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Insulin-Like Growth Factor 1 Treatment Extends Longevity in a Mouse Model of Human Premature Aging by Restoring Somatotroph Axis Function

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Insulin-Like Growth Factor 1 Treatment Extends Longevity in a Mouse Model of Human Premature Aging by Restoring Somatotroph Axis Function Insulin-like growth factor 1 treatment extends longevity in a mouse model of human premature aging by restoring somatotroph axis function Guillermo Mariñoa,1, Alejandro P. Ugaldea,1, Álvaro F. Fernándeza, Fernando G. Osorioa, Antonio Fueyob, José M. P. Freijea, and Carlos López-Otína,2 aDepartamento de Bioquímica y Biología Molecular and bBiología Funcional, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain Edited by Cynthia Kenyon, University of California, San Francisco, CA, and approved August 4, 2010 (received for review March 2, 2010) − − Zmpste24 (also called FACE-1) is a metalloproteinase involved in the Zmpste24 / mice, which constitute an appropriate murine model maturation of lamin A, an essential component of the nuclear of Hutchinson–Gilford progeria, demonstrate a clear dysregula- envelope. Zmpste24-deficient mice exhibit multiple defects that tion of somatotroph axis signaling. In addition, we show that this − − phenocopy human accelerated aging processes such as Hutchinson– alteration is detrimental, given that Zmpste24 / mice treated with Gilford progeria syndrome. In this work, we report that progeroid recombinant IGF-1 show a clear amelioration of progeroid fea- Zmpste24-/− mice present profound transcriptional alterations in tures and significantly extended longevity compared with un- − − genes that regulate the somatotroph axis, together with extremely treated Zmpste24 / mice. high circulating levels of growth hormone (GH) and a drastic reduc- tion in plasma insulin-like growth factor 1 (IGF-1). We also show that Results recombinant IGF-1 treatment restores the proper balance between To gain insight into the alterations associated with the premature aging -/− − − IGF-1 and GH in Zmpste24 mice, delays the onset of many proge- phenotypeobservedinZmpste24 / mice, and considering the increasing roid features, and significantly extends the lifespan of these proge- evidence for the importance of somatotroph axis regulation in longevity, roid animals. Our findings highlight the importance of IGF/GH we analyzed IGF-1 plasma levels in 1-, 2- and 4-mo-old progeroid mice. − − balance in longevity and may be of therapeutic interest for devas- As shown in Fig. 1A,1-mo-oldZmpste24 / mice—which do not yet ex- tating human progeroid syndromes associated with nuclear enve- hibit any obvious progeroid features—already demonstrate a significant lope abnormalities. reduction in circulating IGF-1 levels, which progressively declines as the mice prematurely age. Given that IGF-1 synthesis is regulated mainly by laminopathy | microRNA | progeria | protease | cancer circulating GH, we measured plasma GH concentration in the same − − Zmpste24 / mice. As shown in Fig. 1A, we found that although 1-mo-old ging is a natural process that affects most biological functions mutant mice show circulating GH levels comparable to those from age- Aand appears to be a consequence of the accumulative action matched WT littermates, 2- and 4-mo-old progeroid mice show a drastic, of different types of stressors. Among these, oxidative damage, progressive increase in circulating GH (∼5- and 11-fold, respectively). To telomere attrition, and the decline of DNA repair and protein test whether the somatotroph alterations of mutant mice could be simply turnover systems are thought to be major causes of aging (1, 2). a consequence of their premature aging, we measured plasma levels of Over the last few years, our knowledge of the molecular basis of IGF and GH in 1- and 2-y-old WT mice from the same genetic back- aging has gained mechanistic insight from studies on progeroid ground. As shown in Fig. 1A, the alterations in circulating IGF-1 and GH − − syndromes in which features of human aging are manifested pre- levels seen in Zmpste24 / mice were not observed in aged WT controls. cociously or in an exacerbated form. The vast majority of proge- This suggests that the somatotroph deregulation of progeroid mice is not roid syndromes are a consequence of inefficient DNA repair just a secondary consequence of their premature aging, but rather an early mechanisms or defective nuclear envelope assembly, which ulti- pathological situation that could contribute to the development of the − − mately lead to DNA damage accumulation and chromosome in- progeroid phenotype and reduced lifespan characteristic of Zmpste24 / stability (3). Thus, mutations in the gene encoding lamin A (an mice. Reduced IGF-1 and increased circulating GH are common features essential component of the nuclear envelope) or in Zmpste24 of GH resistance, also known as Laron syndrome (LS) (16). Interestingly, (encoding a metalloproteinase involved in the maturation of lamin some pathological features of LS are also found among the complex − − A) are responsible for several devastating human progeroid syn- phenotypic manifestations of these progeroid