What is the ideal IGF-1 level for longevity?

[mccoy]

8 hours ago, Saul said:

My guess:  Both IGF1 and IGFBP3 are measured in ng/ml.  The article indicates clearly that IGF1 is measured in ng/ml; so one would presume that the same is true for the numerator and denominator of the ratio.

 Yes, that's confusing and deceiving since we would expect, if the article is so rigorous and has been published in an authoritative journal, that the units used in calculating the ratio in graph B would be the same as the one used for the IGF-1 in graph A. We actually don't know that for sure, unless it's specified within the article somewhere.

On the other side, common sense suggests to us that molar ratios are conventionally used in the ratio, otherwise Ron's value, and your value, would be total outliers, which is unlikely, although not impossible.

The above is an example of unfortunately how scientific rigour is not always respected in the nutrition/biology field. In engineering, using a ratio, with a corresponding dimensionless number which can give rise to ambiguities would have been a serious mistake. Let's remember about the failed satellite launch because metrics units of weight (kilograms) were confused with US units (pounds)...

[mccoy]

8 hours ago, Saul said:

Assuming Michael Rae is correct, my most recently measured ratio (using micromoles/nl instead of micrograms/nl) is about .1.  Using the micrograms per nl, about .03.  I was in the CR group tested by Luigi in that study.  I seem to be lower than average in that ratio in the CR group.

Speaking of average, the graph is not a happy choice. We see an upper error bar, but I don't see the average, or the median, nor a lower error bar (in case the distribution is not a normal or a symmetric one around the mean). To know where you, or Ron, are located in that sample, a boxplot would have been much more useful. Maybe in the text or in some annex the authors have reported all the numerical data, then we may build our sample distribution and know to what percentiles your value belongs.

[Ron Put]

I found this study interesting. Apologies if it has been posted already:

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

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.

[Ron Put]

So, I just had my IGF-1 and IGFBP-3 tested again and the results are a bit of a surprise. My IGF-1 has shot up from 171 nine months ago, to just over 200, while my IGFBP-3 has dropped a little. The result is that my IGF-1:IGFBP-3 ratio went from less than 0.13 to 0.16.5.

The weird part is that I have reduced my protein intake from 127% of RDA to 124% of RDA, with a corresponding reduction in methionine intake.

The most significant change over the last three months is the reduction in fat intake, from 112% (Omega-3: 466% and Omega-6: 118%) of RDA, to 88% (Omega-3: 311% and Omega-6: 96%)of RDA.  I've reduced by about 50% the number of nuts I eat, as well as the amount of flax, and avocados.

Finally, I also started taking Berberine, at 1g-2g doses alternating with 1g doses. I just did a quick search, and this may be contributing to the higher IGF-1 results:

Effect of Resistance Training and Berberine Chloride Supplementation on IGF-1, PDGF, and VEGF Gene Expression in Hippocampal Tissue of Diazinon-Poisoned Rats

"Results: The results showed that resistance training and berberine chloride significantly increased the levels of IGF-1, PDGF, and VEGF gene expression in poisoned rats. Conclusions: Based on the results of this study, resistance training and berberine supplementation have significant effects on reducing the harmful effects of diazinon toxin (P < 0.05) and increasing IGF-1, PDGF, and VEGF gene expression in poisoned rats."

Of course, I might be reading this wrong, or the bump may just be a random fluke.

P.S. I should add that I have likely increased my muscle mass a little bit, as I've upped the number of push-ups I do to about 150 per day (30 + 5x25) a couple of times per week, as well as hiking 5-6 days instead of 3-4 days per week, which may also have an effect, I guess.

Edited May 11, 2021 by Ron Put

[Saul]

On 5/11/2021 at 5:01 PM, Ron Put said:

So, I just had my IGF-1 and IGFBP-3 tested again and the results are a bit of a surprise. My IGF-1 has shot up from 171 nine months ago, to just over 200, while my IGFBP-3 has dropped a little. The result is that my IGF-1:IGFBP-3 ratio went from less than 0.13 to 0.16.5.

