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The quest for genetic determinants of human longevity: challenges and insights

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TLDR
Large-scale linkage studies of long-lived families, longitudinal candidate-gene association studies and the development of analytical methods provide the potential for future progress in human studies of longevity.
Abstract
Twin studies show that genetic differences account for about a quarter of the variance in adult human lifespan. Common polymorphisms that have a modest effect on lifespan have been identified in one gene, APOE, providing hope that other genetic determinants can be uncovered. However, although variants with substantial beneficial effects have been proposed to exist and several candidates have been put forward, their effects have yet to be confirmed. Human studies of longevity face numerous theoretical and logistical challenges, as the determinants of lifespan are extraordinarily complex. However, large-scale linkage studies of long-lived families, longitudinal candidate-gene association studies and the development of analytical methods provide the potential for future progress.

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Citations
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Journal ArticleDOI

The origin of individual differences in the course and severity of diseases.

TL;DR: The diversity is formed by the mating of genetically different parents that determines the differences in susceptibility of genetically various parts of the descendant organism.
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Variability in APOE genotype status in human-derived cell lines: a cause for concern in cell culture studies?

TL;DR: It is argued that the apolipoprotein E genotype status and corresponding gene expression level of human-derived cell lines should be considered to better avoid inconsistencies in cell culture studies when different cell lines of the same tissue or organ are used and before extrapolating cell culture data to human physiology in health and disease.

Systems biology of ageing and longevity

TL;DR: The system biology approach combines data-driven modelling, often using the large volumes of data generated by functional genomics technologies, and hypothesis-driven experimental studies to investigate causal pathways and identify their parameter values in an unusually quantitative manner.
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Glucocorticoid resistance and β2-adrenergic receptor signaling pathways promote peripheral pro-inflammatory conditions associated with chronic psychological stress: A systematic review across species.

TL;DR: In this paper, the authors found that chronic stress reliably associates with downregulation in cellular glucocorticoid receptor (GR) sensitivity, alterations in intracellular β-AR signaling, and upregulation in pro-inflammatory biomarkers in peripheral blood.
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Identification of polymorphisms in cancer patients that differentially affect survival with age.

TL;DR: This is the first systematic analysis that combines a large longitudinal data set with a targeted candidate gene approach to examine the effect of genetic variation on survival as a function of age in cancer patients, demonstrating that there are ageing-related genetic elements that differentially affect mortality incancer patients in an age-dependent manner.
References
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Journal ArticleDOI

Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families

TL;DR: The APOE-epsilon 4 allele is associated with the common late onset familial and sporadic forms of Alzheimer9s disease (AD) in 42 families with late onset AD.
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The Future of Genetic Studies of Complex Human Diseases

TL;DR: The identification of the genetic basis of complex human diseases such as schizophrenia and diabetes has proven difficult as mentioned in this paper, and Risch and Merikangas proposed that they can best accomplish this goal by combining the power of the human genome project with association studies.
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Inflamm‐aging: An Evolutionary Perspective on Immunosenescence

TL;DR: The beneficial effects of inflammation devoted to the neutralization of dangerous/harmful agents early in life and in adulthood become detrimental late in life in a period largely not foreseen by evolution, according to the antagonistic pleiotropy theory of aging.
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The impact of heterogeneity in individual frailty on the dynamics of mortality.

TL;DR: Calculations based on Swedish mortality data suggest that standard methods overestimate current life expectancy and potential gains in life expectancy from health and safety interventions, while underestimating rates of individual aging, past progress in reducing mortality, and mortality differentials between pairs of populations.
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Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans

TL;DR: The findings suggest that the insulin/IGF-I pathway ultimately exerts its effect on lifespan by upregulating a wide variety of genes, including cellular stress-response, antimicrobial and metabolic genes, and by downregulating specific life-shortening genes.
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