Association of the K153R polymorphism in the myostatin gene and extreme longevity

Received: 4 August 2012 /Accepted: 10 January 2013 /Published online: 25 January 2013 # American Aging Association 2013

the exonic MSTN variants K153R (rs1805086), E164K (rs35781413), I225T and P198A, in Spanish centenarians (cases, n=156; 132 women, age range – 100 111 years) and younger adults (controls, n=384; 167 women, age <50 years). No subject of either group carried a mutant allele of the E164K, I225T or

Abstract The myostatin (MSTN) gene is a candidate to influence extreme longevity owing to its role in modulating muscle mass and sarcopenia and especial- ly in inhibiting the main nutrient-sensing pathway involved in longevity, i.e. mammalian target of rapa- mycin. We compared allele/genotype distributions of

Antoni L. Andreu and Alejandro Lucia share senior

: N. Garatachea A. Santos

Lozano Facultad de Ciencias de la Salud y del Deporte, Universidad de Zaragoza, Huesca, Spain

Department of Internal Medicine and Therapeutics, Section of Gerontology and Geriatrics, IDR S. Margherita, University of Pavia, Pavia, Italy

Departament de Patología Mitocondrial i Neuromuscular, Institut de Recerca Hospital Universitari Vall d’Hebron, Barcelona, Spain

Cellular Pathophysiology and Clinical Immunology Laboratory, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy

C. Santiago-Dorrego C. Fiuza-Luces T. A. Lucia (*) School of Doctorate Studies and Research, Universidad Europea de Madrid,

Villaviciosa de Odón, Madrid, Spain e-mail: alejandro.lucia@uem.es

Department of Health Sciences, University of Pavia, Pavia, Italy

Myostatin inhibitors, such as MYO-029, have an adequate safety margin and are able to improve the muscle strength/function or muscle contractile prop- erties in some patients with muscular dystrophy (Krivickas et al. 2009; Wagner et al. 2008). Of the identified MSTN variations in humans, the Lys (K)153Arg(R) polymorphism located in exon 2 (rs1805086, 2379 A>G replacement) is one candi- date to influence skeletal muscle phenotypes (Ferrell et al. 1999). The Lys(K)153Arg(R) amino acid replacement is found within the active mature peptide of the myostatin protein; it could influence proteolytic processing with its pro-peptide or affin- ity to bind with the extracellular activin type II receptor (ActRIIB). The MSTN K153R polymor- phism is thus a candidate to influence skeletal muscle phenotypes, included in old people (see Garatachea and Lucía (2013) for a recent review). One of the most robust and well-studied improve- ments in longevity is caused by starvation and genetic

P198A variation. The frequency of the variant R allele was significantly higher in centenarians (7.1 %) than in controls (2.7 %) (P=0.001). The odds ratio of being a centenarian if the subject had the R allele was 3.48 – (95 % confidence interval 1.67 7.28, P=0.001), com- pared to the control group, after adjusting for sex. The results were replicated in an Italian cohort (centenarians, – n=79 (40 women), age range 100 104 years; younger controls, n=316 (155 women), age <50 years), where a higher frequency of the R allele in centenarians (7.6 %) compared to controls (3.0 %) (P=0.004) was indepen- dently confirmed. Although more research is needed, the variant allele of the MSTN K153R polymorphism could be among the genetic contributors associated with exceptional longevity.

Keywords Centenarians . MSTN . Genetics

Garatachea and Lucía (2013) for a recent review). One of the most robust and well-studied improve- ments in longevity is caused by starvation and genetic down-regulation of a nutrient-sensing pathway, namely mammalian target of rapamycin (mTOR) (Fontana et al. 2010; Kenyon 2010). The mTOR pathway is an evolu- tionarily conserved nutrient-sensing pathway that adjusts metabolism and growth to amino acid availabil- ity, growth factors, energy status and stress (Fenton and Gout 2011; Sengupta et al. 2010). A number of studies have demonstrated that myostatin acts as a negative regulator of mTOR-directed signalling (Amirouche et al. 2009; Langley et al. 2002; Lipina et al. 2010; McFarlane et al. 2006; Rios et al. 2004; Sartori et al. 2009; Trendelenburg et al. 2009), which provides sup- port for a potential role of myostatin inhibition in lon- gevity. Myostatin deletion is in fact beneficial for bone density, insulin sensitivity and heart function in senes- cent mice (Morissette et al. 2009). Inhibition of the myostatin receptor ActRIIB increased survival (by 17 %) in myotubularin-deficient mice (Lawlor et al. 2011). An extension of lifespan (+30 %) was also ob- served after therapy with follistatin (a natural antagonist of myostatin) in a mouse model of spinal muscular atrophy (Rose et al. 2009).

Introduction

Human lifespan is a partly heritable phenotype, with ‘ ’ some alleles contributing to longevity assurance , because they enhance the structure and function of the organism (Martin et al. 2007). As we age, we inevitably experience age-associated declines in the systems and organs that determine physical fitness, notably in the skeletal muscle tissue, i.e. sarcopenia. Accelerated age loss of muscle strength is associated with higher mortality risk (Metter et al. 2004; Ruiz et al. 2008); as such, genes potentially associated with higher preservation of muscle function at late life could be associated not only with healthy ageing and lower disability risk but also with longevity. One such candidate is the myostatin (MSTN or growth differen- tiation factor 8) gene (Huygens et al. 2004).