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Gordo

What is the ideal IGF-1 level for longevity?

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On 3/7/2019 at 11:37 AM, Gordo said:

... He also talks about changing protein requirements as we age, <80 you probably only need 0.8g/kg (40-50g protein/day for most people), over 80 you may need up to 50% more protein (about 70g for a 150lb person).  He eats animal products a few times a year.

While it is true that protein consumption and predicted longevity change as a person ages (and the comment made about biological age v chronological age is on point), the preponderance of the evidence is that animal protein is detrimental at any age, when compared to plant protein:

"The associations between animal and plant protein intake and the risk of mortality were examined by a prospective US cohort study involving 131,342 participants and 32 follow-up years [7]. Animal protein intake was related to a higher risk of mortality, particularly CVD mortality. In contrast, higher plant protein intake was associated with lower all-cause mortality. The substitution of animal protein from a variety of food sources, particularly processed red meat, with plant protein was associated with a lower risk of mortality, indicating that the protein source is important for long-term health."
https://www.sciencedirect.com/science/article/pii/S2352396419302397#bb0020

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7 hours ago, Ron Put said:

This is not supported by evidence.

If you accept the idea that avoiding obesity is important for health you might reconsider your position after hearing this brief commentary by Walter Willet:

 

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Such a dumb debate.  Eating more calories than you burn makes you gain weight.  The only real exceptions are the few weird foods that you poop out without absorbing all their calories (some nuts and some fiber).

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31 minutes ago, Gordo said:

... Eating more calories than you burn makes you gain weight.  The only real exceptions are the few weird foods that you poop out without absorbing all their calories (some nuts and some fiber).

Yep. That's a given.

I am not sure what the Walter Willet clip has to do with the subject matter. Eating 5000 calories of white corn is probably not a whole lot of a better idea than eating 5000 calories of bacon. I thought this was a discussion about longevity -- generally, obesity and longevity have an inverse correlation.

The study I pointed out was about substituting plant protein for animal protein, other things being equal. The study concludes that plant protein is significantly better longevity-wise. 

It's also worth noting that traditionally the subject population (Okinawans) consumed about 80% of the average calorie intake of the mainland Japanese population, so they effectively practiced CR. And as 85% of such intake is carbs (bitter leafy stuff and yams), the likelihood of "pooping out" some undigested calories is high).

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Walter Willett: I've even had colleagues who said  you  can't get fat eating carbohydrates because the body can't convert carbohydrate to fat.

Hard to believe anyone at Harvard would make such a ridiculous claim.

 

Quote

Walter Willett: ...the percentage of calories from fat in the diet is not determinant  [of body weight.]

Indeed,   total calories/ energy balance  must be taken into account,  as Gordo pointed out.

Willett's dietary  recommendations:

Quote

At least one-third of early deaths could be prevented if everyone moved to a vegetarian diet, Harvard scientists have calculated.  Dr Walter Willett, professor of epidemiology and nutrition at Harvard Medical School said the benefits of a plant-based diet had been vastly underestimated.  Recent figures from the Office for National Statistics suggested that around 24 per cent or 141,000 deaths each year in Britain were preventable,  but most of that was due to smoking, alcohol or obesity.

But the new figures from Harvard suggest that at least 200,000 lives could be saved each year if people cut meat from their diets. 

https://www.telegraph.co.uk/science/2018/04/26/third-early-deaths-could-prevented-everyone-giving-meat-harvard/

 

Quote

It's worth noting that Willett's comments don't actually use the word “vegetarian”, but rather reference a "healthy" and “more plant-based diet”.

“I didn’t refer to vegetarians for several reasons,” Willett told IFLScience. “First, the replacement issue is critical; if we replace red meat with soda, refined starch, and sugar, we will probably not be better off and might be even worse off.

“However, if we replace it with a mix of nuts, beans, soy foods, and whole grains, we will have lower risks of heart disease, diabetes, and total mortality,” he noted. 

