Twelve Longevity Enhancement Methods Demonstrated in Mice
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Researchers have discovered a large - and continually growing - number of ways to significantly extend healthy and maximum life span in mice. Here I'll list a selection of twelve of the most interesting methods I've seen in past years. Note that I'm omitting a number of studies that show only small (less than 10%) increases in maximum mouse life span, and also leaving out some work in progress that looks likely to enhance life span. For example, Cuervo's work on enhancing autophagy where we're waiting on formal publication of mortality rate data, or enhanced uncoupling protein studies that show median life span increases but not maximum life span increases.

But on with the list:

1) Calorie Restriction, Intermittent Fasting, and Methionine Restriction

Imposition of calorie restriction in mice has been shown to extend life span by around 40% even when initiated comparatively late in life. See for example, the study that is the present rejuvenation Mprize winner:

Here we demonstrate that CR initiated in 19-month-old mice begins within 2 months to increase the mean time to death by 42% and increase mean and maximum lifespans by 4.7 and 6.0 months, respectively. The rate of age-associated mortality was decreased 3.1-fold.

Intermittent fasting, such as alternate day fasting, results in similarly low calorie intake and noteworthy extension of life span, but there is some evidence to think that it operates via a different (though probably overlapping) set of biological mechanisms to calorie restriction.

Methionine restriction has recently come to be more interesting as researchers search for the biological triggers that produce health and longevity benefits in response to calorie restriction. One candidate is the response to the level of methionine, one of the essential amino acids. Diets artificially low in methionine produce extended longevity in mice, though not to the same extent as calorie restriction:

Life span can be extended in rodents by restricting food availability (caloric restriction [CR]) or by providing food low in methionine (Meth-R). Here, we show that a period of food restriction limited to the first 20 days of life, via a 50% enlargement of litter size, shows extended median and maximal life span relative to mice from normal sized litters and that a Meth-R diet initiated at 12 months of age also significantly increases longevity.

2) Growth Hormone Knockout, IGF-1 and Insulin Signalling Manipulation

A breed of dwarf mouse that entirely lacks growth hormone is the present winner of the Mprize for longevity, living 60-70% longer than the compeition's standard laboratory mouse species. This is primarily interesting as a demonstration that insulin signalling and IGF-1 - intimately bound up with growth hormone - are very important to the operations of metabolism that determine life span. These dwarf mice are not very robust: whilst healthy and active, they wouldn't survive outside the laboratory or without good care due to their low body temperature.

You might look at this post from the archives for an introduction to present thinking on IGF-1 and insulin in longevity and metabolism:

insulin and insulin-like growth factor-1 (IGF-1)-like signaling and its downstream intracellular signaling molecules have been shown to be associated with lifespan in fruit flies and nematodes. More recently, mammalian models with reduced growth hormone (GH) and/or IGF-1 signaling have also been shown to have extended lifespans as compared to control siblings. Importantly, this research has also shown that these genetic alterations can keep the animals healthy and disease-free for longer periods and can alleviate specific age-related pathologies similar to what is observed for [calorie restricted] individuals. Thus, these mutations may not only extend lifespan but may also improve healthspan, the general health and quality of life of an organism as it ages.

3) Telomerase Plus p53

A Spanish group published a study in 2008 showing 50% life extension in mice by a suitable combination of enhanced telomerase and p53. The enzyme telomerase extends telomere length thus prolonging the life of individual cells - which usually leads to cancer rather than extended life. p53 on the other hand is an anti-cancer gene that normally reduces life span whilst lowering the risk of cancer - the traditional view being that mechanisms of extended longevity and mechanisms of cancer resistance have evolved to a point of balance. We enterprising humans can always improve on the end results of evolution, however (even if we can't yet manage a decent automated transation of Spanish to English):

So it seems necessary to ask the molecular biologist if, in this battle that they have undertaken jointly against the cancer and the aging, it is only a question of putting telomerase into a mouse to make it immortal. "The answer is no, because telomerase causes more cancer. So that there is a tumor, it must activate telomerase, and if a mouse has more telomerase than the normal thing, for example, making transgenic mice, we know that it will have more tumors. What we have done is to use the Manuel [Serrano's] supermice, because p53 protects against cancer and extends life of the mice 18%, and added the gene of immortality, telomerase, and we obtained that these multitransgenic mice live an average on a 50% more, without cancer.

4) Inactivating the CLK-1 Gene

Reducing the activity of the mitochondria-associated gene clk-1 - lowering the amount of protein generated from its blueprint in other words - boosts mouse longevity by 30% or so. This may be one of the many interventions to work through its effects on mitochondria, the cell's power plants. As we know, mitochondria are very important in aging.

