Is it possible to selectively increase the GF on certain parts of our body? Eg, topical creams for skin? or injections for bones fractures?
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:
3 Likes
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
5 Likes
Just thinking out loud here. If we ignore IGF1 for a second, are there any hormones that decline with age that IMPROVE health outcomes?
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:
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.
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.
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?
3 Likes
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.
5 Likes
@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
1 Like
1 Like
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.
3 Likes
Can we test these at normal labs?
Actually, I don’t know. Maybe IGFBP. I’ll have to ask the local lab. Interpreting the results would be another issue. The ratio IGF-1/IGFBP3 has been used in studies by Luigi Fontana.
2 Likes
https://x.com/siimland/status/1913579283793993965?
And btw Steve - while N=1, he has low Dunedin Pace at least a while ago:
2 Likes
quality of life > marginally longer lifespan
2 Likes
@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
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.
Your SHBG is quite high. So is mine. Why do you think that is?
@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
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.
1 Like
-
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
2 Likes
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:
3 Likes