, we're unlikely to be in as bad shape along these dimensions as men who have low T and FT as a result of metabolic syndrome. I hope this has done more to clarify than confuse. But re-reading, I'm not so sure... --Dean ---------- [1] J Clin Endocrinol Metab. 2015 Oct 21:jc20152460. [Epub ahead of print] The association of reproductive hormone levels and all-cause, cancer and cardiovascular disease mortality in men. Agergaard Holmboe S, Vradi E, Kold Jensen T, Linneberg A, Husemoen LL, Scheike T, Skakkebæk NE, Juul A, Andersson AM. Full Text: http://press.endocrine.org/doi/pdf/10.1210/jc.2015-2460 Abstract CONTEXT: Testosterone levels (T) have been associated with mortality, but controversy exists. OBJECTIVE: To investigate associations between serum levels of total testosterone, SHBG, free testosterone, estradiol, LH and FSH, and subsequent mortality with up to 30 years of follow-up. DESIGN: A prospective cohort study consisting of men participating in four independent population-based surveys (MONICA I-III and Inter99) from 1982 to 2001 and followed until December 2012 with complete registry follow-up. SETTING AND PARTICIPANTS: 5,350 randomly selected men from the general population aged 30, 40, 50, 60 or 70 years at baseline. MAIN OUTCOME MEASURES: All-cause mortality, cardiovascular disease (CVD) mortality and cancer mortality. RESULTS: 1,533 men died during the follow-up period; 428 from CVD and 480 from cancer. Cox proportional hazard models revealed that men in highest LH quartile had an increased all-cause mortality compared to lowest quartile (HR=1.32, 95%CI: 1.14 to 1.53). Likewise, increased quartiles of LH/T and estradiol increased the risk of all-cause mortality (HR=1.23, 95%CI: 1.06 to 1.43, HR=1.23, 95%CI: 1.06 to 1.43). No association to testosterone levels was found. Higher LH levels were associated with increased cancer mortality (HR=1.42, 95%CI: 1.10 to 1.84) independently of smoking status. Lower CVD mortality was seen for men with testosterone in the highest quartile compared to lowest (HR=0.72, 95%CI: 0.53 to 0.98). Furthermore, negative trends were seen for SHBG and free testosterone in relation to CVD mortality, however insignificant. CONCLUSION: The observed positive association of LH and LH/T, but not testosterone, with all-cause mortality suggests that a compensated impaired Leydig cell function may be a risk factor for death by all causes in men. Our findings underpin the clinical importance of including LH measurement in the diagnostic work-up of male patients seeking help for possible androgen insufficiency. PMID: 26488309 ------------ [2] Curr Biol. 2012 Sep 25;22(18):R792-3. doi: 10.1016/j.cub.2012.06.036. The lifespan of Korean eunuchs. Min KJ, Lee CK, Park HN. Free Full Text: http://www.cell.com/current-biology/abstract/S0960-9822(12)00712-9 Abstract Although many studies have shown that there are trade-offs between longevity and reproduction, whether such trade-offs exist in humans has been a matter of debate [1,2] . In many species, including humans, males live shorter than females, which could be due to the action of male sex hormones. Castration, which removes the source of male sex hormones, prolongs male lifespan in many animals, but this issue has been debated in humans [3] . To examine the effects of castration on longevity, we analyzed the lifespan of historical Korean eunuchs. Korean eunuchs preserved their lineage by adopting castrated boys. We studied the genealogy records of Korean eunuchs and determined the lifespan of 81 eunuchs. The average lifespan of eunuchs was 70.0 ± 1.76 years, which was 14.4–19.1 years longer than the lifespan of non-castrated men of similar socio-economic status. Our study supports the idea that male sex hormones decrease the lifespan of men. PMID: 23017989 -------------- [3] Expert Opin Drug Saf. 2014 Oct;13(10):1327-51. doi: 10.1517/14740338.2014.950653. Epub 2014 Aug 19. Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Corona G(1), Maseroli E, Rastrelli G, Isidori AM, Sforza A, Mannucci E, Maggi M. Author information: (1)Azienda-Usl Bologna, Maggiore-Bellaria Hospital, Medical Department, Endocrinology Unit , Bologna , Italy. INTRODUCTION: Recent reports have significantly halted the enthusiasm regarding androgen-boosting; suggesting that testosterone supplementation (TS) increases cardiovascular (CV) events. AREAS COVERED: In order to overcome some of the limitations of the current evidence, the authors performed an updated systematic review and meta-analysis of all placebo-controlled randomized clinical trials (RCTs) on the effect of TS on CV-related problems. Out of 2747 retrieved articles, 75 were analyzed, including 3016 and 2448 patients in TS and placebo groups, respectively, and a mean duration of 34 weeks. Our analyses, performed on the largest number of studies collected so far, indicate that TS is not related to any increase in CV risk, even when composite or single adverse events were considered. In RCTs performed in subjects with metabolic derangements a protective effect of TS on CV risk was observed. EXPERT OPINION: The present systematic review and meta-analysis does not support a causal role between TS and adverse CV events. Our results are in agreement with a large body of literature from the last 20 years supporting TS of hypogonadal men as a valuable strategy in improving a patient's metabolic profile, reducing body fat and increasing lean muscle mass, which would ultimately reduce the risk of heart disease. PMID: 25139126 --------------- [4] Clin Endocrinol (Oxf). 2005 Sep;63(3):280-93. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Isidori AM(1), Giannetta E, Greco EA, Gianfrilli D, Bonifacio V, Isidori A, Lenzi A, Fabbri A. Author information: (1)Cattedra di Andrologia, Universita 'La Sapienza', Rome, Italy. andrea.isidori@uniroma1.it OBJECTIVES: Ageing in men is associated with a gradual decline in serum testosterone levels and a concomitant loss of muscle mass, accumulation of central adiposity, impaired mobility and increased risk of bone fractures. Whether androgen treatment might be beneficial in these subjects is still under debate. We have carried out a systematic review of randomized controlled trials (RCTs) evaluating the effects of testosterone (T) administration to middle-aged and ageing men on body composition, muscle strength, bone density, markers of bone metabolism and serum lipid profile. DATA SOURCE: A comprehensive search of all published randomized clinical trials was performed using the MEDLINE, Cochrane Library, EMBASE and Current Contents databases. REVIEW METHODS: Guided by prespecified criteria, software-assisted data abstraction and quality assessed by two independent reviewers, 29 RCTs were found to be eligible. For each investigated variable, we reported the results of pooled estimates of testosterone treatment using the random effect model of meta-analysis. Heterogeneity, reproducibility and consistency of the findings across studies were explored using sensitivity and meta-regression analysis. RESULTS: Overall, 1,083 subjects were evaluated, 625 randomized to T, 427 to placebo and 31 to observation (control group). Weighted mean age was 64.5 years (range 49.9--77.6) and mean serum testosterone was 10.9 nmol/l (range 7.8--19). Testosterone treatment produced: (i) a reduction of 1.6 kg (CI: 2.5--0.6) of total body fat, corresponding to -6.2% (CI: 9.2--3.3) variation of initial body fat, (ii) an increase in fat free mass of 1.6 kg (CI: 0.6--2.6), corresponding to +2.7% (CI: 1.1--4.4) increase over baseline and (iii) no change in body weight. The effects of T on muscle strength were heterogeneous, showing a tendency towards improvement only at the leg/knee extension and handgrip of the dominant arm (pooled effect size=0.3 standard mean difference (SMD), CI: -0.0 to 0.6). Testosterone improved bone mineral density (BMD) at the lumbar spine by +3.7% (CI: 1.0--6.4%) compared to placebo, but not at the femoral neck, and produced a consistent reduction in bone resorption markers (pooled effect size = -0.6 SMD, CI: -1.0 to -0.2). Testosterone also reduced total cholesterol by 0.23 mmol/l (CI: -0.37 to -0.10), especially in men with lower baseline T concentrations, with no change in low density lipoprotein (LDL)-cholesterol. A significant reduction of high density lipoprotein (HDL)-cholesterol was found only in studies with higher mean T-values at baseline (-0.085 mmol/l, CI: -0.017 to -0.003). Sensitivity and meta-regression analysis revealed that the dose/type of T used, in particular the possibility of aromatization, explained the heterogeneity in findings observed on bone density and HDL-cholesterol among studies. CONCLUSION: The present analysis provides an estimate of the average treatment effects of testosterone therapy in middle-aged men. Our findings are sufficiently strong to justify further interventional studies focused on alternative targets of androgenic treatment carrying more stringent clinical implications, in particular the cardiovascular, metabolic and neurological systems. PMID: 16117815 ------------- [5] Mol Neurobiol. 