The longevity-promoting effect of reducing CLK-1 activity that was initially observed in C. elegans is conserved in three different genetic backgrounds of mice. In 129Sv/JxBalb/c mice for instance, reducing activity of the gene mclk1 (mouse clk-1) results in a prolongation of lifespan of about 32%. The inactivation of mclk1 gene, which encodes a mitochondrial enzyme, decreases reactive oxygen species (ROS) levels, the toxic molecules that damage proteins, lipids and DNA, and this likely explains this increase in lifespan.

5) SkQ, a Mitochondrially Targeted Ingested Antioxidant

A Russian researcher has demonstrated a form of antioxidant that can be targeted to the mitochondria even though ingested. Per the mitochondrial free radical theory of aging, anything that can reduce the damage mitochondria do to themselves via the free radicals they generate in the course of their operation should extend life span. Indeed, SkQ seems to boost mouse life span by about 30%:

The life time of [SkQ ingesting] mice increased by one third on average as compared to that of the reference group mice. Even more demonstrative are experiments with mutant rats, where accelerated ageing - progeria - was observed. SkQ prolonged their life span by three times, besides, it cured them from a large number of senile diseases. They include infarctions, strokes, osteoporosis, hemogram abnomality, reproductive system disorders, behavior change, visual impairment.

6) Genetic Manipulation to Target Catalase to the Mitochondria

A couple of research groups have shown that through either gene therapy or genetic engineering the levels of a naturally produced antioxidant catalase can be increased in the mitochondria. This increases mouse life span, presumably by soaking up some portion of the free radicals produced by mitochondria before they can cause damage. See this for example:

Earlier studies have found that mice would live longer when their genome was altered to carry a gene known as mitochondria-targeted catalase gene, or MCAT. However, such approaches would not be applicable to human. Duan and Dejia Li [took] a different approach and placed the MCAT gene inside a benign virus and injected the virus into the mice. Once injected, Duan and Li tested the mice and found that they could run farther, faster and longer than mice of the same age and sex.

As well as the original work by Rabinovitch:

The mice lived 20 percent longer than normal mice - on average they lived five and a half months longer than the control animals, whose average life span was about two years.

7) Genetic deletion of pregnancy-associated plasma protein A (PAPP-A)

This is another method of reducing cancer incidence and also extending life span by 30% or so, but this time seemingly through manipulation of the insulin signalling system in a more subtle way than previous growth hormone knockout studies. The end results certainly look like a win-win situation: extended life span and less cancer with no downside.

Genetic deletion in mice of pregnancy-associated plasma protein A (PAPP-A), a recently identified metalloproteinase in the insulin-like growth factor system, extends by 30-40% both mean and maximum lifespan with no reduction in food intake or secondary endocrine abnormalities. Furthermore, these mice have markedly reduced incidence of spontaneous tumors. The findings implicate PAPP-A as a critical regulator of lifespan and age-related diseases, and suggest PAPP-A as a possible target to promote longevity.

By now you should be quite convinced that evolution has not optimized for longevity in species like the common mouse. That any number of comparatively simple genetic manipulations or mutations exist to give what appear to be unqualified benefits to longevity and health is an apt demonstration of this fact.

8) Knockout of the adenylyl cyclase type 5 (AC5) gene

Mice lacking the gene for the AC5 protein, which strangely enough appears to be a crucial component of the opioid response in mammals in addition to its other roles, live 30% longer. This is suggested to be due to a more aggressive, effective repair and prevention response to oxidative damage.

The new discovery, that knocking out a single cardiac gene could lengthen lifespan, was an unexpected byproduct of heart research. ... mutant mice lacking [the gene for protein] AC5 were more resistant to heart failure caused by pressure within the heart. But in the process, the research team also realised that the mutant mice lived longer than their normal counterparts. [Now] they report that the treated mice lived 30% longer and did not develop the heart stress and bone deterioration that often accompanies ageing.

9) Metformin used as a calorie restriction mimetic drug

The drug metformin has been demonstrated to act in some ways like calorie restriction in mouse biochemistry, producing a modest 10% gain in maximum life span.

Here we show the chronic treatment of female outbred SHR mice with metformin (100 mg/kg in drinking water) slightly modified the food consumption but decreased the body weight after the age of 20 months, slowed down the age-related switch-off of estrous function, increased mean life span by 37.8%, mean life span of last 10% survivors by 20.8%, and maximum life span by 2.8 months (+10.3%) in comparison with control mice.

