Twelve Longevity Enhancement Methods Demonstrated in Mice

Issue CCLX - September 18, 2010
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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 humans. 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.

Reason is the founder of The Longevity Meme. He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries.  

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