2015 Jul 8. [Epub ahead of print] Low Testosterone Level and Risk of Alzheimer's Disease in the Elderly Men: a Systematic Review and Meta-Analysis. Lv W(1), Du N(1), Liu Y(1), Fan X(1), Wang Y(1), Jia X(2), Hou X(3), Wang B(4). Sex steroids can positively affect the brain function, and low levels of sex steroids may be associated with worse cognitive function in the elderly men. However, previous studies reported contrary findings on the relationship between testosterone level and risk of Alzheimer's disease in the elderly men. The objective of this study was to comprehensively assess the relationship between low testosterone level and Alzheimer's disease risk in the elderly men using a meta-analysis. Only prospective cohort studies assessing the influence of low testosterone level on Alzheimer's disease risk in elderly men were considered eligible. Relative risks (RRs) with 95 % confidence intervals (95 % CI) were pooled to assess the risk of Alzheimer's disease in elderly men with low testosterone level. Seven prospective cohort studies with a total of 5251 elderly men and 240 cases of Alzheimer's disease were included into the meta-analysis. There was moderate degree of heterogeneity among those included studies (I (2) = 47.2 %). Meta-analysis using random effect model showed that low plasma testosterone level was significantly associated with an increased risk of Alzheimer's disease in elderly men (random RR = 1.48, 95 % CI 1.12-1.96, P = 0.006). Sensitivity analysis by omitting one study by turns showed that there was no obvious change in the pooled risk estimates, and all pooled RRs were statistically significant. This meta-analysis supports that low plasma testosterone level is significantly associated with increased risk of Alzheimer's disease in the elderly men. Low testosterone level is a risk factor of worse cognitive function in the elderly men. PMID: 26154489 ------------- [6] BMC Med. 2013 Apr 18;11:108. doi: 10.1186/1741-7015-11-108. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. Xu L(1), Freeman G, Cowling BJ, Schooling CM. Author information: (1)School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, China. Comment in Evid Based Med. 2014 Feb;19(1):32-3. BACKGROUND: Testosterone therapy is increasingly promoted. No randomized placebo-controlled trial has been implemented to assess the effect of testosterone therapy on cardiovascular events, although very high levels of androgens are thought to promote cardiovascular disease. METHODS: A systematic review and meta-analysis was conducted of placebo-controlled randomized trials of testosterone therapy among men lasting 12+ weeks reporting cardiovascular-related events. We searched PubMed through the end of 2012 using "("testosterone" or "androgen") and trial and ("random*")" with the selection limited to studies of men in English, supplemented by a bibliographic search of the World Health Organization trial registry. Two reviewers independently searched, selected and assessed study quality with differences resolved by consensus. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting. RESULTS: Of 1,882 studies identified 27 trials were eligible including 2,994, mainly older, men who experienced 180 cardiovascular-related events. Testosterone therapy increased the risk of a cardiovascular-related event (odds ratio (OR) 1.54, 95% confidence interval (CI) 1.09 to 2.18). The effect of testosterone therapy varied with source of funding (P-value for interaction 0.03), but not with baseline testosterone level (P-value for interaction 0.70). In trials not funded by the pharmaceutical industry the risk of a cardiovascular-related event on testosterone therapy was greater (OR 2.06, 95% CI 1.34 to 3.17) than in pharmaceutical industry funded trials (OR 0.89, 95% CI 0.50 to 1.60). CONCLUSIONS: The effects of testosterone on cardiovascular-related events varied with source of funding. Nevertheless, overall and particularly in trials not funded by the pharmaceutical industry, exogenous testosterone increased the risk of cardiovascular-related events, with corresponding implications for the use of testosterone therapy. PMID: 23597181
  18. [Note: This is my first thread on the new "General Health & Longevity" forum - thanks for making it!] Yet another study has found drinking a surprisingly large number of cups of coffee per day to be health promoting. This new study [1] in the Journal Circulation by Harvard researchers (press release, including a video, here) used epidemiological data from 74,890 women in the Nurses' Health Study, 93,054 women in the Nurses' Health Study 2, and 40,557 men in the Health Professionals Follow-up Study. Participants completed food questionnaires every four years during an average follow-up period of 22.5 years, providing researchers with coffee consumption data. There appeared to be a shallow, U-shaped mortality curve for coffee drinking, with the greatest reduction in non-smoker mortality (15%) among those who consumed 3-5 cups of coffee per day. Greater than 5 cups per day reduced all-cause mortality by slightly less (12%) when compared to never-drinkers. Both caffeinated and decaf coffee was found to reduce mortality. The causes of death that were significantly lower among coffee drinkers were cardiovascular disease, neurological diseases, and suicide. This Harvard study is in agreement with another large, epidemiological study [2] from earlier this year which found an even greater reduction in all-cause and cause-specific morality among a Japanese cohort of 90,000 people followed for 19 years. It too found a sweet spot around 3-4 cups per day, with a reduction in all-cause mortality of 24%. So once again, coffee is found to be good for you. But remember not to drink it too hot, and be sure to filter it, preferably with a paper filter. ---------- [1] Circulation November 16, 2015, Published online before print doi: 10.1161/CIRCULATIONAHA.115.017341 Association of Coffee Consumption with Total and Cause-Specific Mortality in Three Large Prospective Cohorts Ming Ding1; Ambika Satija1; Shilpa N. Bhupathiraju1; Yang Hu1; Qi Sun2; Jiali Han3; Esther Lopez-Garcia4; Walter Willett2; Rob M. van Dam5; Frank B. Hu2* Abstract Background—The association between consumption of caffeinated and decaffeinated coffee and risk of mortality remains inconclusive. Methods and Results—We examined the associations of consumption of total, caffeinated, and decaffeinated coffee with risk of subsequent total and cause-specific mortality among 74,890 women in the Nurses' Health Study (NHS), 93,054 women in the NHS 2, and 40,557 men in the Health Professionals Follow-up Study. Coffee consumption was assessed at baseline using a semi-quantitative food frequency questionnaire. During 4,690,072 person-years of follow-up, 19,524 women and 12,432 men died. Consumption of total, caffeinated, and decaffeinated coffee were non-linearly associated with mortality. Compared to non-drinkers, coffee consumption one to five cups/d was associated with lower risk of mortality, while coffee consumption more than five cups/d was not associated with risk of mortality. However, when restricting to never smokers, compared to non-drinkers, the HRs of mortality were 0.94 (0.89 to 0.99) for ≤ 1 cup/d, 0.92 (0.87 to 0.97) for 1.1-3 cups/d, 0.85 (0.79 to 0.92) for 3.1-5 cups/d, and 0.88 (0.78 to 0.99) for > 5 cups/d (p for non-linearity = 0.32; p for trend < 0.001). Significant inverse associations were observed for caffeinated (p for trend < 0.001) and decaffeinated coffee (p for trend = 0.022). Significant inverse associations were observed between coffee consumption and deaths due to cardiovascular disease, neurological diseases, and suicide. No significant association between coffee consumption and total cancer mortality was found. Conclusions—Higher consumption of total coffee, caffeinated coffee, and decaffeinated coffee was associated with lower risk of total mortality. PMID: 26572796 ------------ [2] Am J Clin Nutr. 2015 May;101(5):1029-37. doi: 10.3945/ajcn.114.104273. Epub 2015 Mar 11. Association of coffee intake with total and cause-specific mortality in a Japanese population: the Japan Public Health Center-based Prospective Study. Saito E(1), Inoue M(1), Sawada N(1), Shimazu T(1), Yamaji T(1), Iwasaki M(1), Sasazuki S(1), Noda M(1), Iso H(1), Tsugane S(1). BACKGROUND: Despite the rising consumption of coffee worldwide, few prospective cohort studies assessed the association of coffee intake with mortality including total and major causes of death. OBJECTIVE: We aimed to investigate the association between habitual coffee drinking and mortality from all causes, cancer, heart disease, cerebrovascular disease, respiratory disease, injuries, and other causes of death in a large-scale, population-based cohort study in Japan. DESIGN: We studied 90,914 Japanese persons aged between 40 and 69 y without a history of cancer, cerebrovascular disease, or ischemic heart disease at the time of the baseline study. Subjects were followed up for an average of 18.7 y, during which 12,874 total deaths were reported. The association between coffee intake and risk of total and cause-specific mortality was assessed by using a Cox proportional hazards regression model with adjustment for potential confounders. RESULTS: We showed an inverse association between coffee intake and total mortality in both men and women. HRs (95% CIs) for total death in subjects who consumed coffee compared with those who never drank coffee were 0.91 (0.86-0.95) for <1 cup/d, 0.85 (0.81-0.90) for 1-2 cups/d, 0.76 (0.70-0.83) for 3-4 cups/d, and 0.85 (0.75-0.98) for >5 cups/d (P-trend < 0.001). Coffee was inversely associated with mortality from heart disease, cerebrovascular disease, and respiratory disease. CONCLUSION: With this prospective study, we suggest that the habitual intake of coffee is associated with lower risk of total mortality and 3 leading causes of death in Japan. © 2015 American Society for Nutrition. PMID: 25762807
