Hi Testosterone, low IGF-1 phenotype

[mccoy]

I wonder if any of you guys may have this phenotype. I tested 5 years ago and I retested it recently and it is confirmed. Presently, these are my lab values,at age 64.5

Testosterone, total = 683 ng/dL = 23.7 nmol/L = about 85th percentile in 60-69 old males
IGF-1 = 99.4 ng/mL = about 25th percentile in 65 old males
Fasting insulin = 5.1uU/mL = about 30-50th percentile estimated value

Of course, the above may have no meaning if the binding proteins of the respective hormones (SHBG and IGF-1 BP) have values far from the median,.

Barring such a hypothesis, I wonder about the meaning of such phenotype in terms of longevity and health. Or maybe there is not very much to say; higher frailty with low IGF-1, potentially higher CVD risk, lesser cancer risk, but lower frailty with hi T, that are contrasting aspects at least partly.

However, the issue is surely more complex. Serum IGF-1 is low, but systemic IGF-1, for example in muscles, may be high. Also, low IGF-1 may reflect a low GH production which maybe would hinder connective tissue regeneration, and I do have some problems in connective tissue.

But I’ll stop here momentarily.

[LukeMV]

An IGF1 between 120-160 ng/ml is associated with the lowest mortality, so you’re a bit low, as I’d expect for a man your age.

Association between IGF‐1 levels ranges and all‐cause mortality: A meta‐analysis

Things that increase IGF1:

• growth hormone secretagogues (Ipamorelin, CJC, MK677, etc)
• HGH
• higher estradiol is also correlated to higher IGF1 levels

[mccoy]

@LukeMV, interesting and updated article. I also remember that Valter Longo suggests an optimum IGF-1 of 140 ng/ml, which constitutes just the punctual optimum in that metanalysis.

I don’t know if that graph represents adequately a low IGF-1 + high testosterone situation. It is a generic graph, which includes a lot of variability, which is reflected in the uncertainty bands (95% CI of the spline model). Also, in the lower-than-optimum region, the studies exhibit a high eterogeneity, as explained in the article.

As detailed in the discussion, the counfind factors may be various, like a reverse causation, similar to that found in U-shaped hazard curves of cholesterol. The lower values could not be that cause of the higher mortality, rather the manifestation of higher morbidity which led to higher mortality.

The putative protection of IGF-1 with regard to CVD mortality may be due to local rather than systemic concentration of IGF-1

Ditto for sarcopenia and osteopenia, systemic values may not be representative of local values.

For example, my IGF-1 is low but I have no sarcopenia, in the contrary I am a good responder to exercise, considering the modest loads I lift. I have some tendons and joints issues but there may be many reasons for that. I have no significant metabolic issues.

An additional very welcome benefit of low IGF-1 may also be lower cancer risk.

Bottom line, I think I’m going be happy with these values but check them and be careful that they don’t decrease below this 100 ng/ml threshold. I’m already eating dairy protein. I may try some of the compounds listed but I’m not sure that they are readily available here at reasonable costs. HGH might be a good remedy for tendons/joints inflammation to exercise perhaps.

[dicarlo2]

I would be curious how this study might look different if it was stratified by age. Youthful levels of IGF-1 are much higher, even past the bone growth stage, than natural levels at old age. I guess they controlled for age somewhere, but I find it hard to believe that a 30 year old with 120 IGF-1 has a lower ACM than a more age appropriate number like 180-200 (off the top of my head), simply because 120 would be indicative of an underlying health issue.

[LukeMV]

Interesting point.

This is unrelated to your post but I’ll also say that I think an artificially elevated IGF1 level through something like HGH or the GH peptides do not increase cancer risk (some studies have shown HGH lowers cancer). It’s the naturally elevated IGF1 that I’d be slightly more mindful of.

[mccoy]

@dicarlo2

I would be curious how this study might look different if it was stratified by age. Youthful levels of IGF-1 are much higher, even past the bone growth stage, than natural levels at old age. I guess they controlled for age somewhere, but I find it hard to believe that a 30 year old with 120 IGF-1 has a lower ACM than a more age appropriate number like 180-200 (off the top of my head), simply because 120 would be indicative of an underlying health issue.

Yes, that aspect is probably one of the factors that generate those wide uncertainty bands. One very intuitive way to work out this drawback is to move along the mean curve if 65 (that’s the mean age), to move following the lower uncertainty curve if closer to 20 and viceversa.

Young ones will start having a significantly >1 mortality risk at about 240 ng/ml. The relationship may even not be valid for this subgroup and probably most databases exclude young people.

