Abstract
Background: the term frailty refers to a condition of increased vulnerability to stressors among older people, leading to a decline in homeostatic reserve. Frailty often leads to falls, hospitalisation and mortality, hence its importance for the delivery of health care to older adults. The pathophysiological mechanisms behind frailty are not well understood, but the decreased steroid-hormone production and elevated chronic systemic inflammation of older people appear to be major contributors.Method: we used a sample of 3,160 individuals aged 50 or older from the English Longitudinal Study of Ageing and assessed their frailty status according to a Frailty Index. We selected 620 single nucleotide polymorphisms in genes involved in the steroid hormone or inflammatory pathways. We performed linear association analysis. The outcome variable was the square root transformation of the Frailty Index, with age and sex entered as covariates.Results: the strongest signal was detected in the pro-inflammatory Interleukin-18 gene (rs360722, P = 0.0021, β = −0.015). Further significant signals were observed in the Interleukin-12 (rs4679868, P = 0.0062, β = −0.008 and rs9852519, P = 0.0077, β = −0.008), low density lipoprotein receptor-related protein 1 (rs1799986, P = 0.0065, β = 0.011) and Selectin-P (rs6131, P = 0.0097, β = −0.01) genes. None of these associations remain significant after Bonferroni correction.Conclusions: we show potential associations between genetic variants of four genes and the frailty index. These genes are involved in the cholesterol transport and inflammatory pathway and, as such, our results provide further support for the involvement of the immunological processes in frailty of the elderly.
Highlights
While it is accepted that the core feature of frailty is increased vulnerability to stressors due to impairments in multiple, interrelated systems that lead to decline in homeostatic reserve and resilience [1], the pathophysiological pathways behind this condition are not well understood.Performance-based measures of frailty, such as the frailty phenotype [2] have found associations between decreased sex hormone levels such as testosterone, dehydroepiandrosterone (DHEA) and its sulphate derivative (DHEAS) and frailty [3, 4]
Testosterone exerts a suppressive effect on proinflammatory cytokines, such as Interleukin-1β (IL-1β) and tumor necrosis factor (TNF) and increases anti-inflammatory cytokine Interleukin-10 (IL-10) [13], whereas DHEA seems to have an effect on Interleukin-6 (IL-6) levels [14]
Our candidate gene association study is the first to investigate the association between the Frailty Index and genes involved in steroid hormone metabolism and inflammatory pathways
Summary
While it is accepted that the core feature of frailty is increased vulnerability to stressors due to impairments in multiple, interrelated systems that lead to decline in homeostatic reserve and resilience [1], the pathophysiological pathways behind this condition are not well understood.Performance-based measures of frailty, such as the frailty phenotype [2] have found associations between decreased sex hormone levels such as testosterone, dehydroepiandrosterone (DHEA) and its sulphate derivative (DHEAS) and frailty [3, 4]. The levels of these hormones gradually decline with age, around 1–3%/year [5, 6] The role that these hormones play in body mass [7, 8], muscle strength [9, 10] and bone mineral density [11, 12] gives biological support to the relation between these sex hormone levels and the performance-based measures of frailty. These hormones have an effect on inflammatory cytokines. Testosterone exerts a suppressive effect on proinflammatory cytokines, such as Interleukin-1β (IL-1β) and tumor necrosis factor (TNF) and increases anti-inflammatory cytokine Interleukin-10 (IL-10) [13], whereas DHEA seems to have an effect on Interleukin-6 (IL-6) levels [14]
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