Do these startling longevity studies mean your lifespan could double?
Biologists have successfully extended the life spans of some mice by as much as 70%, leading many to believe that ongoing experimentation on our mammalian cousins will eventually lead to life-extending therapies in humans. But how reliable are these studies? And do they really apply to humans? We asked the experts.
Before we get into the scientific evidence, it’s important that we do a bit of reality check. Animal models, and mouse models in particular, don’t always translate well to the human realm.

Of mice and humans

In 2006, a JAMA study concluded that, "patients and physicians should remain cautious about extrapolating the findings of prominent animal research to the care of human disease," and that "even high-quality animal studies will replicate poorly in human clinical research."
What’s more, mice are used in nearly 60% of all experiments — and perhaps even more so in life extension research. As Slate's Daniel Engber has argued, mice are among the most unreliable test subjects when it comes to approximating human biological processes. "It's not at all clear that the rise of the mouse — and the million research papers that resulted from it — has produced a revolution in public health," he has said.
Indeed, comparing the aging processes of mice to humans is a precarious proposition at best. Mice, even under the best conditions, don’t tend to live past two to three years. Clearly, humans and mice are prone to significant variations in terms of how and why they age.
Do these startling longevity studies mean your lifespan could double?
And to further complicate the issue, there’s also the mice themselves to consider. As TeloMe’sPreston Estep told me, the typical lab mouse — a strain called Black 6 (C57BL/6) — is by far the most widely used, and they are very different from wild mice in ways likely to be important for life-extension experiments. Further, most lab strains are very inbred and homozygous across large stretches of the genome. These inbred strains have very long telomeres relative to wild mice (a significant factor in biological aging); the average telomere length of Black 6 is many times longer (50 kilobases) than in wild mice (12 kilobases).
“Some important findings have come from experimenting on Black 6 and other inbred strains, but many scientists are choosing an organism that doesn't suit the experiment,” Estep told io9. “Researchers only use these strains in life-extension-related experiments because they are cheap and widely used, which are very bad reasons to use a model organism that produces questionable data.”
Biogerontologist Aubrey de Grey is also concerned about the use of mouse models.
“A mouse lives so much shorter than a human because it has much less thorough automatic, in-built damage repair machinery,” he told io9. “Mice have bigger gaps in that machinery that medicine has to fix.” Achieving radical life extension, or even indefinite aging, in a mouse, therefore, may prove to be substantially more difficult than achieving it in, say, dogs, cats, or humans.
“We may never have a non-aging mouse,” says de Grey, “And I'm sure we won't have one for a long time after we have a non-aging human.
Reason, an expert in longevity research and a blogger at Fight Aging!, agrees with de Grey’s assessment.
“A mouse’s life span is very plastic,” he told me. “It is to be expected that short-lived species have plastic life spans because of evolutionary selection due to famine and similar adverse circumstances. A long-lived species does not need to have as plastic a life span, because that famine lasts just as long whether you are a human or a mouse.”
He points to research in caloric restriction, for example, a dietary regimen that (arguably) confers life extending benefits. The present consensus is that caloric restriction extends life in mice, but not very much in primates.
Moreover, according to Estep, food fed to mice in the labs is basically junk food — about 70% of calories from starch and sugar. “I sometimes call typical caloric restriction experiments in mice "Cookie Restriction," he says. “It’s not surprising that some mice live longer if fed less of this stuff.”
I also spoke to Kevin Perrott, a scientific advisor for the Methuselah Foundation, an organization that seeks to encourage life extension research, including those done on mice.
“Many scientists will tell you that ‘mice are not people’ which is true of course,” he says. “It is also true that we have cured cancer many times in mice with therapies that do not work in humans, so we must be careful about saying that interventions that work in mice will be directly translatable to humans.”
But at the same time, Perrott argues that functional life extension therapies in mice do hold prospects for human longevity. Extending the lifespan of a mouse that normally lives only three years to five by applying a treatment late in its life could capture the imagination of many.
“In this day of the Internet, everyone would be able to view video clips of mice the equivalent of 120 human years in age — healthy, active and being social with their fellows,” he told me. “This would do something, I think, to the human psyche that would enable much more rapid development of interventions for humans, hence the reason for the Methuselah Mouse Prizewhich is designed to create this result.”
Also called the Mprize, this is a science contest designed to accelerate the development of revolutionary new life extension therapies by offering cash prizes to researchers who have made breakthroughs in longevity and rejuvenation research.

