Calorie-restriction, Protein-restriction and free-IGF-1 / SHBG

Studies pertaining to Calorie-restriction (CR), Protein-restriction (PR) and free-IGF-1 and SHBG.

1)

Br J Cancer. 2000 Jul;83(1):95-7.
Hormones and diet: low insulin-like growth factor-I but normal bioavailable androgens in vegan men.

Allen NE, Appleby PN, Davey GK, Key TJ.
Cancer Epidemiology Unit, Imperial Cancer Research Fund, Radcliffe Infirmary, Oxford, UK.

Abstract

Mean serum insulin-like growth factor-I was 9% lower in 233 vegan men than in 226 meat-eaters and 237 vegetarians (P = 0.002).

Vegans had higher testosterone levels than vegetarians and meat-eaters, but this was offset by higher sex hormone binding globulin, and there were no differences between diet groups in free testosterone, androstanediol glucuronide or luteinizing hormone.

PMID: 10883675 [PubMed - indexed for MEDLINE]PMCID: PMC2374537

http://www.ncbi.nlm.nih.gov/pubmed/10883675

Full text PDF: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2374537/pdf/83-6691152a.pdf
PDF file: Hormones and diet-83-6691152a.pdf

2)

Aging Cell. 2008 Oct;7(5):681-7.
Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans.

Fontana L, Weiss EP, Villareal DT, Klein S, Holloszy JO.

Division of Geriatrics & Nutritional Sciences, Washington University School of Medicine, St Louis, MO 63110, USA. lfontana@dom.wustl.edu

Abstract

Reduced function mutations in the insulin/IGF-I signaling pathway increase maximal lifespan and health span in many species. Calorie restriction (CR) decreases serum IGF-1 concentration by ~40%, protects against cancer and slows aging in rodents. However, the long-term effects of CR with adequate nutrition on circulating IGF-1 levels in humans are unknown. Here we report data from two long-term CR studies (1 and 6 years) showing that severe CR without malnutrition did not change IGF-1 and IGF-1 : IGFBP-3 ratio levels in humans. In contrast, total and free IGF-1 concentrations were significantly lower in moderately protein-restricted individuals. Reducing protein intake from an average of 1.67 g kg(-1) of body weight per day to 0.95 g kg(-1) of body weight per day for 3 weeks in six volunteers practicing CR resulted in a reduction in serum IGF-1 from 194 ng mL(-1) to 152 ng mL(-1). These findings demonstrate that, unlike in rodents, long-term severe CR does not reduce serum IGF-1 concentration and IGF-1 : IGFBP-3 ratio in humans. In addition, our data provide evidence that protein intake is a key determinant of circulating IGF-1 levels in humans, and suggest that reduced protein intake may become an important component of anticancer and anti-aging dietary interventions.

PMID: 18843793 [PubMed - indexed for MEDLINE]PMCID: PMC2673798

http://www.ncbi.nlm.nih.gov/pubmed/18843793

Full article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673798/?tool=pubmed

Summary:

Reduced function mutations in the insulin/IGF-I signaling pathway increase maximal lifespan and health span in many species. Calorie restriction (CR) decreases serum IGF-1 concentration by ~40%, protects against cancer and slows aging in rodents. However, the long-term effects of CR with adequate nutrition on circulating IGF-1 levels in humans are unknown. Here we report data from two long-term CR studies (1 and 6 years) showing that severe CR without malnutrition did not change IGF-1 and IGF-1 : IGFBP-3 ratio levels in humans. In contrast, total and free IGF-1 concentrations were significantly lower in moderately protein-restricted individuals. Reducing protein intake from an average of 1.67 g kg -1 of body weight per day to 0.95 g kg -1  of body weight per day for 3 weeks in six volunteers practicing CR resulted in a reduction in serum IGF-1 from 194 ng mL -1 to 152 ng mL -1 . These findings demonstrate that, unlike in rodents, long-term severe CR does not reduce serum IGF-1 concentration and IGF-1 : IGFBP-3 ratio in humans. In addition, our data provide evidence that protein intake is a key determinant of circulating IGF-1 levels in humans, and suggest that reduced protein intake may become an important component of anticancer and anti-aging dietary interventions.