  19. All, On the CR email list Al recently posted a series of studies, included below [1-3], showing that higher levels of serum vitamin D were associated with increased risk of prostate cancer. But the most recent such study Al posted [4], found the opposite - increased vitamin D level was associated with a decreased risk of prostate cancer. What the authors of [4] suggest in the discussion (included below) is that there may be a U-shaped curve between serum vitamin D and prostate cancer risk, with the 'sweet spot' being in the neighborhood of 20-30 ng/ml (or equiv. 50-75 nmol/l) range. The bottom line suggested by [4] appears to be that we want to have sufficient Vitamin D, but not too much, in order to avoid prostate cancer. Of course, men get a lot of their vitamin D from D-fortified dairy products, which may be driving some of this apparent positive association between vitamin D level and prostate cancer, since this recent meta-analysis [5] found: High intakes of dairy products, milk, low-fat milk, cheese, and total, dietary, and dairy calcium, but not supplemental or nondairy calcium, may increase total prostate cancer risk. So it is possible that higher levels of vitamin D are a marker for higher intake of dairy products in the general population, which may be driving the development of prostate cancer. --Dean -------------- [1] Plasma 25-hydroxyvitamin D and prostate cancer risk: the multiethnic cohort. Park SY, Cooney RV, Wilkens LR, Murphy SP, Henderson BE, Kolonel LN. Eur J Cancer. 2010 Mar;46(5):932-6. doi: 10.1016/j.ejca.2009.12.030. Epub 2010 Feb 8. PMID: 20064705 Free PMC Article http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834847/ file:///C:/Documents%20and%20Settings/user/My%20Documents/Downloads/nihms169878%20(1).pdf Abstract The purpose of this study was to examine the relationship of plasma 25-hydroxyvitamin D (25(OH)D) concentrations to prostate cancer within a large multiethnic cohort in Hawaii and California using a nested case-control design. The study included 329 incident prostate cancer cases of African American, Native Hawaiian, Japanese, Latino, and White ancestry, and 656 controls matched on age, race/ethnicity, date/time of blood collection, and fasting status. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI). No association with prostate cancer risk was found in an analysis based on quartiles of 25(OH)D. When clinically defined cutpoints were used, there was no increased risk for the lowest 25(OH)D concentration (OR for <20 vs. 30–<50 ng/ml = 1.10, 95% CI = 0.68-1.78), while there was a suggestive increased risk for higher concentrations (OR for =50 ng/ml = 1.52, 95% CI = 0.92-2.51). The findings from this prospective study of men in the Multiethnic Cohort do not support the hypothesis that vitamin D lowers the risk of prostate cancer. Further follow-up is warranted to determine whether the findings are consistent across ethnic groups. Keywords: 25-hydroxyvitamin D, multiethnic cohort, nested case-control study, plasma, prostate neoplasms --------- [2] Circulating levels of 25-hydroxyvitamin D and prostate cancer prognosis. Holt SK, Kolb S, Fu R, Horst R, Feng Z, Stanford JL. Cancer Epidemiol. 2013 Oct;37(5):666-70. doi: 10.1016/j.canep.2013.07.005. Epub 2013 Aug 20. PMID: 23972671 PMC Article http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864767/ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864767/pdf/nihms517958.pdf Abstract OBJECTIVES: Ecological, in vitro, and in vivo studies demonstrate a link between vitamin D and prostate tumor growth and aggressiveness. The goal of this study was to investigate whether plasma concentration of vitamin D is associated with survivorship and disease progression in men diagnosed with prostate cancer. MATERIALS AND METHODS: We conducted a population-based cohort study of 1476 prostate cancer patients to assess disease recurrence/progression and prostate cancer-specific mortality (PCSM) risks associated with serum levels of 25(OH) vitamin D [25(OH)D]. RESULTS: There were 325 recurrence/progression and 95 PCSM events during an average of 10.8 years of follow-up. Serum levels of 25(OH)D were not associated with risk of recurrence/progression or mortality. Clinically deficient vitamin D levels were associated with an increased risk of death from other causes. CONCLUSIONS: We did not find evidence that serum vitamin D levels measured after diagnosis affect prostate cancer prognosis. Lower levels of vitamin D were associated with risk of non-prostate cancer mortality. KEYWORDS: 1,25(OH)(2)D; 1,25-dihydroxyvitamin D(3); 25(OH) vitamin D; 25(OH)D; ADT; BMI; Cohort studies; Epidemiologic studies; FFQ; HR; Humans; Male; Mortality; PCSM; PCa; PH; PSA; Prognosis; Prostatic neoplasms; Vitamin D/blood*; androgen deprivation therapy; body mass index; food frequency questionnaire; hazard ratio; proportional hazards; prostate cancer; prostate cancer-specific mortality; prostate specific antigen ---------- [3] In older men, lower plasma 25-hydroxyvitamin D is associated with reduced incidence of prostate, but not colorectal or lung cancer. Wong YY, Hyde Z, McCaul KA, Yeap BB, Golledge J, Hankey GJ, Flicker L. PLoS One. 2014 Jun 20;9(6):e99954. doi: 10.1371/journal.pone.0099954. eCollection 2014. Erratum in: PLoS One. 2014;9(9):e109511. PMID: 24949795 Free PMC Article http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4065010/ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4065010/pdf/pone.0099954.pdf Abstract CONTEXT AND OBJECTIVE: Prostate, colorectal and lung cancers are common in men. In this study, we aimed to determine whether vitamin D status is associated with the incidence of these cancers in older men. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: 4208 older men aged 70-88 years in Perth, Western Australia. MAIN OUTCOME MEASURES: Plasma 25-hydroxyvitamin D [25(OH)D] concentration was measured by immunoassay. New diagnoses of prostate, colorectal and lung cancers were determined via electronic record linkage. RESULTS: During a mean follow-up of 6.7±1.8 years, there were 315, 117 and 101 new diagnoses of prostate, colorectal and lung cancer. In multivariate competing risks proportional hazards models, every 10 nmol/l decrease in 25(OH)D concentration was associated with a 4% reduction in prostate cancer incidence (sub-hazard ratio [sHR] 0.96, 95% confidence interval [CI] 0.92-1.00). Every halving of 25(OH)D concentration was associated with a 21% reduction in incident prostate cancer in multivariate analysis (SHR 0.79, 95% CI 0.63-0.99). Following exclusion of prostate cancer cases diagnosed within 3 years of blood sampling, low 25(OH)D <50 nmol/l was associated with lower incident prostate cancer, and higher 25(OH)D >75 nmol/l was associated with higher incidence, when compared to the reference range 50-75 nmol/l, respectively (p = 0.027). Significant associations were also observed when 25(OH)D was modeled as a quantitative variable. No associations were observed between plasma 25(OH)D concentration with incidence of colorectal or lung cancer. CONCLUSION: Lower levels of vitamin D may reduce prostate cancer risk in older men. By contrast, levels of vitamin D did not predict incidence of colorectal or lung cancers. Further studies are needed to determine whether a causal relationship exists between vitamin D and prostate cancer in ageing men. ---------- [4] A prospective study of plasma 25-hydroxyvitamin D concentration and prostate cancer risk. Deschasaux M, Souberbielle JC, Latino-Martel P, Sutton A, Charnaux N, Druesne-Pecollo N, Galan P, Hercberg S, Le Clerc S, Kesse-Guyot E, Ezzedine K, Touvier M. Br J Nutr. 2016 Jan;115(2):305-14. doi: 10.1017/S0007114515004353. Epub 2015 Nov 16. PMID: 26568368 Abstract Mechanistic hypotheses suggest that vitamin D and the closely related parathyroid hormone (PTH) may be involved in prostate carcinogenesis. However, epidemiological evidence is lacking for PTH and inconsistent for vitamin D. Our objectives were to prospectively investigate the association between vitamin D status, vitamin D-related gene polymorphisms, PTH and prostate cancer risk. A total of 129 cases diagnosed within the Supplémentation en Vitamines et Minéraux Antioxydants cohort were included in a nested case-control study and matched to 167 controls (13 years of follow-up). 