Kamis, 19 Mei 2011

Dwarfism may stymie diseases of old age

A mutation in a pathway linked to ageing causes dwarfism, but may protect against cancer and diabetes.

A group of people with dwarfism living in southern Ecuador may hold a genetic secret to healthy ageing, according to a study published today in Science Translational Medicine1.
The Ecuadorians in the study, who have a condition called Laron syndrome caused by a mutation in the growth hormone receptor (GHR) gene, almost never develop cancer or diabetes. Moreover, the mutation seems to trigger a molecular pathway that protects against cell damage and boosts longevity in yeast, worms and mice.

"Almost everything we found in those hundred people and their ancestors, others have shown in mice," says Valter Longo, a molecular geneticist at the University of Southern California, Los Angeles, who led the study.
Longo was eager to test whether a nutrient-sensing and growth pathway that has been linked to ageing in lab organisms such as yeast and mice had a similar role in humans.

The search led Longo to Jaime Guevara-Aguirre, an endocrinologist at the Institute of Endocrinology, Metabolism and Reproduction in Quito, Ecuador. For the past 22 years, Guevara-Aguirre has been tracking the health of 99 individuals with dwarfism, as well as 1,600 of their relatives who lack the mutation in GHR.
Those with the mutation are between about 1 and 1.2 metres tall, owing to their bodies' limited ability to use growth hormone. Compared with relatives without the mutation, their blood contains lower levels of the protein insulin-like growth factor I (IGF-I), which is central to ageing.

Of the 99 people with Laron syndrome in the study, 9 have died. None of them — nor 53 of their relatives with the condition who died before the study began — died of cancer or complications of type 2 diabetes. Only one patient developed cancer — a woman had an ovarian tumour removed in 2008 and has remained cancer-free since. Meanwhile, cancer caused 20% of deaths in relatives without the mutation and type 2 diabetes caused another 5%.

No extended life

But unlike lab organisms with mutations in the IGF-I pathway, such as "Dwarf" mice that live up to 50% longer than normal mice, the Ecuadorians with the GHR mutation did not live any longer than their unaffected relatives. Instead, they were more likely to die of accidents, alcohol-related causes and convulsive disorders such as epilepsy, Longo and his team found.

"We were very disappointed," says Longo. "We were hoping at least to see something like 10%. That may very well be there. They were just born with this problem and they seem to die of all these strange causes."
At the molecular level, however, their blood showed many of the hallmarks of ageing protection seen in other organisms with reduced IGF-I activity. When incubated with cultured human cells, their blood was better at protecting cells from cancer-causing DNA-strand breaks than the blood of relatives that lacked the GHR mutation.

These results support the idea that defects in nutrient-sensing pathways such as IGF-I encourage cells to protect themselves and their DNA, rather than to grow and divide, says Longo. Such cues could also explain why the Ecuadorians with dwarfism rarely develop cancer or diabetes.

However, it is not clear whether they are protected from ageing in general or just from particular diseases, says Matt Kaeberlein, a biochemist at the University of Washington in Seattle. "I don't think we know the answer, but the data are suggesting that this may be influencing several of the processes associated with ageing."

Brian Kennedy, head of the Buck Institute for Research on Aging in Novato, California, says that the study underscores the IGF-I pathway as a target for therapies that prevent age-related diseases. "This is even more evidence that this is a great place to be looking."

Longo suggests that blocking growth hormone and IGF-I signals later in life could protect against age-related disease, without affecting normal growth. However, Kaeberlein says that it is still not clear whether the disease-protection effects seen in the Ecuadorians with dwarfism are due to effects early in life, late in life — or both. "There's lots of important information still to be learned here," he says. 


References:
Guevara-Aguirre, J. et al. Sci. Transl. Med. 70, 70ra13 (2011).
http://www.nature.com/

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