Late Life IGF-1 Inhibition Modestly Extends Life in Female Mice Only

One of the most studied areas of metabolism and its interaction with aging involves the activities of, and relationships between, IGF-1, insulin, growth hormone, and their cell surface receptors, all of which are among the mechanisms strongly influenced by calorie restriction. Genetic engineering to disable growth hormone or its receptor produces dwarf mice that live 60% longer, and IGF-1 can be similarly manipulated to produce a less exceptional life extension. It is worth noting that the equivalent growth hormone loss of function mutants in our species do not live 60% longer, though they may be modestly more resistant to age-related disease. Short-lived species have evolved a far greater plasticity of life span in response to calorie restriction or interventions that directly manipulate the related cellular mechanisms. Development of therapies based upon these findings seem unlikely to produce sufficiently sizable effects on human health to justify the investment, given the range of better alternatives on the table.

Diminished growth hormone (GH) and insulin/insulin-like growth factor-1 (IGF-1) signaling extends lifespan in many laboratory models. Likewise, several dwarf models, including Ames, Snell and growth hormone receptor knockout (GHRKO) mice, are exceptionally long lived. A specific role for IGF-1 receptor (IGF-1R) signaling in the mediation of mammalian longevity was first established in IGF-1R haploinsufficient mice, which lived 33% longer than controls, but unlike other models of reduced somatotropic signaling, this effect was female specific. This unique sex difference was subsequently confirmed in two follow-up studies, though with more modest reported improvements in female lifespan, while a life shortening effect was observed in males. The underlying mechanisms linking reduced IGF-1 signaling to improved mammalian lifespan is thought to involve improved stress defenses and lower risk for proliferative diseases, though the reason for sex differences in this response remains unresolved.

Several examples have also now emerged suggesting the GH/IGF-1 signaling pathway is relevant to human aging, including the discovery of functional mutations in the IGF-1R gene in individuals with exceptional longevity, resulting in relative IGF-1 resistance, and in subjects lacking functional GH receptors (Laron dwarfs). Remarkably, low IGF-1 levels also predict better survival in nonagenarians, and similar to lessons learned in IGF-1R heterozygous mice, this effect is female specific. Thus, given the accumulating evidence across species implicating this pathway as integral to aging and its associated diseases, the development of therapeutics aimed at modulating IGF-1 signaling in humans could prove highly effective as a translational tool to delay aging. However, given that previous demonstrations of longevity resulting from disruption of this pathway occurred either at conception or in young adulthood, whether benefits can be achieved by targeting this pathway later in life is unclear.

Anti-IGF-1 receptor (IGF-1R) monoclonal antibodies (mAbs) were developed for clinical use in treating advanced stage cancers. We postulated that IGF-1R mAbs could represent a viable therapeutic tool to target IGF-1 action, and potentially mimic the beneficial effects associated with diminished IGF-1 signaling observed in animal models. In order to test this possibility, we engineered a murinized version of the anti-IGF-1R mAb, L2-C (L2-Cmu), in order to reduce effector function and enable chronic administration in mice. L2-Cmu proved feasible and well tolerated in older animals, and consistent with genetic models of IGF-1R heterozygosity, improves female healthspan and increases median lifespan by 9%. Importantly, these effects were achieved even though treatment was not initiated until 18 months of age. Thus, these data suggest that late-life targeting of IGF-1R signaling can recapitulate effects observed in genetic models of constitutive IGF-1R haploinsufficiency on lifespan. As IGF-1R mAbs are readily available for human use, these observations warrant further study into potentially harnessing these drugs to target at least some manifestations of aging.

Link: https://doi.org/10.1038/s41467-018-04805-5

Comments

Today at the latest lifespan.io article I got the answer I needed to the final objection I couldn't get my mind around: "We all have to die so new generations can take over".