25-Hydroxyvitamin D (25(OH)D) and PTH concentrations were assessed from baseline plasma samples. Conditional logistic regression models were computed. Higher 25(OH)D concentration was associated with decreased risk of prostate cancer (ORQ4 v. Q1 0·30; 95 % CI 0·12, 0·77; P trend=0·007). PTH concentration was not associated with prostate cancer risk (P trend=0·4) neither did the studied vitamin D-related gene polymorphisms. In this prospective study, prostate cancer risk was inversely associated with 25(OH)D concentration but not with PTH concentration. These results bring a new contribution to the understanding of the relationship between vitamin D and prostate cancer, which deserves further investigation. KEYWORDS: 1; 25(OH)2D 1; 25(OH)D 25-hydroxyvitamin D; 25-Hydroxyvitamin D; 25-dihydroxyvitamin D; 25-dihydroxyvitamin D3 24-hydroxylase; CYP24A1 1; CaSR Ca-sensing receptor; GC vitamin D-binding globulin; MAF minor allele frequency; Nested case–control studies; PTH parathyroid hormone; Parathyroid hormone; Prostate cancer risk; RXR retinoid X receptor; SNP; SU.VI.MAX Supplémentation en Vitamines et Minéraux Antioxydants; VDR vitamin D receptor; gc-globulin or group-specific component Vitamin D is a prohormone synthesised in the skin from UVB exposure and absorbed from scarce dietary sources. It is first converted to 25-hydroxyvitamin D (25(OH)D) – its main circulating form – and then to 1,25-dihydroxyvitamin D (1,25(OH)2D) – its biologically active form. As 25(OH)D-to-1,25(OH)2D conversion and 1,25(OH)2D signalling can take place directly in prostate tissues(1), vitamin D is thought to play a role in the prevention of prostate cancer through pro-differentiation, pro-apoptosis, anti-proliferative and growth control activities, as suggested by experimental studies(2–4). However, so far, epidemiological evidence regarding the relationship between 25(OH)D concentration and prostate cancer risk has been inconsistent. On the basis of a dose–response meta-analysis that involved fifteen prospective studies, the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR)(5), as part of the Continuous Update Project 2014 on prostate cancer, stated that the level of proof for the association between 25(OH)D concentration and prostate cancer risk was still ‘limited-no conclusion’. Most of the studies included in this meta-analysis observed null results. Besides, vitamin D is primarily involved in Ca homoeostasis: 1,25(OH)2D increases Ca concentration through enhanced intestinal Ca absorption, reabsorption of Ca from kidneys and bone resorption. Renal 25(OH)D-to-1,25(OH)2D conversion is induced by parathyroid hormone (PTH) secretion in response to low Ca concentration. 1,25(OH)2D exerts in turn a negative feedback on PTH secretion(6–8). Vitamin D and PTH are thus closely related. To our knowledge, only one prospective study has investigated the association between PTH concentration and prostate cancer risk, with null result(9). Several genes involved in vitamin D metabolism, in particular signalling (vitamin D receptor (VDR) and retinoid X receptor (RXR)), transportation (vitamin D-binding protein, also known as gc-globulin or group-specific component (GC)) and degradation (1,25-dihydroxyvitamin D3 24-hydroxylase (CYP24A1)), or in Ca homoeostasis (Ca-sensing receptor (CaSR)) could also play a role in prostate cancer aetiology(2). Recent meta-analyses found null associations between VDR BsmI, FokI and Cdx2 polymorphisms and prostate cancer risk(10–12). The epidemiological literature dealing with polymorphisms of other genes (GC, CYP24A1, RXR and CaSR) in relation to prostate cancer risk is scarce(13–16). Thus, our objective was to prospectively investigate the associations between prostate cancer risk and vitamin D status (25(OH)D concentration), plasma PTH concentration and polymorphisms of genes involved in vitamin D metabolism. Methods Subjects The Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) study was initially designed as a double-blind placebo-controlled trial (Trial Registration clinicaltrials.gov Identifier: NCT00272428) with purpose to assess the influence of a daily supplementation with nutritional doses of antioxidants (single capsule of a combination of ascorbic acid (120 mg), vitamin E (30 mg), ß-carotene (6 mg), Se (100 µg) and Zn (20 mg) or placebo) on the incidence of CVD and cancers(17). A total of 13 017 participants were enrolled in 1994–1995 for an 8-year-intervention trial and followed up for health events until September 2007. Participants were advised against taking any self-prescribed supplements (vitamin D and others) during the trial. ... Results A total of 129 prostate cancer cases diagnosed within the SU.VI.MAX cohort were included in this study. Mean age at diagnosis was 63·0 years and mean baseline-to-diagnosis time was 8·3 years. Of the cases, 49·2 % had a Gleason’s score =/>7. A total of 167 controls were randomly selected and matched to the cases. Table 1 summarises the characteristics of prostate cancer cases and controls. Compared with controls, prostate cancer cases were more likely to have a lower vitamin D status at baseline and to be better educated. Severe vitamin D deficiency (<10 ng/ml) was observed for 14·0 % of cases and 13·8 % of controls, and vitamin D insufficiency (<20 ng/ml) was observed for 62·8 % of cases and 54·5 % of controls, with no statistically significant difference between cases and controls. A seasonal fluctuation of vitamin D status was observed in controls with decreasing vitamin D status from October to March (shortening days) and increasing vitamin D status in April–May (extending days). All studied SNP respected the Hardy–Weinberg’s equilibrium (P>0·05). The repartition of subjects across the different genotypes was in accordance with that observed in European reference populations (CSHL-HapMap-CEU and 1000GENOMES-phase_1_EUR) for all SNP (P>0·05). 25(OH)D concentration was inversely associated with prostate cancer risk (ORper 1 ng/ml 0·96; 95 % CI 0·93, 1·00; Ptrend=0·04; ORQ4 v. Q1 0·30; 95 % CI 0·12, 0·77; Ptrend=0·007; OR<20 v. =/>20 ng/ml 0·44; 95 % CI 0·23, 0·85; P=0·01, Table 2; ORper 30 nmol/l 0·64; 95 % CI 0·42, 0·97; Ptrend=0·04, data not tabulated). Using the quartile coding this inverse association was observed in particular for cases with a Gleason’s score <7 (sixty-nine cases/ninety controls, ORQ4 v. Q1 0·03; 95 % CI 0·003, 0·40; Ptrend=0·02; data not tabulated), whereas it was not significant for cases with a Gleason’s score =/>7 (sixty cases/seventy-seven controls, ORQ4 v. Q1 0·96; 95 % CI 0·23, 4·05; Ptrend=0·5; data not tabulated). However, using the continuous 25(OH)D variable or the 20 ng/ml cut-off, these associations were not significant in both Gleason’s subgroups. Exclusion of cases diagnosed during the first 5 years of follow-up provided similar results (109 cases/140 controls, ORper 1 ng/ml 0·96; 95 % CI 0·93, 1·00; Ptrend=0·04; ORQ4 v. Q1 0·33; 95 % CI 0·12, 0·86; Ptrend=0·01; OR<20 v. =/>20 ng/ml 0·45; 95 % CI 0·23, 0·89; P=0·02; data not tabulated). No interaction was observed between 25(OH)D concentration and the intervention group of the SU.VI.MAX trial (Pinteraction>0·1 for all codings). Associations between 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone (PTH) plasma concentrations, and prostate cancer risk, from conditional logistic regression, Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) cohort, France (1994–2007) (Odds ratios and 95 % confidence intervals) Table 2 Associations between 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone (PTH) plasma concentrations, and prostate cancer risk, from conditional logistic regression, Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) cohort, France (1994–2007) (Odds ratios and 95 % confidence intervals) % confidence intervals) -------------------------------------------------- - === - ===Quartiles*===Insufficiency - === Per 1 unit increment===Q1 Q2 Q3 Q4 <20 ng/ml =/>20 ng/ml - === OR 95 % CI Ptrend===OR OR 95 % CI OR 95 % CI OR 95 % CI Ptrend OR OR 95 % CI P -------------------------------------------------- 25(OH)D (ng/ml) Cases/controls 129/167 42/32 31/43 25/49 31/43 81/91 48/76 Model 1† 0·96 0·93, 1·00 0·04 1·00 0·44 0·19, 1·04 0·18 0·07, 0·49 0·30 0·12, 0·77 0·007 1·00 0·44 0·23, 0·85 0·01 