Growth Hormone and longevity

#65

Again if you talk with Greg Fahy the developer of this protocol (I have many times), he will be the first to tell you:

  • the befits are from the Thymus regeneration itself and the immune benefits

  • having to use GH is in order to get that generation, not because they wanted for other reasons to increase people’s GH (perhaps even despite)

  • given that they designed it so the growth hormone is only given during a very limited period of time, and with hope of not having to repeat more than a few times during one’s entire life

so for the VAST majority of the time, their patients DO NOT supplement with GH

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#66

And neither do I…

From the paper I provided above

GHRH and GHS stimulate the secretion of GH. Since most AGHD is caused by pituitary lesions, and these patients, unlike healthy seniors, are unresponsive to GHRH or GHS, there are few studies of treatment with these agents.

Theoretically, treatment with GHRH or GHS should lead to more physiologic GH replacement, leading to a pulsatile rather than prolonged elevation in GH and preserving the ability for negative feedback inhibition of GH by increasing IGF-I. GHRH and GHS effects are influenced by the same factors which modulate endogenous GHRH secretion, such as negative feedback by somatostatin. This normal negative feedback regulation would be expected to result in buffering against overdose. The side effects of GHRH treatment are similar in character to GH treatment but are milder and less frequent. Since the GHS are smaller molecules than GH, and generally resistant to digestive enzymes, they can be administered via the oral, transdermal or nasal routes.

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#67

From the paper I referenced.

Mechanistic insights into the role of growth hormone and IGF-I in age-related alterations in cognitive function were assessed in several studies by Sonntag and colleagues demonstrating somatotrophic effects on rodent brain aging (26). These studies suggest that deficiencies in GH and IGF-I contribute to the functional decline in senescent rats whereas augmentation of GH or IGF-I improved cognitive function, increased glucose utilization throughout the brain, increased cortical vascularity, and ameliorated age-related decline in hippocampal neurogenesis**.**

A 2006 study of the effects of 6-months daily treatment with sermorelin acetate, a GHRH analogue, on cognitive function of 89 elderly adults found significant improvement on several cognitive assessments, particularly those involving problem solving, psychomotor processing speed, and working memory, but no change on tests reflecting crystallized intelligence (27). Higher GH levels were associated with higher Wechsler Adult Intelligence Scale performance IQ scores, and greater increases in IGF-1 were associated with higher verbal fluency test scores, while gender, estrogen status, and initial cognitive function did not interact with the GHRH effect on cognition.

A 2013 pilot study of 30 elderly adults given a stabilized analogue of GHRH, tesamorelin, versus placebo, used magnetic resonance spectroscopy to examine the effects of inhibitory and excitatory neurotransmitters (60). After 20 weeks GABA levels were increased in all brain regions, N-acetylaspartylglutamate levels were increased in the dorsolateral frontal cortex, and myo-inositol (an osmolyte linked to Alzheimer disease) levels were decreased in the posterior cingulate, with similar results across adults with mild cognitive impairment (MCI) and those with normal cognitive function. Treatment related changes in serum IGF-1 were positively correlated with changes in GABA and negatively correlated with myo-inositol. There was a favorable treatment effect on cognition (p = .03), but no significant associations were observed between treatment-related changes in neurochemical and cognitive outcomes.

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#68

BPC-157: Is that just a local effect on some specific tissue or a systemic effect as well? I am one of those who suffer from nagging tendons issues when lifting weights, and I hate it.

What is the usual dosage to target the issue of aches in connective tissues?

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#69

That is purported to be systemic, and people suggest to inject near the site of injury if possible. The dosage is usually quite low, and so is the half life (2 hours ). There are a variety of dosages.

For acute injuries, they recommend 200-500 mcg twice a day for a week or two. That can be then reduced to 250 mcg a day for maintenance.

It is usually paired with tb-500, look up wolverine stack and you’ll get some info on that. Bpc increases blood flow to injured tissues, while tb-500 relieves general inflammation resulting from the injury.

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#70

New paper

Diminished signaling via insulin/insulin-like growth factor-1 (IGF-1) axis is associated with longevity in different model organisms. IGF-1 gene is highly conserved across species, with only few evolutionary changes identified in it.