Results and discussion

Fasting and short-term (6 days) CR or protein restriction acutely lower serum IGF-1 concentration in humans (Thissen et al., 1994; Smith et al., 1995). However, it is not known whether long-term CR without malnutrition reduces serum IGF-1 concentration or slows aging in humans. To determine whether the duration of CR or the metabolic and body composition changes associated with CR affect serum IGF-1 concentration in humans, we measured serum IGF-1 and IGFBP-3 in two studies that manipulated energy flux for different periods of time. In one study, 46 middle-aged non-obese individuals [29 women and 17 men, age 57 ± 3 years, body mass index (BMI) 27.3 ± 2.0 kg m −2] (Table 1) were randomized to 1 year of a 20% decrease in energy intake from baseline without a change in energy expenditure (CR, n = 18), a 20% increase in energy expenditure through daily exercise without a change in energy intake (EX, n = 18); or a healthy lifestyle control group (HL, n = 10) (Racette et al., 2006). Energy intake was reduced by 304 ± 408 kcal day − 1 ( p = 0.006) in the CR group, while in the EX and HL groups average daily energy intake was unchanged (Racette et al., 2006). Protein intake remained the same (~16% of total energy intake) in all groups throughout the study (Table 2). At 1 year of treatment, weight loss averaged 8.2 ± 4.8 kg in the CR group, 6.6 ± 5.5 kg in the EX group, and 1.2 ± 2.1 kg in the HL group. Body fat decreased by 6.3 ± 3.8 kg in CR, 5.6 ± 4.4 kg in EX and 0.4 ± 1.7 kg in HL, which corresponded to reductions of 24.9%, 22.3% and 1.2% of baseline body fat mass, respectively (Racette et al., 2006). Surprisingly, we found that, unlike in rodents, the decrease in energy intake in the CR group was not accompanied by a reduction in serum IGF-1 concentration or IGF-1/IGFBP-3 ratio (Fig. 1). Weight-loss induced by exercise training was also not coupled with a decrease in serum IGF-1 and IGFBP-3 levels (Fig. 1). In contrast, as previously reported, and in agreement with the metabolic adaptations that occur in CR mice, 1 year of CR in these volunteers resulted in a significant improvement in insulin sensitivity, and in significant reductions in serum leptin (a circulating hormone that reflects the amount of energy stored in fat tissue), C-reactive protein (a marker of systemic inflammation), insulin and triiodothyronine levels (Racette et al., 2006; Weiss et al., 2006, 2008; Fontana et al., 2007b; Villareal et al., 2007).

In the second study, we evaluated the possibility that longer periods of CR are necessary to reduce serum IGF-1 concentration in humans. Serum IGF-1 and IGFBP-3 concentrations, and IGF-1/IGFBP-3 ratio were assessed in a group of 28 weight-stable members of the Calorie Restriction Society (age 51.6 ± 12.7 year; BMI 19.7 ± 1.8 kg m −2), who had been practicing severe CR with adequate nutrition (at least 100% of the reference daily intake for each nutrient) for an average of 6 years, and in 28 age-matched controls (age 53.6 ± 8.5 year; BMI 25.6 ± 2.5 kg m−2, p = 0.0001 vs. CR) eating a typical Western diet. The Calorie Restriction Society members ate a balanced diet providing approximately 1800 kcal day−1 with 24% calories from protein and 28% calories from fat. The Western diet group ate a typical Western diet containing foods which provided approximately 2500 kcal day−1 with 16% calories from protein and 33.6% calories from fat (Table 3). Energy intake was significantly lower and protein intake was significantly higher in the CR group than in the Western diet group (Table 3). BMI and total body fat were significantly lower in the CR group than in the Western diet in both men and women (Table 4). As in our 1-year CR study, we found that there were no differences in serum IGF-1 and IGFBP-3 concentrations, and IGF-1 : IGFBP-3 ratio between the CR and Western diet groups (Fig. 2). In contrast, as reported previously in a smaller group (Fontana et al., 2004, 2006b; Meyer et al., 2006), fasting insulin, C-reactive protein and triiodothyronine concentration were significantly lower in the CR group than in the Western diet comparison group (Fig. 2). The findings from these two studies demonstrate that 1 year and 6 years of CR do not reduce total and free IGF-1 levels in humans.

