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ScienceWeek
MEDICAL BIOLOGY: ON INSULIN-LIKE GROWTH FACTORS
The following points are made by Ron G. Rosenfeld (New Engl. J. Med. 2003 349:2184):
1) Growth in any species is an extraordinarily complex process, but growth in humans is characterized by a number of unique features. These include dramatic fetal growth (the most rapid phase of human growth), deceleration of growth immediately after birth, a prolonged growth phase during childhood, prepubertal deceleration, and a pronounced adolescent growth spurt. Although some of these aspects are shared with other mammalian species, others are characteristic only of Homo sapiens and are not replicated even in other primates.
2) The intricacy of the human growth curve is the product of an evolutionary process expressing the sum effect of multiple genes whose interplay determines a pattern of growth that reflects the survival needs of our species. Given the complexity of vertebrate and, especially, human growth, it is reasonable to assume that a large number of genetic factors are involved in the control of stature, a hypothesis supported by the existence of multiple clinical disorders characterized by growth failure. It is therefore all the more surprising that a series of elegant investigations in mice, complemented by case studies in humans, have convincingly demonstrated the critical role of the insulin-like growth factor (IGF) system in all phases of mammalian growth, including intrauterine, childhood, and pubertal.
3) The existence of IGFs was first proposed in 1957 on the basis of studies indicating that growth hormone did not directly stimulate the incorporation of sulfate into cartilage but rather acted through a serum factor. This factor was originally termed "sulfation factor", then "somatomedin", and ultimately, insulin-like growth factor I (IGF-I) and II (IGF-II). Subsequent investigations demonstrated that growth hormone (GH), after binding to its transmembrane receptor, initiated a complex signaling cascade leading to transcriptional regulation of the gene for IGF-I and related genes.
4) Thus, the growth characteristics of patients with severe IGF deficiency, resulting from homozygous mutations in the gene for the GH receptor (or the GH signaling protein signal transducer and activator of transcription 5b [Stat5b]), were indistinguishable from those of children with congenital GH deficiency. Such patients typically had only minimal growth attenuation in utero but profound postnatal growth failure, thereby underscoring the critical role of the GH-IGF system in postnatal growth. The contribution of the GH-IGF axis to prenatal growth, however, was less clear, since congenital defects of the secretion or action of GH had limited effects on intrauterine growth and experimental ablation of the pituitary only minimally impaired prenatal growth in animals.
5) The concept that GH-independent IGF production had a role in fetal growth emerged from studies of mouse mutants with defective genes for IGFs or their receptors. Targeted disruption of the mouse gene for IGF-II resulted in a 40 percent reduction in fetal growth but otherwise normal postnatal growth. Disruption of the gene for IGF-I led to a similar decrease in birth weight but was also characterized by persistent postnatal growth failure, so that mice with the gene disrupted grew to only 30 percent of normal size as adults. Most striking, however, were the phenotypic consequences of deletion of the gene for the IGF-I receptor (IGF-IR), a transmembrane tyrosine kinase that mediates the growth-promoting actions of both IGFs. Mice with this deletion had birth weights that were only 45 percent of normal and generally died within hours after birth from respiratory insufficiency resulting from muscular hypoplasia.
New Engl. J. Med. http://www.nejm.org
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SIGNALS FROM THE REPRODUCTIVE SYSTEM REGULATE THE LIFESPAN OF C. ELEGANS.
The following points are made by H. Hsin and C. Kenyon (Nature 1999 399:308):
1) Understanding how the ageing process is regulated is a fascinating and fundamental problem in biology. The authors demonstrate that signals from the reproductive system influence the lifespan of the nematode Caenorhabditis elegans. If the cells that give rise to the germ line are killed with a laser microbeam, the lifespan of the animal is extended.
2) The authors suggest their findings indicate that germline signals act by modulating the activity of an insulin/IGF-1 (insulin-like growth factor) pathway that is known to regulate the ageing of this organism. Mutants with reduced activity of the insulin/IGF-1-receptor homologue DAF-2 have been shown to live twice as long as normal, and their longevity requires the activity of DAF- 16, a member of the forkhead/winged-helix family of transcriptional regulators.
3) The authors find that in order for germline ablation to extend lifespan, DAF-16 is required, as well as a putative nuclear hormone receptor, DAF-12. In addition, the findings suggest that signals from the somatic gonad also influence ageing, and that this effect requires DAF-2 activity.
4) The authors suggest that together their findings imply that the C. elegans insulin/IGF-1 system integrates multiple signals to define the animal's rate of ageing. The authors suggest this study demonstrates an inherent relationship between the reproductive state of this animal and its lifespan, and may have implications for the co-evolution of reproductive capability and longevity.
Nature http://www.nature.com/nature
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GENE THERAPY FOR AGING-RELATED LOSS OF MUSCLE FUNCTION
One of the primary consequences of aging, a consequence which leads to significantly impaired function in the elderly population, is the loss of *skeletal muscle strength and mass. Both of these decrease up to one-third in humans between the ages of 30 and 80 years. In addition, loss of the fastest and most powerful muscle fiber types has been documented. Similar aging-related muscle alterations have been observed in rats and mice, indicating that the trend is maintained in other mammalian species. The mechanisms underlying this aging-related muscle loss have remained unclear, but there is some evidence that so-called "insulin-like growth factor-I" may be involved. The term "insulin-like growth factor" refers to a group of polypeptides structurally homologous to *insulin, and which share many of the biological activities of insulin, but which are apparently biochemically distinct from it. These substances are "mitogens", i.e., they enhance or induce cell division (mitosis). Insulin-like growth factor-I (insulin-like growth factor type I) is a monomer of 70 amino acids.
The following points are made by E.R. Barton-Davis et al (Proc. Nat. Acad. Sci. 1998 95:15603):
1) The authors report an attempt to moderate the aging-related loss of muscle in mice by increasing the regenerative capacity of muscle. The study involved the injection of a genetically engineered virus to direct overexpression (i.e., genome-based protein overproduction) of insulin-like growth factor-I in adult muscle.
2) The authors report that insulin-like growth factor-I expression promotes an average increase of 15 percent in muscle mass and a 14 percent increase in strength in young adult mice, and prevents aging-related muscle changes in old adult mice. In old adult mice, muscle mass and fiber type distributions were maintained at levels similar to those in young adults.
3) The authors propose that these effects are primarily due to stimulation of muscle regeneration via the activation of *satellite cells by insulin-like growth factor-I. The authors suggest this supports the hypothesis that the primary cause of aging-related impairment of muscle function is a cumulative failure to repair damage sustained during muscle utilization.
4) The authors further suggest that gene transfer of insulin-like growth factor-I into muscle could form the basis of a human gene therapy for preventing the loss of muscle function associated with aging, and may be of benefit in diseases where the rate of damage to skeletal muscle is pathologically accelerated.
Proc. Nat. Acad. Sci. http://www.pnas.org
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Notes:
skeletal muscle: (striated muscle, voluntary muscle) Muscle in which cross striations occur in the fibers as a result of regular overlapping of thick and thin filament structures. Although cardiac muscle is not "voluntary" muscle, it is also striated in appearance.
insulin: A protein hormone that promotes uptake by body cells of free glucose and/or amino acids, depending on target cell type.
satellite cells: The satellite cells of skeletal muscle are cells associated with muscle fibers that are believed to play a role in muscle repair and regeneration.
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