This study investigated the whole exome sequencing data from 2,108 individuals in a cohort of Ashkenazi Jewish centenarians, their offspring, and controls without familial longevity to identify functional IGF-1 coding variants. We identified two likely functional coding variants IGF-1:p.Ile91Leu and IGF-1:p.Ala118Thr in our longevity cohort.

Consequently, diminished IGF-1 signaling resulting from these variants may contribute to exceptional longevity in humans.

Given the previously identified role of reduced insulin/IGF-1 signaling in models of longevity, our findings provide additional evidence for the potential role of these gene variants and reduced IGF-1 signaling in human longevity.

Understanding the mechanisms of rare longevity-associated variants found in individuals with exceptional longevity is of paramount importance in advancing our knowledge of how genes that carry these variants regulate downstream signaling of pro-longevity pathways and could serve as promising gerotherapeutic drug targets.

a recent large-scale study involving nearly 450,000 UK biobank participants showed that older adults with higher IGF-1 levels had greater risk of mortality and age-related diseases, indicating that lower IGF-1 levels were beneficial for their survival55. In our longevity cohort, carriers of IGF-1:p.Ala118Thr had significantly lower levels of IGF-1, compared to non-carriers (Fig. 1B).

https://www.nature.com/articles/s41598-025-94094-y#Fig1

featured at the top here:

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#71

How often do you measure your IGF-1 level?

#72

On average perhaps two times a year. How come?

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#73

I need to get mine tested and have never had that test. Is it a stand alone test or in a panel of tests?

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#74

Its stand-alone, I recently got mine checked by Marek Diagnostics ($45):

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#75

@Steve_Combi

That how i’ve done it recently too

If you prefer Quest to Lab Corp you can use UltaLabs instead of Marek to order online without any need for a doctors appointment

—-

Here is mine

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Testosterone has changed more with more sleep, more resistance training and less CR - I think it’s too high for optimal longevity

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… but my SHBG is hopefully offsetting it

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And hence free and bio available T are lower/better from longevity perspective

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#76

Is it possible to selectively increase the GF on certain parts of our body? Eg, topical creams for skin? or injections for bones fractures?

#77

It seems clear that something slows down when IGF/GH are low.

But we don’t have the full story as Sauna use (x16 GH) reduces ACM, HIIT reduces ACM, Deep Sleep (x4 GH) reduces ACM, fasting (x3 GH) may (?) reduce ACM.

As people already said, one way to reconcile both things is that repairing equals growth and that equals “aging” in some way. That could explain why healthspan surely increases in all those interventions but probably maximum lifespan doesn’t.

If we accept this hypothesis, we should strive to conserve as much as possible when young and repair/grow as much as possible late in life.

There seems to exist evidence of this:

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#78

One of the reasons I use secretagogues (peptides that tell the hormone system to make hGH) instead of somatotropin (the synthetic version of hGH) is to more closely mimic how my body worked when I was younger. That can be done with somatotropin with proper timing but it bypasses the function of the pituitary gland, i.e. a replacement therapy. My personal goal is to have all my organs doing their job, not replace their function.

For people with loss of pituitary function, replacement therapy is the only way to go.

GH is naturally released in a pulsatile manner, it is not naturally present at higher levels throughout the day. This is what secretagogue peptides do, when used to support the natural circadian hormone cycle.

This is also why I choose to use CJC 1295 noDAC as opposed to the DAC versions. The DAC version has a much longer half-life and keeps the GH levels high much longer. The noDAC version has a 2 hr half-life and we take it (in combination with Ipamorelin) just before bedtime. Approximately 2 hours into sleep is when our body produces a GH peak, As we age this peak declines, as does IGF-1.

The circulating half-life of hGH is relatively short (20-30 minutes), while its biological half-life is much longer (9-17 hours).

When GH goes high, so does IGF-1 to normalize the GH levels to mitigate insulin resistance that GH causes. This is why there is an insulin management compound required for the TRIIM protocol where they use Metformin for this purpose.

When GH goes low, so does IGF-1. They are a synergistic feedback pair.

