Insulin and IGF-1 in Human Aging and Longevity

The area of cellular metabolism surrounding growth hormone, IGF-1, and insulin is arguably the most studied set of mechanisms linking the operation of metabolism and the pace of aging. It is impacted by calorie restriction, an intervention that reliably slows aging. The longest lived engineered mice are those in which growth hormone signaling is disabled, and there is an equivalent human population with a similar inherited mutation to study. Many of the early attempts at producing long-lived nematode worms involved manipulation of IGF-1/insulin signaling. A greater number of centenarians than younger individuals appear to have favorable IGF-1/insulin signaling, suggesting some survival advantage.

But is this of any practical use when it comes to producing therapies that treat aging and meaningfully lengthen human life spans? After going on for thirty years of study, one has to think that the answer might be no. There is no way forward to radical life extension of decades and restored youth via mimicking calorie restriction, or trying to make metabolism more like that of long-lived people. Most people with the same biochemistry as centenarians die long before reaching that point - the survival advantage doesn't have to be large for centenarians to exhibit a larger proportion of a given trait than the general population. Human growth hormone mutants don't seem to live any longer than the rest of us. And so forth.

These and other, similar points have long led me to think that altering metabolism to age slightly more slowly - via IGF-1 signaling or other aspects of the response to calorie restriction - is just not a good use of research and development funds. It will not help those already aged in any meaningful way. It is a poor strategy for the research community to be undertaking, and it is a major problem that this strategy remains the dominant recipient of resources and attention. If enormous funding is to be invested in this field, let it go towards true rejuvenation research based on repair of the causes of aging, not tinkering with metabolism to produce minor adjustments in aging.

Centenarians are considered the best human model to study biological determinants of longevity having reached the very extremes of the human lifespan. Several studies compared circulating insulin and IGF-1 levels in centenarians with those of younger controls. Metabolic age-dependent remodeling is a physiological process occurring in the whole population. Aging is frequently associated with a decline in glucose tolerance secondary to an increased insulin resistance, but an exception occurs in long-lived people. Researchers found that insulin resistance increased with aging and declined in subjects older than 90 years. Indeed, long-lived subjects showed a higher insulin sensitivity and a better preservation of beta-cell function than younger subjects.

Data on the IGF-1 system in relation to longevity are still controversial in long-lived subjects. One team described an increased plasma IGF-1/IGFBP-3 ratio in healthy centenarians compared to elderly subjects. They hypothesized that this elevated ratio was indicative of a higher IGF-1 bioavailability which contributed to the improved insulin action in centenarians. In contrast, others reported that subjects with at least an A allele of the IGF-1 receptor gene had low levels of free plasma IGF-1 and were more represented among long-lived people.

These conflicting results probably reflect the complexity of the IGF-1 system and ethnic differences in enrolled populations. In addition, centenarians have often been compared to a control group of younger subjects. Therefore, in most of these studies it was not possible to conclude if IGF-1 differences between both groups were related to a different lifespan or reflected a physiological age-dependent IGF-1 decline.

While it is well known that enhanced insulin sensitivity and low insulin levels are associated with an improved survival, there is evidence showing that attenuation of the growth hormone/IGF-1 axis may have beneficial effects in extending lifespan in humans. However, it is still unknown which are the optimal IGF-1 levels during life to live longer and healthier. In addition, IGF-1 receptor sensitivity and activation of the post-receptor pathway were not evaluated in the majority of the study enrolling long-lived subjects. Therefore, it is not possible to define the real activation status of the IGF-1 receptor signaling through the mere dosage of circulating IGF-1 levels. This renders more difficult the identification of pharmacological or environmental strategies targeting this system for extending lifespan and promoting healthy aging.

Nonetheless, striking similarities have been described concerning the endocrine profile between centenarians and subjects after a calorie-restricted diet. The endocrine and metabolic adaptation observed in both models may be a physiological strategy to increase life span through a slower cell growing/metabolism, a slower loss of physiologic reserve capacity, a shift of cellular metabolism from cell proliferation to repair activities and a decrease in accumulation of senescent cells. These mechanisms seem to be, at least in part, mediated through the modulation of the growth hormone/IGF-1/insulin system.

