RE: RE:Wachstumshormon/IGF-1 - 5

Der Zusammenhang zwischen IGF und Lebendauer ist eine U-Funktion. Zumindest bei Ratten, die fasten dürfen:

Zitat

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Transgenic rats with reduced levels of GH exhibit a transgene dose-dependent reduction in levels of IGF-1; rats with a moderate reduction in IGF-1 levels live longer, whereas those with a greater decrease in IGF-1 levels have a reduced life span (20). The latter results suggest that there is an optimal level of the GH–IGF-1 axis to maximize survival in mammals.

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Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake

A Long-lived Mouse Lacking Both Growth Hormone and Growth Hormone Receptor: A New Animal Model for Aging Studies.
https://www.ncbi.nlm.nih.gov/pubmed/27688483

Krafttraining führt NICHT über IGF-1 zu einem Muskelwachstum sondern durch eine lokale Senkung von Myostatin- einem Stoff, der das Muskelwachstum auf natürliche Weise limitiert und im Alter zunehmend exprimiert wird. Krafttraining ist daher in Folge über den IGF-1-Pfad keine Pro-Aging-Tätigkeit! Wenn überhaulpt, dann wirkt IGF-1 nur lokal im betreffenden Muskel, nicht aber via Serum im ganzen Körper.

Zitat

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Resistance training alters plasma myostatin but not IGF-1 in healthy men.

PURPOSE: We determined and compared the magnitude of changes in resting plasma myostatin and IGF-1, muscle strength, and size in response to whole body or local muscle resistance training in healthy men.

METHODS: Volunteers performed high-intensity resistance exercise of major muscle groups of the whole body (N = 11), or of the elbow flexors only (N = 6), twice per week for 10 wk. Strength was assessed by elbow flexor one-repetition maximum (1-RM) and repetitions at 80% of 1-RM, muscle cross-sectional area by MRI, and plasma IGF-1 by RIA and myostatin by Western analyses, before and after the training program.

RESULTS: In subjects of both groups, elbow flexor 1-RM and cross-sectional area increased (P = 0.05) by 30 +/- 8% (mean +/- SD) and 12 +/- 4%, respectively. Individual changes in myostatin ranged from 5.9 to -56.9%, with a mean decrease of 20 +/- 16%, whereas IGF-1 did not change from pre- to posttraining. There were no significant differences in any of the responses of the subjects between the two training programs.

CONCLUSION: Myostatin may play a role in exercise-induced increases in muscle size, its circulating levels decreasing with resistance training in healthy men. Exercise of the whole body versus the elbow flexors alone did not provide a supplementary stimulus in altering resting plasma IGF-1 or myostatin, or in increasing muscle strength or size. Thus, by default, growth factor responses local to the muscle may be more important than circulating factors in contributing to muscle hypertrophy with resistance training.

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http://europepmc.org/abstract/MED/15126711

IGFBP ist ein Bindeprotein, das zirkulierendes IGF durch Bindung unbrauchbar macht. Bei Nachkommen sehr langlebiger Menschen stellte man heraus, dass dieses um so exprimierter ist je insulinsensitiver diese Personen sind. D.h. dass dann IGF nicht mehr systemisch wirken kann. In einem anderen Paper (leider nicht gespeichert) habe ich mal gelesen dass das Muskelgewebe sich durch IGFBP nicht besonders beeindrucken lässt, so dass das IGF dann bevorzugt in diesem Gewebe wirken kann, auch im Falle von niedrigen absoluten (also der Summe aus frei und gebunden) Werten. Das würde so manchen Paradoxon und auch Streit um IGF lösen

Aber eine ganz wichtige Voraussetzung: die insulinsensitivität muss gegeben sein!


Low circulating IGF-I bioactivity is associated with human longevity: Findings in centenarians’ offspring

Zitat

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Centenarians’ offspring represent a suitable model to study age-dependent variables (e.g. IGF-I) potentially involved in the modulation of the lifespan. The aim of the present study was to investigate the role of the IGF-I in human longevity. We evaluated circulating IGF-I bioactivity measured by an innovative IGF-I Kinase Receptor Activation (KIRA) Assay, total IGF-I, IGFBP-3, total IGF-II, insulin, glucose, HOMA2-B% and HOMA2-S% in 192 centenarians’ offspring and 80 offspring-controls of which both parents died relatively young. Both groups were well-matched for age, gender and BMI with the centenarians’ offspring. IGF-I bioactivity (p<0.01), total IGF-I (p<0.01) and the IGF-I/IGFBP-3 molar ratio (p<0.001) were significantly lower in centenarians' offspring compared to offspring matched-controls. Serum insulin, glucose, HOMA2-B% and HOMA2-S% values were similar between both groups. In centenarians' offspring IGF-I bioactivity was inversely associated to insulin sensitivity. In conclusion: 1) centenarians’ offspring had relatively lower circulating IGF-I bioactivity compared to offspring matched-controls; 2) IGF-I bioactivity in centenarians’ offspring was inversely related to insulin sensitivity. These data support a role of the IGF-I/insulin system in the modulation of human aging process.

