Growth Hormone and longevity

#88

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https://x.com/siimland/status/1913579283793993965?

And btw Steve - while N=1, he has low Dunedin Pace at least a while ago:

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#89

quality of life > marginally longer lifespan

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#90

@Virilius The evidence does not suggest that is the correct equation I think

Perhaps to be generous in that direction it might be

Quality of life now

<<<

Longer life and higher quality of life* later (and increased probity if intercepting powerful new therapies in a healthy enough state in the coming decades)

  • like not cancer and dealing with the quality of life of the cancer itself and of chemo and radiation, etc
#91

Are there any good cohort study tracking IGF-1 controlling for relevant confounding factors on different outcomes? Any MR study?

Seems directionally this can be answered what a good level is.

#92

Your SHBG is quite high. So is mine. Why do you think that is?

#93

@stealle It actually looks like it my be a good longevity phenotype to have somewhat high SHBG:

www.rapamycin.news/t/iron-an-underrated-factor-in-aging/6062/27?u=neo

Bryan Johnson’s is somewhat high to and look it to good excercise regime, being fit, lean, metabolically healthy and slight CR:

(For his values go up to the twitter link from @AnUser a dew messages up from my message above

#94

image

We know that a growth factor similar to IGF-1, sometimes called MGF (mechano-growth factor) is secreted locally during resistance exercise, so a systemic low IGF-1 really does not necessarily imply frailty in bones and muscles.

My only observation on your points is that you appear to neglect the IGFBP aspect. We should go into more detail, even as we should when discussing testosterone. The total amount is OK; it’s a reserve in the blood, but the available pool, the quantity that contributes to growth signaling, varies according to the amount of binding to specific proteins, as we’ve seen in some of the preceding posts.

However, I agree that if big data suggests better longevity with low total IGF-1, a lower total IGF-1 probably corresponds on average to lower IGF-1 signaling = free IGF-1. On average would be the key word.

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#95

  • Vitamin D dosage ≤1000 IU/day significantly increased IGF-1 levels.

  • Intervention duration ≤12 weeks significantly increased IGF-1 levels.

  • In cohort study, under 60 years subjects with a higher dietary vitamin D intake had significantly higher IGF-1 levels.

The influence of vitamin D supplementation on IGF-1 levels in humans: A systematic review and meta-analysis

https://www.sciencedirect.com/science/article/abs/pii/S1568163719302302

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#96

Btw I noticed a reference to this study on an older thread, which showed a doubling of the independent CVD risk factor Lp(a) after GH replacement therapy in GH-deficient adults. Might be worth monitoring for those who are using GH or GH-releasing peptides:

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#97

The discovery of HGH-related CJD quickly led to the end of cadaver-sourced HGH in the U.S. and other countries (thankfully, synthetic HGH became available soon after). Still, over two hundred cases of iatrogenic CJD—iatrogenic meaning it was caused by a medical treatment—from tainted HGH have been documented worldwide. Most of these cases were reported between five and 10 years after people had used HGH. But prion disease can sometimes take much longer to manifest in certain people, even decades.

According to this latest report, the woman first visited doctors with tremors and trouble balancing. As is often the case, once symptoms started, her condition rapidly worsened. She was hospitalized just four weeks later, and several days into her stay, she fell into a coma that she would never awaken from.

An autopsy confirmed the woman’s death from CJD but ruled out known genetic causes. And since she received HGH treatment prior to the cadaver ban, it was likely the root source of her illness, the doctors concluded.

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#98

I’m probably the only one here with an anecdotal experience on this. Having checked my Lp(a) a few times, I have not seen any real difference in it whether I have taken HGH or not.

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#99

Reducing IGF-1 is not guaranteed to increase “life span” (although it’s more about health span)

Tim Proctor - via X-com

Mitochondrial mutations may impose a hard limit on lifespan

Reducing IGF-1 signaling, a known lifespan extender, completely failed to extend life in mice with unhealthy mitochondrial DNA

mtDNA health could be the foundation for many other hallmarks of aging

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#100

From discussions above, is the low igf1 camp talking about chronic inhibition of igf1, or something more intermittent?

