Let’s start with a quick introduction to IGF-1:
Insulin-like Growth Factor 1 (IGF-1) is a protein hormone similar in structure to insulin. IGF-1 stimulates cell growth and proliferation, as well as acts as an inhibitor of programmed cell death. IGF-1 is released from the liver when growth hormone is released into the blood stream by the pituitary gland. Once released, IGF-1 stimulates growth in almost every cell in the body, and can also regulate cell growth in nerves cells and cellular DNA synthesis.

The IGF-1 Aging Argument:
Does higher levels of IGF-1 promote aging? Right now there is a definitely maybe consensus on the topic, but there are strong feelings in the pro and con camps.

In CR’ed rats, circulating IGF-1 levels decreased by ~40%; this reduction is believed to protect against cancer and slow aging in these rodents. In several species, lowering IGF-1 reduced functional mutations which increased lifespan. Also, mice deficient in growth hormone receptors have low circulating IGF-1 and increased lifespan. What is not known, is how circulating levels of IGF-1 affect human aging, and if there is an effect, how much?

CR & Protein Restriction and IGF-1 Levels In Humans
First, I want to present a study published in 2008 by Fontana et al: Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentrations in humans. This study reports data from two CR studies (1 and 6 years) showing that severe CRON did not reduce IGF-1 and IGF-1:IGFBP-3 ratios in humans, but both total and free IGF-1 levels were reduced in an additional study with moderately restricted protein intake. Protein was reduced from an average of 1.67g/kg per day to 0.95g/kg for 3 weeks in 6 CR volunteers which resulted in a decline in IGF-1 from 194ng/mL to 152ng/mL.

Serum concentrations of both IGF-1 and IGFBP-3 were measured in two studies to determine whether the duration of CR or body changes associated with CR affected IGF-1 levels in humans.

Study 1: 29 women and 17 men (middle aged, non-obese) were divided into two groups and either decreased calories by 20% for 1 year, or exercised for a net energy loss of 20%. In both groups, protein intake was ~16% of total calories. After one year, the results surprisingly showed that the CR group did not have a reduction in serum IGF-1 concentration or IGF-1:IGFBP-3 ratio; the exercise group also did not show a reduction. However, the CR group did show significant improvement in insulin sensitivity, reductions in serum leptin, C-reactive protein, insulin and triiodothyronine levels which are in accordance to CR mice studies.

Study 2: This study wanted to evaluate longer periods of CR and serum IGF-1 concentrations, so 28 weight stable CRON practitioners who have practiced CRON for an average of 6 years were compared to 28 age-matched controls eating a typical western diet. The CRON practitioners ate ~1800kcal/day with ~24% protein and ~28% fat, while the controls ate ~2500kcal/day with ~16% protein and 33.6% fat. No differences in serum IGF-1 or IGF:IGFBP-3 ratio was observed. However, as with the previous study, fasting insulin, C-reactive protein, and triiodothyronine levels were significantly lower in the CR group.

Additional Protein Restriction Study:
To evaluate low term protein intake and IGF-1, the researchers compared 28 vegans with an approximate protein intake of 0.76g/kg per day (~10%), with 28 CR members who ate a high protein diet of 1.73g/kg per day (~24%). The PR group had a higher energy intake even though their protein intake was lower. Both IGF-1 and IGF-1:IGFBP-3 ratio were significantly lower in the PR group, which was independent of body weight and body fat.

In order to verify that the high protein levels in the CR group were preventing the reduciton in IGF-1, six CR practioners decreased their protein from ~1.67g/kg per day to 0.95g/kg per day for 3 weeks.  After this short 3 weeks period, the IGF-1 serum concentration was ~25% lower in these six individuals. The researches conclude that CR with high protein intakes will not induce a reduction in IGF-1 levels as seen in rodents, and long term protein reduction is thus more effective at reducing IGF-1 levels in humans.

NOTES/ISSUES:
The 1st or last study did not specify types of protein consumed by any of the groups. Mostly animal or plant, maybe a mix? The focus was only on the amount. There could be differences in protein type and IGF1 reduction: plant vs animal. Similarly, the 2nd study didn’t go into detail about protein types with the western diet group, but do know that 21/28 vegans were following a raw diet and obviously 28/28 vegans were consuming all plant protein.

This study also only looked at total protein consumption in relation to IGF-1 levels, but what about other ways to decrease IGF-1? Possibly methionine restriction or glucose reduction? I realize that the totality of the issue is hard to cover in one study, but I just want to bring up the limitations of the scope.

ADDITIONAL THOUGHTS:
A few other thoughts on the topic in general before I move on: First, I want to know the differences (if there are any) between women and men with respect to IGF-1 levels. Also, I keep seeing studies and/or data being used in discussions on people with a defect causing them to have lifetime low IGF-1 levels. These types of people are often not associated with longevity, but have several health complications and a high childhood mortality.

