The GH/IGF-1 axis in ageing and longevity

Abstract

Secretion of growth hormone (GH), and consequently that of insulin-like growth factor 1 (IGF-1), declines over time until only low levels can be detected in individuals aged ≥60 years. This phenomenon, which is known as the 'somatopause', has led to recombinant human GH being widely promoted and abused as an antiageing drug, despite lack of evidence of efficacy. By contrast, several mutations that decrease the tone of the GH/IGF-1 axis are associated with extended longevity in mice. In humans, corresponding or similar mutations have been identified, but whether these mutations alter longevity has yet to be established. The powerful effect of reduced GH activity on lifespan extension in mice has generated the hypothesis that pharmaceutically inhibiting, rather than increasing, GH action might delay ageing. Moreover, mice as well as humans with reduced activity of the GH/IGF-1 axis are protected from cancer and diabetes mellitus, two major ageing-related morbidities. Here, we review data on mouse strains with alterations in the GH/IGF-1 axis and their effects on lifespan. The outcome of corresponding or similar mutations in humans is described, as well as the potential mechanisms underlying increased longevity and the therapeutic benefits and risks of medical disruption of the GH/IGF-1 axis in humans.

Figure 1

Factors of the GH/IGF-1 axis known to influence ageing. The embryonically expressed genes PROP1 (which encodes PROP-1) and POU1F1 (which encodes PIT-1) are involved in pituitary development, including differentiation of pituitary somatotrophic cells. GHRH and somatostatin are released by different populations of hypothalamic neurons and stimulate or inhibit, respectively, GH production and secretion by the somatotrophs in the anterior pituitary. GH binds to GH receptors, which activates the JAK–STAT pathway and induces the production of IGF-1, predominantly in the liver. In the circulation, much of IGF-1 is bound by IGFBPs, which act as carrier proteins and regulators of IGF-1 bioavailability. Pappalysin-1 is an IGFBP-4 protease that increases IGF-1 bioavailability. IGF-1 mediates its effects by binding to IGF-1R and, with less affinity, to IRs in many tissues. Importantly, not only endocrine but also autocrine and paracrine actions of IGF-1 have a crucial role in normal animal physiology. The protein klotho suppresses insulin and IGF-1 action, whereas IRS-1 and IRS-2 transduce signals from the IGF-1R and the IR, resulting in the activation of several pathways, including one that acts via S6K, a downstream effector of mTOR that is linked to IRS-1 via p66shc. Abbreviations: GH, growth hormone; GHR, GH receptor; GHRH, GH-releasing hormone; IGF-1, insulin-like growth factor 1; IGFBP, IGF-1 binding protein; IGF-1R, IGF-1 receptor; IR, insulin receptor; IRS, IR substrate; JAK, janus kinase; mTOR, mammalian target of rapamycin; PIT-1, pituitary-specific positive transcription factor 1; PROP-1, prophet of PIT-1; STAT, signal transducer and activator of transcription; S6K, S6 kinase.

Figure 2

Mouse strains with altered GH signalling. Ghr−/−, lit/lit, GHA, wild-type and bGH transgenic mouse strains (from left to right) were a | photographed and then b | scanned using a digital mammography unit. In this figure, Ghr−/−, GHA and wild-type mice were ~7 months old, the lit/lit mouse was ~5 months old, and the bGH transgenic mouse was ~4 months old. Weights of the mice were 14.4, 17.7, 24.9, 38.7 and 45.6 g, respectively. All except the Ghr−/− mouse are males. An average Ghr– /– male of this age weighs ~17 g. Bone structure is remarkably similar for the various mouse strains; however, kyphosis is typical for transgenic bGH mice. Abbreviations: bGH, bovine GH transgenic; GH, growth hormone; GHA, GH receptor antagonist; Ghr, GH receptor. Courtesy of J. Sattler, Ohio University Heritage College for Osteopathic Medicine, Athens, OH, USA