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http://www.aging-us.com/papers/v4/n9/abs/100484a.html

Growth Hormone and Aging: Updated Review
https://wjmh.org/DOIx.php?id=10.5534/wjmh.180018

Interessanter Thread!

Zitat

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Longevity is impacted by growth hormone action during early postnatal period
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Life-long lack of growth hormone (GH) action can produce remarkable extension of longevity in mice. Here we report that GH treatment limited to a few weeks during development influences the lifespan of long-lived Ames dwarf and normal littermate control mice in a genotype and sex-specific manner. Studies in a separate cohort of Ames dwarf mice show that this short period of the GH exposure during early development produces persistent phenotypic, metabolic and molecular changes that are evident in late adult life. These effects may represent mechanisms responsible for reduced longevity of dwarf mice exposed to GH treatment early in life.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515575/

Liest sich ja zunächst nicht so gut, wenn man an eine GH-Supplementierung dachte!

Zitat

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Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice
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We examine the impact of targeted disruption of growth hormone-releasing hormone (GHRH) in mice on longevity and the putative mechanisms of delayed aging. GHRH knockout mice are remarkably long-lived, exhibiting major shifts in the expression of genes related to xenobiotic detoxification, stress resistance, and insulin signaling. These mutant mice also have increased adiponectin levels and alterations in glucose homeostasis consistent with the removal of the counter-insulin effects of growth hormone. While these effects overlap with those of caloric restriction, we show that the effects of caloric restriction (CR) and the GHRH mutation are additive, with lifespan of GHRH-KO mutants further increased by CR. We conclude that GHRH-KO mice feature perturbations in a network of signaling pathways related to stress resistance, metabolic control and inflammation, and therefore provide a new model that can be used to explore links between GHRH repression, downregulation of the somatotropic axis, and extended longevity.

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https://elifesciences.org/articles/01098


Auf der anderen Seite:

Zitat

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Insulin-like growth factor 1 treatment extends longevity in a mouse model of human premature aging by restoring somatotroph axis function
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Zmpste24 (also called FACE-1) is a metalloproteinase involved in the maturation of lamin A, an essential component of the nuclear envelope. Zmpste24-deficient mice exhibit multiple defects that phenocopy human accelerated aging processes such as Hutchinson–Gilford progeria syndrome. In this work, we report that progeroid Zmpste24-/− mice present profound transcriptional alterations in genes that regulate the somatotroph axis, together with extremely high circulating levels of growth hormone (GH) and a drastic reduction in plasma insulin-like growth factor 1 (IGF-1). We also show that recombinant IGF-1 treatment restores the proper balance between IGF-1 and GH in Zmpste24-/− mice, delays the onset of many progeroid features, and significantly extends the lifespan of these progeroid animals. Our findings highlight the importance of IGF/GH balance in longevity and may be of therapeutic interest for devastating human progeroid syndromes associated with nuclear envelope abnormalities.

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https://www.pnas.org/content/107/37/16268

Könnte andeuten, wie wichtig das hormonelle Gleichgewicht ist und dass seine Störung der wahre Problemverursacher sein könnte.

Nicht direkt zum Thema passend, aber ich hoffe wir können hier auch Hormone allgemein diskutieren:

Zitat

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Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases
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Aging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity. Here we show that loss of function of sul-2, the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones, increases longevity and ameliorates protein aggregation diseases. This increased longevity requires factors involved in germline-mediated longevity (daf-16, daf-12, kri-1, tcer-1 and daf-36 genes) although sul-2 mutations do not affect fertility. Interestingly, sul-2 is only expressed in sensory neurons, suggesting a regulation of sulfated hormones state by environmental cues. Treatment with the specific STS inhibitor STX64, as well as with testosterone-derived sulfated hormones reproduces the longevity phenotype of sul-2 mutants. Remarkably, those treatments ameliorate protein aggregation diseases in C. elegans, and STX64 also Alzheimer’s disease in a mammalian model. These results open the possibility of reallocating steroid sulfatase inhibitors or derivates for the treatment of aging and aging related diseases.

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https://www.nature.com/articles/s41467-020-20269-y

Korrigiert mich wenn ich falsch liege, aber so wie ich das verstanden habe, führt die Inaktivierung dieser Sulfatase dazu, dass die Steroidhormone in ihrer sulfierten, also "inaktiven" bzw. - besser formuliert - abgeänderten Form bleiben. Was dann ja auch eher gegen eine Supplementierung androgener Hormone sprechen könnte (nicht muss). Fraglich aber auch, wie gut man die Ergebnisse dieser Fadenwurm-Studie dann auf den Menschen übertragen kann. Alles was noch weiter von uns entfernt ist als eine Maus sehe ich in Bezug auf die Übertragbarkeit von Studienergebnissen sehr kritisch. Selbst bei Mäusen haut das ja nicht immer hin.