The present pharmaceutical industry search for commercial calorie restriction mimetic drugs is heated and likely to expand in future years, moving out beyond CR metabolism and into anything else where some link can be demonstrated between gene, designer drug, and longevity in mice.

10) FIRKO, or fat-specific insulin receptor knock-out mice

FIRKO mice have less visceral body fat than normal mice, even while eating at the same calorie levels. They live a little less than 20% longer, and this is taken as one line of evidence to show that that possessing a lot of visceral fat is not good for longevity.

Both male and female FIRKO mice were found to have an increase in mean life-span of ~134 days (18%), with parallel increases in median and maximum life-spans. ... Together, these data suggest that maintenance of mitochondrial activity and metabolic rates in adipose tissue may be important contributors to the increased lifespan of the FIRKO mouse.

11) Removal of visceral fat by surgery

Continuing the fat theme, researchers demonstrated last year that you can extend the life span of mice by surgically removing excess visceral fat. It doesn't extend life as much as calorie restriction, but it is significant:

We prospectively studied lifespan in 3 groups of rats: ad libitum fed (AL), 40% caloric restriction (CR) and a group of ad libitum fed rats with selective removal of VF at 5 months of age (VF-). We demonstrate that compared to AL, VF- rats had a significant increase in mean and maximum lifespan and significant reduction in the incidence of severe renal disease.

CR animals demonstrated the greatest mean and maximum lifespan the lowest hazard rate of death as compared to AL rats. Taken together, these observations provide the most direct evidence to date that a reduction in fat mass, and specifically VF, may be one of the possible underlying mechanisms of the anti-aging effect of CR.

You'll find quite a lot in the Fight Aging! and Longevity Meme archives on the mechanisms by which fat is thought to harm long term health and cause low-level damage throughout the body. You might start with these:

12) Overexpression of PEPCK-C, or phosphoenolpyruvate carboxykinase

In this case, researchers have no firm conclusion as to why and how this genetic manipulation works. As in a number of other cases, this investigation wasn't started as a part of any aging or longevity study, and the longevity of these mice is a fortunate happenstance. Nonetheless, here we have a case of what appears to be a more than 50% life extension - though note that the formal life span study has not been published, so you might assume the comments below to refer to the outliers amongst these mice rather than the average.

These mice were seven times more active in their cages than controls. On a mouse treadmill, PEPCK-C mice ran up to 6 km at a speed of 20 m/min while controls stopped at 0.2 km. ... The PEPCK-C mice eat 60% more than controls, but had half the body weight and 10% the body fat ... In addition, the number of mitochondria and the content of triglyceride in the skeletal muscle of PEPCK-C mice was greatly increased as compared to controls. PEPCK-C mice had an extended life span relative to control animals; mice up to an age of 2.5 years ran twice as fast as 6-12 month old control animals. ... they lived almost two years longer than the controls and had normal litters of pups at 30 to 35 months of age (most mice stop being reproductively active at 12 to 18 months).

The full paper, complete with Bruce Springsteen quote, is freely available at PubMedCentral. It outlines the tentative theories of the researchers as to how these mice fit in to present theories of aging and other known longevity manipulations.

We suspect that the major factor responsible for the longevity of the PEPCK-Cmus mice is the very low concentration of insulin in the blood of the mice that is maintained over their lifetime of hyperactivity.
Comments

This is a wonderful summary of a wide variety of research. I think this kind of post is an example of the value of this blog - as there are few places to look all at once at a listing of the success stories of extending lifespan. Very thought provoking and inspiring.

Posted by: Alex J at August 24, 2009 8:24 AM

Agreed. Great post!

Posted by: Michael G.R. at August 24, 2009 12:39 PM

Very interesting!

People are taking human growth hormone in order to increase longevity, and may be having the exact opposite effect.

Cheers!

Posted by: Mark at August 24, 2009 8:06 PM

Also agreed - great post. Great in that it provides a useful summary of the various ways by which mouse lifespan has been extended. This enables the reader to walk away with a (usefully) broad perspective of what sorts of mechanisms influence our own lifespans. This perspective assists the reader in coming up with ideas of hir (his/her) own.

I'm sharing it.

Thanks for the post!

Posted by: Max Peto at August 25, 2009 6:52 PM

I was just going to suggest that you add this to the "Required Reading" but then I saw it there! Excellent post!