Cases/controls 96/123 27/20 23/35 20/35 26/33 57/66 39/57 Model 2† 0·95 0·91, 1·00 0·06 1·00 0·35 0·12, 1·07 0·13 0·04, 0·49 0·25 0·08, 0·81 0·02 1·00 0·43 0·19, 1·00 0·05 Cases/controls 96/123 27/20 23/35 20/35 26/33 57/66 39/57 Model 3† 0·96 0·91, 1·01 0·08 1·00 0·33 0·11, 1·03 0·12 0·03, 0·46 0·28 0·08, 0·95 0·03 1·00 0·43 0·18, 1·01 0·05 -------------------------------------------------- PTH (pg/ml) Cases/controls 129/167 31/43 34/40 34/40 30/44 Model 1† 0·97 0·94, 1·01 0·1 1·00 0·90 0·40, 2·05 0·95 0·40, 2·27 0·66 0·28, 1·55 0·4 Cases/controls 96/123 20/35 30/26 27/30 19/32 Model 2† 0·96 0·91, 1·01 0·09 1·00 1·72 0·60, 4·90 1·95 0·62, 6·18 0·77 0·25, 2·36 0·6 Cases/controls 96/123 20/35 30/26 27/30 19/32 Model 3† 0·96 0·91, 1·01 0·1 1·00 1·63 0·56, 4·77 2·25 0·67, 7·59 0·81 0·25, 2·62 0·8 -------------------------------------------------- Q, quartiles. * Model 1: cut-offs for quartiles of 25(OH)D plasma concentration (ng/ml) and PTH plasma concentration (pg/ml) were, respectively, 12·9/18·2/24·7 and 20·9/26·0/30·6. Models 2 and 3 are restricted to men who provided at least three valid 24 h-dietary records (ninety-six cases/123 controls): cut-offs for quartiles of 25(OH)D plasma concentration (ng/ml) and PTH plasma concentration (pg/ml) were, respectively, 13·7/18·5/25·2 and 20·9/25·9/30·2. † Model 1 was adjusted for age at baseline (continuous, matching factor), intervention group of the initial SU.VI.MAX trial (antioxidants/placebo, matching factor), month of blood draw (October–November/December–January/February–March/April–May), educational level (primary/secondary/superior), physical activity (irregular/<1 h/d walking equivalent/=/>1 h/d walking equivalent), alcohol intake (g/d, continuous), smoking status (never/former/current), height (cm, continuous), BMI (kg/m², continuous, matching factor), family history of prostate cancer (yes/no) and baseline serum prostate-specific antigen concentration (<3/=/>3 ng/l). Model 2 corresponds to model 1 further adjusted for energy intake (without alcohol) (continuous, kJ/d (kcal/d)), dietary intakes of Ca intake (continuous, mg/d) and dairy products (continuous, g/d), plasma Se (continuous, µmol/l) and Alpha-tocopherol (continuous, µmol/l) concentrations. Model 3 corresponds to model 2 with further mutual adjustment for 25(OH)D and PTH plasma concentrations (continuous). Plasma PTH concentration was not associated with prostate cancer risk (ORQ4 v. Q1 0·66; 95 % CI 0·28, 1·55; Ptrend=0·4) (Table 2). This result was similar (124 cases/157 controls) after removing participants with possibly abnormal PTH values that may suggest potential hyperparathyroidism (i.e. PTH=/>50·8 pg/ml if 25(OH)D<20 ng/ml, PTH=/>45·5 pg/ml if 20 ng/ml</=25(OH)D<30 ng/ml and PTH=/>45·3 pg/ml if 25(OH)D=/>30 ng/ml, as previously recommended(22)). Dietary Ca intake was not associated with prostate cancer risk (ninety-six cases/123 controls, ORQ4 v. Q1 0·83; 95 % CI 0·20, 3·43; Ptrend=0·5, data not tabulated), nor did dietary intake of vitamin D (ninety-six cases/123 controls, ORQ4 v. Q1 1·05; 95 % CI 0·40, 2·81; Ptrend=0·7, data not tabulated). All results were similar when models were further adjusted for dietary variables (although some of the results were only borderline significant due to loss of statistical power: ninety-six cases/123 controls), dietary Ca and mutual adjustments for 25(OH)D and PTH. Two-way interactions between 25(OH)D, PTH and dietary Ca intake were not statistically significant (all P>0·1, data not shown). No association was observed between the ten studied vitamin D-related SNP and prostate cancer risk in the codominant (Table 3), dominant and recessive models (data not tabulated). No interaction was observed between the SNP and 25(OH)D concentration (all P>0·1, data not shown). As no association was detected between the ten SNP and prostate cancer with a P value threshold of 0·05, no association was detected after adjustment for multiple testing (Bonferroni correction) (data not shown). Associations between SNP of genes involved in vitamin D metabolism and prostate cancer risk, from conditional logistic regression, Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) cohort, France (1994–2007) (Odds ratios and 95 % confidence intervals) Discussion In this prospective study, plasma 25(OH)D concentration was inversely associated with prostate cancer risk. No association was detected for plasma PTH concentration or the studied SNP. We observed an inverse association between 25(OH)D concentration and prostate cancer risk. Recently, a high v. low meta-analysis by Xu et al.(27) (summary ORhigh v. low 1·17; 95 % CI 1·05, 1·30) and a dose–response meta-analysis by the WCRF(5) (summary RRper 30 nmol/l 1·04; 95 % CI 1·00, 1·07) suggested an increased risk. However, in a previous study by Tuohimaa et al.(28), both high and low 25(OH)D concentrations were associated with increased prostate cancer risk: increased risk was observed for 25(OH)D concentration =/>32 or <15·6 ng/ml compared with 16–23·6 ng/ml. This U-shaped association is supported by the evidence of non-linearity observed in the WCRF dose–response meta-analysis(5). In our study, the range of 25(OH)D concentrations observed (95th percentile=36·3 ng/ml) may be positioned in the left part of this U-shaped curve, which may explain why a decreased prostate cancer risk was observed for 25(OH)D=/>20 ng/ml (insufficiency) or =/>18·2 ng/ml (median) compared with 25(OH)D<20 or <12·9 ng/ml (quartile 1 (Q1)), respectively. Consistently, a recent study by Kristal et al.(29) observed a decreased prostate cancer risk associated with 25(OH)D concentrations between 23·3 and 29·2 ng/ml (3rd quintile) compared with 25(OH)D<17·7 ng/ml (1st quintile). In contrast, some studies observing an increased risk may involve 25(OH)D concentrations situated in the right part of the U-shaped curve. For example, Brandstedt et al.(9) observed an increased risk for 25(OH)D concentrations=/>34 ng/ml compared with 25(OH)D concentrations</=27·2 ng/ml, and Meyer et al.(30) observed an increased risk for 25(OH)D concentrations=/>28 ng/ml compared with 25(OH)D concentrations between 20 and 28 ng/ml. Studies observing non-significant results may involve middle-range concentrations (such as the study by Skaaby et al.(31)). However, this point remains unclear as some studies that involved high 25(OH)D concentrations observed non-significant results(32,33), and some other studies observed a significant direct association between prostate cancer risk and 25(OH)D concentrations, even at relatively low levels(34). Thus, further studies are needed that take into account the distribution of 25(OH)D concentrations in the studied population and its position in the potential U-shaped curve. In addition, it has been suggested that large seasonal fluctuations of vitamin D status may also contribute to explain the positive association between 25(OH)D concentration and prostate cancer risk in some studies(35), adding to the complexity of this relationship. In the SU.VI.MAX cohort (Touvier et al.(21) and Table 1), seasonal fluctuation of vitamin D status was moderate with the lowest 25(OH)D concentrations observed in late winter/early spring (shorter days), consistently with the existing literature in France(36) and in other countries such as the USA(37–39). The potentially protective role of vitamin D in prostate carcinogenesis observed in our study is supported by mechanistic hypotheses. Indeed, prostate cells can express the 25(OH)D-to-1,25(OH)2D conversion enzyme and the vitamin D receptor(1) and vitamin D is thought to be involved in several cell regulation pathways: pro-differentiation, pro-apoptosis, anti-proliferation and cell growth(2–4). In our study, when 25(OH)D was coded into quartiles, a decreased prostate cancer risk was observed for Gleason’s score <7 but not for Gleason’s score =/>7. However, when using the other codings (continuous and 20 ng/ml cut-off), the association was non-significant in both cancer subgroups. As statistical power was limited in stratified analyses, these results should be considered with caution and further explored in large prospective studies. Thus far, the results regarding potential differences according to prostate cancer stage/grade are unclear, as shown in the WCRF meta-analysis(5), where no difference was observed between advanced/high-grade or non-advanced/low-grade prostate cancers (non-significant results in both groups), or in a recent study by Kristal et al.