The weird part is that I have reduced my protein intake from 127% of RDA to 124% of RDA, with a corresponding reduction in methionine intake.

The most significant change over the last three months is the reduction in fat intake, from 112% (Omega-3: 466% and Omega-6: 118%) of RDA, to 88% (Omega-3: 311% and Omega-6: 96%)of RDA.  I've reduced by about 50% the number of nuts I eat, as well as the amount of flax, and avocados.

Finally, I also started taking Berberine, at 1g-2g doses alternating with 1g doses. I just did a quick search, and this may be contributing to the higher IGF-1 results:

Effect of Resistance Training and Berberine Chloride Supplementation on IGF-1, PDGF, and VEGF Gene Expression in Hippocampal Tissue of Diazinon-Poisoned Rats

"Results: The results showed that resistance training and berberine chloride significantly increased the levels of IGF-1, PDGF, and VEGF gene expression in poisoned rats. Conclusions: Based on the results of this study, resistance training and berberine supplementation have significant effects on reducing the harmful effects of diazinon toxin (P < 0.05) and increasing IGF-1, PDGF, and VEGF gene expression in poisoned rats."

Of course, I might be reading this wrong, or the bump may just be a random fluke.

P.S. I should add that I have likely increased my muscle mass a little bit, as I've upped the number of push-ups I do to about 150 per day (30 + 5x25) a couple of times per week, as well as hiking 5-6 days instead of 3-4 days per week, which may also have an effect, I guess.

My May 7 Tests:

CRP < 3 mg/L

IGF1  85 ng/mL

IGFBP3  3,020 ng/mL

[Ron Put]

You are doing great, Saul.

[Saul]

😊

[Alex K Chen]

Isn't low IGF1 most of the time, but with intermittent pulsing (eg to activate stem cells) - ideal?

[Sibiriak]

On 8/13/2020 at 9:41 PM, mccoy said:

My IGF-1 turned to be pretty low, 90 ng/ml at age 60. My protein intake is pretty significant, often RDA+30% and higher, with dairy proteins rich in methionine.  So it is the reverse of what it should be according to theory. My total testosterone instead turned out to be pretty high, almost at the upper bound of the interval for my age.

I also have quite low IGF-1 and quite high testosterone (above the upper bound for my age), with mid-range DHEA-S,   which got me thinking that it might not be advisable to  jump to conclusions looking  at these biomarkers in isolation.    Could it be that high testosterone compensates for some of the potential negative effects of low IGF-1?    

Ron Put linked to a study earlier in this thread that  supports the idea of looking at hormonal biomarkers as an interactive group, rather than separately. (Note: the study only deals with potential negative effects of low IGF-1,  not high IGF-1.)

Relationship Between Low Levels of Anabolic Hormones and 6-Year Mortality in Older Men (full text)

Quote

Conclusions 

Age-associated decline in anabolic hormone levels is a strong independent predictor of mortality in older men. Having multiple hormonal deficiencies rather than a deficiency in a single anabolic hormone is a robust biomarker of health status in older persons.

It is currently believed that anabolic-catabolic imbalance that favors catabolism is a key factor of accelerated aging in men.¹ The imbalance is mostly related to abnormalities in 3 anabolic endocrine axes, gonadal, adrenal, and somatotropic, with a decline in testosterone, dehydroepiandrosterone sulfate (DHEA-S), and insulinlike growth factor 1 (IGF-1), respectively.¹ Anabolic impairment may facilitate the decline in muscle mass, increase in fat mass, development of insulin resistance, and several medical conditions that, in turn, affect mortality.^1,2

