Mitochondrial Haplogroup X is associated with successful aging in the Amish

Abstract

Avoiding disease, maintaining physical and cognitive function, and continued social engagement in long-lived individuals describe successful aging (SA). Mitochondrial lineages described by patterns of common genetic variants (“haplogroups”) have been associated with increased longevity in different populations. We investigated the influence of mitochondrial haplogroups on SA in an Amish community sample. Cognitively intact volunteers aged ≥80 (n=261) were enrolled in a door-to-door survey of Amish communities in Indiana and Ohio. Individuals scoring in the top third for lower extremity function, needing little assistance with self-care tasks, having no depression symptoms, and expressing high life satisfaction were considered SA (n=74). The remainder (n=187) were retained as controls. These individuals descend from 51 matrilines in a single 13 generation pedigree. Mitochondrial haplogroups were assigned using the 10 mitochondrial single nucleotide polymorphisms (mtSNPs) defining the nine most common European haplogroups. An additional 17 mtSNPs from a genome-wide association panel were also investigated. Associations between haplogroups, mtSNPs, and SA were determined by logistic regression models accounting for sex, age, body mass index, and matriline via generalized estimating equations. SA cases were more likely to carry Haplogroup X (OR=7.56, p=0.0015), and less likely to carry Haplogroup J (OR=0.40, p=0.0003). Our results represent a novel association of Haplogroup X with SA and suggest that variants in the mitochondrial genome may promote maintenance of both physical and cognitive function in older adults.

Functional Recurrent Mutations in the Human Mitochondrial Phylogeny: Dual Roles in Evolution and Disease

“…Takasaki (2009) 3. Courtenay et al (2012)Within G3 b X2b b Within U6a b Within HV1a b 24G15928AT b 1. Association with idiopathic repeated pregnancy loss.…”

“…Similar to the T3394C RNM, the RNM G15927A (table 2, mutation number 23) that was identified as nodal in lineages B5b, a sub-lineage of G3, a sub-lineage of U6a, a sub-lineage of HV1a, and X2b associated with longevity in the frame of two of these lineages, that is, B5b (Takasaki 2009) and X2 (Courtenay et al 2012). However, low resolution of the X2 haplogroup assignment in the latter study prevented us from drawing more conclusive phenotypic association of the G15927A variant.…”

Mito-nuclear co-evolution: the positive and negative sides of functional ancient mutations

“…mtDNA common variants altered the penetrance of disease-causing mutations, such as that of Leber’s hereditary optic neuropathy (LHON; Brown et al, 2002 ; Howell et al, 2003 ; Hudson et al, 2007 ; Zhang et al, 2010 ). Association was discovered between mtDNA common variants and altered susceptibility to various types of complex diseases in humans such as type 2 diabetes ( Mohlke et al, 2005 ; Fuku et al, 2007 ; Cormio et al, 2009 ; Feder et al, 2009 ), several heart diseases ( Castro et al, 2006 ; Nishigaki et al, 2007 ; Kofler et al, 2009 ; Palacin et al, 2011 ; Strauss et al, 2013 ), a variety of neurological phenotypes ( Chinnery et al, 2000 ; Carrieri et al, 2001 ; Pyle et al, 2005 ; Amar et al, 2007 ; Jones et al, 2007 ), age related macular degeneration ( Heher and Johns, 1993 ; Jones et al, 2007 ; Canter et al, 2008 ; SanGiovanni et al, 2009 ; Udar et al, 2009 ; Mueller et al, 2012b ; Kenney et al, 2013 ; Tilleul et al, 2013 ), but also of phenotypes such as longevity ( Rose et al, 2001 ; Dato et al, 2004 ; Shlush et al, 2008 ; Cai et al, 2009 ; Dominguez-Garrido et al, 2009 ; Takasaki, 2009 ; Courtenay et al, 2012 ), and sperm motility ( Ruiz-Pesini et al, 2000 ; Montiel-Sosa et al, 2006 ). Mammalian cell lines in which the mtDNA was depleted (Rho0 cells) and repopulated with different mitochondria carrying a diverged mtDNA genetic background showed differences in production of reactive oxygen species ( Moreno-Loshuertos et al, 2006 ; Mueller et al, 2012a ; Tiao et al, 2013 ), calcium uptake ( Kazuno et al, 2006 ), OXPHOS function ( Ji et al, 2012 ), and mtDNA copy number ( Suissa et al, 2009 ).…”

APOE4, oxidative stress and decreased repair capacity - a no-brainer. Faulty lipid metabolism and increased levels of oxidative damage may be risk factors in the pathogenesis of late-onset dementia

“…Sub-haplogroup N9a has also been found to protect its carriers from diabetes type 2 and metabolic syndrome [109] therefore, the protective effects against adverse outcomes after stroke may have been indirect. Mitochondrial haplogroups J, U, K and T and the unrelated haplogroup X were consistently seen more commonly in healthy individuals over 90 than in the healthy 'younger old' [95,110,111]. Carriership of haplogroup K (common in Western Europe and the British Islands) may protect against transient ischaemic attack and ischemic stroke [112].…”