Independent associations of TOMM40 and APOE variants with body mass index

The TOMM40-APOE variants are known for their strong, antagonistic associations with Alzheimer's disease and body weight. While a stronger role of the APOE than TOMM40 variants in Alzheimer's disease was suggested, comparative contribution of the TOMM40-APOE variants in the regulation of body weight remains elusive. We examined additive effects of rs2075650 and rs157580 TOMM40 variants and rs429358 and rs7412 APOE variants coding the ε2/ε3/ε4 polymorphism on body mass index (BMI) in age-aggregated and age-stratified cohort-specific and cohort-pooled analysis of 27,863 Caucasians aged 20–100 years from seven longitudinal studies. Minor alleles of rs2075650, rs429358, and rs7412 were individually associated with BMI (β = −1.29, p = 3.97 × 10−9; β = −1.38, p = 2.78 × 10−10; and β = 0.58, p = 3.04 × 10−2, respectively). Conditional analysis with rs2075650 and rs429358 identified independent BMI-lowering associations for minor alleles (β = −0.63, p = 3.99 × 10−2 and β = −0.94, p = 2.17 × 10−3, respectively). Polygenic mega-analysis identified additive effects of the rs2075650 and rs429358 heterozygotes (β = −1.68, p = 3.00 × 10−9), and the strongest BMI-lowering association for the rs2075650 heterozygous and rs429358 minor allele homozygous carriers (β = −4.11, p = 2.78 × 10−3). Conditional analysis with four polymorphisms identified independent BMI-lowering (rs2075650, rs157580, and rs429358) and BMI-increasing (rs7412) associations of heterozygous genotypes with BMI. Age-stratified conditional analysis revealed well-powered support for a differential and independent association of the rs429358 heterozygote with BMI in younger and older individuals, β = 0.58, 95% confidence interval (CI) = −1.18, 2.35, p = 5.18 × 10−1 for 3,068 individuals aged ≤30 years and β = −4.28, CI = −5.65, −2.92, p = 7.71 × 10−10 for 6,052 individuals aged &gt;80 years. TOMM40 and APOE variants are independently and additively associated with BMI. The APOE ε4-coding rs429358 polymorphism is associated with BMI in older individuals but not in younger individuals.</p

Trade-offs in the effects of the apolipoprotein E polymorphism on risks of diseases of the heart, cancer, and neurodegenerative disorders: Insights on mechanisms from the long life family study

The lack of evolutionary established mechanisms linking genes to age-related traits makes the problem of genetic susceptibility to health span inherently complex. One complicating factor is genetic trade-off. Here we focused on long-living participants of the Long Life Family Study (LLFS), their offspring, and spouses to: (1) Elucidate whether trade-offs in the effect of the apolipoprotein E e4 allele documented in the Framingham Heart Study (FHS) are a more general phenomenon, and (2) explore potential mechanisms generating age- and gender-specific trade-offs in the effect of the e4 allele on cancer, diseases of the heart, and neurodegenerative disorders assessed retrospectively in the LLFS populations. The e4 allele can diminish risks of cancer and diseases of the heart and confer risks of diseases of the heart in a sex-, age-, and LLFS-population-specific manner. A protective effect against cancer is seen in older long-living men and, potentially, their sons (>75 years, relative risk [RR](>75)=0.48, p=0.086), which resembles our findings in the FHS. The protective effect against diseases of the heart is limited to long-living older men (RR(>76)=0.50, p=0.016), as well. A detrimental effect against diseases of the heart is characteristic for a normal LLFS population of male spouses and is specific for myocardial infarction (RR=3.07, p=2.1×10(−3)). These trade-offs are likely associated with two inherently different mechanisms, including disease-specific (detrimental; characteristic for a normal male population) and systemic, aging-related (protective; characteristic for older long-living men) mechanisms. The e4 allele confers risks of neurological disorders in men and women (RR=1.98, p=0.046). The results highlight the complex role of the e4 allele in genetic susceptibility to health span