Willett emphasized that this isn't about a “simple dichotomy between being a vegetarian or not,” but instead the continuously lower risks related to greater shifts to a plant-based diet, with "healthy food replacing animal-based foods."

https://www.iflscience.com/health-and-medicine/harvard-professor-says-this-kind-of-diet-would-cut-preventable-deaths-by-a-third/all/

 

Edited by Sibiriak

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There may be an interesting genetic component to IGF-1 levels, too, at least among men, which facilitates speedier decline in IGF-1 after about the age of 85 and thus promotes longevity (as long as they make it there):

"Males showed an age-related increase in the A-allele of rs2229765 and a change in the plasma level of IGF-1, which dropped significantly after 85 years of age (85+ group). In the male 85+ group, A/A homozygous subjects had the lowest plasma IGF-1 level. We found no clear correlation between rs2229765 genotype and IGF-1 in the females.

Conclusion

These findings confirm the importance of the rs2229765 minor allele as a genetic predisposing factor for longevity in Italy where a sex-specific pattern for IGF-1 attenuation with ageing was found."

https://bmcgeriatr.biomedcentral.com/articles/10.1186/1471-2318-9-19

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TAt a first reading the article was not very clear, so I'll have to delve deeper into it.

The following plot though shows extremely scattered values of IGF-1 with age and the correlation coefficient is close to zero. (r=-0.18).

In the technical fields, such a coefficient would suggest no correlation at all.

I really do not understand how the basic assumption of a study can be based on such scattered and almost uncorrelated data.

 

image.png.26e68527d5a42c9beb18fc2b0d1ee11a.png

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And to make the whole IGF-1 thing more confusing, an older article:

"Elderly men with higher activity of the hormone IGF-1--or insulin-growth factor 1--appear to have greater life expectancy and reduced cardiovascular risk, according to a new study.

IGF-1 is a hormone similar in molecular structure to insulin. It is released from the liver and plays an important role in childhood growth and continues to have anabolic effects in adults.

In this study, researchers evaluated 376 healthy elderly men between the ages of 73 and 94 years. A serum sample was taken from each subject at the beginning of the study and researchers were contacted about the status of the participants over a period of eight years.

Subjects with the lowest IGF-1 function had a significantly higher mortality rate than subjects with the highest IGF-1 bioactivity. These results were especially significant in individuals who have a high risk to die from cardiovascular complications.

These new findings come as a result of a new form of testing for IGF-bioactivity. Researchers in this study used a new method, a bioassay, to measure the function of IGF-1 in the blood. Compared to commonly used methods to measure IGF-1, the IGF-1 bioassay gives more information about the actual function (bioactivity) of circulating IGF-1 in the body.

"The bioassay allowed us to more clearly see the association between high circulating IGF-1 bioactivity and extended survival," said Michael Brugts, MD, of the Erasmus Medical Center in Rotterdam, The Netherlands and lead author of the study. "Interestingly, we could not find such a relationship when IGF-1 in blood was measured with the more commonly used methods."

Immunoassays, commonly used previously to determine IGF-1 circulation levels, remove certain proteins that interfere with accurate measurements. Recent studies however have found that these proteins are important modulators of IGF-1 bioactivity. The bioassay used in this study does not disregard or remove this protein, thus enabling researchers to have a more accurate understanding of IGF-1 function. ..."
https://www.sciencedaily.com/releases/2008/05/080527084252.htm

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Elderly men with higher activity of the hormone IGF-1--or insulin-growth factor 1--appear to have greater life expectancy and reduced cardiovascular risk, according to a new study.

It's critical to note that IGF-1 bioactivity, as measured in that 2008 study,  is not the same as total IGF-1 or free IGF-1.

Low Circulating Insulin-Like Growth Factor I Bioactivity in Elderly Men Is Associated with Increased Mortality (2008)

https://academic.oup.com/jcem/article/93/7/2515/2598506

Quote

Discussion

This 8-yr prospective study in elderly men showed that higher circulating IGF-I bioactivity is associated with better overall survival. Individuals in the lowest quartile of IGF-I bioactivity had a 1.8-fold increased mortality risk compared with individuals in the highest quartile. Interestingly, for total and free IGF-I measurements as well as for the total IGF-I/IGFBP-3 ratios, we could not find such relationship

[...] The IGF-I KIRA was used to measure IGF-I bioactivity (13, 14), which was significantly associated with other IGF-I system parameters measured by immunoassay. However, none of these associations had correlation coefficients greater than 0.5. This suggests that in comparison with immunoassays, the KIRA produces different information about circulating IGF-I.