I think the teleology is wrong when we're talking about programmed death. The usual programmed death meme goes something like this. I'm a great big tree, and I've got all these little trees that are growing underneath me; they're my progeny, and I have to die to give them space to get to the sun. This becomes no longer science because I don't know how you test this; to me, science is something you can test, and if you can't test it, then stop calling it science; it becomes philosophy.

Posted by: Norse at June 27th, 2018 8:22 AM

There was a calculation that even if people never aged nor got any diseases the median lifespan would be around 2500 years if we have the same rate of accidents as now. So, we eventually die. Just much later...

Posted by: cuberat at June 27th, 2018 10:00 AM

Hi Norse, just a 2 cents. It boils down to a question of ethics.
Individual vs Group. Selfishness Gain vs Selflessness Giving. People see you as unselfishly giving back by letting your progeny replace you once you are old. "Everyone ages/becomes old/dies -> it is ''normal/natural cycle'' for a functioning society based on human turnover- by aging/dying replacement, thus dying/aging/getting old/being replaced by your children
is Ethical/normal/Justified -> thus, we must die for the society and its ''advancement''. Who knew turnover = advancement.
It is ironic because, though overpopulation would strain resources and overcrowd space while increasing population problems (killings or such), it would actuality increase wealth by more tax payers, working longer, albeit in the future people won't work as long anymore because of automation (death of jobs, too few jobs for too many people. The only jobs left might be artistic or autonomous work independently from outside company, i.e. you work for your own self. Autobotization and neural A.I. will replace humans (ironically, like old people getting replaced by their kids. Robots, per say, will do more and better than us, saving money and time, humans will limit this Autobotization but I see it being more advanced and taking over many human jobs)))).

Autobotization vs Eternal Life vs No Jobs/Still taxed/welfare/universal salary vs resources strain/autobots will create lacking resources... It thus becomes a very independent vs dependent, individual vs total population, selfish vs generous,
individual vs gov problem. And, generally, there, ethics and morals are what determine the outcome , because people think 'individually' 'collectively'/what is Good for the individual but above that, for the whole population 'the collective society/Everyone'. It is why I see clashing between independent individual vs gov, gov could disappear if they use
ethics antics (moral duty for the good of everyone/every aging old taxpayer that they Must die and be replaced by their kids, because it is a ''fair/viable'' ''working balance'' (..fair to who?.. the gov? or the Dead elderly taxpayer? Or, to the 'in the making taxpayer' kids who replace us one day, thus fair to the society/its procreative survival/the couples who decide to make kids)).
It's a clusterfck, and catch22.

@cuberat

Hi cuberat, just a 2 cents, if a hermit life I believe the human could live 5000 years.
Great Basin Bristle Cone Pines live up to 5000 years, albeit they shed their parts, the roots are original not the rest, the roots are supposedly about 5000 years old while the trunk/rest is regenerated and no more than 300 years old between each regeneration is completed (this pine's meristem have meristematic stem cells and telomerase has been detected in the entire tree, it is active in long cyclic bouts))). If a standing-still tree out in the open (though with no predators per say, except fungi/bacteria causing tree death/birds eating leaves or damaging it/the nasty weather/daily UV radition/chemicals and man-made pollution) it lives that long.
Humans living (boring but safe) cloistered life like a hermit monk staying inside/under a rock/a cave or abbey would drop the accidental death odds % quite substantially. Enough so, to double that to 5000 years.
Things will change over 5000 years - it is the change that can kill you, if you adapt or not,
you may not need to adapt if living cloistered life away from society and still, being capable of filling your primary basic needs (food, air, logistic). Living ignorantly in a bubble has its plus (ignorance is bliss/what you do not know does not affect you/
Out of Sight - Out of Mind/sometimes knowing is worse (for you) than not knowing)). The main dangers if living cloistered life is in home accidents (''jump in a bathtub with a connected toaster'', drown/fall in your bathtub, slip/break a bone/fall akwardly, if living with other recluse people they may kill you accidentally (kitchen knife while cooking (change for plastic utensils), having an argument/they lose it/kill you in rage, living alone is sad but less danger (living with others they may save your life if you get diseased/sick/in need of outside hospital care/you can't care for your own self (living alone) and need supervision for you/your health.