(29), where a decreased prostate cancer risk was observed whatever the Gleason’s score. The lack of association between the ten studied SNP and prostate cancer risk in our study does not seem to support the protective role of vitamin D in prostate carcinogenesis suggested by our results on plasma 25(OH)D concentration. However, in this study, statistical power was limited in the analyses of SNP, especially for the homozygote mutant genotypes. This could explain the null associations observed. Consistent with our findings, several meta-analyses(10–12) and one recent prospective study(13) found null associations between VDR BsmI, FokI and Cdx2 polymorphisms and prostate cancer risk. Another study (not included in these meta-analyses) observed an increased prostate cancer associated with VDR BsmI GG genotype among men in the first tertile of plasma 25(OH)D concentration. The epidemiological literature dealing with the other studied polymorphisms is scarce. One study(13) observed an increased prostate cancer risk associated with GC rs4588 T allele or GC rs7041 A allele. In SU.VI.MAX(21), these alleles were associated with a lower vitamin D status. Another study(15) observed a decreased lethal prostate cancer risk associated with CaSR rs1801725 among men with low plasma 25(OH)D concentration. To our knowledge, no study has investigated the other selected SNP (CYP24A1 rs4809958, RXR rs7861779 and rs12004589 and CaSR rs4678174) in relation to prostate cancer risk. Besides, other vitamin D-related SNP than the ones included in the present study may also be associated with prostate cancer risk, as observed by Mondul et al.(14), and deserve further investigation. Plasma PTH concentration was not associated with the risk of prostate cancer. To our knowledge, our study was only the second to investigate this relationship, the first one having observed null results(9). In a previous study performed in the SU.VI.MAX cohort(22), we observed an inverse correlation between 25(OH)D and PTH concentrations, with a threshold value for PTH when 25(OH)D was approximately 30 ng/ml. Thus, it could be expected that PTH concentration would decrease as 25(OH)D concentration increases. Mechanistic data are unclear regarding a potential involvement of PTH in prostate carcinogenesis. Although some data have suggested a potential pro-carcinogenic role of PTH(40–42) (potential mitogenic activity in preneoplastic lesions), others support a potential protective role. Indeed, high PTH concentration may decrease growth hormone secretion, thereby decreasing circulating insulin-like growth factor-1 (IGF-1) concentration(43,44); IGF-1 being considered as a potential risk factor for prostate cancer(45,46). Thus, further investigation is needed on the association between PTH concentration and prostate cancer risk. Strengths of our study pertained to its prospective design, long follow-up, simultaneous assessment of 25(OH)D and PTH plasma concentrations, vitamin D-related gene polymorphisms and dietary intakes, and the consideration of numerous confounding factors. However, limitations should be acknowledged. First, blood Ca concentration was not available in our study. Ca concentration would have provided more information regarding the association between 25(OH)D, PTH, Ca and prostate cancer risk. Dietary Ca intake was available, but intakes within normal range are poorly correlated with blood Ca concentration(47), which is under homoeostatic control. Second, only one plasma 25(OH)D and PTH measurement was available at baseline. Repeated measures could have been of interest to study their evolution across time. Third, although the number of cases was appropriate for the analyses described here, it has limited our ability to perform separate analyses in specific subgroups, in particular regarding genetic polymorphisms or prostate cancer grade. Finally, the observed inverse association between vitamin D status and prostate cancer could be partly explained by reverse causality, considering the long lasting development of this cancer. However, results were similar when excluding cases diagnosed within the first 5 years of follow-up, thus arguing against reverse causality. In this prospective study, the association between vitamin D and prostate cancer risk was addressed through 25(OH)D concentration, polymorphisms of vitamin D-related genes and PTH concentration. Prostate cancer risk was inversely associated with 25(OH)D concentration but not with PTH concentration. These results, supported by mechanistic data, bring a new contribution to the understanding of the relationship between vitamin D and prostate cancer risk and deserve further exploration. ------ [5] Am J Clin Nutr. 2015 Jan;101(1):87-117. doi: 10.3945/ajcn.113.067157. Epub 2014 Nov 19. Dairy products, calcium, and prostate cancer risk: a systematic review and meta-analysis of cohort studies. Aune D(1), Navarro Rosenblatt DA(1), Chan DS(1), Vieira AR(1), Vieira R(1), Greenwood DC(1), Vatten LJ(1), Norat T(1). Author information: (1)From the Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway (DA and LJV); the Department of Epidemiology and Public Health, Imperial College, London, United, Kingdom (DA, DANR, DSMC, ARV, RV, and TN); and the Biostatistics Unit, Centre for Epidemiology and Biostatistics, University of Leeds, Leeds, United Kingdom (DCG). BACKGROUND: Dairy product and calcium intakes have been associated with increased prostate cancer risk, but whether specific dairy products or calcium sources are associated with risk is unclear. OBJECTIVE: In the Continuous Update Project, we conducted a meta-analysis of prospective studies on intakes of dairy products and calcium and prostate cancer risk. DESIGN: PubMed and several other databases were searched up to April 2013. Summary RRs were estimated by using a random-effects model. RESULTS: Thirty-two studies were included. Intakes of total dairy products [summary RR: 1.07 (95% CI: 1.02, 1.12; n = 15) per 400 g/d], total milk [summary RR: 1.03 (95% CI: 1.00, 1.07; n = 14) per 200 g/d], low-fat milk [summary RR: 1.06 (95% CI: 1.01, 1.11; n = 6) per 200 g/d], cheese [summary RR: 1.09 (95% CI: 1.02, 1.18; n = 11) per 50 g/d], and dietary calcium [summary RR: 1.05 (95% CI: 1.02, 1.09; n = 15) per 400 mg/d] were associated with increased total prostate cancer risk. Total calcium and dairy calcium intakes, but not nondairy calcium or supplemental calcium intakes, were also positively associated with total prostate cancer risk. Supplemental calcium was associated with increased risk of fatal prostate cancer. CONCLUSIONS: High intakes of dairy products, milk, low-fat milk, cheese, and total, dietary, and dairy calcium, but not supplemental or nondairy calcium, may increase total prostate cancer risk. The diverging results for types of dairy products and sources of calcium suggest that other components of dairy rather than fat and calcium may increase prostate cancer risk. Any additional studies should report detailed results for subtypes of prostate cancer. © 2015 American Society for Nutrition. PMID: 25527754
  20. There has been a lot of media attention over the last few days about whether cancer is caused mainly by "intrinsic factors" (i.e. "bad luck" - i.e. mutations that just happen when stem cells replicate which lead to cancer) or "extrinsic factors" (colloquially, "bad behaviors" - i.e. our lifestyle choices, like smoking, diet, exercise, etc.). The controversy stems from two recent papers, [1] and [2], both of which seem to come to conflicting conclusions. In [1], the authors looked at different organs and compared the cancer rates in those organs with the number of stem cell divisions that occur in those organs. They found a high correlation - i.e. the more stem cells have to divide to maintain an organ over a person's or animal's lifetime, the more likely it is that cancer will occur in that organ. The authors of [1] (and especially the media covering the study when it first came out earlier this year) appear to interpret this to mean that most incidents of cancer can be chalked up to 'bad luck', rather than bad lifestyle choices or other environmental factors. To quote from the abstract of [1]: These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to "bad luck," that is, random mutations arising during DNA replication in normal, noncancerous stem cells. In what appears to be a direct response to [1], the authors of [2] did a somewhat different analysis, using epidemiological data to show that the relatively simple model to predict various cancer rates from the number of stem cell divisions doesn''t fit the data well at all. They conclude instead that 70-90% of cancer rates are a result of extrinsic factors, like exposure to carcinogens from smoking, foods, environment etc. It isn't from this paper, but here is a very interesting table from this popular press article (originally from the American Cancer Society) estimating the percentage of risk coming from extrinsic factors, and what those specific extrinsic factors are, for various types of cancer: So how to reconcile the seemingly conflicting studies? One of the authors of [2] had what I thought was a good analogy in this interview to explain the apparent discrepancy. He likened cancer to playing Russian roulette. Some organs have a high rate of stem cell division, correspond to spinning the chamber and pulling the trigger many times, while other organs require you to "take a chance" with stem cell division much less often. This represents the intrinsic difference between various organs. In this analogy, extrinsic factors (e.g. smoking, diet, lifestyle, etc.) determine the number of bullets in the gun's chamber. With more bullets in the chamber, there is a greater chance that on any one round (i.e. stem cell division), you'll get unlucky and the division will go badly, resulting in cancer. Take home message - since we can't really change the number of stem cell divisions our organs require to function and maintain themselves, it is important for cancer prevention to minimize our exposure to extrinsic factors that increase the risk of bad stem cell divisions that result in cancer, by following a healthy diet and lifestyle. --Dean ------------- [1] Science. 