[...] Of interest is the observed discrepancy between IGF-I bioactivity and free IGF-I in our study. Both parameters are believed to be informative about the fraction of circulating total IGF-I that interacts with the IGF-IR [ IGF-I receptor ]. Mean IGF-I bioactivity was significantly greater than mean free IGF-I level, and correlation between these parameters was poor. An explanation could be that the IGF-I KIRA is more sensitive than free IGF-I levels in estimating the concentration of circulating IGF-I that interacts with the IGF-IR...

 

 

Also this proviso should be kept in mind:

Quote

[...]it remains to be seen whether reduced IGF-I bioactivity is an endocrine contributor to mortality risk or simply an epiphenomenon related to overall health/resistance to inflammation.

 

And there is this key point:

Quote

In this study, a relatively high circulating IGF-I bioactivity was associated with a lower mortality risk. This is in contrast to results reported in animal studies, where low circulating IGF-I levels were associated with increased survival. An explanation could be that in these animal studies, effects of IGF-I on the rate of aging were studied during lifelong exposure, whereas our study provides insight into IGF-I activity only toward the end of life.

 

Edited by Sibiriak

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Sibiriak:     According to Michael Rae and others,  IGF-1 measurements alone are not really informative;  you also  need  to look at the IGF-1/ IGFBP-3 ratio  to assess the biological activity  of the IGF-1 [" a higher level of IGFBP-3 at a given IGF-1 level (hence, a lower IGF-1:IGFBP-3) means less free IGF-1 and lower biological activity."   https://www.crsociety.org/topic/16981-what-is-the-ideal-igf-1-level-for-longevity/?tab=comments#comment-31176

 

I'll probably get my IGF-1 tested in the near future, largely out of curiosity,  but an  IGFBP-3 test doesn't seem feasible for me at this time,  not to mention IGF-I KIRA, lol.   Ideally,  my level won't deviate too drastically from Longo's suggested 140 ng/ml,  but if it comes in quite low I would consider increasing my protein intake (currently is around .7g/kg), something I would be expecting to do anyway at some future point following the Longo/Levine/Fontana lines of thought.

Edited by Sibiriak

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Thanks for the great summary, Sibiriak. I am still confused though, because they effectively say that there is no correlation between longevity in humans and total IGF-1 or IGF-1/IGFBP-3 ratio, only with IGF-1 bioactivity. The study I cited above also appears to indicate higher IFG-1 being beneficial until about 85 and then lower IFG-1 being beneficial to survival.

See also this one:

"It’s not quite the elixir of life, but researchers have at last identified gene variants that make people live longer. Men may miss out, as all carriers identified so far are women. They are also slightly shorter than average.

...

Both mutations affect the receptor for insulin-like growth factor 1 (IGF1), a driver of bodily growth and maturity, especially during puberty. By making the receptor slightly faulty, the mutations may disrupt IGF1 binding and decelerate the process of maturation and ageing.

 

In support, they found circulating levels of IGF1 to be 37% higher in carriers of the mutation, probably to compensate for the underperforming receptor. Carriers were also 2.5 centimetres shorter on average than the general population. ..."

https://www.newscientist.com/article/dn13403-long-life-genes-found-in-100-year-old-humans/

 

I am debating if I should dramatically reduce my (plant) protein intake (currently at about 1.4g per kg), since my IGF-1 is now above 180. My guess is this will adversely affect muscle mass, which is also an issue. And then I look at the human studies about IGF-1 and am starting to think that maybe I shouldn't worry so much about IGF-1 levels (confirmation bias may also play a role in my case) 🙂

 

Edited by Ron Put

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On 8/18/2019 at 2:03 PM, mccoy said:

The following plot though shows extremely scattered values of IGF-1 with age and the correlation coefficient is close to zero. (r=-0.18).

In the technical fields, such a coefficient would suggest no correlation at all.

I really do not understand how the basic assumption of a study can be based on such scattered and almost uncorrelated data.

mccoy, I think the issue with the scatterplot in that particular figure is that the relationship they are describing is not linear, so r=0.18 is misleading in this context.

Note this statement:

"age-related increase in the A-allele of rs2229765 and a change in the plasma level of IGF-1, which dropped significantly after 85 years of age (85+ group). In the male 85+ group, A/A homozygous subjects had the lowest plasma IGF-1 level."
 