Still, 2500 is pretty miraculous already, not Eternal, but 'like' being near' Eternal (obviously, a far Stretch from being Truly Eternal (2500 vs Eternity)). For humans, going from a mere 100... to... 2500 years is akin to the gift of Eternal life.
The fact a living thing reaches 5000, 5000 is plausible if extremely unlikely (because of extrinsic accidental death odds % as you said, if excluding intrinsic biological aging. Living a cloistered life would mitigate these odds but there would still be the ''hazard'' of over 5000 years - Change, and the hazard odds it brings (it's tied/similar to death odds). We don't know what can happen/change/how life will really be in such extremely far future/how this (change, or not) affects you (or, not))).

The question that remains:

If gov exists, Will You Be Allowed Legally and Able From Your Own Will/Health Preservation/Age Reversal by Biorejuvenation

To Live 2500 years? Will the gov let yoy, or want us dead by 120-150 MAX AGE LIMIT? How would AdG respond to that, to a gov that wants to Limir Maximum Lifespan?

Insurrection ?

Just a 2 cents.

Posted by: CANanonymity at June 27th, 2018 12:25 PM

Technically speaking we can hardly imagine living 25 hundred years. Even living 120 in youthful state is already pushing it.
Now we can easily imagine 60s are the new forties. 80s are the new fifties and 40s are the new twenties but for real. From there we can do a small leap of 90s are the new sixties, and 120s are the new 80s (or sixties, depending on the advancements). That is easy to imagine and easy to accept. Now, when you get to have 120s as the new forties it is close to LEV.

Posted by: cuberat at June 27th, 2018 3:06 PM

Again with the government mandated lifespan conjecture?

Posted by: Ham at June 27th, 2018 4:17 PM

Hi Ham, just a 2 cents, I am not trying to make histeria, it just is a very plausible scenario,
but I feel this possible problem could very much materialize (what sadness if it would, you
could forget about LEV it would never happen nor be legally allowed, for ethical societal reasons,
this could really be what will happen (I sure hope not as I believe in LEV and living however long You can, not however long a gov decides you too.). As you said, people will object to dying at 90 or 120,
but so what, they may object by the millions, the gov could decide to not move an inch
and keep the 120 Limit, or it might negociate for a lifespan of 300 give or take;

This certainly is not LEV nor living how long you can/how long Your Body allows it

Age Limit-Free

The only thing left is gov dissapearing/people revolt fighting (WW3?) to have The Right
To Live However Long They Want/They Can/Their Body Allowing It

@cuberat

I agree it is still unfathomable, we barely 120...

But is it, really? 120 is nothing in the grand scheme of things, especially, when trees live 5000 years or jellyfish are eternal.
We have to Start to Fathom it.
A success in my mind is 2x the current maximum (122), if we reach 200-250, it's a small success below that it will be unsuccew,
I would prefer LEV like everyone who does not wish die (ever, if possible), or even a 'limited' 5000 like a pine tree.

Posted by: CANanonymity at June 27th, 2018 5:16 PM

But you are making hysteria. The whole thing is kind of arbitrary and not something I would file under "very plausible", especially if people are living that long and in good health. As in, not draining resources, time, and effort in a decrepit state. Not to mention, most of the countries where any of this would be available are already likely below replacement level birth rates. Do you really think every government in the world is going to agree to something like that?

Maybe you're right. I just don't see it.

Posted by: Ham at June 27th, 2018 5:35 PM

I also don't see governments going anywhere, anytime soon.