These data provide evidence that, in contrast to the decrease in IGF-1 in rodents, a reduction of IGF-1 expression is not a component of the adaptive response to long-term CR in humans. On the other hand, fasting for 10 days markedly reduces serum IGF-1 concentration into the range observed for growth hormone-deficient patients (Thissen et al., 1994). Moreover, the changes of serum IGF-1 during fasting and refeeding are closely correlated with the rate of excretion of urinary urea, a marker of nitrogen balance and protein intake (Clemmons et al., 1981). Therefore, we conducted additional studies to evaluate the importance of long-term protein intake in modulating serum IGF-1 concentration in humans. In one study, we evaluated serum IGF-1 and IGFBP-3 concentrations, and IGF-1 : IGFBP-3 ratio in 28 vegans who had been consuming a moderately protein-restricted (PR) diet (0.76 g kg−1 per day; ~10% of intake from protein) for ~5 years age-matched with 28 members of the Calorie Restriction Society who consume a high-protein diet (1.73 g kg−1 per day; ~24% of energy intake from protein) (Table 3). Protein intake was significantly lower in the moderately PR group than in the CR group, while energy intake tended to be higher (Table 3). Both serum IGF-1 concentration and IGF-1 : IGFBP-3 ratio were significantly lower in the moderately PR diet group than in the severe CR diet group, whereas fasting insulin and C-reactive protein were similarly low in the moderately low-protein vegan and CR groups (Fig. 2), as previously reported in a smaller group of raw food vegans (Fontana et al., 2006a, 2007a). This effect of a moderate protein restriction is independent of body weight and body fat content, as serum total and free IGF-1 concentrations were lower in the moderately PR group than in the severe CR high-protein diet group, despite the PR groups’ higher body weight, BMI and body fat content (Table 4).

It also seemed possible that the CR groups’ rather high protein intake (~24% of the calories from protein; 1.73 g kg−1 per day of protein) may have prevented a reduction in IGF-1 level. As a first step in evaluating this possibility we were able to arrange for six of the CR volunteers to reduce their protein intake from 1.67 ± 0.1 g kg−1 of body weight per day to a protein intake of 0.95 ± 0.1 g kg−1 of body weight per day for 3 weeks. This short-term isocaloric reduction of protein intake resulted in a 25% reduction in serum IGF-1 concentration (from 194 ± 34 ng mL−1 to 152 ± 41 ng mL−1; p = 0.01) in the six CR individuals, suggesting that the high protein intake was preventing a reduction in IGF-1 levels in response to CR.
In conclusion, our findings demonstrate that, unlike in rodents, long-term severe CR does not reduce total and free IGF-1 levels in healthy humans if protein intake is high. In addition, our data suggest that chronic protein intake is more powerful than calorie intake in modulating circulating IGF-1 concentration in humans. This is important because the median protein requirement of the healthy adult population is 0.65 g kg−1 per day and the reference daily intake (97.5th percentile) is 0.83 g kg−1 of body weight per day (Rand et al., 2003) that is close to the protein intake of our vegan group in this study. In contrast, half of the US males are eating 40% or more protein (≥ 1.34 g kg−1 per day) than the reference daily intake (Moshfegh et al., 2005), which is presently considered to be harmless and, according to public opinion and advocators of ‘low-carb’ diets, may even be beneficial. More studies are necessary to understand the biological and clinical implications of a chronic high protein intake, especially in sedentary people with a positive family history for cancer. In addition, more studies are needed to understand the effects of PR and methionine restriction on metabolism, disease prevention and longevity in humans, because several studies in rodents have shown major beneficial effects (Richie et al., 1994; Miller et al., 2005; Pamplona & Barja, 2006; Sanz et al., 2006). Finally, these findings underscore the importance of dietary macronutrient intake in regulating metabolic events, and suggest that reduced protein intake may become an important component of anti-aging and anticancer dietary interventions, due to the importance of IGF-1 in the biology of aging (Sonntag et al., 1999; Flurkey et al., 2001; Holzenberger et al., 2003; Ikeno et al., 2003; Kenyon, 2005; Kurosu et al., 2005; Bonkowski et al., 2006; Russell & Kahn, 2007) and in the pathogenesis of many human tumors (Samani et al., 2007; Sachdev & Yee, 2007).

3)

J Clin Endocrinol Metab. 2000 Jan;85(1):293-6.

Diet and sex hormone-binding globulin.

Longcope C, Feldman HA, McKinlay JB, Araujo AB.

University of Massachusetts Medical School, Worcester 01655, USA.