Then look at the A/As in this figure and their plasma IGF-1 at 70-85 and then at 85+, compared to G/G and G/A:


988850921_ScreenShot2019-08-19at11_22_57.png.488be2ef6ebbfe7757fcd19bf1308237.png
 

Edited by Ron Put

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Ron, I agree, the genotype A/A exhibits the lowest IGF-1 range in males with age > 85, whereas other genotypes do not exhibit such a drop, so maybe study of the A/A genotype in males > 85 years might be of relevance to longevity. Not a big takehome lesson, nothing immediately applicable by ourselves methinks.

And back to the IGF-1 plot, I really don't see any correlation even in the non linear fashion. Besides, the values are so scattered and there are such montruos outliers that no practical conclusions can be reached. 

I believe so far the only scheme we could agree upon is to take as a reference Valter Longo's 140 ng/mL, check our values, try to comply by adjusting our protein and especially methionine intake. If the values are pretty far from Longo's optimum, then there might be some particular issue to figure out.

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These are the podcast notes in the PA-Rhonda epipsode. Some optimum values for IGF-1 are displayed. source:

 

J Clin Endocrinol Metab. 2011 Sep;96(9):2912-20. doi: 10.1210/jc.2011-1377. Epub 2011 Jul 27.

Meta-analysis and dose-response metaregression: circulating insulin-like growth factor I (IGF-I) and mortality.

image.png.465961d8dc2b9ae14d0698bb2062f8b5.png

Edited by mccoy

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According to the above metanalysis by Burgers et al., 2011, Low levels of IGF-1 are bad for either CVD risk and cancer risk. High levels are bad for cancer risk.

My doubt is that the optimum range for minimum cancer risk seems to be pretty narrow, let's say in the 100-125 ng/ml interval. Keeping the IGF-1 constantly within this range would probably be very hard. Also, the whole range stands below Longo's optimum value of 140 ng/ml-

The takehome lesson is pretty clear though. CR practitioners should check that IGF-1 is not too low, resulting in increased all causes mortality.

Conversely, non CR practitioners should check that it is not too high.

Dr. Fuhrman's 100-150 optimum range seems to be relatively accurate but maybe too excessive in the higher end of the interval , according always to the Burgers et al. metanalysis.

Edited by mccoy

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Good points and data, mccoy. I am still unsure I grasp the data, or at least am not entirely comfortable with what I am grasping from the data.

Part of it may be my confusion of what constitutes "high" levels in a lot of the studies (apart from the Longo studies). From what I read, it would appear that higher IGF-1 levels are beneficial, up to close to 200 ng/ml, as long as one does not have cancer. If cancer is present, then IGF-1 is detrimental. Yet other studies find no relation between IGF-1 and longevity, unless too low or too high.

Even looking at the levels in Fig. 2 above, the A/A homozygous subjects show about 200 ng/ml on average at the age of 75-85, which is actually rather high for that age (kind of like Okinawans having higher levels of testosterone than the general population).

Again, this is likely my own confirmation bias talking, but the questions it rises are still valid, I think.

Edited by Ron Put

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4 hours ago, Ron Put said:

From what I read, it would appear that higher IGF-1 levels are beneficial, up to close to 200 ng/ml, as long as one does not have cancer. If cancer is present, then IGF-1 is detrimental.

Ron, I could not read the full article by Burgers et al. since presently sci-hub is not reachable from here. Judging by the plots only, even at 150 ng/ml the hazard ratio is pretty high for cancer, whereas it's zero for CVD. I must confess the scale on the Y axis makes me wonder, it reads log hazard ratio but there is a zero and negative numbers which clashes with the definition of logarithms. So I dont't know the exact parameter and if there is some tricky scale effects which amplifies the vertical scale.

Higher IGF-1 is ostensibly beneficial to the nervous system and skeletal muscle-system, but I know no literature about that. Very regular exercise according to Longo may substitute higher IGF-1 to boost muscle protein synthesis and avoid sarcopenia. In such a way it would be possible not to increase protein when over 65. In theory, at least.

Obviously, familiarity with cancer or previous cancers would suggest strongly to try and do whatever is possible to keep IGF-1 at the optimum range of 100-120 mg/ml, if it is possible at all to manage IGF-1 in such an accurate fashion (probably not).

Also, if familiarity or previous cancers are present, it makes sense to adopt a more accurate risk level analyzing IGFBP and free IGF-1, if we have data, benchmarks, optimum ranges about them to guide us in a preventional scheme. 