The contribution of single hormonal deficiency to age-related morbidity and mortality has been described in previous studies. Shores et al³ showed that testosterone, the main anabolic hormone in men, is a predictor of mortality in male veterans. The extent to which this finding is valid for the general population is still in question. According to Roth et al,⁴ DHEA-S has been considered one of the mediators of the relationship between caloric restriction and longevity in both animals and humans. Barrett-Connor et al⁵ found that low DHEA-S levels predict cardiovascular mortality in older men, and Cappola et al⁶ found that in older disabled women the relationship between DHEA-S and mortality is not linear. However, further studies⁷ performed in the older population were unable to validate these findings. Signaling of IGF-1 has been considered a determinant of longevity, probably because of beneficial effects on muscle, vasculature, and metabolism.⁸ However, although IGF-1 was shown to be a predictor of cardiovascular mortality in older men,^9,10 the role of IGF-1 as a single determinant of longevity is still debated.¹¹

On the basis of these contradictory data, it is unlikely that a single anabolic hormone deficiency could be considered a reliable index of the aging process. Interestingly, plurihormonal dysregulation rather than single hormonal derangement has been associated with the frailty syndrome^12,13 or the metabolic syndrome in older men.¹⁴ In men with chronic heart failure, deficiency of more than 1 anabolic hormone identifies patients with higher mortality rates.¹⁵ However, data concerning the relationship between parallel deficiency of anabolic hormones and mortality in a general population of older men, regardless of specific disease, are still lacking. Using data from the Aging in the Chianti Area (InCHIANTI) study, we hypothesized that a decline in the level of multiple anabolic hormones rather than in a single hormone predicts mortality during a 6-year follow-up in older men.

 

Quote

[...]We found that independent of age and multiple potential confounders, low circulating levels of multiple anabolic hormones, including testosterone, IGF-1, and DHEA-S (in the lowest quartiles of the population), were an independent predictor of mortality during 6 years of follow-up in older men. On the contrary, serum levels of each of these hormones considered separately were not associated with significantly differential mortality.

Quote

[...]Interestingly, in this study, we did not find any significant association between decline in a single hormone level and overall mortality.

Quote

[...]Multisystem disorders that are widely prevalent in aging, such as the metabolic syndrome, frailty syndrome, and chronic heart failure, are more significantly associated with multiple hormonal dysregulation rather than a single hormonal derangement.^12-15 Studies¹⁵ have found that the risk of death increases progressively with the number of dysregulated hormones and becomes 2.5 times higher when 3 hormones are dysregulated compared with no dysregulation.

It is conceivable that DHEA-S, testosterone, and IGF-1 have synergistic effects. For example, DHEA-S can be converted to testosterone in peripheral tissues, and some of the peripheral actions of both DHEA-S and testosterone may be mediated via tissue-generated IGF-1.^25,34,35 In preliminary analyses performed in the Baltimore Longitudinal Study on Aging population, both DHEA-S and testosterone had a joint protective effect on 30-year mortality rates.³⁶

 

 

 

 

Edited May 25, 2021 by Sibiriak

[mccoy]

Another limitation of the study of the systemic IGF-1 is that it ignores local concentrations, like the MGF (mechanogrowth factor), an IGF analog that concentrates in muscle tissues after resistance exercise.

There might even be some local IGF analog in the nervous system, whose health seems to be positively correlated to the presence of IGF-1 (just a speculation).

Today I just listened to the Attia-Norton podcast, where Layne Norton just hinted at the above, calling the MGF an autocrine, or pericrine hormone ( I had no idea local hormonal secretions had this definition).

 

[mccoy]

Another concept to ponder upon would be the IGF-1 and HGH correlation. Low systemic IGF-1 would mean low growth hormone, which is a hypertrophy factor for muscle tissues but particularly for connective tissue. On the other hand, testosterone definitely commands muscle tissue hypertrophy.

I agree that the real world seems to be much more complex than much of the simplified scientific models proposed by the literature.

[mccoy]

Re-pasting and extract from an Attia-Rhonda podcast cited in an earlier post. Neurogenesis by IGF-1 is cited, and since it has been observed that exercise is one of the 3 boosters of neurogenesis, via BDNF increase, that might be some other autocrine IGF analog at work (my speculation)

 

[Sibiriak]

14 hours ago, mccoy said:

Layne Norton just hinted at the above, calling the MGF an autocrine, or pericrine  [paracrine] hormone ( I had no idea local hormonal secretions had this definition).