mice. Both Zmpste24 / dromes, including Hutchinson–Gilford progeria, atypical Werner mice and LS patients have reduced muscle development, strength, and syndrome, restrictive dermopathy, and mandibuloacral dysplasia endurance, as well as decreased bone mineral density, and both exhibit (3–7). The elucidation of the molecular mechanisms underlying alopecia, skin atrophy, and hypoglycemia (8, 16, 17). these diseases has been facilitated by the generation and analysis of As a first step to elucidating the molecular determinants for the − − Lmna-andZmpste24-deficient mice, which exhibit profound nu- GH/IGF-1 axis alteration observed in Zmpste24 / mice, we per- clear architecture abnormalities and multiple histopathological formed a detailed analysis of our previously reported transcriptome data defects that phenocopy human progeroid syndromes (8–12). of liver from these progeroid mice (9). In addition to the reported In recent years, somatotroph [i.e., growth hormone (GH)/ insulin-like growth factor 1 (IGF-1)] signaling has been identified as a major regulator of longevity from nematodes to man (13). Author contributions: G.M., A.P.U., J.M.P.F., and C.L.-O. designed research; G.M., A.P.U., Paradoxically, studies have shown that reduced somatotroph Á.F.F., F.G.O., and A.F. performed research; G.M., A.P.U., F.G.O., A.F., J.M.P.F., and C.L.-O. signaling is a common feature of both long-lived model organisms analyzed data; and G.M., A.P.U., and C.L.-O. wrote the paper. and progeroid mice harboring alterations in DNA-repair mecha- The authors declare no conflict of interest. nisms (14, 15). However, to date no studies have been undertaken This article is a PNAS Direct Submission. to evaluate whether the down-regulation of IGF-1 signaling ob- 1G.M. and A.P.U. contributed equally to this work. served in premature aging is a beneficial adaptive response or 2To whom correspondence should be addressed. E-mail: [email protected]. a detrimental event that directly contributes to the development This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. of progeroid features. In the present work, we report that 1073/pnas.1002696107/-/DCSupplemental. 16268–16273 | PNAS | September 14, 2010 | vol. 107 | no. 37 www.pnas.org/cgi/doi/10.1073/pnas.1002696107 Downloaded by guest on September 27, 2021 A 1,2 14 ** els 1 12 10 0,8 8 0,6 * 6 relative leve * 0,4 * elative levels 4 IGF-1 ** GH re 0,2 2 0 0 1th2th4th11-month 2-month 4-month 1-year 2-year2 1th2th4th11-month 2-month 4-month 1-year 2-year2 Fig. 1. Somatotroph axis alterations in − − Zmpste24+/+ Zmpste24-/- Zmpste24+/+ Zmpste24-/- Zmpste24 / mice. (A) Plasma concentration of IGF-1 (Left)andGH(Right)inWTmice 1,5 110110 ** 3,5 (blue bars) and Zmpste24−/− mice (red bars). B 9090 * The depicted values indicate a progressive 7070 3 5050 reduction of circulating IGF-1 together with 2,5 * 1 3030 a progressive increase of plasma GH in −/− 7,57.5 * 2 Zmpste24 mice. (B)qPCRevaluationof xpression xpression mRNA levels of key genes for somatotroph e expression ee 1,5 5.05 axis in liver. Blue bars represent WT mice, 0,5 − − * ** 1 whereas red bars correspond to Zmpste24 / Relativ Relative e 2.5 * Relative e mice. Error bars indicate the SEM between 2,5 0,5 replicates. At least eight WT and eight mu- 0 0.00 0 tant animals were used for each assay. *P < Igf1 Igfbals Igf1r Igfbp1 Ghr Stat5a Socs2 0.05; **P < 0.005, one-tailed t test. changes in glucose and lipid metabolism genes (17, 18) and the marked pressor of cytokine signaling 2) mRNA levels were up-regulated in up-regulation of components of the p53-signaling pathway (9), we ob- these progeroid mice (Fig. 2B). Although the functions of these two served that many genes involved in somatotroph axis signaling were genes are antagonistic (Socs2 down-regulates GH signaling, whereas − − transcriptionally altered in the liver of Zmpste24 / mice (Table 1). To Stat5a is one of the main transducers of this pathway), both genes are further evaluate these results, we performed a quantitative PCR (qPCR) transcriptionally up-regulated in response to GH in the liver (22, 23). analysis of selected GH/IGF-1 axis genes in liver samples from Therefore, the finding of increased mRNA levels for both factors in − − − − Zmpste24 / mice. As shown in Fig. 1B, mRNA levels of IGF-1 were Zmpste24 / progeroid mice is likely linked to the abnormally high cir- significantly lower in mutant mice compared with their control litter- culating GH levels. Taken collectively, the transcriptional alterations in − − mates. Similarly, mutant mice showed reduced levels of Igfals transcripts components of the somatotroph axis seen in Zmpste24 / progeroid encoding the IGF-binding protein acid labile subunit, which has been mice, together with the fact that IGF-1 mRNA and protein levels remain associated with reduced levels of circulating IGF-1 in vivo (19, 20). In reduced in presence of high circulating GH levels, point to a situation contrast, Igfbp1, the up-regulation of which is also associated with a re- of GH resistance similar to that reported for some humans with − − duced effective IGF-1 concentration (21), was transcriptionally up- Hutchinson–Gilford progeria (24).
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