Further confounding factors may be IGF-1 receptor sensitivity and activation of the post-receptor pathway. An optimum plasma IGF-1 may turn out to result in high IGF-1 signaling effects (for example in the mTOR pathway) in the presence of high receptor sensitivity and the other way around

Maybe I'll have to listen again to the Peter Attia podcast with Barzilai, where they discuss IGF-1 and longevity. I remember Barzilai said that the lower IGF-1 in some more longeve people may be reverse causation (they are not more longeve because of the low IGF-1 but they are approaching death and the drop in IGF-1 is a consequence of that)

Edited by mccoy

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Published online 2019 Feb 1. doi: 10.3389/fendo.2019.00027
PMCID: PMC6367275
PMID: 30774624

ROLE of IGF-1 System in the Modulation of Longevity: Controversies and New Insights From a Centenarians' Perspective

 

Abstract

Human aging is currently defined as a physiological decline of biological functions in the body with a continual adaptation to internal and external damaging. The endocrine system plays a major role in orchestrating cellular interactions, metabolism, growth, and aging. Several in vivo studies from worms to mice showed that downregulated activity of the GH/IGF-1/insulin pathway could be beneficial for the extension of human life span, whereas results are contradictory in humans. In the present review, we discuss the potential role of the IGF-1 system in modulation of longevity, hypothesizing that the endocrine and metabolic adaptation observed in centenarians and in mammals during caloric restriction may be a physiological strategy for extending lifespan through a slower cell growing/metabolism, a better physiologic reserve capacity, a shift of cellular metabolism from cell proliferation to repair activities and a decrease in accumulation of senescent cells. Therefore, understanding of the link between IGF-1/insulin system and longevity may have future clinical applications in promoting healthy aging and in Rehabilitation Medicine.

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Effect of calorie restriction or protein intake on circulating levels of insulin like growth factor I in humans: A systematic review and meta-analysis.
Kazemi A, Speakman JR, Soltani S, Djafarian K.
Clin Nutr. 2019 Aug 10. pii: S0261-5614(19)30312-7. doi: 10.1016/j.clnu.2019.07.030. [Epub ahead of print]
PMID: 31431306
https://sci-hub.tw/10.1016/j.clnu.2019.07.030
Abstract
Calorie restriction (CR) and reductions in protein intake in rodents result in increased lifespan and reduced levels of IGF-1. However, the changes in IGF-1 in humans in response to CR and elevated protein intake are confused. We conducted a systematic review and meta-analysis to investigate the effect of Calorie restriction (CR) or increase in protein intake on IGF-1 in humans. The systematic review protocols have been developed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines. Two separate systematic searches were undertaken: first for the effect of CR and second on the effect of increase in protein intake on IGF-1. PubMed, SCOPUS and ISI Web of Science databases were searched. In the meta-analysis of the calorie restriction studies, twelve studies met the inclusion criteria (8 clinical trials and 4 observational studies). The meta-analysis of both clinical trials and observational studies revealed no significant effect of CR on IGF-1 (clinical trials: standardized mean difference (SMD) = 0.002 ng/ml, 95% CI -0.14 to 0.14 ng/ml, p = 0.98; observational studies (SMD = -1.14 ng/ml, 95% CI -1.9 to -0.38 ng/ml, p = 0.003). In the meta-analysis of protein intake studies (six studies), a significant increase in circulating IGF-1 levels in response to increases in dietary protein was revealed (SMD = 0.4 ng/ml, 95% CI 0.18-0.61 ng/ml, p < 0.001). In conclusion, in humans, CR was not associated with a significant change in circulating IGF-1. However an increase in protein intake was associated with increased levels of circulating IGF-1.
KEYWORDS:
Aging; Calorie restriction; IGF-1; Insulin like growth factor 1; Protein intake

Edited by AlPater

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5 hours ago, AlPater said:

In conclusion, in humans, CR was not associated with a significant change in circulating IGF-1. However an increase in protein intake was associated with increased levels of circulating IGF-1.