2015 Jan 2;347(6217):78-81. doi: 10.1126/science.1260825. Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Tomasetti C(1), Vogelstein B(2). Full text via sci-hub.io: http://www.sciencemag.org.sci-hub.io/content/347/6217/78.full Some tissue types give rise to human cancers millions of times more often than other tissue types. Although this has been recognized for more than a century, it has never been explained. Here, we show that the lifetime risk of cancers of many different types is strongly correlated (0.81) with the total number of divisions of the normal self-renewing cells maintaining that tissue's homeostasis. These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to "bad luck," that is, random mutations arising during DNA replication in normal, noncancerous stem cells. This is important not only for understanding the disease but also for designing strategies to limit the mortality it causes. PMID: 25554788 -------- [2] Nature. 2015 Dec 16. doi: 10.1038/nature16166. [Epub ahead of print] Substantial contribution of extrinsic risk factors to cancer development. Wu S(1,)(2), Powers S(1,)(2,)(3), Zhu W(1,)(2), Hannun YA(2,)(3,)(4,)(5). Free Full text: http://www.nature.com/articles/nature16166.epdf Recent research has highlighted a strong correlation between tissue-specific cancer risk and the lifetime number of tissue-specific stem-cell divisions. Whether such correlation implies a high unavoidable intrinsic cancer risk has become a key public health debate with the dissemination of the 'bad luck' hypothesis. Here we provide evidence that intrinsic risk factors contribute only modestly (less than ~10-30% of lifetime risk) to cancer development. First, we demonstrate that the correlation between stem-cell division and cancer risk does not distinguish between the effects of intrinsic and extrinsic factors. We then show that intrinsic risk is better estimated by the lower bound risk controlling for total stem-cell divisions. Finally, we show that the rates of endogenous mutation accumulation by intrinsic processes are not sufficient to account for the observed cancer risks. Collectively, we conclude that cancer risk is heavily influenced by extrinsic factors. These results are important for strategizing cancer prevention, research and public health. PMID: 26675728
  21. Al Pater posted study [1] to the CR email list (thanks Al), that was a meta-analysis of studies of the relationship between vitamin intake and stomach (gastric) cancer risk. It found that several vitamins, including Vitamin A, C and E, in modest doses, could indeed reduce the risk of stomach cancer by about 25%. But high doses of those same vitamins resulted in an increased risk of almost the same magnitude. They also observed that modest doses of these vitamins were only beneficial for gastric cancer when they came from food (plants or animals) - vitamin supplements showed no such benefits. The authors speculate that the reason could be differences in bioavailability of vitamins from foods vs. pills: The current study also draws attention to the fact that vitamins from food (plant or animal) contribute more to reductions in GC risk than synthetic vitamin supplements. Some investigators have noted that the bioavailability of vitamins differs depending on whether the vitamin comes from food or is synthetic, which could explain the results. For example, Carr reported differences in bioavailability between synthetic and kiwifruit-derived vitamin C in a randomized crossover pharmacokinetic study [ref]. But it seems at least as plausible to me that the benefits come not just from these specific vitamins (heck, in the case of vitamin E alone there is really a whole family of vitamins rather than just a single vitamin E), but from the many beneficial phytochemicals in foods, for which these three vitamins are merely markers. --Dean --------- [1] Vitamin intake reduce the risk of gastric cancer: meta-analysis and systematic review of randomized and observational studies. Kong P, Cai Q, Geng Q, Wang J, Lan Y, Zhan Y, Xu D. PLoS One. 2014 Dec 30;9(12):e116060. doi: 10.1371/journal.pone.0116060. eCollection 2014. Review. PMID: 25549091 Free PMC Article http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4280145/ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4280145/pdf/pone.0116060.pdf Abstract AIM: The association between vitamin intake and gastric cancer (GC) has been widely debated due to the relatively weak evidence. In this study, a meta-analysis of prospective and well designed observational studies were performed to explore this association. METHODS: MEDLINE, Cochrane Library, and Sciencedirect were searched for studies of vitamin consumption and gastric cancer. This produced 47 relevant studies covering 1,221,392 human subjects. Random effects models were used to estimate summary relative risk (RR). Dose-response, subgroup, sensitivity, meta-regression, and publication bias analyses were conducted. RESULTS: The RR of gastric cancer in the group with the highest vitamin intake was compared to that of the lowest intake group. Total vitamin intake was 0.78 (95% CI, 0.71-0.83). In 9 studies that individuals were given doses at least 4 times above the tolerable upper intake (UL) vitamins, the RR was 1.20 (95% CI, 0.99-1.44). However, in 17 studies that individuals received doses below the UL, the RR was 0.76 (95% CI, 0.68-0.86). Dose-response analysis was conducted on different increments in different types of vitamins (vitamin A: 1.5 mg/day, vitamin C: 100 mg/day, vitamin E: 10 mg/day) intake with a significant reduction in the risk of gastric cancer, respectively, 29% in vitamin A, 26% in vitamin C, and 24% in vitamin E. CONCLUSION: This meta-analysis clearly demonstrated that low doses of vitamins can significantly reduce the risk of GC, especially vitamin A, vitamin C, vitamin E. Table 2. Subgroup analyses of vitamins intake and gastric cancer Risk. Heterogeneity test ------------------------------------ Group NO. of reports RR (95%) Chi^2 P(I^2) ------------------------------------\ Vitamin source plant 15 0.79(0.69,0.89) 36.96 0.002 65 animal 11 0.78(0.68,0.89) 25.93 0.0003 61 drug supplement 16 0.95(0.80,1.13) 33.09 0.58 55
  22. Diet & Colon Cancer Prevention While researching the Adventists diet study for prostate cancer prevention, Al Pater kindly pointed me to a similar study [1] of diet and colon cancer risk among the Adventists in the AHS-2 study by the same authors (thanks Al!). It followed 96,000 Adventists of both genders for an average follow-up time of 7.3 years to see which diets were associated with a reduced risk of colon cancer. As expected, all vegetarians combined were 22% less likely than omnivores to develop any form of colon cancer during the follow-up (HR 0.78: 95% CI, 0.64-0.95). Here is the breakdown of colon cancer risk by various types of vegetarian diets, again relative to omnivores: Vegans 0.84 (95% CI, 0.59-1.19); lacto-ovo vegetarians 0.82 (95% CI, 0.65-1.02); pescovegetarians, 0.57 (95% CI, 0.40-0.82) semivegetarians, 0.92 (95% CI, 0.62-1.37) For colon cancer, it appears to be the pesky pesco-vegetarians who have the lowest risk of colon cancer. But vegans win overall, at least among this healthy Adventist population relative to all cancers (not just prostate or colon cancer), according to [2]. From the abstract: ... vegan diets showed statistically significant protection for overall cancer incidence (HR, 0.84; 95% CI, 0.72-0.99) in both genders combined. Here is the diagram from [2] comparing the overall cancer risk for different forms of vegetarian diets, relative to omnivores: If we look at the male & female line (first highlight) or the male-only line (second highlight) in the fully adjusted model (including adjusting for BMI), it is only the vegan dietary pattern that reaches the level of 0.05 significance, and is P < 0.05 for the combined gender group. The other vegetarian subgroups failed to show a statistically significant lower overall risk of cancer relative to omnivores. Go ahead - call my Dr. Greger. But thems