tcarter2 at elp.rr.com
Tue Jun 18 09:28:36 EST 2002
Not much action here, used to be a pretty good group. This is from a Google thread which can be seen at
As Steve points out there has been a plenitude of studies which taken in whole indicate that every other day feeding or fasting on weekends do not extend life in rodents. Nor is every other day calorie restricted feeding significantly better than limited daily feeding. But the fasts may have been too short. Below I post a fairly recent abstract indicating the efficacy of a four day fast. Unfortunately this study shares a common fault with many others in that it compares the intervention group with an ad lib (pig-out) control group rather than a group on a more normal diet. I have put the lead author on my author watch list in hopes that he will follow up this study with on that restricts calories in both groups. If the results turn out to be synergistic I will definitely consider the regimen. I have fasted five days several times and once for seven days. In every case after the second day I had no hunger at all, this is a commonly reported phenominum.
A word of caution on growth hormone, whose effects are largely mediated by IGF-1. This substance is now regarded by most as pro-aging. A dearth of it and it's mediator, IGF-1 prolongs life and an excess of it shortens life in rodents and is related to a shorter life in humans (bigger humans have shorter lives). Its effects seem to mediated in part by decreased insulin sensitivity. Insulin is bit by bit coming to be regarded as a "death" hormone along with cortisol. I also include three abstracts supporting this fact, which the second one calls "well known". A reason for some past confusion on this insulin link could be that insulin sensitivity seems to be increased by GH in GH deficient humans. I include an abstract to this effect and three others on GH and longevity which I happen to have.
Mech Ageing Dev 2000 May 18;115(1-2):61-71 Influence of short-term repeated fasting on the longevity of female (NZB x NZW)F1 mice. Sogawa H, Kubo C. Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582, Fukuoka, Japan. sogawa at cephal.med.kyushu-u.ac.jp Caloric restriction in rodents is well known to retard the rate of aging, increasing mean and maximum life-spans, and inhibit the occurence of many age-associated diseases. However little is known about the influence of short term repeated fasting on longevity. In this study, female (NZB x NZW)F1 mice were used to test the physiological effect of short-term repeated fasting (4 consecutive days, every two weeks). The results showed that fasting mice survived significantly longer than the full-fed mice, in spite of the fasting group having a heavier body weight than the control group. Mean survival times for fasting control mice were 64.0+/-15.3 and 47.9+/-9.4 weeks, respectively. Short-term repeated fasting manipulation was also effective on the prolongation of lifespan in autoimmune-prone mice. PMID: 10854629
Wien Med Wochenschr 2001;151(18-20):426-9 [Growth hormone in the elderly man] [Article in German] Riedl M, Kotzmann H, Luger A. Klinische Abteilung fur Endokrinologie und Stoffwechsel, Universitatsklinik fur Innere Medizin III, Wahringer Gurtel 18-20, A-1090 Wien. Many symptoms being part of the growth hormone deficiency syndrome in adults like decrease in muscle mass and bone mineral content, increase in fat mass, and skin atrophy are observed also with ageing. Indeed, short term trials with growth hormone administration to persons over 60 years old revealed that many of these symptoms could be reversed by growth hormone. However, recent reports of an association of high insulin-like growth factor-1 (IGF-1)-concentrations and increased risk of prostate, lung, colon and breast cancer as well as a possible decrease of insulin sensitivity prohibit currently the use of growth hormone in an attempt to reverse a normal ageing process. Prospective, randomised and placebo-controlled long-term trials are necessary to prove safety and efficacy of growth hormone therapy in the ageing population before it can be recommended. In addition, no data are available as to the right growth hormone dose and the correct monitoring. Expectations of the society and the search for the fountain of youth should not motivate physicians to leave the firm ground of evidence based medicine and prescribe experimental therapies to healthy older persons. PMID: 11817251