Thanks for the video.  I skipped through a lot of the beginning stuff (long video!)... found the discussion at around 1:54.   I was familiar with the autocrine/paracrine/endocrine  distinctions in the context of the myokine concept:

Muscles and their myokines (2011)

Quote

Summary

In the past, the role of physical activity as a life-style modulating factor has been considered as that of a tool to balance energy intake. Although it is important to avoid obesity, physical inactivity should be discussed in a much broader context. There is accumulating epidemiological evidence that a physically active life plays an independent role in the protection against type 2 diabetes, cardiovascular diseases, cancer, dementia and even depression.  For most of the last century, researchers sought a link between muscle contraction and humoral changes in the form of an ‘exercise factor’, which could be released from skeletal muscle during contraction and mediate some of the exercise-induced metabolic changes in other organs such as the liver and the adipose tissue.

We have suggested that cytokines or other peptides that are produced, expressed and released by muscle fibres and exert autocrine, paracrine or endocrine effects should be classified as ‘myokines’. Given that skeletal muscle is the largest organ in the human body, our discovery that contracting skeletal muscle secretes proteins sets a novel paradigm: skeletal muscle is an endocrine organ producing and releasing myokines, which work in a hormone-like fashion, exerting specific endocrine effects on other organs. Other myokines work via paracrine mechanisms, exerting local effects on signalling pathways involved in muscle metabolism. It has been suggested that myokines may contribute to exercise-induced protection against several chronic diseases.

Exercise-induced myokines in health and metabolic diseases (2014)

Quote

Abstract

Skeletal muscle has been emerging as a research field since the past 2 decades. Contraction of a muscle, which acts as a secretory organ, stimulates production, secretion, and expression of cytokines or other muscle fiber-derived peptides, i.e., myokines. Exercise-induced myokines influence crosstalk between different organs in an autocrine, endocrine, or paracrine fashion. Myokines are recently recognized as potential candidates for treating metabolic diseases through their ability to stimulate AMP-activated protein kinase signaling, increase glucose uptake, and improve lipolysis. Myokines may have positive effects on metabolic disorders, type 2 diabetes, or obesity. Numerous studies on myokines suggested that myokines offer a potential treatment option for preventing metabolic diseases. This review summarizes the current understanding of the positive effects of exercise-induced myokines, such as interleukin-15, brain-derived neurotrophic factor, leukemia inhibitory factor, irisin, fibroblast growth factor 21, and secreted protein acidic and rich in cysteine, on metabolic diseases.

 

Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases (2018)

 

Edited May 26, 2021 by Sibiriak

[Mike Lustgarten]

Reductions in serum IGF-1 during aging impair health span

https://pubmed.ncbi.nlm.nih.gov/24341939/

[Sibiriak]

Insulin-like Growth Factor-1 and IGF Binding Proteins Predict All-Cause Mortality and Morbidity in Older Adults  (2020)

https://www.mdpi.com/2073-4409/9/6/1368/htm

 

Quote

Abstract

While the growth hormone/insulin-like growth factor-1 (GH/IGF-1) pathway plays essential roles in growth and development, diminished signaling via this pathway in model organisms extends lifespan and health-span. In humans, circulating IGF-1 and IGF-binding proteins 3 and 1 (IGFBP-3 and 1), surrogate measures of GH/IGF-1 system activity, have not been consistently associated with morbidity and mortality. In a prospective cohort of independently-living older adults (n = 840, mean age 76.1 ± 6.8 years, 54.5% female, median follow-up 6.9 years), we evaluated the age- and sex-adjusted hazards for all-cause mortality and incident age-related diseases, including cardiovascular disease, diabetes, cancer, and multiple-domain cognitive impairment (MDCI), as predicted by baseline total serum IGF-1, IGF-1/IGFBP-3 molar ratio, IGFBP-3, and IGFBP-1 levels.