Posted by: Ham at June 27th, 2018 5:39 PM

I should have specified more precisely (my bad),

The reasons you brought out are biological/economics than pure ethics, I am mostly repeating what fatalists ethicists are saying, their's is pure' ethics: ''Should there be a limit to lifespan once purpose on earth accomplished ? How much years is Enough years? Is eternal life devoid of natural death morally and ethically right? Overpopulation, resource drought? Bored out? People will be healthier/older/longer/taxpaying by working longer/better economy thus they could live 500 years.. and that is A-OK? A society that keeps on living becomes individualistic and selfish despite everyone living forever around you. It is artificial construction not natural human life cycle. Eternal dictators would enslave us forever, Etc etc''

Note that I am just resuming what they are saying, I don't believe most of their claims because of logical fallacies in them. and because there are solutions that ethically sensible 'enough'.

I agree too that with low birth rates it makes no sense to reduce the population count by having the elderly die, instead of rejuvenating them to keep on living/be productive members of society/stop population count from dwindling in the face of low birth rates.
But thir argument is the inverse, overpopulation, we are already overpopulating earth (near 8 billion people, nearly 11 billion in 2050 (China 1 billion/India +1 billion, and Africa as a whole huge chunk. China even had to curb number of kids per couple as a law, that much it is a dire overpopulating situation - they have to 'self-limit' themselves that is how bad it is (what doesn't say that China will curb Maximum Lifespan Too while it's at it, it seems about too already), population keeps on growing/not slowing anytime soon, overcrowding; of course, they mostly mean in poor countries with extremely high birth rates, not in wealthily countries were birth rates are dropping and there is a need for immigration to offset dwindling numbers)).

It is possible that govs will never disappear indeed. It could spell the end of LEV if fatalists ethicists convey that all in all it is still better to die and be replaced by your kids, rather than overpopulate/as productive working 'still living on' elders not dying.

I hope not and hope the govs see they have everything tp Gain by keeping people alive, forever they can/LEV,
Not limit lifespan.

Posted by: CANanonymity at June 27th, 2018 6:46 PM

Any government contemplating doing what CANanonymity says will not be elected into power, plus it would violate the human right to live. People who already exist are more important than those who have yet to be born.

Posted by: Scott emptage at June 28th, 2018 3:21 AM

Completely agree Scott. But it's all pointless conjecture at the moment anyway. Cross bridges when you come to them!

Posted by: Steven B at June 28th, 2018 3:54 AM

@Norse
I think your metaphor works if you want to describe why the costly clinical trials system actually benefits the major pharmaceutical corporations since it hinders small start-ups (I bring that up because that is the metaphor I used recently), but I don't think it fairly captures the programmed aging theorists' evolutionary arguments. If I have it correctly, they propose that species that regulate their population will be favored since that would promote ecosystem stability.

Twenty-five years ago my ex-boyfriend who had rather abruptly dumped me came back for a visit and had me read a literature review he had written entitled 'Are Ecosystems Cybernetic?' (I guess his mom was busy); it was a rather exhaustive review of the empirical evidence on the subject. Now, I love control systems and emergent properties and complexity and all that, and the circumstances being what they were, I was hoping for something I would find pleasing to my neurons. Unfortunately I had to admit that the answer was a resounding no - ecosystems are not cybernetic. Perhaps there is new research that counters his conclusion.

Some aspects of aging appear to be programmed, but I think these are possibly manifestations of host / parasite evolution, some of which might be ghosts of battles fought eons ago. I could be wrong .

No matter, I don't think anyone thinks that the evolution of aging or any other process should dictate social policy. There are situations in which sibling cannibalism has evolved as an adaptive strategy, that doesn't mean that we should eat our younger brothers and sisters.

Posted by: CD at June 28th, 2018 3:57 PM

Anyway, that argument that "you must die or there will not be enough resources for the next generation" is counterfactual and very dangerous:

https://www.youtube.com/watch?v=yeaqWSh491A

Posted by: Antonio at June 28th, 2018 4:27 PM

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