I'm not sure as to construe the above, since the 'significant' increas was reported as a standardized mean difference of 0.4 ng/ml, which is not a very intuitive quantity. A very small SMD means very little difference between groups and the difference in means is scaled to the standard deviation, so scattered data make any differences in mean less significant.

definition of SMD:

 

image.png.d26769b340520afae7228913903cc158.png

 

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Relationship Between Low Levels of Anabolic Hormones and 6-Year Mortality in Older MenThe Aging in the Chianti Area (InCHIANTI) Study

Methods  Testosterone, IGF-1, DHEA-S, and demographic features were evaluated in a representative sample of 410 men 65 years and older enrolled in the Aging in the Chianti Area (InCHIANTI) study. A total of 126 men died during the 6-year follow-up. Thresholds for lowest-quartile definitions were 70 ng/dL (to convert to nanomoles per liter, multiply by 0.0347) for bioavailable testosterone, 63.9 ng/mL (to convert to nanomoles per liter, multiply by 0.131) for total IGF-1, and 50 μg/dL (to convert to micromoles per liter, multiply by 0.027) for DHEA-S. Men were divided into 4 groups: no hormone in the lowest quartile (reference) and 1, 2, and 3 hormones in the lowest quartiles. Kaplan-Meier survival and Cox proportional hazards models adjusted for confounders were used in the analysis.

Results  Compared with men with levels of all 3 hormones above the lowest quartiles, having 1, 2, and 3 dysregulated hormones was associated with hazard ratios for mortality of 1.47 (95% confidence interval [CI], 0.88-2.44), 1.85 (95% CI, 1.04-3.30), and 2.29 (95% CI, 1.12-4.68), respectively (test for trend, P <.001). In the fully adjusted analysis, only men with 3 anabolic hormone deficiencies had a significant increase in mortality (hazard ratio, 2.44; 95% CI, 1.09-5.46 (test for trend, P <.001).

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.



And this is an interesting observation about DHEA-S levels in men correlating with longevity:



Long-term study links DHEAS to longevity in men

Among these variables, the researchers found that high levels of DHEAS were the most strongly linked to a longer life. The relationship between DHEAS and longevity remained even after the researchers adjusted for glucose levels, age and blood pressure.

But before the 15-year follow-up point, there was no difference in longevity among men based on DHEAS levels, the researchers note, which may help explain why some past research found no relationship between the hormone and longevity.

Edited by Ron Put

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To further add to my confusion about IGF-1:

"The main findings of this study are twofold. First, consistent with the lower prevalence of diabetes observed earlier, non-fasted serum glucose levels were lower in the offspring of familial nonagenarians when compared to their partners. Second, we did not observe differences in non-fasted serum levels of IGF-1, IGFBP3 or in height between the groups of offspring and partners, nor in the rate of the decline of levels of IGF-1 or IGFBP3 over chronological age. Taken together, these data indicate that familial longevity is associated with differences in glucose handling, which are not explained by major differences in IGF-1 and/or IGFBP3 levels.

The link between reduced IIS activity and longevity is evolutionarily conserved from worms to rodents, with effects on longevity often being stronger in the female sex. However, separating the roles of insulin and IGF-1 in mammals has been very difficult and generated much controversy. Because the actions of GH, insulin and IGF-1 are largely interwoven, genetic modification of the GH/IGF-1 axis in mammals also entails differences in the regulation of glucose metabolism. Interestingly, the hallmark phenotype of all long-lived mouse models containing mutations that induce GH/IGF-1 deficiency or resistance, is their enhanced insulin sensitivity [6]. Previously, we observed a lower prevalence of diabetes in the offspring group [3]. Here, we show that after exclusion of all diabetics, lower non-fasted glucose levels were observed in the group of offspring of familial nonagenarians as compared to the partners. The lower non-fasted glucose levels in offspring compared to partners are suggestive of a better glucose handling and/or higher insulin sensitivity in familial longevity, which is in line with the hallmark phenotype observed in the many long-lived mammalian IIS mutants. Other data also support a link between preserved insulin sensitivity and human longevity. While insulin sensitivity generally declines with age in humans [25], sporadic long-lived centenarians have been shown to exhibit an exquisite insulin sensitivity, comparable to that of young adults [26]."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806046/

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Hi Ron,

See the follow up Leiden Longevity Study publication, Association analysis of insulin-like growth factor-1 axis parameters with survival and functional status in nonagenarians of the Leiden Longevity Study (1).

There they found that "lower IGF-1/IGFBP3 molar ratios conferred a survival benefit at the age of ninety years or older [and] Secondly, lower IGF-1/IGFBP3 molar ratios were associated with better functional status at the age of ninety years or older."