Posted by: Tim at August 26, 2009 4:51 AM

Helpful research, I'm also agree with this comment :

Great in that it provides a useful summary of the various ways by which mouse lifespan has been extended. This enables the reader to walk away with a (usefully) broad perspective of what sorts of mechanisms influence our own lifespans. This perspective assists the reader in coming up with ideas of hir (his/her) own.

Posted by: Enhance Your Life at February 8, 2010 9:21 PM

Only a small number of these interventions -- Calorie Restriction, Methionine Restriction, Growth Hormone Knockout, IGF-1 and Insulin Signalling Manipulation -- have actually been shown to extend maximum lifespan in normal, healthy mice. Intermittent Fasting is a pseudo-exception: it extends maximum lifespan when and to the degree that it concomitantly induces Calorie restriction, and not when it doesn't. As to the other interventions, as I noted in a recent SENS Foundation CSO Blog post:

"Much of the distraction in the literature of biogerontology, and an even higher ratio of studies cited and promoted in the popular media and the dietary supplement industry, derives from methodologically-poor lifespan studies in mice (or occasionally rats). ... In these studies, an increase in mean or maximal lifespan is reported, relative to short-lived controls, and claimed to be informative about the universal, degenerative aging process and the prospects for extending healthy life in humans living in the developed world. And the claim typically persists for decades once widely-cited, despite the best efforts of serious investigators to critique weak methodologies and flawed interpretation, or even robust demonstrations of a null effect in healthy animals (as the two independent demonstrations that resveratrol does not extend lifespan in nonobese, wild-type mice over a wide range of doses)."

Posted by: Michael at April 21, 2011 1:14 PM

The danger is the bureaucrat effect, where the least qualified person will become placed into the position to create the greatest possible amount of damage. That natural antioxidant increased in the mitochondria would need research in primates prior to reaching humans, then only the wealthy people at first. These difficulties with scale is one of part of technology's difficulties when being applied.

Those difficulties with intellectual property rights will need to be addressed. With people needing to pay for inheriting genetic changes along with possible discrimination, being part of the complexity. The upper classes will be able to employ the legal specialist needed to evaluate the legal complications as these relate to genetically modified organisms, even when those are people. These complexities will need to be worked out while society does change, just like autofluorescence.

An exposure to UVB-Damage will cause a autofluorescence compound to be made called melanin, this is from dissipating photon energy quickly with sunscreen users getting health consequences. This use of specialized information does reveal why bureaucratic types fail to manage thing correctly. The Internal conversion (chemistry) told of in Wikipedia doe list this as a method of reducing radiation damage. Those corrective practices such as sunscreen do increase damage yet the bureaucratic approach is to blindly trust advertising and other misinformation.

Posted by: Brent Emery Pieczynski at September 11, 2011 12:01 PM

"(as the two independent demonstrations that resveratrol does not extend lifespan in nonobese, wild-type mice over a wide range of doses)"-Michael

The fact that it worked on the obese implies it offers some protection from the complications of obesity(metabolic syndrome, diabetes, cardiovascular disease, etc.). If the causes of death in normal mice(which i've heard mostly die from cancer, though haven't verified) differ from those in humans(for example cardiovascular disease is the number one killer), the conclusion I draw is that resveratrol could very well be effective on man and species closer to man.

"Intermittent Fasting is a pseudo-exception: it extends maximum lifespan when and to the degree that it concomitantly induces Calorie restriction, and not when it doesn't."-Michael

Intermittent fasting combined with calorie restriction has been seen in some areas to be more effective than calorie restriction alone. And it seems to improve autophagocytosis and antioxidant capacity of cells. Why such does not improve lifespan in rodents with regular non-cr calorie consumption is a good question, could do again with causes of death that limit lifespan of mice, maybe the cancer defenses of mice are simply not good enough to benefit from such.

Experiments in higher organisms should be an interesting avenue of research.

Posted by: Darian Smith at October 27, 2011 9:11 AM

~PLEASE READ~

Because of the immortal jellyfish, which is biologically immortal by swapping between premature and mature stages repeatedly, why don't people then realize that its possible sexual maturation increases aging?

They should test in mice delayed or prevented sexual maturation to see the effect it has on life spans.

It'd be nice if they notice this idea, so quote me if you second this! Or post this idea where appropriate.

Posted by: Ty at January 25, 2012 1:11 PM

from mprize.org
"Dwarf mice...lack growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH), (and) live much longer than their normal siblings, and exhibit many symptoms of delayed aging."

There is more going on with these mice than just the lack of GH and a receptor.

