Abstract
Human longevity is in part genetically determined, and the insulin/IGF-1 signal transduction (IIS) pathway has consistently been implicated. In humans, type 2 diabetes is a frequent disease that results from loss of glucose homeostasis and for which new candidate polymorphisms now rapidly emerge from genome wide association studies. In the Leiden Longevity Study (n=2415), the offspring of long lived siblings ("offspring") who are genetically enriched for longevity were shown to have a more beneficial metabolic profile compared to their environmentally matched partners ("controls"), including better glucose tolerance. We tested whether the "offspring" carry a lower burden of diabetes risk alleles. Fifteen polymorphisms derived from genome wide association (GWA) scans in type 2 diabetes were tested for association with parameters of glucose metabolism in offspring and controls, and burden of risk alleles was compared between offspring and controls. Among all participants, a higher number of type 2 diabetes risk alleles associated with a higher prevalence of diabetes (P=0.011) and higher serum concentration of glucose (P<0.016) but not insulin (P=0.450). None of the polymorphisms differed in frequency between the offspring and controls (all P>0.05), nor did the mean total number of risk alleles (P=0.977). The association between polymorphisms and glucose levels did not differ between controls and offspring (Pinteraction=0.523). The better glucose tolerance of the "offspring" is not explained by a lower burden of type 2 diabetes risk alleles, suggesting that specific mechanisms determining longevity exist.
Highlights
Human longevity is characterized at middle age by lower prevalence of myocardial infarction, hypertension and type 2 diabetes [1]
Middle aged offspring of long-lived families exhibit lower plasma levels of glucose and higher insulin sensitivity. This is in concordance with the findings from animal studies which revealed that the insulin/IGF1 signal transduction pathway is involved in lifespan
Offspring from nonagenarian siblings had a lower prevalence of diabetes mellitus and hypertension as well as a slightly lower prevalence of myocardial infarction
Summary
Human longevity is characterized at middle age by lower prevalence of myocardial infarction, hypertension and type 2 diabetes [1]. Middle aged offspring of long-lived families exhibit lower plasma levels of glucose and higher insulin sensitivity. This is in concordance with the findings from animal studies which revealed that the insulin/IGF1 signal transduction pathway is involved in lifespan (reviewed in [2]). Type 2 diabetes (T2D) is characterized by an increased insulin resistance. Insulin resistance as well as the prevalence of T2D increases with age. Long-lived subjects, such as centenarians and nonagenarian siblings, as well as their offspring, were found to exhibit a remarkably decreased prevalence of type 2 diabetes. Offspring of longlived siblings were found to have better glucose tolerance and higher insulin www.impactaging.com
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