Increased Longevity in Mice by Removing Cardiotrophin 1

Here is an question to think on while you recover from the excesses of the recent holiday: should we expect there to be, in humans, mice, or other species, many simple genetic alterations that are unambiguously beneficial for the individual, yet which evolution did not select for? Another way of looking at this question: why is it that there exist a range of ways to engineer slightly-genetically-altered mice that are stronger, healthier, and longer-lived than the standard wild variants?

The classical answer to this question suggests that these improvements come with fitness costs in the wild, or - more subtly - have the effect of dramatically reducing ability to survive under some rare combination of environmental circumstances. This is obviously the case when you look at mice lacking growth hormone, which live 60-70% longer than their peers, but are absolutely unfit for life in the wild due to their small size and, more importantly, issues with maintaining body temperature due to that small size. But for unambiguously all-round beneficial mutations like myostatin knockout, one has to think harder about how this could be a disadvantage.

Here is another example of a mutation that everyone would want for their offspring, should it turn out to work much the same way in humans:

Absence of Cardiotrophin 1 Is Associated With Decreased Age-Dependent Arterial Stiffness and Increased Longevity in Mice

Cardiotrophin 1 (CT-1), an interleukin 6 family member, promotes fibrosis and arterial stiffness. We hypothesized that the absence of CT-1 influences arterial fibrosis and stiffness, senescence, and life span. In senescent 29-month-old mice, vascular function was analyzed by echotracking device. Arterial histomorphology, senescence, metabolic, inflammatory, and oxidative stress parameters were measured.

Survival rate of wild-type and CT-1-null mice was studied. ... The wall stress-incremental elastic modulus curve of old CT-1-null mice was shifted rightward as compared with wild-type mice, indicating decreased arterial stiffness. Media thickness and wall fibrosis were lower in CT-1-null mice. CT-1-null mice showed decreased levels of inflammatory, apoptotic, and senescence pathways, whereas telomere-linked proteins, DNA repair proteins, and antioxidant enzyme activities were increased. CT-1-null mice displayed a 5-month increased median longevity compared with wild-type mice.

The absence of CT-1 is associated with decreased arterial fibrosis, stiffness, and senescence and increased longevity in mice likely through downregulating apoptotic, senescence, and inflammatory pathways. CT-1 may be a major regulator of arterial stiffness with a major impact on the aging process.

I look forward to the day on which one can take a flight across the Pacific as a medical tourist, drop into a reputable clinic, and have a few genetic alterations done: myostatin, cardiotrophin 1, and others that arise and are shown to have no downsides for people living in a society with access to modern medicine.


Intriguing ideas. I would expect such gene alteration clinics to crop up within the next decade.

But rather than to permanently alter such life extending genes, one might prefer the installation of a "switch" for adjusting the genes, or turning the genes on and off over suitable intervals.

Perhaps via optogenetics or other means, a method of periodically tuning the genes for specific purposes might give us the best of all worlds -- or at least an acceptable compromise.

Posted by: Al Fin at November 24th, 2012 11:09 AM

> Should we expect there to be, in humans, mice, or other species,
> many simple genetic alterations that are unambiguously beneficial
> for the individual, yet which evolution did not select for?

Whether or not we expect it, there are several such examples that are copiously documented, and that suggests to me that there are countless more that are not documented in detail.

Reznick's guppies
Hanson & Hakimi's mice

This is but one of many indications that we cannot understand aging via individual selection alone. There is an element of programmed aging needed to explain these examples. Other evidence for the same thesis:
- affirmative modes of aging in semelparous animals and plants
- 2 ancient modes of aging in protozoans still active in higher life forms today: cellular senescence and apoptosis
- relatedness of genes that regulate aging over vast evolutionary distances

Posted by: Josh Mitteldorf at November 25th, 2012 8:12 PM

It's not at all clear that myostatin knockout is an "unambiguously all-round beneficial mutation." The animals in which it was shown to be beneficial were not normal mice, but atherosis-prone mutant mice with their LDL receptors knocked out, who were then fed a high-fat/high-cholesterol diet. The fact that you can do something to ameliorate the miserable lives of such creatures doesn't mean that doing the same thing to healthy animals would also be beneficial; nor does the very limited number of benefits observed and lack of deleterious effects observed from the limited set of metabolic parameters they examined mean that there were no harms. No proper necropsy was done -- they only examined the liver and the arteries -- and we have no idea what their lifespan was.

In normal mice or humans, myostatin knockout can be expected to prematurely deplete stem cell populations, and is known in mice to lead to larger muscles of lower specific force capacity.

Posted by: Michael at November 26th, 2012 4:40 PM
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