For me, if it’s between having chronically low igf1 and retaining muscle and bone mass so I can hike in my 70s, I know what I’ll choose. I liken it to mtor inhibition in that sense.

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#101

This is a million dollar question, in my mind. Can we “have our cake and eat it too” by keeping IGF-1 in the high-normal range and then periodically do (for instance) 5-day fasting-mimicking protocols to temporarily decrease IGF-1/insulin and clean out the sludge/reboot the system?

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#102

Well, I think the evidence is that IGF-1 is downstream of mTOR so when we take rapamycin we are also inhibiting IGF-1. So I think even with current rapamycin protocols we are getting some of this benefit of lower IGF-1/GH on a pulsatile basis.

It would be interesting to test IGF-1 levels over the rapamycin dosing cycle to see what the exact impact is… if anyone tries this, please report back. IGF-1 testing is pretty cheap - I think about $35 from some of our regular blood testing sites mentioned frequently here.

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#103

This is a good idea. Measuring igf1 before and after a rapamycin cycle seems like a good enough proxy for measuring mtor inhibition activity.

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#104

I wonder why you recall the evidence that IGF-1 is downstream of mTOR. It surely is one of the upstream signals, the insulin/IGF-1 signal, through the PI3K/Akt pathway.

We might envisage however some downstream signal resulting in an inhibitory effect on the production of IGF-1 in the liver, but according to interrogations to a couple of AIs, it seems not the case, on the contrary, it would seem that there may be an opposite effect. Here, Deepseek was very detailed.

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#105

Please tell me if mTOR inhibition by rapamycin can have some effects on circulating plasma IGF-1

Yes, rapamycin-mediated mTOR inhibition can increase circulating plasma IGF-1 levels, despite mTOR being a downstream effector of IGF-1 signaling. This counterintuitive effect is well-documented in both preclinical and clinical studies. Here’s a breakdown of the mechanisms, evidence, and implications:

1. Key Evidence

  • Animal Studies:
    • In mice/rats, rapamycin consistently elevates plasma IGF-1 by 20–50% after acute or chronic treatment.
    • Example: A 2020 study (Aging Cell) showed a 36% IGF-1 increase in aged mice after 3 months of rapamycin.
  • Human Data:
    • Renal transplant patients on rapamycin (sirolimus) exhibit higher serum IGF-1 vs. those on other immunosuppressants.
    • Healthy adults in trials (e.g., Science Translational Medicine, 2014) show similar trends, though effects vary by dose/duration.

2. Mechanisms Behind the Increase

The rise in IGF-1 occurs despite mTORC1 inhibition, primarily due to compensatory feedback loops:

Mechanism Description
Growth Hormone (GH) Surge Rapamycin disrupts mTORC1-mediated negative feedback on the hypothalamus/pituitary, leading to increased GH secretion → stimulates hepatic IGF-1 production.
Reduced IGF-1 Utilization Tissues (e.g., muscle, liver) may develop transient resistance to IGF-1, reducing its clearance from circulation.
Hepatic Adaptation Liver cells increase IGF-1 synthesis to counter perceived “insufficiency” from blocked mTOR signaling.

3. Paradox: IGF-1 Elevation vs. mTOR Blockade

While IGF-1 levels rise, rapamycin still inhibits IGF-1’s downstream actions:

  • Tissue-Specific Effects:
    • mTORC1 inhibition blocks IGF-1 signaling in peripheral tissues (e.g., muscle, fat), even with elevated plasma IGF-1.
  • Functional Decoupling:
    • The bioactivity of IGF-1 may be reduced due to altered binding proteins (e.g., IGFBP-1/2 upregulation).