Link: https://doi.org/10.3389/fendo.2019.00027

Comments

Hi there ! Just a 2 cents.

I agree, we should be putting more energy towards rejuvenation than continuously running around circles and throwing money on déjà vu stuff (such as IGF, mostly 'been there done that' stuff now) that leads to no concrete action but just 'research..for reseach' (with most of these studies ending with : 'we hope the data will be used 'some way' to make a therapy or something....99% of the time nothing 'serious' happens/no action on said discovered infos). I think even there is a sort of 'blindness' or let's - 'we Must research Some more - something we already know' because 'Researching - For Reseaching'...you have to 'keep people busy' doing something with their time - it's ironic because life is about 'Time'...and one day you lack it..and they are 'self-defeating' running in circles around same stuff...Is there more to learn? Of course, we still don't know much; but, instead of continuously 'blindly' researching and 'Shoveling clouds' (vapor), well we could do Actions (as in creating the darn therapies or least trying). So, 'it's all talk'...and not much 'walk', we have to 'walk the talk' and 'walk the walk', not just talkie talkie. Or, as Stephen King, once said: 'One day, you have to stop 'reading' about [how to] writing...and start writing [yourself]''.

I think the biogerontology domain is its own ennemy, and completely blind sometimes (like the litterature analyzing not its forte), like someone Very Procrastinating, that never gets anything done, but 'seek infos/find infos/'search''..if they were Google 'searchers' they would Number.1...but on the bit of 'doing something about it' they would be number -1.

With that said (let's talk.. for talk, as we wait Other people to make these actions/therapies 'happen'),

''Data on the IGF-1 system in relation to longevity are still controversial in long-lived subjects. One team described an increased plasma IGF-1/IGFBP-3 ratio in healthy centenarians compared to elderly subjects. They hypothesized that this elevated ratio was indicative of a higher IGF-1 bioavailability which contributed to the improved insulin action in centenarians. In contrast, others reported that subjects with at least an A allele of the IGF-1 receptor gene had low levels of free plasma IGF-1 and were more represented among long-lived people. ''

IGF is a growth factor, an antagonistic pleitropic growth factor - meaning it saves you, it improves your health (your fitness), it increases mTOR/muscle fiber formation, a good thing, you need your health to live.

The reverse negative (antagonistic/negative) is that it increase senescence/reduces replicative bouts. mTOR is a senescence geroconvertor, you need it for senescence, and IGF is direct link to it.

Growth hormone are important for growth and body growth/size, and, as said, keeping your health. Such as, it iwas demonstrated in the brain, IGF-receptors are in high numbers in the brain and all over body; cutting IGF/IGF-R can drastically kill neurons, because for fitness they need it..but as said, double-edged sword (antagonistic pleitropy), too much IGF = accelerated replicative senescence.

Hence, why the discrepancy and contradictory nature of the results in various contradicting researchs.

Long-lived centenarians have a 'rapid form' of IGF if you will (this was demonstrated in house flies..where the long-lived ones had 'quick' IGF if I could say it that way...in the sense that they 'minimal' exposure to IGF - but Whenever it was called - if Functioned Well and Fast...and then it disappeared. Thus, Rapid/Quick Action And Release. So, minimum levels of IGF provided the longest lifespan: Reduced exposure to IGF/insulin signaling/reduced DAF/increased SIR...and improved health for the 'little IGF' there is. But, the nueance, is that there is Not - No IGF, there Is IGF, you need it...Dosed. IGF is life saving because it restores neuronal function and it activates Neuregulin/BDNF/Brain Derived Neutrophic Factor..all this helps improve neuron health. And it's why, the 'non-senile' 'healthier' centenarians Still had More IGF or a 'special' 'fast' version of it VS centenarians who are unhealthy and senile/demential/soon to die. Thus, antagonistic pleitropy at play.
Fitness/sexual reproduction (IGF/GH/sex hormones) vs Longevity (replicative senescence/epigenetics); the 'inbetween' is low-dose IGF but not extinction either; too much IGF = acceleration of aging/increased insulin spikes (hyperinsulinemia/type II diabetes)/increase insulin signaling - accelerated mTOR senescence cell entry; thus a balance/trade-off between frailty/fitness/health vs longevity/aging).