As IGF-1 levels seem to be used as a proxy for GH levels in blood tests and that low IGF-1 levels are associated with longevity, thereby indicating that low GH levels by proxy are desired, I wonder if the insulin interplay is being missed as part of the “longevity” equation in this triple-play of interactions. We know that poorly controlled insulin levels (not even with diagnosed T2D, even before that presents) are an issue for longevity and that the earlier in life these levels are normalized the greater the benefit for health span.

So who is the bad guy in this equation? hGH? IGF-1? Insulin?

In conclusion, GH stimulates IGF-1 levels and insulin concentrations, the latter mainly by inducing insulin resistance. IGF-1 decreases GH levels by growth hormone releasing hormone (GHRH)-dependent feedback mechanisms. Insulin increases liver GHR expression, making the liver more GH-sensitive, leading to an increase in IGF-1 and a decrease in GH. On the other hand, low portal insulin levels (e.g., during prolonged fasting) reduce hepatic GHR expression, thereby reducing IGF-1 levels and increasing GH concentrations by the lack of IGF-1 feedback on pituitary GH secretion

https://www.e-enm.org/journal/view.php?doi=10.3803/EnM.2024.101

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#79

Just thinking out loud here. If we ignore IGF1 for a second, are there any hormones that decline with age that IMPROVE health outcomes?

#80

ChatGPT says “maybe”, but with trade-offs:

Great question — most age-related hormone declines are usually linked to negative health effects, but there are a few hormones where reduced levels with age might be beneficial in certain contexts. Here’s a quick breakdown:

:brain: Hormones That Decline With Age and May Improve Health Outcomes:

1. Insulin

  • Trend with Age: Insulin sensitivity tends to decrease, but basal insulin levels can vary.
  • Health Implication: Chronically high insulin is linked to insulin resistance, metabolic syndrome, and type 2 diabetes.
  • Potential Benefit of Lower Insulin: Lower fasting insulin (if from improved sensitivity, not pancreas dysfunction) is associated with better metabolic health and longevity.

2. IGF-1 (Insulin-like Growth Factor 1)

  • Trend with Age: Declines with age.
  • Health Implication: High IGF-1 is linked to increased cancer risk (especially prostate, breast, and colorectal).
  • Potential Benefit of Lower IGF-1: May reduce cancer risk and promote longevity. Some centenarians have lower IGF-1 activity.

:pushpin: Note: Low IGF-1 can also impair muscle and bone maintenance, so the context (e.g., age, sex, activity level) matters.

3. Testosterone (in men)

  • Trend with Age: Declines gradually after age ~30.
  • Health Implication: Low T is linked to reduced muscle mass and mood changes — but very high T is associated with increased cardiovascular risk and prostate issues.
  • Potential Benefit of Lower T: Moderately lower T levels may reduce risk of some hormone-sensitive cancers.

:balance_scale: However, the benefits of testosterone decline are controversial. This one is more of a “double-edged sword.”

4. Estrogen (in women, post-menopause)

  • Trend with Age: Drops sharply during menopause.
  • Health Implication: Estrogen protects bones and the cardiovascular system, but high lifetime exposure is linked to breast and endometrial cancer.
  • Potential Benefit of Lower Estrogen: Reduced risk of certain cancers.

Again, it’s complex — lower estrogen can increase cardiovascular and bone risks.

5. Growth Hormone (GH)

  • Trend with Age: Declines significantly from youth.
  • Health Implication: High GH is linked to increased cancer and diabetes risk.
  • Potential Benefit of Lower GH: Lower cancer risk, slower aging in some models.

TL;DR

Hormones like IGF-1, insulin, and growth hormone declining with age might contribute to increased longevity and reduced cancer risk. But there’s a trade-off — muscle mass, bone density, and quality of life might suffer if levels dip too low.

Would you like to explore how some of these declines relate to caloric restriction, longevity, or disease prevention strategies?

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#81

Not sure the mechanism but my psoriasis and urticaria (10+yrs) disappeared within 7 days of adding BPC157 /TB 500 to my CJC 1295/Ipamorelin at night. I can only conjecture that it might be similar to the Thymus rejuvenation protocol? It is not why I am taking them, but I will take a beneficial side effect! I can now tolerate medications/foods that I have never been able to take (ezetimibe, nuts) without a breakout.

