A major goal of aging research is identifying genetic targets that could be used to slow or reverse aging – changes in the body and extend limits of human lifespan. However, majority of genes that showed the anti-aging and pro-survival effects in animal models were not replicated in humans, with few exceptions. Potential reasons for this lack of translation include a highly conditional character of genetic influence on lifespan, and its heterogeneity, meaning that better survival may be result of not only activity of individual genes, but also gene–environment and gene–gene interactions, among other factors. In this paper, we explored associations of genetic interactions with human lifespan. We selected candidate genes from well-known aging pathways (IGF1/FOXO growth signaling, P53/P16 apoptosis/senescence, and mTOR/SK6 autophagy and survival) that jointly decide on outcomes of cell responses to stress and damage, and so could be prone to interactions. We estimated associations of pairwise statistical epistasis between SNPs in these genes with survival to age 85+ in the Atherosclerosis Risk in Communities study, and found significant (FDR < 0.05) effects of interactions between SNPs in IGF1R, TGFBR2, and BCL2 on survival 85+. We validated these findings in the Cardiovascular Health Study sample, with P < 0.05, using survival to age 85+, and to the 90th percentile, as outcomes. Our results show that interactions between SNPs in genes from the aging pathways influence survival more significantly than individual SNPs in the same genes, which may contribute to heterogeneity of lifespan, and to lack of animal to human translation in aging research.
PURPOSE: Increasing health care costs, longer life expectancy, improved breast cancer (BC) survival, and higher levels of complex comorbidities have important implications for future Medicare expenditures. METHODS: Data from the SEER program linked to Medicare claims records were used. Women with BC (cases) were categorized into 3 groups on the basis of their year of diagnosis (1998, 2003, or 2008) and were propensity score matched to women without a BC diagnosis (controls). All stage and stage-specific longitudinal changes in survival, morbidity levels using the Elixhauser index, and Medicare expenditures in 2018 dollars were calculated and compared. RESULTS: More than 15% of BC cases were diagnosed in patients over the age of 85 years. The prevalence of most comorbidities increased over time. Costs among cases increased between 1998 and 2008. Spending directly correlated with the stage of disease at diagnosis, with the lowest per-patient costs in the ductal carcinoma in situ (DCIS) subgroup ($14,792 in 1998 and $19,652 in 2008) and the highest in those with distant cancer ($37,667 in 1998 and $43,675 in 2008). Assuming no significant changes in the distribution of BC stage or age at diagnosis, the total annual costs of caring for patients with BC in women 65 years of age or older at diagnosis increased by at least $1.1 billion between 1998 and 2008. CONCLUSION: Improvements in BC survivorship are associated with intensive use of health care resources and substantially higher downstream costs among Medicare beneficiaries. Appropriate planning, in both the fiscal and the oncology care infrastructure, is required to prepare the health system for these emerging health care trends.
Objective: To directly compare the effect of incident age 68+ traumatic brain injury (TBI) on the risk of diagnosis of clinical Alzheimer's disease (AD) in the general population of older adults, and between male veterans and nonveterans; to assess how this effect changes with time since TBI. Setting and Participants: Community-dwelling traditional Medicare beneficiaries 68 years or older from the Health and Retirement Study (HRS). Design: Fine-Gray models combined with inverse-probability weighting were used to identify associations between incident TBI, post-TBI duration, and TBI treatment intensity, with a diagnosis of clinical AD dementia. The study included 16 829 older adults followed over the 1991-2015 period. For analyses of veteran-specific risks, 4281 veteran males and 3093 nonveteran males were identified. Analysis of veteran females was unfeasible due to the age structure of the population. Information on occurrence(s) of TBI, and onset of AD and risk-related comorbidities was constructed from individual-level HRS-linked Medicare claim records while demographic and socioeconomic risk factors were based on the survey data. Results: Later-life TBI was strongly associated with increased clinical AD risk in the full sample (pseudo-hazard ratio [HR]: 3.22; 95% confidence interval [CI]: 2.57-4.05) and in veteran/nonveteran males (HR: 5.31; CI: 3.42-7.94), especially those requiring high-intensity/duration care (HR: 1.58; CI: 1.29-1.91). Effect magnitude decreased with time following TBI (HR: 0.72: CI: 0.68-0.80). Conclusion: Later-life TBI was strongly associated with increased AD risk, especially in those requiring high-intensity/duration care. Effect magnitude decreased with time following TBI. Univariate analysis showed no differences in AD risk between veterans and nonveterans, while the protective effect associated with veteran status in Fine-Gray models was largely due to differences in demographics, socioeconomics, and morbidity. Future longitudinal studies incorporating diagnostic procedures and documentation quantifying lifetime TBI events are necessary to uncover pathophysiological mediating and/or moderating mechanisms between TBI and AD.
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