Just a 2 cents.

Posted by: CANanonymity at March 8th, 2019 4:43 PM

Very good 2cents. Do you think a 60 year old would be better off injecting Ipamorelin (IPA) a synthetic peptide that increases IGF? I find the controversy confusing.

Posted by: August at March 8th, 2019 8:35 PM

Hi August ! Thank you for that and the question. Just a 2 cents.

I agree with you, there is still much confusion/ambiguity surrounding HGH (human growth hormones) and IGF connected to that. There has been so many stories, from very good to real bad, it's hard to say if it's worth it or not. This peptide is quite interesting, Ipamorelin or also Semorelin, act through the ghrelin hormone/endocrine system, thus increase HGH and IGF levels (since ghrelin increases IGF/HGH, and why before/at/during early feeding, ghrelin rises to give the 'hunger' feeling, felt in stomach. Ghrelin studies are all over the place, much like it's inverse one - leptin (the sasiety hormone, that makes you feel 'full'/not wanting more food - after having eaten fully to 'your appetite' (of course people with big appetites have more ghrelin activity than leptin, that'S clear; oftenly this can lead to obesity (ghrelin was associated with that). Wtih that said, if in dosed control, no ghrelin has many great benefits, and you can see muscle formation/tighter skin/more collagen (more EGF, IGF, VEGF even, pretty much every GF (growth factor) under the sun and, yes, HGH (human growth hormones) becomes more visible/produced from pituitary gland and more pineal gland output too).

Now to answer your question, I would say that Ipamorelin would be good yes for increasing IGF/HGH/mTOR levels, making a stronger/leaner/tigher/better skin/muscle body - thus, fitness improvement (and that's what IGF/mTOR is all about and behind these changes).

Now you might be wondering, ''but what about the 'other' thing of 'too much' IGF is toxic..?'' yes, exactly, that still applies; too much a good thing can be just as bad as too little (at least, in this case, it's true). If I were you, I would 'dose' my Ipamorelin injectinos, and see what kind of changes your body shows, it will become visible (litterally), you might gain muscle mass, more sexual performance, 'feel healthier/peppier/more energy', youther skin/smooth/collagen/pulpous/feel younger face/less wrinkles/less sagggin skin, some gray hair will fall-off/disappear/or become 'healthier/shinier lustruous haircoat (more natural hair thin-oil)' and old 'young hair' color show again, less sleepy/lethargic, more sharp mind/happier/less negative thought/less stressed, you may gain some weight (not necessarily -just muscle, but a combo of BAT/WAT (brown/white adipose tissue) + muscle + possible more subcutaneous fat (layering 'natural padding' (increase adipocytes/some Help insulin activity (depending on skeletal location) while some are detrimental), but not necessarily 'sub-visceral fat' the bad kind that clogs/surrouds organ tissues and 'chokes' them)). IGF will restore 'the you' and improve your you to the correct one - of your body/size; you will be at much better fitness.

IGF is truly two-faced and tricky, because we can detect higher levels of it in both thin/healthy/athelete people vs fat/health/non-athelete sedentary people...some people are more obese and they could have higher IGF - Still. I've seen this with certain obese people or let'S say, people that are larger by nature and their skeletal stature was just 'that way' bigger...so they are more 'fat'...but their health was nearly perfect (from doctor results). Demonstrating, that it's more complicated : external body fat vs internal body fat vs thin vs obese (I was thin - always, and nearly died of atherosclerosis, not just obese fat people die of atherosclerosis, even very thin ones. In general, yes, being obese is bad news and accerlates many peorblems down the road..so keep a correct BMI is much more important (just correcting your BMI (and by taking Ipamorelin, you woul increase ghrelin/IGF, you would gain muscle/replace/burn visceral fatty tissue; which would make lose weigth but gain 'mass muscle weight' which is good for fitness 'become lean & muscled' (less % of fat in your body, more % of muscle mass). And, you certainly don't need to be Ultra-muscled, just muscled enough to keep your health/improve fitness, and thus, IPA would allow that, by activating ghrelin and then IGF/HGH/GFs/other growth hormones. Your metabolism would allow increase in speed (making you burn excess fat faster too, as it would be used for energy instead of relying on the glucose pathways).
PGC-1a is often the master regulator behind this (fat burning), but IGF is on the major master regulator (above PGC) that nearly-entirely controls the 'fitness/health/growth/sex/GH/endocrine' axis of our bodies; and including cell cycling dynamics (that affect senescence/inflammation/SASP), for it works in tandem with mTOR. It also touches on energy (glucose/insulin) and a myriad of gene pathways (SIR/DAF/FOXO...histones/chromosomes and even epigenetics).