To reconcile these findings with the earlier work you cited they speculate:

Quote

These disparate results suggest that the possible benefits of low IGF-1/IGFBP3 ratios may differ according to age and birth cohorts. One of the possible explanations is that with advancing age, the IGF-1/IGFBP3 ratio changes and that those individuals that adapt to a lower IGF-1/IGFBP3 ratio have a survival advantage in old age. Another possibility is selective survival of participants with constitutively lower IGF-1/IGFBP3 ratios. It is possible that selective advantage of variation in the IIS pathway may only become detectable at advanced ages.

This is within the context of an overall literature whereby a " large number of studies have reported an association between reduced IIS activity and longevity in various model organisms as well as in human studies showing life extending effects of reduced IGF-1 signaling."  

For more on this literature see ROLE of IGF-1 System in the Modulation of Longevity: Controversies and New Insights From a Centenarians' Perspective (2).  The references in this brief piece cite some of the classic studies to unpack further. 

With regard to targets, I agree with Michael that provided nutritional adequacy and no other pertinent contraindications or individual and medical condition exceptions, that simulating IGF-1/IGFBP3 ratios more closely approximating the "low protein" group than the "low calorie" and "standard American diet" groups is likely generally better: See the first page of this thread where Sibiriak helpfully provided the link-out to the earlier thread

Consistent with the bar chart that Michael reproduced from the Aging Cell paper is data from (1).   A ratio of  ~ 0.09-0.15 may be optimal.

References

(1). van der Spoel E, Rozing MP, Houwing-Duistermaat JJ, Slagboom PE, Beekman M, de Craen AJ, Westendorp RG, van Heemst D. Association analysis of insulin-like growth factor-1 axis parameters with survival and functional status in nonagenarians of the Leiden Longevity Study. Aging (Albany NY). 2015 Nov;7(11):956-63. doi: 10.18632/aging.100841. PubMed PMID: 26568155; PubMed Central PMCID: PMC4694065.

(2) Vitale G, Pellegrino G, Vollery M, Hofland LJ. ROLE of IGF-1 System in the Modulation of Longevity: Controversies and New Insights From a Centenarians' Perspective. Front Endocrinol (Lausanne). 2019 Feb 1;10:27. doi: 10.3389/fendo.2019.00027. PubMed PMID: 30774624; PubMed Central PMCID: PMC6367275.

 

 

Edited by Mechanism

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This may not be of interest,  but  there appears to be an unclear relation between tomato lycopene and IGF-1.

Tomato lycopene extract supplementation decreases insulin-like growth factor-I levels in colon cancer patients.

Walfisch S1 et al.
Eur J Cancer Prev. 2007 Aug;16(4):298-303.

 

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Abstract

Epidemiological studies have shown that high serum levels of insulin-like growth factor-I are associated with an increased risk of colon and other types of cancer. The aim of this study was to determine whether short intervention with dietary tomato lycopene extract will affect serum levels of the insulin-like growth factor system components in colon cancer patients. The study had a double-blind, randomized, placebo-controlled design. Colon cancer patients (n=56), candidates for colectomy, were recruited from the local community a few days to a few weeks before surgery. Personal and medical data were recorded. Plasma concentrations of insulin-like growth factor-I and II and insulin-like growth factor-I-binding protein-3 were assayed by routine laboratory methods. Lycopene was assayed by high-performance liquid chromatography.

Plasma lycopene levels increased by twofold after supplementation with tomato lycopene extract. In the placebo-treated group, there was a small nonsignificant increase in lycopene plasma levels. The plasma concentration of insulin-like growth factor-I decreased significantly by about 25% after tomato lycopene extract supplementation as compared with the placebo-treated group (P<0.05). No significant change was observed in insulin-like growth factor-I-binding protein-3 or insulin-like growth factor-II, whereas the insulin-like growth factor-I/insulin-like growth factor-I-binding protein-3 molar ratio decreased significantly (P<0.05).

Given that high plasma levels of insulin-like growth factor-I have been suggested as a risk factor for various types of cancer including colon cancer, the results support our suggestion that tomato lycopene extract has a role in the prevention of colon and possibly other types of cancer.

