Saying that the frailty phenotype arises from geneenvironment interactions doesn't move us very far forward as these interactions are pervasive throughout biology. Nonetheless, the emerging work on the genetics of aging, age-associated diseases, and age-associated functional decline will become increasingly relevant to our understanding of frailty (Johnson et al., 1996; Hamet et al., 2003; Gurland et al., 2004; Martin 2005; Hadley et al., 2005). Although genes likely influence the development of frailty, environmental influences probably predominate. For example, a twin study of the genetic contribution to late-life disability found that although genetic factors did play a significant role, environmental factors were more important (Gurland et al., 2004). Genetic influences will operate partially, if not primarily, through the mechanism of susceptibility to diseases.
A few studies about the potential relationship between genetic polymorphism and frailty have been published. The Apolipoprotein E (ApoE) gene has been referred to as a frailty gene (Gerdes et al., 2000). Epislon 2 carriers are more likely to survive to extreme old age, but epsilon 4 carriers are less likely. The differential mortality rates for the various ApoE genotypes extend into extreme old age (Corder et al., 2000). Genetic influences on immune and muscle function will likely be relevant to frailty research, but no consistent picture has emerged yet. Genetic variation in intraleukin-6 (IL-6) was not associated with frailty in older women (Walston et al., 2005), but a significant genetic association with the IL-10 promoter gene has been found (van den Biggelaar et al., 2004). In the latter study, those genetically predisposed to lower cytokine production seemed predisposed to frailty. As will be seen, this seems to go against the prevailing thinking about the pathogenesis of frailty. Polymorphism in the insulin-like growth factor-2 (IGF2) was modestly associated (only 1% of the variance was attributable to IGF2 genotype) with grip strength in men aged 64 to 74 (Sayer et al., 2002). Those with the AA genotype were marginally stronger than those with the GG genotype. Angiotensin-converting enzyme (ACE) gene polymorphism is associated with response to physical training (Montgomery et al., 1999). Low ACE activity was associated with a greater response to intensive physical training in young white male British Army recruits.
Interestingly, other studies have shown that the use of ACE-inhibitors for hypertension is associated with maintained muscle mass, muscle strength, and walking speed in older individuals (Onder et al., 2002; Di Bari et al., 2004). The issue of age-dependent regulation of gene expression requires study. Transcriptional profiling of human frontal cortex from individuals aged 26 to 106 showed both reduced expression of certain genes (e.g., involved with synaptic transmission and vesicular transport) and the induction of genes (e.g., involved with stress response and DNA repair) after the age of 40 (Lu et al., 2004). The greatest diversity in gene expression was seen between 40 and 70 when a switchover in genetic expression seems to occur. Middle and early old age may represent a critical period for the development of frailty in our later life.
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