The last I would say, is dose it, because too much hormone input can have dire consequences; and, as said, all this in pleiotropic fashion (antagonistically), it's only meant as a 'sex reproduction evolution', meaning all this happens to improve your sexual capability/virility/fertility so you increase specie survival by having offspring (for specie survival/continuity). It's not about 'longevity', it's about 'doing your purpose on earth (procreate)' and then once done, it's pleiotropy ('late negative effect' of genes becomes bad later on) antagonistic in old age. It's why centenarians have low IGF/special version...but they Keep It Steady...they always have some and their variant, is great and 'in bursts/minimal exposure'...hence, 'just enough'/not too much either.

Just a 2 cents.

Posted by: CANanonymity at March 9th, 2019 12:42 AM

Thank you! Excellent information. Due to diet and exercise my BMI is 19 - but I think I'll try it, along with low dose (7.5 mg) of pioglitazone per day to increase subcutaneous fat - the loss of which causes wrinkles. pio increases ppar gamma which decreases Tgf-b therefore allowing fibroblasts to convert to dermal fat cells. At least I think that's how it works... The combo should be quite helpful. I'm afraid that at 60 vanity is edging out desire to be a centenarian. Thanks for such a straight answer!

Posted by: August at March 9th, 2019 12:37 PM

CANanonymity wins the thread with the first post. People are probably happy to see more and more research on aging. But there is definitely an opportunity cost to the research into things like this. Even though it should be studied, and it may throw up a few surprises and new perspectives, it is probably one of the least helpful of all the Hallmarks of aging.

The point being that every dollar spend on anything related to calorie restriction is a dollar taken away from more promising research into the primary hallmarks (epigenetics/proteostasis/genome stability/telomeres). Even stem cells still have a huge potential payoff, comparably. But people love this idea of messing with metabolism, perhaps because it feels more close to our own loved experiences. After all, I can do calorie-restriction right now with little knowledge or investment. And if we talk to friends and family outside our little circle of early-adopters, you will find that the only things on the radar are ancient ideas about diet and exercise. Goof luck with living more than a year or two longer with diet and exercise. And I'm guessing the same could be said for most nutrient sensing interventions.

I would offer David Sinclair's great work as an exception to this. But even David is now saying that he sees the most promise in epigenetic and cellular reprogramming. I think that is the emerging consensus as to where things should go.

Posted by: OP2040 at March 11th, 2019 7:13 AM

OP2040, I agree, the metabolism ideas are 'inside the box' thinking, which people are comfortable with. Like even the reality that at best you could gain a couple years from a lifetime of calorie restriction, means the ideas are not that scary to people.

It is a good point that the calorie restriction type of ideas are also something the average person can understand, whereas things like senolytics are outside of their understanding.

Part of my problem with the whole idea of exercise and dieting is how many people can actually maintain it over the long run. And I am talking here about avoiding being obese, as opposed to a healthy body weight person trying to add a year or two to their lifespan. Something like 95% of obese people who try to lose weight are unable to maintain the weight loss over the long run. So on paper, a rigorous diet and exercise regime could benefit them, but in the actual real world, 5% success rate is really not much better than placebo.

Posted by: aa3 at March 13th, 2019 1:29 PM

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