Now, to me it would make sense that if any benefits were obtained from lower IGF-1 levels, it would happen AFTER childhood (you know, that time in our lives where we do the most of our growing). Just like we wouldn’t recommend CR to a child, why would low IGF-1 levels benefit a child when they are growing (or should be growing) at rapid rates? With the multitude of studies for me to go through, I can’t help but place the significance of these defect/mutation studies (in terms of longevity) very low on my concern level. However, with that being said, I find it almost impossible to ignore these studies completely, especially ones concerning mutations in mice because they are relatively common.

This topic will require a Part II-B, maybe a C, but I want to present one mini-review before continuing to the next post with more studies.

On of the main issues in the study of IGF-1 in relation to human longevity, is understanding how the mouse model correlates to the human model. Many in the CR world do not place much weight on the worm and insect models (and some dismiss even the mouse models) because they are so far removed from us and our systems are much more complex. With that being said, now let’s move to review.

This mini-review actually deals with genetically altered mice. The main reason to study these altered mice is to learn more about their endocrine mechanisms so therapies can be discovered and hopefully successfully applied to normal aging mice, and then to humans. These mice are living 20-70% longer lives (depending on diet, gender, defect, and genetic history) for a reason; understanding the why for these mice will hopefully translate into help for human longevity research.

Below is a table showing 4 types of mutant mice, type of defect, the effect of the defect, characteristics, and average increase in lifespan.

The authors note that even given this knowledge, they can only speculate *which* the direct and indirect consequences are responsible for the increased longevity. However, studies comparing these altered mice with genetically unaltered mice have narrow down the possibilities which link GH/IGF-1 singling to delayed aging.


Metabolic rate and oxidative damage:
Reduced GH/IGF-1, insulin, and thyroid hormone would be expected to lead to a reduced oxidative metabolism as well as reduced generation of reactive oxygen species (think ‘free radicals’). Support for this is observed in the Ames dwarf mice where oxidative damage of proteins, lipids, and mitochondrial DNA is reduced.

Stress Resistance:
In Vitro (note this is in a ‘test tube’, so take that as you will) studies of isolated cells from 3 types of altered mice survive significantly longer when exposed to cytotoxic stress.


Insulin Signaling:
Increased insulin sensitivity and low insulin levels combined with ‘low normal’ glucose levels may also lead to longevity in these mice. Human centenarians tend to be exceptionally insulin sensitive, which is rare because insulin resistance usually increases with age. The absence of GH signaling may lead to enhanced insulin sensitivity in adult life. However there is a discrepancy in these mice findings: one type of mouse bred to have a GH deficiency and PRL resistance developed insulin resistance and metabolic syndrome, while the Ames mouse (listed in table above) also has a GH deficiency and PRL resistance but experienced the opposite effects (increased longevity). However, since many other variables are at play here, this mechanism still cannot be ruled out.

Body Size:
Almost all long lived altered mice are much smaller than their genetically normal counterparts. This size correlation is also seen in domesticated dogs, laboratory rats, and even in humans. However, the authors do note that reduced size is not likely to lead to delayed aging in and of itself, but may somehow be related.

Gonadal Function:
The authors also note a correlation in delayed reproductive development and reduced fertility and longevity in these mice. If this relationship holds true, it could explain why high levels of GH/IGF-1 are more common: natural selection. However, the authors also note that the contribution of this factor to longevity appears to be minor.

Brain IGF-1 and Congnitive Function:
The Ames dwarf and GHRKO mice did not differ in learning ability from their normal counterparts, but did maintain youthful levels of cognition into very advanced age even though GH and IGF-1 were below detectable levels. This comes as a paradox to the researchers because both GH and IGF-1 are known to exert important neuro-stimulatory and neuro-protective effects.

RELEVANCE TO HUMANS!?!
Finally, the reason you have all been holding your breath! Can any of this research be extrapolated to humans? Maybe, and here is why: (even though so much more needs to learned about this system)

Since the IGF-1/insulin (or equivalent) signaling pathways are known to contribute to longevity in yeast, worm, insects, and rodents, the leap to suggesting this pathway can somehow have longevity effects in humans is reasonable. Increased insulin sensitivity is seen in centenarians, and it is well known that insulin resistance causes detrimental effects. The real issue is discovering the mechanism so we can not only manipulate the system, but know how much of a longevity effect we can create.

Thus, the GH/IGF-1 signaling pathway likely plays a role in human longevity. The question now becomes:

Even the proponents against this longevity theory will imply there may be some effects, but they just aren’t convinced they play a large role to be taken very seriously.

However, this makes me wonder: Since we know CR’ed mice do have lower IGF-1, but CR’ed humans have to additionally moderately restriction protein to get the lowered IGF-1 effect, how can we easily dismiss this difference as an indication that we do not need to follow a *moderate* protein restricted diet even though the mice did not (maybe). If the mice followed a higher protein diet but still had low IGF-1 levels, shouldn’t humans be more concerned with the possibility of needing to lower their IGF-1 levels, or at least conducting research to know if this discrepancy is of concern?

Disclaimer: The above speculation is my own assertion based on collective hearsay: I have not yet found a paper showing CR mice with a high protein diet *and* low IGF-1 levels, but this has been implied throughout my readings. I am still looking for such a paper, but please step up of you have a lead for me! This is an intense and very complex topic, and if I misstep please inform me. I am trying to present this in a very unbiased manner!