Abstract

The serum concentration of sex hormone-binding globulin (SHBG) is inversely related to weight and in animal studies is inversely related to protein intake. As SHBG can affect the biological activity of testosterone and estradiol, we wished to determine the role of protein intake on SHBG levels in men. Using data from the Massachusetts Male Aging Study we examined cross-sectional relationships between dietary components and SHBG levels in 1552 men (aged 40-70 yr) for whom these factors were known. Analyzed by multiple regression, controlling for testosterone and estradiol levels, age (P<0.001) and fiber intake (P = 0.02) were positively correlated to SHBG concentration, whereas body mass index (P<0.001) and protein intake (P<0.03) were negatively correlated to SHBG concentration. The intakes of calories, fat (animal or vegetable), and carbohydrate were not related to SHBG concentration.

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We conclude that age and body mass index are major determinants of SHBG concentrations in older men, and fiber and protein intake are also significant contributors to SHBG levels, but total caloric intake and the intake of carbohydrate or fat are not significant. Thus, diets low in protein in elderly men may lead to elevated SHBG levels and decreased testosterone bioactivity. The decrease in bioavailable testosterone can then result in declines in sexual function and muscle and red cell mass, and contribute to the loss of bone density.

PMID: 10634401 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/10634401

Full article: http://jcem.endojournals.org/cgi/content/full/85/1/293

Discussion:

The MMAS comprises a random sampling of men aged 40–70 yr in the Boston, MA, area. It is thus a good representation of that particular area and is representative of men between the ages of 40–70 yr. The data used in this study allowed us to address a number of shortcomings of previous studies, suggesting a link between dietary composition and SHBG. First, it is important to account for other factors that are associated with diet and SHBG, such as age, anthropometrics, and testosterone levels. Many earlier studies of the relation of dietary components to SHBG levels did not consider these factors. By using the broad spectrum of data in the MMAS, we were able to control for demographic, anthropometric, and hormonal factors, all of which could confound any association between diet and SHBG. Second, with the large, randomly selected sample of men who participated in the MMAS, the findings presented can be extrapolated to a broader population than those in other studies based on samples of convenience. Furthermore, the size of the MMAS database allowed us to conduct subgroup analyses that have not been possible in several other small scale studies.

The concentration of SHBG was significantly correlated with age and anthropometrics. These results confirm the findings of others (30, 31). However, we found that weight, which is often used as a predictor of SHBG concentration (10), was not an independent predictor of SHBG when controlled for BMI and WHR. Future investigations should consider measuring BMI and WHR rather than (or in addition to) weight.

The dietary components that correlated best with SHBG levels were protein and fiber. Protein intake, which is marginally significant when tested by simple correlation, is more strongly significant when tested using multiple regression. Thus, the lower the protein intake, the higher the concentration of SHBG. This mirrors our findings in rabbits (20) and indicates that protein intake can be an important control of SHBG level.

The mechanism by which protein intake can be a controlling factor on SHBG concentration is uncertain. One of the major controlling factors on SHBG synthesis is insulin. This intake of protein has been shown to increase insulin levels (32), and insulin has been shown to reduce SHBG levels (33, 34). The effect of protein on SHBG could be mediated in part by its effect on insulin, with a low protein intake leading to low insulin levels and release of the inhibition of SHBG synthesis. If this were to be the mechanism by which protein effects SHBG levels, one would expect that carbohydrate (CHO) intake, a stimulus for insulin release, would also effect SHBG levels. However, we could find no significant relationship between CHO intake and SHBG levels when tested by simple correlation or controlling for other factors. Therefore, it is likely that the relationship of protein intake to SHBG levels involves more than a possible effect on insulin, but it is unclear from our data what that may be. It should be noted that low protein intake was directly correlated with CHO, fat, and caloric intake, so that the lower intake of protein was not being replaced by increased CHO or fat.

It has been suggested that fat intake may be related to SHBG levels (35, 36). In this sample the simple correlation between animal fat and SHBG is significant. However, when controlled for potential confounders such as age, hormones, and anthropometrics, the association no longer remains.

There is conflicting evidence on the importance of fiber intake to SHBG levels. Our finding that fiber intake is correlated positively to SHBG levels, even after controlling for age, testosterone and estradiol, BMI, WHR, and protein intake is at variance with an earlier report indicating a negative correlation between fiber and SHBG. However, other research indicates that increasing fiber intake is associated with higher SHBG. Why our present results are at variance with those of Dorgan et al. (37) is not clear, but in that study the caloric intake was almost twice that in the present study, and the study design and analysis were different from those of the present study and those of the study by Adlercreutz et al. (38).