[mccoy]

@LukeMV

This is unrelated to your post but I’ll also say that I think an artificially elevated IGF1 level through something like HGH or the GH peptides do not increase cancer risk (some studies have shown HGH lowers cancer). It’s the naturally elevated IGF1 that I’d be slightly more mindful of.

I wonder though how it would be possible a difference between natural and artificial growth factors. They seem to inhibit directly FOXO by the PDK1- Akt path and activate mTOR by such path plus another one. I mean, there should be a structural difference between natural and artificial growth factors such as that the artificial molecules would not be able to bind to the respective receptors.

Also, I’m aware of the thymus rejuvenation experiments based on HGH and led by Dr. Fahey, but they are not without controversy.

[LukeMV]

A theory is that slightly high end/above range IGF1 is only associated with increased cancer risk but isn’t actually causal.

(I’m not talking about the crazy high IGF1’s as a result of tumors. That’s different.)

[mccoy]

I must say I did not study the subject adequately. Pure association is not causation, but if the correlation is significant and there is a sound mechanistic hypothesis, then the likelihood of causation itself starts growing.

The usual narrative from Longo, Fontana, and even from the vegan community is that elevated levels of IGF-1 trigger proliferative signals, so in some conditions it may be favorable to the proliferation of cancer cells, which are avidly searching nutrients like glucose and growth factors to multiply anomalously. So, according to this narrative, it would be a causal factor.

Valter Longo has a very high reputation, but of course, he’s not infallible. I’ll try and find some metanalysis or umbrella analyses on the issue.

[AnUser]

See IGF-1 inhibitor aging studies in dogs as well or other animals, and IGF-1 deficiency dwarfism.

[mccoy]

@AnUser

IGF-1 deficiency dwarfism.

Ah, yes thanks for reminding, the Laron dwarfs and all the experiments led on IGF-1R knocked out mice, that’s the supporting data Longo constantly cites.

Laron dwarfs seem to be immune from cancer, diabetes and most metabolic issues. They have strong deficiencies in GH receptors, so their IGF-1 is extremely low.

The main effect is dwarfism. The side effect is incredible health, even if with a horrible diet and lifestyle.

[AnUser]

The question is, what if your IGF-1 is low from diet or lifestyle after growth phases (where I guess most of the side effects of dwarfism come from?).

I don’t believe U-shape (non-linear) associations that much, unless it’s obvious what’s causing the increase in mortality or whatever and what the confounding factors are.

[mccoy]

@AnUser

The question is, what if your IGF-1 is low from diet or lifestyle after growth phases (where I guess most of the side effects of dwarfism come from?).

Can you please elucidate, I don’t understand your question

[AnUser]

I think any negative side effects from low IGF-1 in dwarfism might be the impact on growth in e.g childhood.
Does that make sense?
I’m tired so I operate at 5% capacity.

[mccoy]

@AnUser

I’m tired so I operate at 5% capacity.

Ah Ah, no probs about the low battery level, I myself struggle to keep the charge up.

It may be, that the amazingly substantial beneficial side effects are only reaped when IGF-1 deficiency acts upon some mechanisms at growth.

Presently, I have no clear opinions on that. Longo does not suggest to seek low values of systemic IGF-1, he says the optimum is 140 ng/ml, the same cited in the article posted by Luke.

However, Longo implies that people over about 65 may refrain to eat more protein if they exercise with weights every day. he porbably alludes to the secretion of local IGF-1 in muscle and nervous tissue.

[mccoy]

So far I couldn’t find much recent material, the studies on IGF-1 and cancer appear mostly to date back to early 2000 and previously.

This Lancet article is interesting, but they are cautious in determining a substatial cause-effect relationship.

ArticlesVolume 363, Issue 9418p1346-1353April 24, 2004

Download Full Issue

Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis

Dr Andrew G Renehan, PhDa arenehan@picr.man.ac.uk ∙ Marcel Zwahlen, PhDc ∙ Prof Christoph Minder, PhDc ∙ Sarah T O’Dwyer, MDa ∙ Prof Stephen M Shalet, MDb ∙ Prof Matthias Egger, MDc,d

Affiliations & NotesArticle InfoLinked Articles (1)

Summary

Background

Insulin-like growth factor (IGF)-I and its main binding protein, IGFBP-3, modulate cell growth and survival, and are thought to be important in tumour development. Circulating concentrations of IGF-I might be associated with an increased risk of cancer, whereas IGFBP-3 concentrations could be associated with a decreased cancer risk.