Trotzdem ist es für mich etwas ernüchternd, diese Studien zu lesen. Vor allem, wenn man sich vor Augen führt, welche negativen Auswirkungen sinkende Hormonlevel haben können, ist die Erkenntnis, dass es auch positive zu geben scheint recht bitter. Ich würde mir eine Studie wünschen, in der man Mäusen ab dem Erwachsenenalter alle relevanten Hormone supplementiert, um diese auf dem Level einer erwachsenen Maus zu halten. Zumindest Estradiol scheint Mäuserichen ja helfen zu können. Bei weiblichen Mäusen erreichte man anscheinend positive Effekte durch das Blockieren von IGF-1.
Wer nun eine Erklärung erwartet wird enttäuscht, da ich selbst auch noch verwirrt bin. Im worst case erlaubt uns die Herunterregelung verschiedener Hormone ein längeres Leben und erhöht dafür die Wahrscheinlichkeit anderer Probleme (Trade-off).

Zitat

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Growth Hormone and Aging: New Findings
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A very interesting recent study addressed the issue of potential utility of GH for rejuvenation, that is reversal of the process of aging. In this study, ten healthy men, ranging in age from 51 to 65 years, were treated for one year with a combination of GH, metformin, and dehydroepiandrosterone [81]. The treatment was designed to promote restitution of thymic function and it did produce beneficial changes in several immunological parameters. Moreover, it reduced the biological age of the subjects as assessed by measurements of DNA methylation (the “methylation clock”). Report of these findings was followed by publication of a commentary on the likely utility of this therapeutic approach for protection from Covid-19 infection and Covid-19-induced pathology and complications [82]. These findings are not likely to end the controversy concerning GH as an anti-aging agent. The authors focus on evidence that GH can improve various facets of immune system maintenance and its responses to infection and cite important supporting evidence. However, GH was also reported to have pro-inflammatory effects by promoting cell senescence and secretion of pro-inflammatory cytokines while reducing the secretion of anti-inflammatory adiponectin [26, 27, 28, 83].

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https://wjmh.org/DOIx.php?id=10.5534/wjmh.200201

Ein spannendes Review, das auch nochmal die Trade-Offs aufzeigt (bitte selbst lesen, der kurze Ausschnitt wird dem Review nicht gerecht). Nun wäre es spannend zu wissen, ob man die negativen Effekte einer GH-Supplementierung reduzieren könnte, um somit nur die Vorteile zu erhalten?
Ich sehe das ja so: Können wir Jugend ohne jugendliche Hormonlevel zurückerlangen? Eher nicht. Was bleibt uns also außer die Hormontherapie und zu versuchen, diese so optimal und risikoarm wie möglich zu machen oder ohne extern zugeführte Hormone weitestgehend normal zu altern?

Wie immer: Es handelt sich nur um meine Gedanken, bitte keine Empfehlungen daraus ableiten!

Zitat von lupor im Beitrag #114

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Was bleibt uns also außer die Hormontherapie und zu versuchen, diese so optimal und risikoarm wie möglich zu machen oder ohne extern zugeführte Hormone weitestgehend normal zu altern?

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Association between IGF-1 levels ranges and all-cause mortality: A meta-analysis
https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13540

Growth hormone isoform responses to GABA ingestion at rest and after exercise: https://pubmed.ncbi.nlm.nih.gov/18091016/

Oral Supplementation Using Gamma-Aminobutyric Acid and Whey Protein Improves Whole Body Fat-Free Mass in Men After Resistance Training: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522239/

IGF-1 Gene Transfer Modifies Inflammatory Environment and Gene Expression in the Caudate-Putamen of Aged Female Rat Brain
https://link.springer.com/article/10.1007/s12035-022-02791-w

Eine Kurzzeittherapie mit IGF-1 könnte ich mir als sehr vielversprechend bei Long Covid vorstellen. Vor allem wenn überwiegend die Hirnregion betroffen sein sollte. Intravenös macht aber nur wirklich Sinn dabei.

Looking at IGF-1 through the hourglass
https://www.aging-us.com/article/204257/pdf

Disruption of growth hormone receptor in adipocytes improves insulin sensitivity and lifespan in mice
https://academic.oup.com/endo/advance-ar...409?login=false

Protective role of IGF-1 and GLP-1 signaling activation in neurological dysfunctions
https://www.sciencedirect.com/science/ar...3852?via%3Dihub

Natürlich auch bei Long Covid interessant.

Long-Term IGF1 Stimulation Leads to Cellular Senescence via Functional Interaction with the Thioredoxin-Interacting Protein, TXNIP
https://www.mdpi.com/2073-4409/11/20/3260/htm