The results of this study have implications for research and clinical practice. In future research of diet and SHBG, the examination of relations between diet and SHBG levels should control for the potential confounding effects of numerous factors, such as age, hormone profiles, and anthropometrics. With regard to practice, in our previous work (39) an increase in SHBG and a related decrease in testosterone have been noted to occur in men as they age. With regard to practice, the inverse relationship between protein and SHBG suggests that in elderly men a high protein diet could increase bioavailable testosterone and mitigate the effects of the age-related decrease in that hormone. Intervention studies will be necessary to verify this.

4)

Obstet Gynecol. 2000 Feb;95(2):245-50.
Diet and sex-hormone binding globulin, dysmenorrhea, and premenstrual symptoms.

Barnard ND, Scialli AR, Hurlock D, Bertron P.
Department of Obstetrics and Gynecology, Georgetown University School of Medicine, Washington, DC, USA. nbarnard@pcrm.org

Abstract

OBJECTIVE: To test the hypothesis that a low-fat, vegetarian diet reduces dysmenorrhea and premenstrual symptoms by its effect on serum sex-hormone binding globulin concentration and estrogen activity.

METHODS: In a crossover design, 33 women followed a low-fat, vegetarian diet for two menstrual cycles. For two additional cycles, they followed their customary diet while taking a supplement placebo pill. Dietary intake, serum sex-hormone binding globulin concentration, body weight, pain duration and intensity, and premenstrual symptoms were assessed during each study phase.

RESULTS: Mean (+/- standard deviation [SD]) serum sex-hormone binding globulin concentration was higher during the diet phase (46.7 +/- 23.6 nmol/L) than during the supplement phase (39.3 +/- 19.8 nmol/L, P < .001). Mean (+/- SD) body weight was lower during the diet (66.1 +/- 11.3 kg) compared with the supplement phase (67.9 +/- 12.1 kg, P < .001). Mean dysmenorrhea duration fell significantly from baseline (3.9 +/- 1.7 days) to diet phase (2.7 +/- 1.9 days) compared with change from baseline to supplement phase (3.6 +/- 1.7 days, P < .01). Pain intensity fell significantly during the diet phase, compared with baseline, for the worst, second-worst, and third-worst days, and mean durations of premenstrual concentration, behavioral change, and water retention symptoms were reduced significantly, compared with the supplement phase.

CONCLUSION: A low-fat vegetarian diet was associated with increased serum sex-hormone binding globulin concentration and reductions in body weight, dysmenorrhea duration and intensity, and premenstrual symptom duration. The symptom effects might be mediated by dietary influences on estrogen activity.

PMID: 10674588 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/10674588

Source: http://www.ncbi.nlm.nih.gov/pubmed/10674588

5)

Calorie-restriction, Protein-restriction and free-IGF-1

Aging Cell. 2008 Oct;7(5):681-7.
Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans.

Fontana L, Weiss EP, Villareal DT, Klein S, Holloszy JO.

Division of Geriatrics & Nutritional Sciences, Washington University School of Medicine, St Louis, MO 63110, USA. lfontana@dom.wustl.edu

Abstract

Reduced function mutations in the insulin/IGF-I signaling pathway increase maximal lifespan and health span in many species. Calorie restriction (CR) decreases serum IGF-1 concentration by ~40%, protects against cancer and slows aging in rodents. However, the long-term effects of CR with adequate nutrition on circulating IGF-1 levels in humans are unknown.

Here we report data from two long-term CR studies (1 and 6 years) showing that severe CR without malnutrition did not change IGF-1 and IGF-1 : IGFBP-3 ratio levels in humans. In contrast, total and free IGF-1 concentrations were significantly lower in moderately protein-restricted individuals. Reducing protein intake from an average of 1.67 g kg(-1) of body weight per day to 0.95 g kg(-1) of body weight per day for 3 weeks in six volunteers practicing CR resulted in a reduction in serum IGF-1 from 194 ng mL(-1) to 152 ng mL(-1).

These findings demonstrate that, unlike in rodents, long-term severe CR does not reduce serum IGF-1 concentration and IGF-1 : IGFBP-3 ratio in humans. In addition, our data provide evidence that protein intake is a key determinant of circulating IGF-1 levels in humans, and suggest that reduced protein intake may become an important component of anticancer and anti-aging dietary interventions.

Source: http://www.ncbi.nlm.nih.gov/pubmed/18843793
Full: http://onlinelibrary.wiley.com/doi/10.1111/j.1474-9726.2008.00417.x/full






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