Physical robustness and resilience among long-lived female siblings: A comparison with sporadic long-livers

Long-lived individuals are central in studies of healthy longevity. However, few pro-longevity factors have been identified, presumably because of phenocopies , i.e. individuals that live long by chance. Familial longevity cases may include less phenocopies than sporadic cases and provide better insights into longevity mechanisms. Here we examined whether long-lived female siblings have a better ability to avoid diseases at ages 65+ (proxy for robustness ) and/or survive to extreme ages (proxy for resilience ) compared to sporadic long-livers. A total of 1,156 long-lived female siblings were selected from three nationwide Danish studies and age-matched with sporadic long-lived female controls. Outcomes included cumulative incidence of common health disorders from age 65 and overall survival. Long-lived female siblings had lower risks of some but not all health conditions, most significantly, depression (OR=0.74; 95%CI=0.62-0.88), and less significantly hypertensive (OR=0.84; 95%CI=0.71-0.99) and cerebrovascular (OR=0.73; 95%CI=0.55-0.96) diseases. They also had consistently better survival to extreme ages (HR=0.71; 95%CI= 0.63-0.81) compared to sporadic long-livers. After adjustment for the diseases, the association with mortality changed only marginally suggesting central role of better physiological resilience in familial longevity. Due to their consistently better resilience, familial longevity cases could be more informative than sporadic cases for studying mechanisms of healthy longevity

Physical Robustness and Resilience Among Long-Lived Female Siblings: A Comparison With Sporadic Long-Livers

Background: Long-lived individuals are central in studies of determinants of healthy longevity. However, few pro-longevity factors have been identified, presumably because of “phenocopies”, i.e. individuals that live long by chance. Familial longevity cases may include less phenocopies than sporadic cases and provide better insights into longevity mechanisms. Here we examined whether long-lived female siblings have a better ability to avoid common diseases at ages 65+ (proxy for “robustness”) and/or survive to extreme ages (proxy for “resilience”) compared to sporadic long-livers. Methods: 1,156 long-lived female siblings were selected from three nationwide Danish studies (DOS, GeHA, LLFS) and age-matched with sporadic long-lived female control from the Danish population. Outcomes included cumulative incidence of common health disorders from age 65, and overall survival from 2006 onwards. Logistic and Cox models were used to evaluate incidence and survival respectively. Results: Long-lived female siblings had significantly lower risks of hypertensive (OR=0.84; 95\.71-0.99) and cerebrovascular (OR=0.73; 95\.55-0.96) diseases and depression (OR=0.74; 95\.62-0.88) at ages 65+, and better survival to extreme ages (HR=0.71; 95\.63-0.81) compared to sporadic long-livers. After adjusting for diseases above, the association with mortality changed only marginally (HR=0.73 (0.64-0.83)). Conclusion: Familial longevity cases could be more informative for studying mechanisms of healthy longevity than sporadic cases. Long-lived female siblings demonstrate better physical robustness and resilience than their age-peers from general population, which might be attributed to a genetic component in familial longevity

Cancer Risk and Behavioral Factors, Comorbidities, and Functional Status in the US Elderly Population

About 80% of all cancers are diagnosed in the elderly and up to 75% of cancers are associated with behavioral factors. An approach to estimate the contribution of various measurable factors, including behavior/lifestyle, to cancer risk in the US elderly population is presented. The nationally representative National Long-Term Care Survey (NLTCS) data were used for measuring functional status and behavioral factors in the US elderly population (65+), and Medicare Claims files linked to each person from the NLTCS were used for estimating cancer incidence. The associations (i.e., relative risks) of selected factors with risks of breast, prostate, lung and colon cancers were evaluated and discussed. Behavioral risk factors significantly affected cancer risks in the US elderly. The most influential of potentially preventable risk factors can be detected with this approach using NLTCS-Medicare linked dataset and for further deeper analyses employing other datasets with detailed risk factors description

