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    • The Lothian Birth cohorts of and are studies that

    2018-10-29

    The Lothian Birth cohorts of 1921 and 1936 are studies that were initiated in 1999 and 2004 respectively, originally aimed at uncovering the genetic determinants of cognitive aging. These are follow up studies to the Scottish mental survey that tested the intelligence of almost all children aged 11 that attended Scottish school in 1932 and 1947 and were later recruited for the longitudinal study at the mean age of 79 and 70. In addition to genetic determinants, several other factors like physical fitness, inflammatory profile, renal function, VitB12 and folate, psycho-social and economic status were found to be associated with lifetime cognitive aging (Deary et al., 2012). The Leiden 85+ longitudinal study began in 1997 with 599 individuals aged 85 and older inhabiting the city of Leiden in Netherlands. They were followed up for the next five years with particular focus on inflammation and vascular factors linked with aging. These studies uncovered an association between atherosclerosis and dementia in old age (Vinkers et al., 2005). Extending the Leiden 85+ study, the Newcastle 85+ study comprises over 1000 individuals that were recruited in 2006 at the age of 85. This study included interested participants without regard to their health status thereby avoiding selection bias in the cohort. This design captured the broad spectrum of health in the oldest individuals, with reported outcomes linked to various biological and social factors (Collerton et al., 2007). Another highly informative avenue of investigation includes the study of exceptional longevity. These studies investigate parameters related to aging in centenarians, semi-super agers >105years of age, and super agers >110years of age. The New England Centenarian Study was founded in 1995 at Boston University and expanded to the multi-center Long Life Family Study established in 2006. The latter is a prospective study of 5000 subjects from >500 families that are enriched for exceptional longevity. Notably the New England Centenarian study reported that the extension of longevity is associated with a procyanidin b2 in morbidity so that in addition to having a longer life these centenarians have a longer period of health (Andersen et al., 2012), suggesting that multiple aspects of aging are off-set and delayed in this cohort. Genetic analysis identified the TOMM40/ApoE locus as important for very long life (Sebastiani et al., 2012). ApoE is the gene encoding apolipoprotein E involved in lipid transport and cholesterol metabolism, and the importance of the TOMM40/APOE locus in longevity was confirmed in a meta-analysis of data from 5 cententarian studies from USA, Europe and Japan (Sebastiani et al., 2013). The Longevity Genes Project based in the Albert Einstein College of Medicine investigates the basis for longevity in a founder population of Ashkenazi Jews. The cohort includes over 500 individuals with exceptional longevity, over 700 of their offspring, and a further 600 unrelated individuals. Here also a connection to lipid metabolism has been made including genes involved in lipoproteins and cholesterol metabolism (Barzilai et al., 2003), and the adipose derived signaling peptide adiponectin, a regulator of lipid fuel utilization (Atzmon et al., 2008). Interestingly, adiponectin is implicated in the mechanisms of CR and linked to enhanced longevity in rodents (see below). Adiponectin was also identified as a longevity associated gene in a Polish Centenarian study (Roszkowska-Gancarz et al., 2012). The Okinawa Centenarian Study (OCS) investigates the role of genetics and lifestyle factors in regulation of longevity in a distinct Japanese cohort. The OCS was initiated in 1975 and since then over 900 centenarians have been enrolled (Willcox et al., 2016). A candidate approach identified FOXO3a, a transcription factor linked to insulin signaling as being important in longevity (Willcox et al., 2008), a finding that was confirmed in the Southern Italian Centenarian study (Anselmi et al., 2009). Signaling pathways down stream of insulin and insulin like growth factor (IGF-1) have been clearly linked to longevity in short lived species, where genetic studies in a range of species have demonstrated the ability to target this pathway to manipulate aging (Kenyon, 2010).