SAGE KE Bulletin Board

To Age or Not to Age, Partner

23 October 2003

Corinne Price, Arlan Richardson, J. Randy Strong

The rolling hills of Texas ranchland was the backdrop of a recent workshop where nearly 100 research scientists from all parts of the world gathered to share and discuss their work and ideas on the interrelationship between IGF (insulin growth factor) signaling, aging, and apoptosis. The presentation schedule was rigorous and intense, but participants had time to congregate for brainstorming sessions in a causal, relaxed atmosphere, allowing new professional connections and collaborations to form, and even to take in a little horseback riding and a few margaritas.

Talks and posters at the workshop illustrated a continuing controversy over whether reduced insulin/IGF-1 signaling has a beneficial effect on aging and extends life span in mammals as it does in the invertebrates C. elegans and Drosophila. For example, Andrzej Bartke, Southern Illinois School of Medicine, presented his work on Ames dwarf mice. These mice exhibit a smaller body size and produce lower than normal amounts of growth hormone, circulating IGF-1, insulin, prolactin, and thyroid stimulating hormone (TSH). The dwarf mice show increased resistance to oxidative stress and have longer life spans than do their wild-type littermates. They also show delays in the appearance of age-related pathology and traits, such as memory impairment and declines in locomotor activity.

In contrast, Bill Sonntag, Wake Forest School of Medicine, and Joe D�Ercole, University of North Carolina, discussed the importance of IGF-1 in brain function and the amelioration of age-related memory impairment. D�Ercole�s group showed that transgenic mice that overexpress IGF-1 specifically in the brain display increased neuron and oligodendrocyte numbers, as well as a marked increase in myelination in the developing brain. Mutant mice with ablated IGF-1 and IGF-1 receptor expression exhibit brain growth retardation along with a variety of other growth deficits. These studies confirm that IGF-1 particpates in neural development such that it stimulates neurogenesis and synaptogenesis, facilitates oligodendrocyte development, promotes neuron and oligodendrocyte survival, and stimulates myelination.

Other experiments conducted with these mouse models indicate that IGF-1 also has a role in recovery from neural injury. Sonntag described studies showing that IGF-1 concentrations in rat brains are reduced with age and that administration of IGF-1 into the brain increases cerebral glucose utilization, neurogenesis in the hippocampus, and the number of NMDA receptors in the hippocampus, as well as improves memory in aged animals. He also presented results with dw/dw rats (a dwarf of the Lewis strain), which are deficient in growth hormone and IGF-1, but have normal amounts of TSH and other hormones. His findings bolster the idea that low concentrations of IGF-1 are deleterious. For example, dw/dw rats exhibit memory deficits compared to wild-type rats. These results appear to be contrary to the attenuation of age-related memory decline reported by Bartke in the Ames dwarf mice.

On the other hand, Dr. Shimokawa, Nagasaki University Graduate School of Biomedical Sciences, described transgenic rats that express varying amounts of an anti-sense growth hormone mRNA. These dwarf rats all have lower amounts of GH, IGF-1, and insulin than wild-type rats. However, rats that are homozygous for the transgene have a shorter life span than do wild-type or heterozygous transgenic animals. Rats that are heterozygous for the anti-sense transgene show a slight increase in life span over that of wild-type rats, and caloric restriction extends the life span for both the wild-type and heterozygous animals. He concluded that an optimal concentration of GH is necessary for an enhanced longevity and that too little GH can reduce life span.

These talks provide a snapshot of a continuing controversy over the role of GH and insulin/IGF-1 signaling in mammalian life span determination.
The workshop is the second of these annual events that focus on aging-related topics and are hosted by the San Antonio Nathan Shock Center for Excellence in the Basic Biology of Aging, an NIA-sponsored Center. Last year�s workshop focused on the effects of caloric restriction on the aging processes. Although the theme for next year�s workshop has not yet been decided, The San Antonio Nathan Shock Center has reserved the ranch for next year�s meeting to be held between the 13th and 17th of October 2004.
Some participants have shared their photographs taken at this year�s workshop, which are available here.

---Corinne Price, Arlan Richardson, and J. Randy Strong

Science of Aging Knowledge Environment. ISSN 1539-6150