 

Lycopene supplementation elevates circulating insulin-like growth factor binding protein-1 and -2 concentrations in persons at greater risk of colorectal cancer. (2007)

 

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Abstract

BACKGROUND:

Higher circulating insulin-like growth factor I (IGF-I) concentrations have been related to a greater risk of cancer. Lycopene intake is inversely associated with cancer risk, and experimental studies have shown that it may affect the IGF system, possibly through an effect on IGF-binding proteins (IGFBPs).

OBJECTIVE:

The objective of our study was to investigate the effect of an 8-wk supplementation with tomato-derived lycopene (30 mg/d) on serum concentrations of total IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3.

DESIGN:

We conducted a randomized, placebo-controlled, double-blinded crossover study in 40 men and 31 postmenopausal women with a family history of colorectal cancer, a personal history of colorectal adenoma, or both.

RESULTS:

Lycopene supplementation significantly (P = 0.01) increased serum IGFBP-1 concentrations in women (median relative difference between serum IGFBP-1 concentrations after lycopene supplementation and after placebo, 21.7%). Serum IGFBP-2 concentrations were higher in both men and women after lycopene supplementation than after placebo, but to a lesser extent (mean relative difference 8.2%; 95% CI: 0.7%, 15.6% in men and 7.8%; 95% CI: -5.0%, 20.6% in women). Total IGF-I, IGF-II, and IGFBP-3 concentrations were not significantly altered by lycopene supplementation.

CONCLUSIONS:

This is the first study known to show that lycopene supplementation may increase circulating IGFBP-1 and IGFBP-2 concentrations. Because of high interindividual variations in IGFBP-1 and IGFBP-2 effects, these results should be confirmed in larger randomized intervention studies.

 

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In conclusion, lycopene supplementation did not influence serum total IGF-I and IGFBP-3 concentrations in our randomized, placebo-controlled, double-blinded crossover trialin a population at greater risk of colorectal cancer. However, lycopene supplementation may decrease IGF-I bioavailability by increasing IGFBP-1and-2concentrations. Thus,it may provide a means of ultimately reducing colorectal cancer risk and potentially the risks of other major cancers such as prostate and premenopausal breast cancer. However, interindividual variation in IGFBP-1and -2 effects was high, possibly complicated by differences in fasting duration and, consequently, insulin concentrations.Therefore, results must be confirmed in larger randomized intervention studies with control for the duration of fasting.

 

Effect of lycopene supplementation on insulin-like growth factor-1 and insulin-like growth factor binding protein-3: a double-blind, placebo-controlled trial.

Eur J Clin Nutr. 2007 Oct;61(10):1196-200.
Quote

Abstract

OBJECTIVE:

Studies have suggested a link between lycopene and insulin-like growth factor-1 (IGF-1). The aim of this study was to test the effect of lycopene supplementation on IGF-1 and binding protein-3 (IGFBP-3) status in healthy male volunteers. DESIGN, SETTING, SUBJECTS AND INTERVENTION: This was a 4 week randomized, double-blind, placebo-controlled study of lycopene supplementation (15 mg/day) in healthy male volunteers (n=20). Fasting blood samples were collected at baseline and after 4 weeks. Samples were analysed for lycopene by high-performance liquid chromatography (HPLC) and IGF-1 and IGFBP-3 by enzyme-linked immunosorbent assay (ELISA). Changes in end points from baseline were compared in those who received placebo versus those who received the lycopene supplement.

RESULTS:

Median change in lycopene from baseline (post-supplement - baseline) was higher in subjects in the intervention than those on placebo (lycopene group 0.29 (0.09, 0.46); placebo group 0.03 (-0.11, 0.08) micromol/l; median (25th, 75th percentiles), P<0.01). There was no difference in median change in IGF-1 concentrations (lycopene group -0.6 (-2.6, 1.9); placebo group -1.15 (-2.88, 0.95) nmol/l, P=0.52), or median change in IGFBP-3 concentrations (lycopene group 245 (-109, 484); placebo group 101 (-34, 234) nmol/l, P=0.55) between intervention and control groups. Change in lycopene concentration was associated with the change in IGFBP-3 in the intervention group (r=0.78; P=0.008; n=10).

CONCLUSIONS:

Lycopene supplementation in healthy male subjects has no effect on IGF-1 or IGFBP-3 concentrations in a healthy male population. However, the association between change in lycopene concentration and change in IGFBP-3 in the intervention group suggests a potential effect of lycopene supplementation on IGFBP-3.

 

 

 

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