Genetically-predicted life-long lowering of low-density lipoprotein cholesterol is associated with decreased frailty: A Mendelian randomization study in UK biobank

Abstract

Background High circulating low-density lipoprotein cholesterol (LDL-C) is a major risk factor for atherosclerosis and age-associated cardiovascular events. Long-term dyslipidaemia could contribute to the development of frailty in older individuals through its role in determining cardiovascular health and potentially other physiological pathways. Methods We conducted Mendelian randomization (MR) analyses using genetic variants to estimate the effects of long-term LDL-C modification on frailty in UK Biobank ( n = 378,161). Frailty was derived from health questionnaire and interview responses at baseline when participants were aged 40 to 69 years, and calculated using an accumulation-of-deficits approach, i.e. the frailty index (FI). Several aggregated instrumental variables (IVs) using 50 and 274 genetic variants were constructed from independent single-nucleotide polymorphisms (SNPs) to instrument circulating LDL-C concentrations. Specific sets of variants in or near genes that encode six lipid-lowering drug targets ( HMGCR , PCSK9 , NPC1L1 , APOB , APOC3 , and LDLR ) were used to index effects of exposure to related drug classes on frailty. SNP-LDL-C effects were available from previously published studies. SNP-FI effects were obtained using adjusted linear regression models. Two-sample MR analyses were performed with the IVs as instruments using inverse-variance weighted, MR-Egger, weighted median, and weighted mode methods. To address the stability of the findings, MR analyses were also performed using i) a modified FI excluding the cardiometabolic deficit items and ii) data from comparatively older individuals (aged ≥60 years) only. Several sensitivity analyses were also conducted. Findings On average 0.14% to 0.23% and 0.16% to 0.31% decrements in frailty were observed per standard deviation reduction in LDL-C exposure, instrumented by the general IVs consisting of 50 and 274 variants, respectively. Consistent, though less precise, associations were observed in the HMGCR -, APOC3 -, NPC1L1 -, and LDLR -specific IV analyses. In contrast, results for PCSK9 were in the same direction but more modest, and null for APOB . All sensitivity analyses produced similar findings. Interpretation A genetically-predicted life-long lowering of LDL-C is associated with decreased frailty in midlife and older age, representing supportive evidence for LDL-C's role in multiple health- and age-related pathways. The use of lipid-lowering therapeutics with varying mechanisms of action may differ by the extent to which they provide overall health benefits.

The degree of frailty as a translational measure of health in aging

“…They will offer complementary information to understanding the degree of frailty or the overall biological age, based on tailored features that explicitly relate to putative aging mechanisms. Moving forward, cohort studies can provide that level of detail for new aging treatments and relate them to clinically detectable grades of frailty 63,[217][218][219] . A focus on multimorbidity to study the treatment of what are termed 'aging-related rather than disease-specific outcomes' is already under way 220 , as is a testing program of established interventions from the US National Institute of Aging in a genetically heterogenous mouse model [220][221][222] .…”

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“…If the permselective barrier function of the endothelium is weakened, molecules, such as modified LDL, and monocytes will enter the subendothelial space via circulation to initiated chronic inflammation and immune disorders. According to current consensus, the primary event in atherosclerotic lesion development is local endothelial activation and permeability enhancement, which may be associated with hemodynamic forces occurring at the sites prone to atherosclerosis (3)(4)(5).…”

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“…More studies are needed to explore if treatment of dyslipidemia may decrease geriatric functional impairment. 16 …”