Sci. Aging Knowl. Environ., 11 June 2003
No Small Advantage
Diminutive mice don't necessarily gain extra time
Key Words: Snell dwarf Ames dwarf Laron syndrome
Short rodents got no reason to live longer. That's not a line from a Randy Newman song but the conclusion of a new study. The work shows that miniature mice don't always outlast their normal-sized counterparts and implicates reduced insulin concentrations in greater longevity.
Labs teem with long-lived dwarf mice (see Bartke Viewpoint) that produce too little growth hormone or don't respond to it properly. Such mice usually have several metabolic modifications that might stretch longevity, including reductions in blood glucose, insulin, and insulin-like growth factor-1 (IGF-1). Sorting through these possible influences on life span has been a bear. But help might come from molecular endocrinologists Karen Coschigano and John Kopchick of Ohio University, Athens, who didn't set out to study aging. Kopchick's team previously created two novel lines of dwarf mice. One had a disabled gene for the growth hormone receptor (GHR), rendering cells in these rodents deaf to the hormone's commands. The other produced a growth hormone antagonist (GHA), a molecule that vies with the hormone to bind the receptor, thus reducing the hormone's effectiveness. Preliminary studies suggested that the two lines differed in several measures, including life span. However, the altered mice hailed from separate strains, so disparities could stem from their independent ancestries.
To dilute differences in heredity, the team repeatedly crossbred each altered line with a common lab strain. When the researchers compared the new, genetically similar lines, they found that in many ways the GHA animals fell between the controls and the GHR knockouts. For instance, GHA mice showed a 20% reduction in IGF-1 concentrations, compared with unmodified controls; disabling the receptor gene slashed the normal value by 80%. The GHA mice started out as runts, weighing 40% less than normal mice at 1 month of age. But they gained ground during adulthood and were only about 14% smaller than controls by 11 months; the receptor-disabled mice plateaued at about 60% less than controls. Blood insulin values, however, remained normal in the GHA animals and declined by 10% to 26% in the receptor-lacking rodents. Furthermore, the GHA animals lived no longer than normal, whereas the receptor-deficient animals enjoyed 21% to 40% more time. These observations suggest that the mice "uncouple the dwarf phenotype from metabolic activity" and that small size doesn't guarantee longevity, says Kopchick. Because IGF-1 concentrations fell in both kinds of mice but insulin amounts plunged only in the long-lived rodents, the work supports the hypothesis that reduced insulin quantities help prolong life. "I think insulin is the key," says Kopchick.
Disentangling the factors that shape life span is extremely difficult, says James Nelson, a biogerontologist at the University of Texas Health Science Center in San Antonio. This study adds to our understanding by eliminating differences between strains as the source of the effects, he says. However, he cautions that the data don't rule out the size benefit. The weight difference between 11-month-old GHA and normal mice was slight. But if the conclusions hold up, researchers will have to downsize their estimates of the rewards of being small.
--Mitch Leslie; suggested by James M. Harper and Lynnette Gerhold
June 11, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150