Parental longevity conferred a reduced diabetes risk in a population selected for their high risk for T2D. To our knowledge, this is the first study to prospectively evaluate the association of parental longevity with diabetes incidence assessed objectively. This protective association is comparable to the benefit reported from DPP and other clinical trials of pharmacological interventions in those at high risk (35
The children of long-lived parents may age more successfully than those of short-lived parents. Analysis from cross-sectional studies showed that for every 10 additional years, the parents lived beyond age 54 their children had approximately a 20% reduction in the risk for chronic conditions (36
). In our cohort, there was a significant trend of reduced diabetes risk related to paternal longevity, apparently independent of demographic, clinical, and metabolic risk factors. A similar pattern was seen for maternal longevity, but it was less evident when adjusting for the same confounding factors. Lower diabetes risk has been found in the offspring of long-lived parents. The offspring of centenarian Ashkenazi Jews had lower prevalence of diabetes than age-matched controls (4
). In the Leiden Longevity Study, the offspring of nonagenarians siblings had a lower mean FPG and insulin levels and better glucose tolerance than their partners (37
). This cohort also showed lower mortality and prevalence of myocardial infarction, hypertension, and diabetes (38
) and more favorable lipoprotein particle profiles (39
). Lower risk of Alzheimer’s disease and memory decline was found in the offspring of parents with exceptional longevity (40
). Similarly data from the English Longitudinal Study of Aging showed that parental life span is positively associated with cognitive functioning at older age and with decreased likelihood of occurrence of chronic diseases (41
Premature maternal or paternal death, relative to living past 80 years, had virtually the same effects on the offspring’s diabetes risk (adjusted hazard ratio 0.70 [95% CI = 0.50–0.97] for fathers and 0.71 [0.50–1.02] for mothers). The slightly wider CI for mothers is explained by the smaller size of the referent group (premature mortality) for mothers, 156, than for fathers, 229. The trend over all age groups was linear in fathers but less uniform in mothers (), a difference attributed to the smaller size of the maternal referent group.
In the cross-sectional assessment of study participants, we found that CHD history at baseline was lower in fathers in the paternal longevity groups. This is consistent with results reported in a Northern Ireland and France study showing that family history and parental longevity, although related, may act independently in predicting 5-year incidence of coronary events in middle-aged men (42
Studies on candidate gene polymorphisms in centenarians have shown a positive association with longevity, whereas other loci have been linked to the development of age-related diseases (43
). Association with genes involved in inflammation, insulin/insulin-like growth factor-1 signaling pathway, lipid metabolism, and oxidative stress has been described (6
). Although some have shown inconsistent results, which may be related to population-specific interactions between gene pools and environment (45
), others have shown consistent association with the apolipoprotein E (46
) and the forkhead box 03A (FOXO3A) (49
). The Framingham Study showed that longevity and aging traits were associated with single-nucleotide polymorphisms, although in those analyses none of the associations achieved genome-wide significance (53
). Recent targeted investigation showed three top-ranking markers located in the genes DUSP6, NALP1, and PERP involved in the induction of apoptosis and other diverse pathways linked to longevity or the aging process (54
The advent of genome-wide association screening has uncovered many loci newly associated with T2D (55
). A recent report from the Leiden Longevity Study found that well-established T2D gene variants were associated with higher glucose levels. However, no difference in the frequency of these polymorphisms was found between the offspring of long-lived siblings and their controls, suggesting that the better glucose tolerance reported in the offspring is not explained by a lower burden of these T2D risk alleles and rather protective alleles for longevity may be involved (57
). Once longevity genes are better established, future analysis of these genes, their gene-to-gene interactions, shared good health habits, and gene-to-environment interactions (58
) may provide further insights on the effect that parental longevity has on the risk for diabetes and other chronic diseases. Similarly, the assessment of the effect that changes in diet and physical activity have on biomarkers of longevity can provide insights to understand mechanisms of healthier aging in participants at high risk for T2D.
We acknowledge the limitations of our study. The reported ages of live and deceased parents on the parental history questionnaire were not validated, and we did not ascertain causes of death. Therefore, the association of diabetes risk with parental longevity/premature death, based on mortality related to chronic diseases (ie, cardiovascular disease, diabetes, and cancer), may have been diluted due to traumatic causes of death (ie, accidents, war, homicides, and suicides). In addition, self-selection of participants into the study led to inclusion of those with parental diabetes and potentially with history of parents with CHD and premature death. Finally, because the DPP participants were fairly young, many had parents who were still alive, not yet 80 years or older, and consequently could not be used for this analysis. If vital statistics on these younger fathers (n = 883) and mothers (n = 1,402) can be updated, then more will attain the age of 80 years or die before that age and thus be informative for our analysis.
In summary, we have shown that parental longevity is associated with lower diabetes incidence in adults at high risk for T2D. The assessment of parental longevity may provide information for risk stratification of these individuals, adding information beyond that suggested by glucose intolerance and associated cardiovascular risk factors. Future studies of candidate genes, epigenetic factors, and biomarkers for longevity may provide a better understanding of the mechanism whereby parental longevity may lead to reduction of diabetes risk.