Extending life spans

Okay, now that I’ve gone out of my way to demonstrate the limitations of experimenting on mice, here are some of the most significant life-extending interventions made to date:
Calorie restriction, intermittent fasting, and methionine restriction: Studies have shown that calorically restricted mice can have their life spans extended by as much as 40% even when the restriction is started late in life. Diets artificially low in methionine, an amino acid, produce extended longevity in mice, though not to the same extent as calorie restriction.
Telomerase enhancement: Researchers have produced several demonstrations of extended life and reduced cancer rates in mice, through the use of various gene therapy combinationsinvolving increased telomerase expression and extra copies of cancer suppression genes such as P53. Estep pointed me to several experiments, including Blasco's telomerase overexpression and TA-65-treated mice, and van Duersen and colleagues' clearance of senescent cells. But as he reminded me, these experiments were done on Black 6 mice.
Do these startling longevity studies mean your lifespan could double?
“Consider one example of how this might create a problem,” says Estep. “Van Duersen’s mouse was a progeria model with super-long telomeres. They have a switch that clears senescent cells and delays age-related decline, but this might not occur to the same degree, if at all, in an organism with normal length telomeres, because unnaturally high levels of stem cell proliferation are required to replace the cleared senescent cells.”
A good follow-up experiment, he says, would be to use a wild-type mouse with a switch to remove senescent cells, plus and minus a telomerase activator, to determine whether or not telomere length plays a limiting role in a mouse model with greater human relevance.
You can read more about extending life spans in mice via telomerase expression here and here.
Over-expression of PEPCK-C: Emily Anthes, the author of Frankenstein’s Cat: Cuddling Up To Biotech’s Brave New Beasts, brought this one to my attention. She wrote to me in an email:
Essentially, what scientists did was engineer mice that made elevated levels of PEPCK-C, a metabolic enzyme involved in glucose production, in their muscles. The most noticeable effect was the rodents' supercharged endurance — the animals were dubbed "marathon mice" because they could run 25 times farther than their unmodified counterparts. But this single genetic tweak had other effects, as well, including adding two years to the animals' life spans — a significant boost for creatures that normally only live a few years to begin with. And interestingly, the modified female mice also remained fertile for twice as long as "normal" mice.
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 competition's standard laboratory mouse species. This may be 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. Unfortunately, these dwarf mice are not very robust; they’re healthy and active, but they wouldn't survive outside the laboratory or without good care due to their low body temperature.
Inactivating the CLK-1 gene: By reducing the activity of the mitochondria-associated gene CLK-1 (thereby lowering the amount of protein generated) mice longevity was boosted by about 30%. This may be one of the many interventions to work through its effects on mitochondria, the cell's power plants — and a very important factor in aging. In another mitochondria-related study, Russian researchers demonstrated a form of antioxidant, SkQ, that can be targeted to the mitochondria even when ingested, again boosting life span in mice by about 30%.
Genetic manipulation to target catalase to the mitochondria: By using either gene therapy or genetic engineering, researchers have shown that 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.
In addition to these experiments, researchers have also extended the lives of mice via:

Looking ahead

Now, as interesting as these studies appear, and after considering the limitations of mouse models, such approaches are unlikely to herald the future of life-extending therapies in humans.
“Virtually everything demonstrated to date to extend life in mice has been a form of gene therapy or metabolic manipulation,” says Reason, “It changes the pace of aging, but isn't rejuvenation.”
His conjecture is that the research community will never get much past the 100% life extension for mice, with the current outer limit settling around 60-70% for growth hormone receptor knockout mice.
“To create longer lives, you need to work on rejuvenation attainted by repairing the cell- and tissue-level damage that causes aging, not just finding ways to gently slow aging by slowing down the pace at which that damage accumulates,” he told me. “The future of mouse longevity is SENS (Strategies for Engineered Negligible Senescence), which is a radically different approach to any of the work currently extending life in mice.”