"reduced secretion of insulin, increased hepatic sensitivity to insulin actions, reduced plasma glucose, reduced generation of reactive oxygen species, improved antioxidant defenses, increased resistance to oxidative stress, and reduced oxidative damage"

There were separate experiments that showed exogenous administration of HGH to mice increased their life expectancy somewhat-so the whole story here is complicated.

Posted by: Randall Burns at April 25, 2012 3:54 AM

i think there is a higher dimensional intervention in aging/lifespan. A physically active animal ( or human ) is highly favored by the environment/society( and by God ) than the lazy ones. Those who practice fasting or food restriction are favore by higher beings than those glutonnous ones. Small bellied individuals are highly pleasing to the eyes of GOD than to those big bellied person that resembles a burmese python that has just swallowed an alligator

Posted by: rejie quimiguing at August 27, 2012 12:19 PM

These are therapies not possible now, but a few ideas I've come up with.
a. Mitochondria transplant, seeing as they are incapable of passing through cell walls nor do they replicate on their own, drinking a solution of 'healthy' mitochondria with a digestable fat coating to allow transport one way across the membrane upon injection or ingestion.
b. Creating synthetic receptors or signals of cancer, i.e. when cancer related miRNA is activated, you have it also activate a synthetic gene or protein, that is expressed on the membrane surface to activate apoptosis.
c. Ingesting fullerenes by mice and low calorie diet, when compared to just a low calorie diet lived almost double... from memory its was 42 months to 24 months respectively.
d. Nanoparticle with adhered synthetic or bacterially developed enzymes to degrade 'junk'
e. Same things with enzymes that remove known pathological glycosylation.
f. Quantifying the long lived proteins, fats, sugars, etc that increase with aging by comparing 1 years old rats to 2 year old rats tissue, taking the difference and seeing which can be processed with normal genes being re-regulation and which we cannot degrade. Has this been done?

Posted by: Julian Poulton-King at October 14, 2012 7:07 PM

@Julian Poulton-King

Regarding (a), mitochondrial transplant appears to be possible via an infusion, per a recent technology demonstration. See:

https://www.fightaging.org/archives/2012/09/a-way-to-insert-new-mitochondria-into-cells.php

Regarding (c), the community is pretty skeptical about that study. It didn't appear in an aging-related journal, and the results are way beyond reasonable. See:

https://www.fightaging.org/archives/2012/04/a-puzzling-fullerene-study.php

Posted by: Reason at October 14, 2012 7:12 PM

@Reason
Thanks for the quick reply! Check out my response in that article.
Knowing their non-toxic is fantastic at least, going to be an important tool in these ventures anyway.
I've been experimenting with T10 dextran coated iron oxide nanoparticles, obviously not the same as fullerenes, but still a very interesting tool, I've been testing if the coating is giving the particle antioxidant abilities because of it's the (basically) indigestable sugar chains (glucose) creating a high surface area which are largely made from hydroxyl groups, I hypothesised this act's as a 'sink' for reactive oxygen species converting them to water. i.e. (H+) + (OH-) -> H20. Basically out competing the other chemicals they react with to become water, with this reaction, so that the other stuff doesn't get as damaged. Will post when I've done the stats for my results :) or should I just post my abstract?

Posted by: Julian Poulton-King at October 14, 2012 8:05 PM

hi----it als0 just feels better to not eat so much=easy

Posted by: John RHODES at December 4, 2012 10:08 AM

I'm struck by the issue of:
a) increased life span in mature mice given HGH
b) increased life span in mice with a GH receptor missing
c) increase lifespan in GH deficient mice

These are _all_ documented in published papers(see below).

What I'm curious about:
would dwarf mice life longer if given exogenous HGH later on in life?
which would live longer given supplemental GH, the GH knockout mice or the GH deficient mice?

If the GH knockout Mice lived longer when being given exogenous GH
would that be evidence of another, poorly understood receptor
for GH?

These experiments just haven't been done yet.

http://www.ncbi.nlm.nih.gov/pubmed/2002700?dopt=Abstract

http://www.ncbi.nlm.nih.gov/pubmed/21325617?dopt=Abstract

I'm not sure quite what is going on here. It is plausible to me that lower levels of GH early in life are beneficial-as are higher levels later on in life.

Posted by: Randall Burns at December 21, 2012 5:25 PM

I really appreciate this article. Since 2009 there have been a few new things that strongly increase mammal lifespan. Polyamines like spermidine are thought to be among the reasons that the yogurt LKM512 more than triples survival of mice at 45 weeks. the graph at the PMID paper describes the effect http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3156754/

Posted by: Beanangel300 at May 1, 2013 4:53 PM
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