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#82

@RapAdmin not sure if ChatGPT will distinguish between short term health vs healthspan vs longevity without that being explicitly included in the prompt (and its answer above seems to address the question in a bit of mixed together way).

@LukeMV from a longevity optimization perspective one might want to also consider T / Free T / Bio available T not being too high

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#83
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#84

Thanks for a very detailed report on the main forms of Testosterone. It is very interesting to notice how the quantity of bioavailable T in your case is at the opposite of the lab range with respect to total T. Unfortunately, this suggests to us the poor usefulness of the total T parameter since it doesn’t reflect the amount directly available for the body, which governs biological signaling.

A similar situation unfolds with IGF-1. It binds strongly to IFGBP-3, so total IGF-1 may not be representative of the amount available to its receptors in the various cells of the body.

I asked deepseek to elaborate, it goes into detail but that’s the basic rationale.

My concern now is that the quantities of total T and total IGF-1 we rely upon may be a very poor indicator of their actual biological action.

The relationships among total IGF-1, free IGF-1, and bioavailable IGF-1 revolve around how IGF-1 (Insulin-like Growth Factor 1) is distributed in the bloodstream and its accessibility to tissues. Here’s a structured breakdown:

1. Total IGF-1

  • Definition: The entirety of IGF-1 in circulation, including all bound and unbound forms.
  • Binding:
    • ~95–99% is bound to IGF-binding proteins (IGFBPs), primarily IGFBP-3 in a stable ternary complex with an acid-labile subunit (ALS). This complex acts as a reservoir, prolonging IGF-1’s half-life.
    • Smaller fractions bind to other IGFBPs (e.g., IGFBP-1, -2, -5).
  • Measurement: Routinely measured in clinical settings via immunoassays, reflecting overall IGF-1 production (largely driven by growth hormone).

2. Free IGF-1

  • Definition: The unbound, biologically active fraction (~1% of total IGF-1) that can directly interact with IGF-1 receptors.
  • Significance: Represents the immediately available pool for cellular activity. However, its low concentration makes precise measurement challenging.

3. Bioavailable IGF-1

  • Definition: Includes free IGF-1 plus IGF-1 bound to low-affinity IGFBPs (e.g., IGFBP-1, -2) that can readily release IGF-1 for tissue uptake.
  • Exclusion: Excludes IGF-1 in the stable ternary complex (IGFBP-3 + ALS), which is less accessible.
  • Dynamic Regulation: Influenced by factors like nutrition, stress, or proteases that modify IGFBP levels or cleavage (e.g., fasting ↑ IGFBP-1, altering bioavailability).

Key Relationships

  • Total IGF-1 = Free IGF-1 + IGF-1 bound to all IGFBPs (including ternary complex).
  • Bioavailable IGF-1 ≈ Free IGF-1 + IGF-1 loosely bound to low-affinity IGFBPs (e.g., IGFBP-1, -2).

Functional Implications

  • Activity: Free IGF-1 is the most active form, while bioavailable IGF-1 reflects the “dynamic pool” accessible to tissues.
  • Clinical Relevance:
    • Total IGF-1 levels indicate systemic GH activity (e.g., elevated in acromegaly, low in GH deficiency).
    • Bioavailable IGF-1 better correlates with physiological effects (e.g., growth, metabolism) but is harder to measure directly.
    • Conditions altering IGFBPs (e.g., liver disease, malnutrition) may disrupt bioavailable IGF-1 without affecting total levels.

Regulatory Factors

  • Growth Hormone (GH): Stimulates hepatic IGF-1 and IGFBP-3 production.
  • Nutrition: Fasting ↑ IGFBP-1, which may paradoxically ↓ bioavailable IGF-1 by sequestering it.
  • Proteases: Cleave IGFBPs (e.g., in inflammation), releasing IGF-1 into the bioavailable pool.

In summary, total IGF-1 reflects overall production, free IGF-1 is the active fraction, and bioavailable IGF-1 encompasses the dynamic, tissue-accessible pool. Their interplay determines IGF-1’s biological impact, with clinical assessments often focusing on total IGF-1 due to measurement practicality.

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