Mechanisms limiting body growth in mammals.
Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
Recent studies have begun to provide insight into a long-standing mystery in biology-why body growth in animals is rapid in early life but then progressively slows, thus imposing a limit on adult body size. This growth deceleration in mammals is caused by potent suppression of cell proliferation in multiple tissues and is driven primarily by local, rather than systemic, mechanisms. Recent evidence suggests that this progressive decline in proliferation results from a genetic program that occurs in multiple organs and involves the down-regulation of a large set of growth-promoting genes. This program does not appear to be driven simply by time, but rather depends on growth itself, suggesting that the limit on adult body size is imposed by a negative feedback loop. Different organs appear to use different types of information to precisely target their adult size. For example, skeletal and cardiac muscle growth are negatively regulated by myostatin, the concentration of which depends on muscle mass itself. Liver growth appears to be modulated by bile acid flux, a parameter that reflects organ function. In pancreas, organ size appears to be limited by the initial number of progenitor cells, suggesting a mechanism based on cell-cycle counting. Further elucidation of the fundamental mechanisms suppressing juvenile growth is likely to yield important insights into the pathophysiology of childhood growth disorders and of the unrestrained growth of cancer. In addition, improved understanding of these growth-suppressing mechanisms may someday allow their therapeutic suspension in adult tissues to facilitate tissue regeneration.
A complex growth-related genetic program occurs in multiple organs during juvenile life. A, Venn diagrams showing the number of genes down-regulated and up-regulated with age by microarray analysis in mouse and rats. The analysis included genes that showed age regulation (P < 0.05; ≥2.0-fold) in mouse kidney, lung, and heart or in both rat kidney and lung. The substantial overlap indicates that the program was highly conserved during the 20 million yr since the two species diverged. B, Heat maps based on the same set of genes. Each row corresponds to a single gene. Green, Down-regulation with age; red, up-regulation. Scale values are log2 (fold difference). C, A knockout phenotype was reported for 139 of the genes in this same gene set. For the down-regulated genes, knockout frequently resulted in decreased body size, suggesting that many down-regulated genes in this program are growth promoting. D, Bioinformatic analyses of these age-regulated genes using Ingenuity Pathway Analysis (IPA) 7.1 and GeneGO also suggest that many of the genes that are down-regulated with age serve to regulate proliferation. For IPA, the five most overrepresented molecular, cellular, or physiological functions are shown (solid bars, P value; striped bars, number of significant genes involved). For GeneGO, all significant (P < 0.05) map folders are shown. [Reproduced from J. C. Lui et al.: FASEB J 24:3083–3092, 2010 (113).]
Model for a mechanism that restricts juvenile body growth. In early life, multiple growth-promoting genes are well expressed, leading to rapid growth. However, growth causes down-regulation of these growth-promoting genes (perhaps through epigenetic mechanisms) which causes growth to slow. Progression of this negative feedback loop would eventually cause the growth rate to approach zero.
The decline in the human linear growth rate is not due to declining circulating IGF-I levels. First row, In humans, height increases rapidly in early childhood but eventually plateaus in adolescence (216). Second row, The linear growth velocity (first derivative of the height curve) decreases dramatically during infancy, more gradually during childhood, briefly rises during the pubertal growth spurt, and then resumes its decline, approaching zero (216). Third to fifth rows, As growth is slowing, there is a general increase in total IGF-I and IGFBP-3, both of which are stimulated by GH, as well as an increase in free IGF-I (derived from reference 52).