Methods

We did a systematic review and meta-regression analysis of case-control studies, including studies nested in cohorts, of the association between concentrations of IGF-I and IGFBP-3 and prostate, colorectal, premenopausal and postmenopausal breast, and lung cancer. Study-specific dose-response slopes were obtained by relating the natural log of odds ratios for different exposure levels to blood concentrations normalised to a percentile scale.

Findings

We identified 21 eligible studies (26 datasets), which included 3609 cases and 7137 controls. High concentrations of IGF-I were associated with an increased risk of prostate cancer (odds ratio comparing 75th with 25th percentile 1·49, 95% CI 1·14–1·95) and premenopausal breast cancer (1·65, 1·26–2·08) and high concentrations of IGFBP-3 were associated with increased risk of pre-menopausal breast cancer (1·51, 1·01–2·27). Associations were larger in assessments of plasma samples than in serum samples, and in standard case-control studies compared with nested studies.

Interpretation

Circulating concentrations of IGF-I and IGFBP-3 are associated with an increased risk of common cancers, but associations are modest and vary between sites. Although laboratory methods need to be standardised, these epidemiological observations could have major implications for assessment of risk and prevention of cancer.

[mccoy]

I tried to question the Gemini AI and I must say the answer is pretty exhaustive and at least at first reading it appears overall reasonable. It also provides one or more link for every assertion it makes.

IGF-1 and cancer, is there any correlation or causation, the nature of such correlations causations, what the specialized medical literature says in updated studies

The relationship between IGF-1 (Insulin-like growth factor 1) and cancer is complex and has been the subject of extensive research. Here’s a breakdown of the current understanding based on specialized medical literature:

Correlation and Causation:

• Correlation:
  • Epidemiological studies have shown a positive association between higher circulating levels of IGF-1 and an increased risk of several cancers, including:
    • Breast cancer
    • Prostate cancer
    • Colorectal cancer
  • This means that individuals with higher IGF-1 levels are statistically more likely to develop these cancers.
• Causation:
  • While correlations are clear, establishing direct causation is more challenging. However, recent studies, particularly those using Mendelian randomization, provide stronger evidence for a causal role, especially in certain cancers like breast cancer.
  • Mendelian randomization studies use genetic variations as proxies for IGF-1 levels, reducing the influence of confounding factors. These studies have strengthened the evidence that IGF-1 can directly contribute to cancer development.

Nature of Correlations and Causations:

• Mechanisms:
  • IGF-1 promotes cell proliferation and inhibits apoptosis (programmed cell death), both of which are key processes in cancer development.
  • IGF-1 signaling pathways, such as the Ras/Raf/ERK and PI3K/Akt/mTOR pathways, play a critical role in cancer cell growth and survival.
  • IGF-1 can also influence cancer progression by promoting angiogenesis (the formation of new blood vessels) and metastasis (the spread of cancer).
• Specific Cancers:
  • Breast Cancer:
    • Studies have shown a probable causal role of the IGF-1 pathway in breast cancer development, particularly estrogen receptor-positive (ER+) breast cancer.
  • Prostate Cancer:
    • IGF-1 signaling is strongly implicated in prostate cancer development and progression, including metastasis and therapy resistance.
  • Colorectal Cancer:
    • Elevated IGF-1 levels are associated with increased risk, contributing to cell proliferation in the colon.
• Factors Influencing IGF-1 Levels:
  • Growth hormone (GH) is a primary regulator of IGF-1 production.
  • Diet, particularly high protein and dairy consumption, can influence IGF-1 levels.
  • Obesity is also associated with increased IGF-1 levels, further linking it to cancer risk.

Key Points from Updated Studies:

• Recent research emphasizes the importance of IGF-1 signaling in cancer progression and its potential as a therapeutic target.
• Studies are increasingly focusing on the role of IGF-1 receptor (IGF-1R) signaling and its interactions with other signaling pathways.
• The relationship between IGF-1 and cancer is multifactorial, with genetic, environmental, and lifestyle factors playing a role.

It’s important to note that research in this area is ongoing, and a complete understanding of the complex interplay between IGF-1 and cancer is still evolving.

[mccoy]

An example of the attached references.

[LukeMV]

I posted this elsewhere but it also belongs here. Came out today

Dr. Greg Fahy: Thymus Regeneration & Boosting The Immune System For Longevity

[mccoy]

Study of almost 400,000 confirms that higher blood levels of IGF-1 are a risk...