4. Implications for Longevity & Disease

  • Aging Research:
    • Rapamycin extends lifespan in model organisms despite raising IGF-1. This challenges the dogma that low IGF-1 is universally pro-longevity.
    • Elevated IGF-1 may support maintenance of metabolic/immune functions in specific contexts.
  • Cancer Risk Concerns:
    • High IGF-1 is linked to tumor progression, but rapamycin’s direct anti-tumor effects (e.g., angiogenesis inhibition) likely offset this risk.
  • Metabolic Effects:
    • Increased IGF-1 could theoretically aid glucose regulation, though rapamycin often induces insulin resistance.

5. Final Comment

Rapamycin reliably increases circulating IGF-1 due to disrupted feedback loops, but this does not negate its therapeutic benefits. The dissociation between IGF-1 levels and signaling highlights the complexity of hormone-mTOR crosstalk. In aging or disease contexts, mTOR inhibition’s net effects (e.g., reduced inflammation, enhanced autophagy) appear to outweigh theoretical risks from elevated IGF-1. However, long-term human data are still evolving, and individualized risk assessment remains crucial.

Sources:

  • Cell Metabolism (2014): Feedback loop between mTOR/S6K1 and GH/IGF-1.
  • Nature Communications (2021): Rapamycin’s tissue-specific IGF-1 effects.
  • JCI Insight (2019): Human trials showing IGF-1 elevation with sirolimus.
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#106

I don’t know if there is a camp that specifically suggests targeting IGF-1 reduction, maybe proponents of Caloric Restriction, maybe some vegan doctors like Dr. Greger or others. But apparently the issue is more complicated, since reduction in systemic IGF-1 may not be coupled to reduction in tissues, and the above providing that total IGF-1 is sufficient as a parameter or it is necessary to evaluate its binding proteins as well.

In my n=1 case, I have chronic (probably epigenetically induced) lowish IGF-1, in the range of 90-100 ng/mL, but muscle mass is not low, on the contrary it takes little exercise to me to induce hypertrophy. Evidently, there are more mechanisms in action, like the local IGF-1 release in muscle tissues induced by resistance exercise (paracrine regulation).

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#107

Again, I’m posting the outlook provided on the specific aspect by Deepseek R1, that seems pretty reasonable.

can you please detail the relationship among circulating IGF-1 and local IGF-1 in muscle, bone and nervous tissues

The relationship between circulating (endocrine) IGF-1 and locally produced (autocrine/paracrine) IGF-1 in tissues is complex and tissue-specific, involving distinct regulatory mechanisms and functions. Below is a detailed breakdown for muscle, bone, and nervous tissues:

1. Muscle Tissue

Circulating IGF-1

  • Source: Primarily liver-derived (endocrine).
  • Role:
    • Maintains basal muscle mass and metabolic homeostasis.
    • Activates systemic growth via PI3K/Akt and mTOR pathways.
  • Regulation:
    • Pulsatile GH release stimulates hepatic IGF-1 synthesis.
    • Suppressed during fasting/stress; elevated postprandially.

Local IGF-1 (Muscle-Specific Isoforms: IGF-1Ea, IGF-1Eb, MGF)

  • Source: Produced by myocytes and satellite cells (autocrine/paracrine).
  • Role:
    • Hypertrophy: IGF-1Ea promotes muscle growth via Akt/mTOR.
    • Repair: Mechano-growth factor (MGF, IGF-1Ec) is rapidly induced after injury to activate satellite cells.
  • Key Distinction:
    • Local IGF-1 responds to mechanical load (exercise) or damage, while circulating IGF-1 reflects systemic metabolic status.

Crosstalk

  • Circulating IGF-1 can cross capillary barriers but contributes <20% to muscle IGF-1 receptor (IGF-1R) activation.
  • Local IGF-1 dominates during tissue repair/hypertrophy.
  • Rapamycin paradox: Inhibits mTOR in muscle → blunts local IGF-1 action → compensatory ↑ in circulating IGF-1 (via GH feedback).