Diabetes 2001 Aug;50(8):1891-900 Growth hormone induces cellular insulin resistance by uncoupling phosphatidylinositol 3-kinase and its downstream signals in 3T3-L1 adipocytes. Takano A, Haruta T, Iwata M, Usui I, Uno T, Kawahara J, Ueno E, Sasaoka T, Kobayashi M. First Department of Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan. Growth hormone (GH) is well known to induce in vivo insulin resistance. However, the molecular mechanism of GH-induced cellular insulin resistance is largely unknown. In this study, we demonstrated that chronic GH treatment of differentiated 3T3-L1 adipocytes reduces insulin-stimulated 2-deoxyglucose (DOG) uptake and activation of Akt (also known as protein kinase B), both of which are downstream effects of phosphatidylinositol (PI) 3-kinase, despite enhanced tyrosine phosphorylation of insulin receptor substrate (IRS)-1, association of IRS-1 with the p85 subunit of PI 3-kinase, and IRS-1-associated PI 3-kinase activity. In contrast, chronic GH treatment did not affect 2-DOG uptake and Akt activation induced by overexpression of a membrane-targeted form of the p110 subunit of PI 3-kinase (p110(CAAX)) or Akt activation stimulated by platelet-derived growth factor. Fractionation studies indicated that chronic GH treatment reduces insulin-stimulated translocation of Akt from the cytosol to the plasma membrane. Interestingly, chronic GH treatment increased insulin-stimulated association of IRS-1 with p85 and IRS-1-associated PI 3-kinase activity preferentially in the cytosol. These results indicate that cellular insulin resistance induced by chronic GH treatment in 3T3-L1 adipocytes is caused by uncoupling between activation of PI 3-kinase and its downstream signals, which is specific to the insulin-stimulated PI 3-kinase pathway. This effect of GH might result from the altered subcellular distribution of IRS-1-associated PI 3-kinase. PMID: 11473053
Am J Obstet Gynecol 2002 Mar;186(3):512-7 Human placental growth hormone causes severe insulin resistance in transgenic mice. Barbour LA, Shao J, Qiao L, Pulawa LK, Jensen DR, Bartke A, Garrity M, Draznin B, Friedman JE. Department of Medicine, University of Colorado Health Sciences Center, Denver, USA. OBJECTIVE: The insulin resistance of pregnancy is considered to be mediated by human placental lactogen, but the metabolic effects of human placental growth hormone have not been well defined. Our aim was to evaluate the effect of placental growth hormone on insulin sensitivity in vivo using transgenic mice that overexpress the human placental growth hormone gene. STUDY DESIGN: Glucose and insulin tolerance tests were performed on 5 transgenic mice that overexpressed the human placental growth hormone variant gene and 6 normal littermate controls. The body composition of the mice was assessed by dual-energy radiograph absorptiometry, and free fatty acid levels were measured as a marker of lipolysis. RESULTS: The human placental growth hormone levels in the transgenic mice were comparable to those attained in the third trimester of pregnancy. These mice were nearly twice as heavy as the control mice, and their body composition differed by a significant increase in bone density and a small decrease in percentage of body fat. Fasting insulin levels in the transgenic mice that overexpressed placental growth hormone were approximately 4-fold higher than the control mice (1.57 +/- 0.22 ng/mL vs 0.38 +/- 0.07 ng/mL; P <.001) and 7 times higher 30 minutes after glucose stimulation (4.17 +/- 0.54 ng/mL vs 0.62 +/- 0.10 ng/mL; P <.0001) with no significant difference in either fasting or postchallenge glucose levels. Insulin sensitivity was markedly decreased in the transgenic mice, as demonstrated by an insignificant decline in glucose levels after insulin injection compared with the control mice, which demonstrated more than a 65% reduction in glucose levels (P <.001). CONCLUSION: Human placental growth hormone causes insulin resistance as manifested by fasting and postprandial hyperinsulinemia and minimal glucose lowering in response to insulin injection. Human placental growth hormone is a highly likely candidate to mediate the insulin resistance of pregnancy. PMID: 11904616
J Clin Endocrinol Metab 2002 May;87(5):2121-7 Effects of seven years of GH-replacement therapy on insulin sensitivity in GH-deficient adults. Svensson J, Fowelin J, Landin K, Bengtsson BA, Johansson JO. Research Centre for Endocrinology and Metabolism, Sahlgrenska University Hospital, SE-413 45 Goteborg, Sweden. johan.svensson at medic.gu.se The few trials in GH-deficient (GHD) adults that have investigated the long-term effects of GH-replacement therapy on insulin sensitivity have shown conflicting results. In this study, insulin sensitivity was determined using the hyperinsulinemic, euglycemic clamp technique in 11 GHD adults at baseline and after 6 months, 1 yr, 2 yr, and 7 yr of GH-replacement therapy. Furthermore, insulin sensitivity