406 C.D. McMahon et al. in more detail below (see Section 4.5). While high levels of vitamin D can be deleterious, the opposite is also true since age-related lack of vitamin D may contribute to reduce signalling through the IGF-1 pathway (discussed in more detail below). Vitamin D deficiency is extremely prevalent in the elderly and can result in myopathy with loss of muscle strength and selective loss of fast myofibres similar to sarcopenia (Janssen et al. 2002). A second and more direct influence of Klotho on ageing is via inhibition of insulin and IGF-1 signalling. Life-span is extended in C. elegans with loss-of- function mutations in the insulin receptor homologue daf-2, in the PI3-kinase homologue age-1 and in the forkhead transcription factor (FOXO) homologue daf- 16. Similarly, loss-of-function mutations in the insulin receptor homologue (ins) and insulin receptor substrate homologue (chico) in Drosophila result in an exten- sion of life-span. Likewise, mutations that disrupt the GH/IGF-1 axis in mammals extend life-span despite causing dwarfism (Bartke et al. 2001). Klotho does not affect appetite and, therefore, the longevity of mice overexpressing Klotho occurs without calorie restriction, despite restriction of vitamin D and phosphates ameliorating the deleterious effect of absence of Klotho (Kurosu et al. 2005). Most likely, extension of life-span occurs via the inhibition of the insulin and GH/IGF-1 axes (Bartke 2006). Mutations in Klotho have been found in human populations that are associated with longevity. Specifically, a double mutation (V352 and S370 collectively termed KL-VS) confers an advantage in the heterozygous state in European, African-American, Ashkenazi Jews and Italians (Arking et al. 2002, 2005; Invidia et al. 2010). The mutation increases (1.6 fold) the secretion of Klotho in cultured cells and, therefore, longevity may be associated with increased concen- trations of the secreted forms of Klotho in blood (Arking et al. 2002). It remains unclear whether the effect of Klotho on vitamin D and hyperphos- phatemia are independent of the actions on insulin/IGF-1 signalling (Fig. 4 insert) or if there is an interaction between these phenomena to influence ageing. 4.5 Vitamin D and Kidneys Vitamin D is an essential hormone for maintaining muscle function and concentra- tions decline in blood with age in conjunction with frailty (Tuohimaa 2009). Restoring physiological concentrations of vitamin D help protect against frailty in old age (Janssen et al. 2002). Vitamin D is produced in the skin from cholesterol- derived precursors. Subsequent steps are hydroxylation to 25(OH) vitamin D3 in the liver and a final hydroxylation step occurs in the proximal tubules of the kidney to produce the active form 1,25(OH) 2 vitamin D 3 (Ebert et al. 2006). The enzyme responsible for this final step in the kidney is 1a hydroxylase, which is downregu- lated in aged rats on low phosphate or calcium diets. Klotho decreases activity of 1a hydroxylase, which is consistent with increased concentrations of vitamin D in Klotho null mice (Imai et al. 2004). Activity and synthesis of vitamin D is restored by treatment with IGF-1, concentrations of which also decline with ageing, which 407Role of IGF-1 in Age-Related Loss of Skeletal Muscle Mass and Function suggests a causal link (Wong et al. 1997, 2000). In fact, there is a positive relationship between concentrations of vitamin D and IGF-1 in blood and higher concentrations of each hormone are associated with reduced prevalence of the metabolic syndrome in middle-aged subjects (Hypponen et al. 2008). The role of vitamin D in ageing is not yet clear with conflicting points of view. Notably, elevated vitamin D is implicated in advanced senescence that occurs in Klotho- and FGF23-deficient mice (Kuro-o 2008). In contrast, absence of vitamin D signalling also induces enhanced ageing (Keisala et al. 2009; Tuohimaa 2009). More recent studies have clarified this discrepancy to some extent and show that hyperphosphatemia is the more likely causative factor underlying the etiology of premature senescence in Klotho-deficient ageing due to failure of FGF23 to activate the FGF/Klotho receptor complex. After binding to its cytosolic receptor, vitamin D directs IGF-1 to activate the MAPK pathway and