2. Bone Tissue

Circulating IGF-1

  • Source: ~80% liver-derived.
  • Role:
    • Stimulates longitudinal bone growth (epiphyseal plates).
    • Regulates osteoblast proliferation and bone matrix deposition.
  • Evidence: Liver-specific IGF-1 KO mice show 30% reduced bone mass.

Local IGF-1 (Produced by Osteoblasts/Osteocytes)

  • Role:
    • Osteoblast survival: Autocrine IGF-1 prevents apoptosis.
    • Bone remodeling: Coordinates osteoblast-osteoclast coupling.
    • Mechanotransduction: Osteocytes produce IGF-1 in response to mechanical stress.
  • Regulation:
    • Load-dependent (e.g., exercise ↑ local IGF-1).
    • Suppressed by glucocorticoids/inflammation.

Crosstalk

  • Circulating IGF-1 delivers systemic anabolic signals.
  • Local IGF-1 fine-tunes site-specific bone formation/repair.
  • Synergy: Circulating IGF-1 enhances osteoblast sensitivity to locally produced IGF-1.

3. Nervous Tissue (Brain & Nerves)

Circulating IGF-1

  • Source: Liver-derived, crosses blood-brain barrier (BBB) via transporters.
  • Role:
    • Neuroprotection: Reduces oxidative stress, inhibits apoptosis.
    • Synaptogenesis: Enhances dendritic arborization.
    • Regulates cerebral glucose uptake.
  • Limitations: Only 10–20% of serum IGF-1 enters the brain.

Local IGF-1 (Produced by Neurons, Glia)

  • Role:
    • Myelination: Oligodendrocytes require autocrine IGF-1 for differentiation.
    • Neurogenesis: Neural stem cells in hippocampus depend on paracrine IGF-1.
    • Axon guidance: Locally synthesized IGF-1 guides growth cones.
  • Regulation:
    • Activity-dependent (e.g., learning ↑ neuronal IGF-1).
    • Reduced in neurodegeneration (Alzheimer’s/Parkinson’s).

Crosstalk

  • Circulating IGF-1 maintains basal neurotrophic support.
  • Local IGF-1 drives activity-dependent plasticity/repair.
  • Critical nuance: Brain IGF-1R activation relies more on local than circulating IGF-1.

Key Overarching Principles

  1. Functional Specialization:
    • Circulating IGF-1: Systemic growth/metabolism.
    • Local IGF-1: Tissue-specific adaptation (repair, loading, plasticity).
  2. Regulatory Independence:
    • Local IGF-1 escapes GH control (e.g., exercise ↑ muscle IGF-1 without GH).
  3. Compensation:
    • Loss of circulating IGF-1 ↑ local production (and vice versa).
  4. Therapeutic Implications:
    • Targeting local IGF-1 (e.g., MGF for muscle repair) may avoid systemic risks (e.g., cancer from elevated serum IGF-1).

Final Comment

While circulating IGF-1 provides broad anabolic support, tissue-specific IGF-1 is the dominant regulator of plasticity, repair, and functional adaptation in muscle, bone, and nervous systems. This duality explains why serum IGF-1 levels poorly predict tissue outcomes (e.g., rapamycin ↑ serum IGF-1 but inhibits muscle mTOR). Future therapies must target local IGF-1 dynamics to effectively treat tissue-specific disorders (e.g., sarcopenia, osteoporosis, neuropathy).

Sources:

  • Muscle: Cell Metabolism (2015) on MGF; Journal of Physiology (2020) on exercise-induced IGF-1.
  • Bone: Bone Research (2019) on osteocyte IGF-1; Endocrinology (2016) on liver IGF-1 KO.
  • Nervous: Nature Reviews Neuroscience (2018); Journal of Neuroscience (2021) on BBB transport.
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