in the GHD patients was compared with that in 11 matched control subjects at baseline and with that in 11 other matched controls at study end. The mean initial GH dose was 1.10 mg/d. The dose was gradually lowered; and after 7 yr, the mean dose was 0.61 mg/d. A sustained reduction in body fat and a sustained increase in fat-free mass were observed. Serum high-density lipoprotein-cholesterol (HDL-C) increased, and serum low-density lipoprotein-cholesterol (LDL-C) decreased, after 7 yr of treatment. Fasting blood glucose was transiently increased during the first year of GH replacement. The glucose infusion rate/body weight (GIR/BW), as measured using the hyperinsulinemic, euglycemic clamp technique, was unaltered during GH-replacement therapy. The comparisons with the control subjects revealed that GIR/BW in the GHD patients was 45% of that in the control subjects at baseline; whereas, at study end, the GIR/BW was 71% of that in the control subjects (P = 0.06 vs. baseline). This could suggest that GH-replacement therapy may prevent the age-related decline in insulin sensitivity in GHD patients. PMID: 11994351
J Gerontol A Biol Sci Med Sci 2001 Aug;56(8):B340-9
Mutant mice with a combined deficiency of growth hormone (GH), prolactin, and thyrotropin, and knockout mice with GH resistance, live longer than their normal siblings. The extension of life span in these animals is very large (up to 65%), reproducible, and not limited to any particular genetic background or husbandry conditions. In addition to demonstrating that genes control aging in mammals, these findings suggest that GH actions, growth, and body size may have important roles in the determination of life span. We describe the key phenotypic characteristics of long-living mutant and knockout mice, with an emphasis on those characteristics that may be related to delayed aging in these animals. We also address the broader topic of the relationship between GH, growth, maturation, body size, and aging, and we attempt to reconcile the well-publicized antiaging action of GH with the evidence that suppression of GH release or action can prolong life.
Cell loss in glands (Bartke's session). The 30% extension of maximum lifespan by loss of genes involved in growth hormone production is well known to the participants; it is a sterling example of a spectacular breakthrough that was given virtually no airtime in the science media. A recent advance of comparable significance was the nearly complete reversal of thymic involution by IGF-7. Sample literature reference: Aspinall et al, Biochem Soc Trans 28:250-254.
Mech Ageing Dev 2002 May;123(9):1229-44 Implications for the insulin signaling pathway in Snell dwarf mouse longevity: a similarity with the C. elegans longevity paradigm. Hsieh CC, DeFord JH, Flurkey K, Harrison DE, Papaconstantinou J. Department of Human Biological Chemistry and Genetics, The University of Texas Medical Branch, 613 Basic Science Building, Rt. 0643, 7755-0643, Galveston, TX, USA Mutation analyses in the nematode, Caenorhabditis elegans, and mice have identified genes that increase their life-span via hormonal signal transduction, i.e. the insulin/insulin-like growth factor-1 (IGF-1) pathway in nematodes, and the growth hormone (GH)-thyriod stimulating hormone (TSH)-prolactin system in Snell dwarf mouse mutants. We have shown that the GH deficiency due to Pit1 mutation in the long-lived Snell dwarf mice may decrease circulating insulin levels, thereby resulting in a decreased activity of the insulin/IGF-1 signaling pathway. The data presented are consistent with our hypothesis that the decreased circulating insulin levels resulting from the Pit1 mutation mimics a physiological state similar to that proposed to occur in the long-lived C. elegans, daf-2 mutant. Our studies demonstrate a series of changes in components of the insulin/IGF-1-signaling pathway that suggest a reduction-of-function of this pathway in the aged dwarf. These include a decreased IRS-2 pool level, a decrease in PI3K activity and its association with IRS-2 and decreased docking of p85alpha to IRS-2. Our data also suggest a preferential docking of IRS-2-p85alpha-p110alpha in the aged dwarf liver and IRS-2-p85alpha-p110beta in the aged control. We speculate that the preference for the p110alpha-containing complex may be a specific characteristic of a downstream segment of the longevity-signaling cascade. We conclude that the Pit1 mutation may result in physiological homeostasis that favors longevity, and that the Snell dwarf mutant conforms to the nematode longevity paradigm. (Which is less IGF-1 equals longer life span) PMID: 12020945
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