the data... --Dean ----------- [1] JAMA Intern Med. 2015 May;175(5):767-76. doi: 10.1001/jamainternmed.2015.59. Vegetarian dietary patterns and the risk of colorectal cancers. Orlich MJ(1), Singh PN(2), Sabaté J(1), Fan J(2), Sveen L(2), Bennett H(2), Knutsen SF(1), Beeson WL(2), Jaceldo-Siegl K(1), Butler TL(2), Herring RP(2), Fraser GE(1). IMPORTANCE: Colorectal cancers are a leading cause of cancer mortality, and their primary prevention by diet is highly desirable. The relationship of vegetarian dietary patterns to colorectal cancer risk is not well established. OBJECTIVE: To evaluate the association between vegetarian dietary patterns and incident colorectal cancers. DESIGN, SETTING, AND PARTICIPANTS: The Adventist Health Study 2 (AHS-2) is a large, prospective, North American cohort trial including 96,354 Seventh-Day Adventist men and women recruited between January 1, 2002, and December 31, 2007. Follow-up varied by state and was indicated by the cancer registry linkage dates. Of these participants, an analytic sample of 77,659 remained after exclusions. Analysis was conducted using Cox proportional hazards regression, controlling for important demographic and lifestyle confounders. The analysis was conducted between June 1, 2014, and October 20, 2014. EXPOSURES: Diet was assessed at baseline by a validated quantitative food frequency questionnaire and categorized into 4 vegetarian dietary patterns (vegan, lacto-ovo vegetarian, pescovegetarian, and semivegetarian) and a nonvegetarian dietary pattern. MAIN OUTCOMES AND MEASURES: The relationship between dietary patterns and incident cancers of the colon and rectum; colorectal cancer cases were identified primarily by state cancer registry linkages. RESULTS: During a mean follow-up of 7.3 years, 380 cases of colon cancer and 110 cases of rectal cancer were documented. The adjusted hazard ratios (HRs) in all vegetarians combined vs nonvegetarians were 0.78 (95% CI, 0.64-0.95) for all colorectal cancers, 0.81 (95% CI, 0.65-1.00) for colon cancer, and 0.71 (95% CI, 0.47-1.06) for rectal cancer. The adjusted HR for colorectal cancer in vegans was 0.84 (95% CI, 0.59-1.19); in lacto-ovo vegetarians, 0.82 (95% CI, 0.65-1.02); in pescovegetarians, 0.57 (95% CI, 0.40-0.82); and in semivegetarians, 0.92 (95% CI, 0.62-1.37) compared with nonvegetarians. Effect estimates were similar for men and women and for black and nonblack individuals. CONCLUSIONS AND RELEVANCE: Vegetarian diets are associated with an overall lower incidence of colorectal cancers. Pescovegetarians in particular have a much lower risk compared with nonvegetarians. If such associations are causal, they may be important for primary prevention of colorectal cancers. PMCID: PMC4420687 PMID: 25751512 ------------ [2] Cancer Epidemiol Biomarkers Prev. 2013 Feb;22(2):286-94. doi: 10.1158/1055-9965.EPI-12-1060. Epub 2012 Nov 20. Vegetarian diets and the incidence of cancer in a low-risk population. Tantamango-Bartley Y(1), Jaceldo-Siegl K, Fan J, Fraser G. Author information: (1)Department of Epidemiology and Biostatistics, Loma Linda University, School of Public Health, Loma Linda, CA 92350, USA. ytantamango@hotmail.com BACKGROUND: Cancer is the second leading cause of death in the United States. Dietary factors account for at least 30% of all cancers in Western countries. As people do not consume individual foods but rather combinations of them, the assessment of dietary patterns may offer valuable information when determining associations between diet and cancer risk. METHODS: We examined the association between dietary patterns (non-vegetarians, lacto, pesco, vegan, and semi-vegetarian) and the overall cancer incidence among 69,120 participants of the Adventist Health Study-2. Cancer cases were identified by matching to cancer registries. Cox proportional hazard regression analysis was conducted to estimate hazard ratios, with "attained age" as the time variable. RESULTS: A total of 2,939 incident cancer cases were identified. The multivariate HR of overall cancer risk among vegetarians compared with non-vegetarians was statistically significant [hr, 0.92; 95% confidence interval (CI), 0.85-0.99] for both genders combined. Also, a statistically significant association was found between vegetarian diet and cancers of the gastrointestinal tract (HR, 0.76; 95% CI, 0.63-0.90). When analyzing the association of specific vegetarian dietary patterns, vegan diets showed statistically significant protection for overall cancer incidence (HR, 0.84; 95% CI, 0.72-0.99) in both genders combined and for female-specific cancers (HR, 0.66; 95% CI, 0.47-0.92). Lacto-ovo-vegetarians appeared to be associated with decreased risk of cancers of the gastrointestinal system (HR, 0.75; 95% CI, 0.60-0.92). CONCLUSION: Vegetarian diets seem to confer protection against cancer. IMPACT: Vegan diet seems to confer lower risk for overall and female-specific cancer than other dietary patterns. The lacto-ovo-vegetarian diets seem to confer protection from cancers of the gastrointestinal tract. PMCID: PMC3565018 PMID: 23169929
  23. It appears from this article that the World Health Organization is on the verge of declaring bacon, sausage and processed meat carcinogens, and red meat generally as a probably carcinogen, perhaps as early as tomorrow. To quote from the article: In doing so, the WHO would likely be classifying these processed food items in the same category as cigarettes and asbestos. Given the meat industry lobbying power in the US, this will likely be a pretty big deal, and cause quite a bit of controversy. It will be interesting to see how it plays out. Perhaps they'll sue the WHO for defamation like they did Oprah. --Dean
  24. [Here is another one for the future "Non-CR Health & Longevity" Forum...] This is pretty preliminary, but looks extremely promising for the treatment of many types of cancer. Here is a popular press article on the breakthrough, and the press release from the University of Copenhagen where the research has been done. Here is original published study [1] these stories are in reference to, but please don't try to understand the abstract unless you are a cancer researcher! Here are some highlights of the research, in plain English from the pop press articles: In the hunt for a vaccine against malaria in pregnant women, scientists have discovered that certain malaria proteins can be used to attack the majority of tumour types [at least in mice - DP]. The carbohydrate that the malaria parasite attaches itself to in the placenta in pregnant women is identical to a carbohydrate found in cancer cells. In the laboratory, scientists have created the protein that the malaria parasite uses to adhere to the placenta and added a toxin. The malaria protein and toxin combination seeks out the cancer cells [and not other, healthy cells - DP] and is absorbed. The toxin is released inside the cancer cells and then kills them. The University of Copenhagen collaborated with researchers from the University of British Columbia to test thousands of samples from brain tumours to leukemias [also including prostate, non-Hodgkins lymphoma, and bone cancer - DP]. They believe the malaria protein is able to attack more than 90% of all types of tumours. So far, trials have only been conducted on mice. Researchers aim to begin human trials within four years. Looks pretty promising! --Dean -------------- [1] Cancer Cell. 2015 Oct 12;28(4):500-14. doi: 10.1016/j.ccell.2015.09.003. Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein. Salanti A(1), Clausen TM(2), Agerbæk MØ(3), Al Nakouzi N(4), Dahlbäck M(5), Oo HZ(4), Lee S(6), Gustavsson T(5), Rich JR(7), Hedberg BJ(7), Mao Y(8), Barington L(5), Pereira MA(5), LoBello J(9), Endo M(10), Fazli L(6), Soden J(11), Wang CK(6), Sander AF(5), Dagil R(5), Thrane S(5), Holst PJ(5), Meng L(8), Favero F(12), Weiss GJ(13), Nielsen MA(5), Freeth J(11), Nielsen TO(14), Zaia J(8), Tran NL(9), Trent J(9), Babcook JS(7), Theander TG(5), Sorensen PH(15), Daugaard M(16). Plasmodium falciparum engineer infected erythrocytes to present the malarial protein, VAR2CSA, which binds a distinct type chondroitin sulfate (CS) exclusively expressed in the placenta. Here, we show that the same CS modification is present on a high proportion of malignant cells and that it can be specifically targeted by recombinant VAR2CSA (rVAR2). In tumors, placental-like CS chains are linked to a limited repertoire of cancer-associated proteoglycans including CD44 and CSPG4. The rVAR2 protein localizes to tumors in vivo and rVAR2 fused to diphtheria toxin or conjugated to hemiasterlin compounds strongly inhibits in vivo tumor cell growth and metastasis. Our data demonstrate how an evolutionarily refined parasite-derived protein can be exploited to target a common, but complex, malignancy-associated glycosaminoglycan modification. PMID: 26461094
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