BioWorld International Correspondent
LONDON - The prospects of developing a drug that could lengthen the human life span have brightened, with the discovery that mice have a gene that predicts how long they live.
Martin Holzenberger, a principal investigator at INSERM in Paris, told BioWorld International, "This paper shows that life span in mice is genetically regulated and confirms in a mammalian species what was discovered in worms and fruit flies only a few years ago. This also means that there may be pharmacological ways of changing life span in mammals."
Holzenberger and his colleagues have found that mice expressing only half the normal amount of protein from the gene that encodes the type 1 receptor for insulin growth factor (IGF1R) lived longer than wild-type mice.
The mouse model also could be useful to those searching for molecules that inhibit IGF1R. "Because IGF itself is implicated in the growth of a number of tumor types, several pharmaceutical companies have been searching for an efficient inhibitor of the IGF receptor," Holzenberger said. "Cancers seem to be able to recruit the IGF signaling pathway to promote their own growth, so by inhibiting IGF1R, it may be possible to slow or arrest tumor growth."
The team reported its results in a paper published online Dec. 4, 2002, by Nature, titled "IGF-1 receptor regulates life span and resistance to oxidative stress in mice."
Studies in the first half of the 1990s had already identified genes in the worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster that controlled longevity in these species. As these genes were homologues of the murine gene encoding IGF1R, Holzenberger and his colleagues decided to investigate what role this gene played in mice.
Knockout mice lacking both copies of IGF1R died shortly after birth, but those which lacked just one copy of IGF1R lived significantly longer than their wild-type littermates, with females living 33 percent longer than wild-type females. These heterozygotes had levels of IGF1R that were about half those in wild-type mice.
Although similar mutants in Drosophila and Caenorhabditis frequently had other abnormalities, such as reduced fertility or dwarfism, Holzenberger said, the heterozygous knockout mice were apparently completely healthy. "This is an important point," he said, "because if you would like to modulate life span pharmacologically, you would not want to induce unacceptable side effects."
One of the major causes of aging is known to be oxidative stress. The team therefore decided to carry out experiments to test whether the knockout mice reacted differently to oxidative stress. Animals were injected with a substance that causes reactive oxygen molecules to form in cells. "We found that the heterozygous knockout mice resisted this challenge longer than the wild-type mice," Holzenberger said. "This could be one explanation for why the knockout mice live longer - perhaps because they can repair such damage better, or maybe because they do not produce such high levels of reactive oxygen species in the first place."
The next question is what effect reducing the expression of the IGF1R gene would have in humans.
Holzenberger said, "If you wanted to increase life span by interfering with IGF1R in humans or animal models, you would have to reduce its function by about half, perhaps by blocking the receptor with inhibitors, or by inhibiting its ligand, IGF, or by using molecules that reduce the signal transduction downstream from the receptor. But it is still hypothetical whether increased longevity could be produced by such strategies. Many other studies have to be done first before we can try this."
Holzenberger and his colleagues also are interested in human studies that would examine the correlation, if any, between expression of the human IGF1R gene and longevity. "We all know that there are some people who are long-lived and appear relatively youthful, while others look old before their time. It is possible that there are certain alleles of the IGF1R gene which are perhaps only weakly expressed, and confer advantages such as longer life span," he said.
Next, the researchers are investigating what happens when they produce a mouse that has a tissue-specific knockout, one in which only the tissues of the central nervous system are affected by a mutation of IGF1R. In their Nature paper, they write: "Homozygous mice for this mutation are microcephalic, sterile and have a complex neuroendocrine dysfunction, but heterozygous mice are healthy and are useful for life span studies."