ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Nat Commun. 2018 19;9:2394.

“Somatopause” causes the physiological decline over time in GH secretion leading to low IGF-I levels in aging subjects. GH has been proposed as an anti-aging therapy, but with no evidence of beneficial effects and with some potential risks [1,2]. Therefore, current guidelines do not recommend GH therapy as anti-aging treatment [3].

Conversely, the possibility of slowing aging by negatively affecting GH signaling has been demonstrated in many animal models. Mutations that reduce GH activity were associated with increased longevity [2] as well as with reduced cancer and diabetes incidence. IGF-IR plays a key role in modulating mammalian lifespan [4] and its mutations have been described in centenarians [5]. Low IGF-I levels predict longer survival in females with exceptional longevity [6]. The mechanism by which reduced IGF-I signaling influences lifespan is unknown, both improved stress defenses and lower cancer susceptibility are likely involved. Collectively, these data suggest that the pharmacological modulation of GH pathway may be used to prolong lifespan.

This elegant study evaluated the effects of IGF-IR signaling inhibition on longevity. 18 months old CB6F1 male and female mice, weekly treated with IGF-IR monoclonal antibodies (L2-Cmu, Amgen Inc; 20 mg/kg) until 24 months of age or until natural death were investigated to determine the effects on aging outcomes. The authors showed that targeting IGF-IR signaling in late life of these mice improves aging. Consistently with previous reports, the major positive effects occurred in female mice, which experienced a 9% increase of lifespan, a reduced incidence of cancer and systemic inflammation, with restoration of some cytokines to a more youthful profile. No difference in weight or body composition was observed in females, whereas male animals showed decreased weight and lean mass. Insulin levels were unaffected in all tissues in both sexes. Endurance performance and strength as well as improvement in cardiac function were observed in female mice but not in males. The sex dimorphism may depend on a different hormonal milieu or on differences in drug metabolism. Interestingly, these effects on ageing occurred even though the treatment was initiated later in life when IGF-IR modulation is likely safer than in younger ages.

This study has the merit to experimentally prove the efficacy of selective targeting of IGF-IR in improving ageing. However, before planning to translate this evidence in clinical trials the protective effect of IGF-I towards osteoporosis, type 2 diabetes, cerebrovascular and cognitive decline has to be taken into account [6].

References: 1. Liu H, Bravata DM, Olkin I, Nayak S, Roberts B, Garber AM, Hoffman AR. Systematic review: the safety and efficacy of growth hormone in the healthy elderly. Ann Intern Med 2007;146:104–115.

2. Junnila RK, List EO, Berryman DE, Murrey JW, Kopchick JJ. The GH/IGF-1 axis in ageing and longevity. Nat Rev Endocrinol 2013;9:366–376.

3. Thorner MO. Statement by the Growth Hormone Research Society on the GH/IGF-I axis in extending health span. J Gerontol A Biol Sci Med Sci 2009;64:1039–1044.

4. Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A, Even PC, Cervera P, Le Bouc Y. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 2003;421:182–187.

5. Suh Y, Atzmon G, Cho MO, Hwang D, Liu B, Leahy DJ, Barzilai N, Cohen P. Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci U S A 2008;105:3438–3442.

6. Milman S, Atzmon G, Huffman DM, Wan J, Crandall JP, Cohen P, Barzilai N. Low insulin-like growth factor-1 level predicts survival in humans with exceptional longevity. Aging Cell 2014;13:769–771.