Single gene deletion boosts lifespan
Mutant mice live longer, age slower and eat more.
Researchers have created a mutant mouse that lives longer despite eating more and weighing less — all thanks to the loss of a single protein.
Without this protein, the body is less susceptible to the heart-pounding effects of the hormone adrenaline, and may become more resistant to some forms of stress.
Scientists are already developing drugs to inhibit this protein, called type 5 adenylyl cyclase (AC5). "Clearly we would be very interested in such a compound," says cardiologist Stephen Vatner, who is part of the team that discovered this effect.
Currently, the main focus of ageing research is on using calorie restriction as a way of activating a metabolic 'fountain of youth'. The new discovery, that knocking out a single cardiac gene could lengthen lifespan, was an unexpected byproduct of heart research.
Vatner, together with Junichi Sadoshima and other colleagues at the New Jersey Medical School at the University of Medicine and Dentistry of New Jersey in Newark, had initially set out to determine whether getting rid of AC5 leads to a healthier heart.
Drugs that block adrenaline signalling, called beta-blockers, are known to help patients who have had heart attacks or suffer from an irregular heartbeat. As the researchers revealed in 2003, mutant mice lacking AC5 were more resistant to heart failure caused by pressure within the heart1.
But in the process, the research team also realised that the mutant mice lived longer than their normal counterparts. Now, in a paper published in Cell this week2, they report that the treated mice lived 30% longer and did not develop the heart stress and bone deterioration that often accompanies ageing.
AC5 could boost longevity by reducing the trauma caused when chemically reactive forms of oxygen accumulate. The accrued damage from these molecules is thought to contribute to ageing. AC5 mutants make more of a protein called ERK2, which regulates oxidative-stress responses. When Vatner and his colleagues increased ERK2 levels in budding yeast, these yeast lived longer.
There are several mysteries about the mice lacking AC5. Young mutants weigh the same as their normal counterparts, but elderly AC5 mutants weigh less — even though they eat more. That suggests a metabolic change, says Vatner, which could be mimicking calorie restriction.
It is also possible that mice without AC5 are more resistant to cancer, Vatner adds. "The major reason that old mice die is not because of heart failure," says Vatner. "The majority of normal mice die from some sort of tumour." It is possible, he says, that the mutants are longer lived because they are able to stave off tumour formation.
The wonder drug
All of that makes an AC5 inhibitor sound like a miracle drug, but the solution may not be that simple.
In the absence of AC5, mutant mice still respond to adrenaline, but the hormone's effect on the heart is less pronounced. But adrenaline responses come in handy during stressful 'fight-or-flight' situations, cautions Michael Bristow, a cardiologist at the University of Colorado Health Sciences Center in Denver. AC5 is part of a complicated pathway, he adds, and the full ramifications of knocking it out are not yet known.
There could also be mental side-effects, notes H. Kirk Hammond, a cardiologist at the University of California, San Diego in La Jolla. Mice that lack AC5 do not respond as well to morphine or antipsychotic drugs such as haloperidol.
Both Bristow and Hammond agree that the results are exciting and that they open up a new avenue of ageing research. But Hammond adds that although an AC5 inhibitor may make a fine drug for protecting the heart, there are more straightforward options for boosting longevity. "I think first what I would do is get people to slow down on the highway, stop eating Big Macs and stop smoking," says Hammond.
- Okumura, S. et al. Proc. Natl Acad. Sci. USA 100, 9986-9990 (2003).
- Yan, L. et al. Cell 130, 247-258 (2007).