Two recent articles published in Science identify the GH/IGF-I axis as playing a major role in the aging process of many species including humans.  The data persuasively  argue that components of this axis may negatively affect longevity.  The majority of the data support the hypothesis that limited secretion of IGF-I promotes long life.  A brief synopsis follows.

In yeast, down-regulation of intracellular signaling pathways that are dependent on glucose increases the life span of the organisms up to 300%. In worms (C. elegans), loss-of-function mutations of a gene called Daf-2 encoding an ortholog of the IGF-I receptor extend survival up to 300%.  In the fly, inactivation of the gene encoding the insulin receptor increases longevity up to 200%.  Mice with homozygous inactivating mutations in Prop-1, Pit-1, or Ghr survive 25%-65% longer than do wild-type mice.  Since mice with a defect in the GH receptor have high serum GH, the decrease in IGF-I signaling probably is the common factor responsible for the extended life of the mutant animals, insects, etc.  Partial caloric restriction in rodents and possibly in monkeys also increases life span.  Decreased synthesis of IGF-I and lowering of serum concentrations of glucose and insulin occur simultaneously with caloric restriction.

Since IGF-I acts in part by increasing transcription through the mitogen-activated protein kinase pathway (MAPK),¹ which promotes cell division and growth, attenuation of this pathway possibly reduces the potential for lethal errors in this system.  Since IGF-I decreases the activities of anti-oxidant enzymes such as superoxide dismutase and catalase, there is reduced ability in the presence of IGF-I to respond to stress and thus enhanced susceptibility to cellular damage; accordingly, inhibition of this property of IGF-I would be expected to augment the stress response.  Caloric restriction also increases the longevity of the Prop-1 deficient or Ames mouse; thus, the mechanisms by which caloric restriction and IGF-I deficiency act to increase life span may differ.  In rodents, partial caloric restriction increases the immune response to infectious agents and attenuates the destructive cellular immune changes of aging.  This thereby decreases the incidence of degenerative and inflammatory diseases and tumor formation.

In adult humans, hypopituitarism is associated with abnormal lipid metabolism, atherosclerosis, and early death. Yet, acromegalic subjects with excess GH secretion also have a shortened life span, and critically ill patients who receive exogenous GH have a greater mortality rate than do those with similar illnesses not so treated. Since patients with PROP-1 deficiency or patients with inactive GH receptors (who do not have ACTH deficiency), do not succumb at an early age and may even live exceedingly long,² Tatar et al suggest that perhaps ACTH rather than GH deficiency is responsible for early death in humans with pan-pituitary dysfunction.  The authors further suggest that pharmacological agents designed to reduce IGF-I levels be explored as extenders of life span.

 

Longo VD, Finch CE. Evolutionary medicine: From dwarf model systems to healthy centenarians? Science 2003;299:1342-1346.

 

Tatar M, et al. The endocrine regulation of aging by insulin-like signals. Science 2003;299:1346-1351.

 

Editor’s Comment: The authors point out that glucose/insulin/GH/IGF-I and their signaling pathways may actually decrease rather than prolong life span.  While experimental findings cannot always be directly translated into analysis in humans, the authors’ conclusions merit consideration when we prescribe GH for our adult patients.  These findings also should cause those who claim that GH is an effective anti-aging agent in non-GH deficient elderly adults to reconsider this recommendation.  Body weight control combined with an efficient exercise program is likely to be far more effective in lengthening life than is administration of GH to adults without GH deficiency.  The need to maintain adequate glucocorticoid replacement therapy in adults with panhypopituitarism must also be emphasized to minimize stress.

Other papers in the Science series are also worth reviewing, particularly one by Hasty et al³ describing aging defects due to genetic abnormalities in genome maintenance (transcription, DNA repair, DNA helicase activity).  Bluher et al⁴ recently reported that mice with loss of the insulin receptor only in adipose tissue had extended life span.  In addition, an extensive review on caloric restriction and extension of life is available on the internet.⁵

 

Allen W. Root, MD

 

References

1. Pearson G, et al. Endocrine Rev 2001;22:153-183.

2. Rosenfeld RG, et al. Endocrine Rev 1994;15:369-390.

3. Hasty P, et al. Science 2003;299:1355-1359.

4. Bluher M, et al. Science 2003;299:572-574.

5. Masoro EJ. Science’s SAGE KE 2003; http://sageke.sciencemag.org/cgi/content/full/sageke;2003/8/re2