 

All-cause mortality was positively associated with IGF-1/IGFBP-3 molar ratio (HR 1.28, 95% CI 1.05–1.57) and negatively with IGFBP-3 (HR 0.82, 95% CI 0.680–0.998). High serum IGF-1 predicted greater risk for MDCI (HR 1.56, 95% CI 1.08–2.26) and composite incident morbidity (HR 1.242, 95% CI 1.004–1.538), whereas high IGFBP-1 predicted lower risk for diabetes (HR 0.50, 95% CI 0.29–0.88)

 

In conclusion, higher IGF-1 levels and bioavailability predicted mortality and morbidity risk, supporting the hypothesis that diminished GH/IGF-1 signaling may contribute to human longevity and health-span.

 

Edited June 15, 2021 by Sibiriak

[mccoy]

I like how all researchers agree on optimal IGF-1 serum values...😓

Edited June 15, 2021 by mccoy

[Todd Allen]

5 hours ago, mccoy said:

I like how all researchers agree on optimal IGF-1 serum values...😓

Some prefer to die from degenerative diseases such as sarcopenia and Alzheimer's.  Others prefer to die from cancer.

[Sibiriak]

6 hours ago, mccoy said:

I like how all researchers agree on optimal IGF-1 serum values...

 I saw that coming!    We already know, of course,  that IGF-1 is a double-edged sword.

In any case, the 2013 study posted by Mike L is a narrowly-focused modified-mouse study that makes no claim about optimal IGF-1 serum levels in humans.   It's not directly comparable to the 2020 human study I posted.

Quote

... we developed an inducible liver IGF-1-deficient (iLID) mouse that allows temporal control of serum IGF-1. Deletion of liver Igf -1 gene at one year of age reduced serum IGF-1 by 70% and dramatically impaired health span of the iLID mice.

Quote

Using the iLID model, we induced IGF-1 deficiency after the critical phase of growth and development and followed the mice up to two years of age. We have found that in iLID mice reductions in serum IGF-1 and concomitant increases in GH levels during aging associated with increased liver weight, systemic and liver inflammation, increased oxidative stress, and increased incidence of hepatic tumors, although this did not reach significance.

We postulate that this phenotype relates to the unopposed action of high GH levels on hepatocytes,

[...] we show, for the first time, that elevations in GH late in life have detrimental effects on the liver.

 

 

Edited June 16, 2021 by Sibiriak

[mccoy]

The figure is from the Zheng et al. article posted by Sibiriak. How do you guys read it?

That's a kaplan-meier model, to survival curve. In the X-axis we have time, in the Y axis percent of individuals survived at time X. In blue we have lower values, presumably lower IGF-1 values. I would tend to read that after time unit 8 (years?) 75% of males with lower IGF-1 survive, whereas 85% of males with higher IGF-1 survive, so it seems to be the other way around:

Males with lower total IGF-1 values would tend to survive less.

In this graph it would be the other way around, that is males with lower IGF-1 have lower mortality ratio, although not statistically significant.

Other graphs would show that IGFBP governs, other that lower IGF-1 is beneficial against morbidities.

Even this article is not totally lacking confusion, at least this is my potentially erroneous feeling.

[Ron Put]

On 6/18/2021 at 2:30 PM, mccoy said:

Even this article is not totally lacking confusion, at least this is my potentially erroneous feeling.

I have decided that the evidence is inconsistent enough for me to pay much attention. It may be just because my own IGF-1 is stubbornly higher than 160, and I am just looking for comfort in my own bias, but I am also genuinely confused.

I don't know if this has been posted here before:

Functionally significant insulin-like growth factor I receptor mutations in centenarians

Results

Height and IGFI Levels in the Offspring of Centenarians.

