21 July 2007. The search for the fountain of youth did not end with Ponce de Leon. Rather, the quest has picked up again lately as researchers have begun to understand the biology of aging and its link to lifespan and disease. Two papers this week deal with distinct mechanisms of anti-aging that have been implicated in Alzheimer disease and other neurodegenerative disorders. In yesterday’s Science, Akiko Taguchi, Lynn Wartschow, and Morris White at Harvard Medical School show that reducing insulin signaling specifically in the brain extends the life of mice. Their results suggest that forces which lower insulin levels—diet, exercise, and weight control—might help us live longer by protecting our brains. That protection might extend to AD as well, where the same factors of diet, inactivity, and overweight raise the risk of disease (see ARF related news story), and derangements in insulin levels or signaling may contribute to AD pathology (see ARF meeting report).
In the second paper, this one in the July 19 Nature, the anti-aging effect comes from a different pathway. Manuel Serrano and colleagues at the Spanish National Cancer Research Center in Madrid demonstrate that boosting levels of the tumor suppressor p53 and its partner Arf slows aging in mice by elevating antioxidant defenses. In neurodegenerative disease, p53 has been implicated as the executioner, mediating the neuronal response to toxic insults like APP products or huntingtin protein (see ARF related news story and ARF news story). The new results raise the possibility that during normal aging, the Arf/p53 pathway could have a protective effect.
First, to insulin and aging. Lower signaling through the insulin pathway causes lifespan extension in worms and flies, and changes in insulin levels are one possible explanation for the life-prolonging effects of calorie restriction in higher animals. White and colleagues messed with insulin signaling in mice by knocking out a key substrate for the insulin receptor tyrosine kinase, insulin receptor substrate 2 (Irs2). Previously, they showed that Irs2-null mice suffer metabolic derangements, diabetes, and early death. The current work analyzes heterozygotes that appear metabolically normal early in life. As the Irs2+/- mice age, they become overweight, but remain sensitive to insulin, a characteristic associated with longevity. Indeed, the Irs2+/- mice lived 17 percent longer than wild-type animals.
In flies and worms, reduced insulin signaling in neurons increases lifespan, so the researchers asked if this was also true in mice by creating a brain-specific Irs2 knockout. These mice ate more, were overweight, and displayed insulin resistance, two metabolic changes that should shorten their lives. Despite this, the heterozygous knockouts lived 18 percent (5 months) longer, and the homozygous knockouts survived 14 percent longer than control mice. The mice show some positive metabolic effects—they were more active, and their glucose utilization and antioxidant response to eating resembled young mice more than control aged mice. The authors conclude that, just as in worms and flies, the results “point to the brain as the site where reduced insulin-like signaling can have a consistent effect to extend mammalian life span.”
Besides insulin, the body’s defenses against cancer may come into play against aging, too, according to the second paper, in which the Spanish group reports that mice with increased but normally regulated levels of the tumor suppressor protein p53 and its stabilizer Arf seem to age more slowly. The mice show both strong cancer resistance and decreased levels of aging-associated oxidative damage.
The p53 protein is a cell’s alarm system, sensing stress and triggering the death of heavily damaged cells. The investigators wondered if p53 might also play a role in response to the low-level, chronic stress that accompanies aging. To probe this question, first authors Ander Matheu and Antonio Maraver generated mice with an extra copy of the p53 and Arf genes under the control of their endogenous promoters. Mice with one extra copy of either gene were resistant to cancer, and adding both together gave even higher protection. While either gene alone did not significantly affect lifespan, the two together produced a 16 percent extension of median lifespan. This is similar to the effect seen with calorie restriction, but unlike calorie restriction, Arf/p53 augmentation did not increase the maximum lifespan. The changes in death rates were not due to differences in the incidence of cancer, since comparison of cancer-free mice from both groups produced a similar shift in median lifespan.
The results suggest that the Arf/p53 pathway can inhibit at least some part of the aging process, and the researchers went on to show that the Arf/p53-enhanced mice also showed changes in biochemical markers of aging, including neuromuscular coordination, hair growth, and the accumulation of phosphorylated histone lesions. The differences in aging correlated with decreased levels of reactive oxygen species in the mice, and the researchers demonstrated that Arf/p53 drove expression of a panel of presumably protective antioxidant genes. The protective effect of these genes was dramatically demonstrated by an increase in the resistance of Arf/p53 mice to a lethal dose of paraquat, a strong oxidative agent.
“We propose that the spectra of genes activated by p53 under normal physiological conditions have a global antioxidant effect, thus decreased aging-associated oxidative damage,” the authors conclude. Reactive oxygen species have been linked to various neurodegenerative diseases including Alzheimer’s and Parkinson’s, so the work opens the possibility that Arf/p53 might play a protective role not only for cancer, but in normal aging and in age-related neurodegenerative diseases.—Pat McCaffrey.
Taguchi A, Wartschow LM, White MF. Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science. 2007 July 20; 317:369-372. Abstract
Matheu A, Maraver A, Klatt P, Flores I, Garcia-Cao I, Borras C, Flores JM, Vina J, Blasco MA, Serrano M. Delayed ageing through damage protection by the Arf/p53 pathway. Nature. 2007 Jul 19;448(7151):375-379. Abstract