this is mediated by PKC and Ca 2+ (Morelli et al. 2000). The activated vita- min D receptor directly binds to and dephosphorylates Src, which allows Shc to be phosphorylated and outcompete the insulin receptor complex (IRS) for access to the IGF-1 receptor (Fig. 4) (Buitrago et al. 2000; Morelli et al. 2000; Sasaoka et al. 2001; Boland et al. 2002; Sekimoto and Boney 2003; Lieskovska et al. 2006). In support, pharmacological or transgenic inhibition of Src, prevents activation of MAPK (Boney et al. 2001; Sasaoka et al. 2001). Therefore, reduced or excessive concentrations of vitamin D could compromise MAPK signalling in skeletal muscle and tight regulation of this pathway is essential for normal health and ageing and both hypo- and hypervitaminosis D can accelerate ageing (Tuohimaa 2009). Finally, it is worth noting that renal damage is prevalent in older subjects. Kidney function progressively declines with age and 11% of individuals older than 65 years without hypertension or diabetes had stage 3 or worse chronic kidney disease (Coresh et al. 2003, 2005). A similar increase in lesions occurs in aged rats, but these are reduced with a concomitant increase in life span in rats maintained on a calorie restricted diet and further improved (30%) when coupled with suppression of the GH/IGF-1 axis via hemizygote expression of an antisense transgene for GH (Zha et al. 2008). An emerging postulate is that renal function is crucial for health and, therefore, longevity and is consistent with the greatest expression of Klotho in the kidney and in close proximity to synthesis of vitamin D (Zha et al. 2008). Perhaps the etiology of sarcopenia can be explained, at least in part, by the progres- sive damage to the kidneys during ageing, which is accompanied by perturbed synthesis of vitamin D and Klotho. As a consequence, vitamin D and Klotho are not produced in sufficient quantities to regulate the insulin and IGF-1 signalling axes. In conjunction, the GH/IGF-1 axis is downregulated in the kidney in chronic kidney disease and the bioavailability of IGF-1 is further reduced due to resistance to GH and an increased abundance of IGFBP-1, -2, -4 and -6. This ageing-associated decline of the GH/IGF-1 axis may help reduce glomerular sclerosis and prolong glomerular function (Mak et al. 2008). Note that chronic kidney disease is associated with major disturbances in the GH/IGF axis (pre and post receptor with huge increases in IGFBPs (Mahesh and Kaskel 2008). 408 C.D. McMahon et al. Clearly, regulation of the GH/IGF-1 axes is crucial for healthy ageing and there is a close and as yet unclear relationship between nutrition, Klotho and vitamin D (indicated in Fig. 4). 5 Therapies to Increase IGF-1 Signalling Although it was a widely held notion that sarcopenia was directly related to an age-related decline in GH secretion, this view has been contested and numerous studies in humans do not support a benefit of GH administration on muscle pro- tein synthesis (Lynch et al. 2005). Synthetic peptides that cause the release of GH (GH secretagogues, e.g. benzoazepines and their analogues) have been used clini- cally but their efficacy is unclear, as are the benefits of commercial hormone replacement therapies (Borst and Lowenthal 1997). Overall, simple hormone “top up” strategies to restore hormone levels in the elderly have not been successful, especially if they have not been performed in conjunction with a resistance exer- cise program (Lynch et al. 2005). There is some promise of treating elderly sub- jects (65–90 years) with GH together with testosterone, which increased concentrations of IGF-1 more than either treatment alone and increased strength (Huang et al. 2005; Sattler et al. 2009). The benefits of over-expression of IGF-1 on age-related muscle wasting have started to be tested in transgenic animal models (Chakravarthy et al. 2001; Musaro et al. 2001). Transgenic over-expression of IGF-1, as well as its down- stream target Akt, results in muscle hypertrophy (Bodine et al. 2001; Chakravarthy et al. 2001). In addition, genetic activation of Akt antagonizes signalling that leads to muscle atrophy: for example, over-expression of the constitutively active Akt was sufficient to block muscle wasting following short term (7 days) denervation (Bodine et al. 