Because plasma levels of IGFI in centenarians do not reflect their levels at a younger age, we compared the levels of IGFI in offspring of centenarians to controls without a family history of longevity to identify a potential alteration in the IGF signaling pathway, which may contribute to exceptional longevity. Remarkably, female offspring (n = 105) showed 35% higher serum IGFI levels (P < 0.01) compared with female controls (n = 67), suggesting a possible alteration in the GH/IGF pathway in the longevity of females (Fig. 1 A). This phenomenon was gender-specific, as IGFI levels in male offspring (n = 92) and male controls (n = 42) were identical (Fig. 1 A). To distinguish whether the high IGFI is caused by increased production or is a result of IGF insensitivity, we assessed maximal reported height, a necessary parameter because of the height shrinkage that occurs in the elderly. Female offspring were 2.5 cm shorter compared with controls (P < 0.001), whereas the height of males was identical in offspring and controls (Fig. 1 B). Thus, a likely explanation for this finding is that the higher IGFI levels represent a compensatory response to reduced IGFIR signaling, which would also be associated with a small decrease in maximal height, (although a less bioactive IGFI molecule is also a possibility). Remarkably, this combination of a female-specific effect on longevity, higher IGFI levels, with a small reduction in auxological growth, is highly reminiscent of a report on female mutant mice haploinsufficient for the IGFIR, which display nearly identical features, including gender-specific lifespan extension

[mccoy]

 

8 hours ago, Ron Put said:

Thus, a likely explanation for this finding is that the higher IGFI levels represent a compensatory response to reduced IGFIR signaling, which would also be associated with a small decrease in maximal height, (although a less bioactive IGFI molecule is also a possibility).

Maybe the confusion is due to the existence of many variables, like the cited IGF1R (the IGF-1 receptor protein), whose oscillations cause contrary oscillations in the IGF-1 concentration, with the same final biological effects (the receptors govern the IGF-1 signal reaching the interior of the cell).

So, IGF-1, IGF1BP, IGF-1R, systemic IGF.1, local IGF1, IGF-1 - like mechanoreceptors in muscles, the system is a complex one, and the solution often not exactly workable.

As to the optimum value, it may even vary across individuals: IGF1BP governs the active form of circulating IGF-1 and IGF1R governs the power of the signal reaching the cell. Plus, there are various forms of IGF and IGFBP ....

[alexthegra8]

Sorry for what may appear to be an intuitive question --

If adhering to a 30% calorie restriction protocol, would a high fat low protein diet (animal fat) raise IGF levels ?

in comparison to:

a high fat low protein (plant fat)?

a low fat low protein diet?

 

Thanks,

Edited August 17, 2021 by alexthegra8

[mccoy]

On 8/17/2021 at 4:18 PM, alexthegra8 said:

Sorry for what may appear to be an intuitive question --

If adhering to a 30% calorie restriction protocol, would a high fat low protein diet (animal fat) raise IGF levels ?

in comparison to:

a high fat low protein (plant fat)?

a low fat low protein diet?

 

Thanks,

In theory, IGF-1 should decrease by methionine and protein moderation. I don't know about fats, theoretically neutral but might influence IGF-1 by other paths.

In reality, things are different. Last year I had a very low IGF-1, although eating lots of yogurt, with high quantities of methionine.

[alexthegra8]

16 hours ago, mccoy said:

In theory, IGF-1 should decrease by methionine and protein moderation. I don't know about fats, theoretically neutral but might influence IGF-1 by other paths.

In reality, things are different. Last year I had a very low IGF-1, although eating lots of yogurt, with high quantities of methionine.

interesting...perhaps there is something to eating animal products that have high saturated fat contents and their relation to IGF-1? I always considered yogurt to be a "soft" animal product, especially the low fat ones...

[mccoy]

5 hours ago, alexthegra8 said:

interesting...perhaps there is something to eating animal products that have high saturated fat contents and their relation to IGF-1? I always considered yogurt to be a "soft" animal product, especially the low fat ones...

Actually I have no idea, Yogurt was mainly nonfat, but surely Leucine and methionine rich. One punctual measure of course is not representative of the IGF-1 signal across the year; I also exhibited high testosterone and the same combination (low IGF-1, high T) has been reported by another member of this forum, so I'm not apparently an outlier (unless we are both outliers?)