Medical Cost Trajectories and Onsets of Cancer and NonCancer Diseases in US Elderly Population

Time trajectories of medical costs-associated with onset of twelve aging-related cancer and chronic noncancer diseases were analyzed using the National Long-Term Care Survey data linked to Medicare Service Use files. A special procedure for selecting individuals with onset of each disease was developed and used for identification of the date at disease onset. Medical cost trajectories were found to be represented by a parametric model with four easily interpretable parameters reflecting: (i) prediagnosis cost (associated with initial comorbidity), (ii) cost of the disease onset, (iii) population recovery representing reduction of the medical expenses associated with a disease since diagnosis was made, and (iv) acquired comorbidity representing the difference between post- and pre diagnosis medical cost levels. These parameters were evaluated for the entire US population as well as for the subpopulation conditional on age, disability and comorbidity states, and survival (2.5 years after the date of onset). The developed approach results in a family of new forecasting models with covariates

Physical resilience after a diagnosis of cardiovascular disease among offspring of long-lived siblings

Health benefits of longevity-enriched families transmit across generations and a lower incidence of cardiovascular diseases (CVD) have been shown to contribute to this phenomenon. In the current study, we investigated whether the offspring of long-lived siblings also have better survival after a CVD diagnosis compared to matched controls, i.e., are they both robust and resilient? Offspring of long-lived siblings were identified from three nationwide Danish studies and linked to national registers. Offspring with first diagnosis of acute myocardial infarction, chronic ischemic heart disease, heart failure or cerebrovascular disease between 1996 and 2011 were included and matched with two controls from the Danish population on sex, year of birth and diagnosis, and type of CVD. Stratified Cox proportional-hazards models on the matching data were performed to study 10-year overall survival. A total of 402 offspring and 804 controls were included: 64.2% male with a median age at diagnosis of 63.0. For offspring and controls, overall survival was 73% and 65% at 10 years from diagnosis, respectively. Offspring of long-lived siblings had a significantly better survival than controls, and this association was slightly attenuated after controlling for marital status, medication and Charlson Comorbidity Index score simultaneously. This study suggested that offspring of long-lived siblings not only show lower CVD incidence but also a better survival following CVD diagnosis compared to matched population controls. The higher biological resilience appears to be a universal hallmark of longevity-enriched families, which makes them uniquely positioned for studying healthy aging and longevity mechanisms.</p

Interactions Between Genes From Aging Pathways Significantly Influence Risk of Alzheimer’s Disease

Age is major risk factor for AD; however, relationships between aging and AD are not well understood. Decline in physiological resilience is universal feature of human aging that may also play role in AD. Aging-related pathways (such as IGF-I/P53/mTOR-mediated) that are involved in tissue resilience work in concert to decide outcomes of cell responses to stress/damage, such as survival, apoptosis, autophagy, etc. We hypothesized that interplay among genes in these pathways may influence AD risk as result of epistasis (GxG). We estimated effects of pairwise epistasis between SNPs in 53 genes from respective pathways on AD risk in the LLFS compared with other data (HRS, CHS, LOADFS). We found significant (fdr\lt;0.05) GxG effects on AD risk in older adults across datasets. The SNP rs11765954 in CDK6 gene was involved in top GxG effects on AD in all datasets, when paired with SNPs in BCL2 and PPARGC1A. The CDK6 role in AD could be pleiotropic, depending on its activity in neurons: CDK6 expression is needed for DNA repair and neuronal survival; however, CDK6 overexpression may lead to the cell cycle reentry in postmitotic neurons resulting in apoptosis, which may contribute to neurodegeneration. CDK6 was earlier found to interfere with BCL2 effects on apoptosis, and with PPARGC1A effects on energy metabolism, which might contribute to observed GxG between these genes. We conclude that interactions among genes from biologically connected aging pathways may significantly influence AD risk. Uncovering such GxG effects has a potential to yield new genetic targets for AD prevention/treatment