2001). While elevated IGF-1 is less efficient than Akt in blocking muscle atrophy, up-regulation of IGF-1 can slow down muscle atro- phy in some but not all models of muscle wasting: e.g. transgenic muscle spe- cific over-expression of IGF-1 reduced the rate of atrophy resulting from denervation at 1 month, but not at 2 months following nerve transaction (Shavlakadze et al. 2005a). The challenge is to translate these experimental benefits of muscle restricted elevated IGF-1 to the clinical situation. It is noted that systemic administration of IGF-1 is not recommended as this results in hypertrophy of cardiac muscle and heart failure and also prostate cancer (Shavlakadze and Grounds 2003). In support, transgenic over-expression of human IGF-1 within skeletal muscle in Rska-actin/ hIGF-I mice that also elevated circulating IGF-1 throughout development had no hypertrophic effect on skeletal muscle (Shavlakadze et al. 2006) and resulted in enlarged seminal vesicles (Shavlakadze et al. 2005b). Since IGF-I and GH have overlapping as well as independent effects on somatic growth (Lupu et al. 2001) (and it is estimated that the overlapping GH/IGF-I effect makes 34% contribution to the total weight, IGF-I alone contributes 35% and GH alone 14%), it is possible 409Role of IGF-1 in Age-Related Loss of Skeletal Muscle Mass and Function that the absence of muscle hypertrophy in these Rska-actin/hIGF-I mice is a result of decreased systemic GH. In addition, elevated systemic IGF-1 might down-regu- late IGF-1 receptors and increase IGF-1 binding proteins to ablate the effects of elevated IGF-1 in these mice (Shavlakadze and Grounds 2003). Such experiments emphasise that systemic elevation of IGF-1 is not a promising approach. This accords with the view that the autocrine/paracrine mode of IGF-1 action is the principal mechanism for stimulating muscle growth/hypertrophy. The targeted elevation of IGF-1 selectively only within adult skeletal muscle remains an appeal- ing option although this may only be effective as a hypertrophic agent to amplify a growth-related stimulus, that can be produced by regeneration or possibly resis- tance exercise in adults. The efficacy of this approach to prevent sarcopenia awaits validation. 6 Conclusions Loss of skeletal muscle mass with ageing is associated with a decline in the GH/ IGF-1 axis, however it is not know to what extent such decline contributes to sar- copenia. Evidence supports the role of IGF-1 to reduce the rate of muscle wasting in some atrophy models, but extensive data are not yet available for sarcopenia. Therapeutic strategies using GH or IGF-1 have mixed success unless administered in conjunction with androgens and exercise. While these strategies show some promise in reducing sarcopenia over a short term, there are contraindications sug- gesting that they may increase the risk of tumorigenesis and cardiovascular dis- ease. We await with interest results from transgenic studies in which IGF-1 is increased in skeletal muscle alone, which may not incur the same pathologies as endocrine-mediated treatments. Currently, the protein content of a diet may be a safer strategy to increase concentrations of IGF-1 which, in conjunction with exer- cise may slow the rate of sarcopenia. In contrast, other studies suggest that the decline in the GH/IGF-1 axis may favour a slower decline in muscle mass and confer a longer, healthier life. Indeed, the evidence presented here from worms, insects and mammals suggests that there is an evolutionarily conserved pathway via which caloric restriction, Klotho and loss of function mutations in GH/INS/ IGF axes act to regulate a common signal transduction pathway to confer a reduced rate of sarcopenia and longer life. Therefore, a pertinent question to ask in summary is ‘should we intervene on the natural decline or should we manage the decline in the GH/IGF-1 axis to maintain healthy muscle in old age’? Part of this management might be to maintain expression of IGF-1 locally in muscle, but not systemically. Acknowledgements Grateful acknowledgement is made by the authors for research funding from the National Health and Medical Research Council of Australia (MG, TS), and the Foundation for Research, Science and Technology (CM). 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