Unraveling genetic origin of aging-related traits: evolving concepts.

Discovering the genetic origin of aging-related traits could greatly advance strategies aiming to extend health span. The results of genome-wide association studies (GWAS) addressing this problem are controversial, and new genetic concepts have been fostered to advance the progress in the field. A limitation of GWAS and new genetic concepts is that they do not thoroughly address specifics of aging-related traits. Integration of theoretical concepts in genetics and aging research with empirical evidence from different disciplines highlights the conceptual problems in studies of genetic origin of aging-related traits. To address these problems, novel approaches of systemic nature are required. These approaches should adopt the non-deterministic nature of linkage of genes with aging-related traits and, consequently, reinforce research strategies for improving our understanding of mechanisms shaping genetic effects on these traits. Investigation of mechanisms will help determine conditions that activate specific genetic variants or profiles and explore to what extent these conditions that shape genetic effects are conserved across human lives and generations.

[1]  A. Yashin,et al.  The role of lipid‐related genes, aging‐related processes, and environment in healthspan , 2013, Aging cell.

[2]  Rafael Tabarés-Seisdedos,et al.  Inverse cancer comorbidity: a serendipitous opportunity to gain insight into CNS disorders , 2013, Nature Reviews Neuroscience.

[3]  Conor V. Dolan,et al.  TATES: Efficient Multivariate Genotype-Phenotype Analysis for Genome-Wide Association Studies , 2013, PLoS genetics.

[4]  A. Yashin,et al.  Polygenic effects of common single-nucleotide polymorphisms on life span: when association meets causality. , 2012, Rejuvenation research.

[5]  J. Veltman,et al.  De novo mutations in human genetic disease , 2012, Nature Reviews Genetics.

[6]  Qiong Yang,et al.  Methods for Analyzing Multivariate Phenotypes in Genetic Association Studies. , 2012, Journal of probability and statistics.

[7]  Jacob A. Tennessen,et al.  Evolution and Functional Impact of Rare Coding Variation from Deep Sequencing of Human Exomes , 2012, Science.

[8]  Sudha Seshadri,et al.  Inverse association between cancer and Alzheimer’s disease: results from the Framingham Heart Study , 2012, BMJ : British Medical Journal.

[9]  A. Yashin,et al.  Age Patterns of Incidence of Geriatric Disease in the U.S. Elderly Population: Medicare‐Based Analysis , 2012, Journal of the American Geriatrics Society.

[10]  Avis J. Thomas,et al.  Lifetime risks of cardiovascular disease. , 2012, The New England journal of medicine.

[11]  G. Gibson Rare and common variants: twenty arguments , 2012, Nature Reviews Genetics.

[12]  P. Visscher,et al.  Five years of GWAS discovery. , 2012, American journal of human genetics.

[13]  F. Agakov,et al.  Abundant pleiotropy in human complex diseases and traits. , 2011, American journal of human genetics.

[14]  George M. Martin The biology of aging: 1985–2010 and beyond , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[15]  C. Finch,et al.  Speed-bumps ahead for the genetics of later-life diseases. , 2011, Trends in Genetics.

[16]  A. Yashin,et al.  Trade‐off in the effects of the apolipoprotein E polymorphism on the ages at onset of CVD and cancer influences human lifespan , 2011, Aging cell.

[17]  Eleftheria Zeggini,et al.  The effect of next-generation sequencing technology on complex trait research , 2011, European journal of clinical investigation.

[18]  E. Zeggini Next-generation association studies for complex traits , 2011, Nature Genetics.

[19]  A. Cuervo,et al.  Protein homeostasis and aging: The importance of exquisite quality control , 2011, Ageing Research Reviews.

[20]  N. Schork,et al.  Contemporary human genetic strategies in aging research , 2011, Ageing Research Reviews.

[21]  P. Visscher,et al.  Estimating missing heritability for disease from genome-wide association studies. , 2011, American journal of human genetics.

[22]  C I Amos,et al.  Evolutionary evidence of the effect of rare variants on disease etiology , 2011, Clinical genetics.

[23]  A. Kraja,et al.  Genetics of Hypertension and Cardiovascular Disease and Their Interconnected Pathways: Lessons from Large Studies , 2011, Current hypertension reports.

[24]  B. Stranger,et al.  Progress and Promise of Genome-Wide Association Studies for Human Complex Trait Genetics , 2011, Genetics.

[25]  J. Cauley,et al.  Age-related decline in bone density among ethnically diverse older men , 2011, Osteoporosis International.

[26]  A. Yashin,et al.  Heritability estimates of endophenotypes of long and health life: the Long Life Family Study. , 2010, The journals of gerontology. Series A, Biological sciences and medical sciences.

[27]  B. Crespi,et al.  Annals of the New York Academy of Sciences the Origins and Evolution of Genetic Disease Risk in Modern Humans , 2022 .

[28]  A. Yashin,et al.  Trade-offs between cancer and other diseases: do they exist and influence longevity? , 2010, Rejuvenation research.

[29]  Tanya M. Teslovich,et al.  Biological, Clinical, and Population Relevance of 95 Loci for Blood Lipids , 2010, Nature.

[30]  C. Finch,et al.  Next-generation sequencing in aging research: Emerging applications, problems, pitfalls and possible solutions , 2010, Ageing Research Reviews.

[31]  B. Crespi,et al.  Xmrks the spot: life history tradeoffs, sexual selection and the evolutionary ecology of oncogenesis , 2010, Molecular ecology.

[32]  Fredrik Barrenäs,et al.  Network properties of human disease genes with pleiotropic effects , 2010, BMC Systems Biology.

[33]  Jason H. Moore,et al.  Missing heritability and strategies for finding the underlying causes of complex disease , 2010, Nature Reviews Genetics.

[34]  Constantin Polychronakos,et al.  Comparative genetic analysis of inflammatory bowel disease and type 1 diabetes implicates multiple loci with opposite effects. , 2010, Human molecular genetics.

[35]  M. Xiong,et al.  Genome-wide gene and pathway analysis , 2010, European Journal of Human Genetics.

[36]  A. Yashin,et al.  Beta2-adrenergic receptor gene polymorphisms as systemic determinants of healthy aging in an evolutionary context , 2010, Mechanisms of Ageing and Development.

[37]  P. Shannon,et al.  Analysis of Genetic Inheritance in a Family Quartet by Whole-Genome Sequencing , 2010, Science.

[38]  M. King,et al.  Genetic Heterogeneity in Human Disease , 2010, Cell.

[39]  A. Yashin,et al.  Polymorphisms in the ACE and ADRB2 genes and risks of aging-associated phenotypes: the case of myocardial infarction. , 2010, Rejuvenation research.

[40]  D. Goldstein Common genetic variation and human traits. , 2009, The New England journal of medicine.

[41]  Caleb E. Finch,et al.  Evolution of the human lifespan and diseases of aging: Roles of infection, inflammation, and nutrition , 2009, Proceedings of the National Academy of Sciences.

[42]  Ku Chee Seng,et al.  How Many Genetic Variants Remain to Be Discovered? , 2009, PloS one.

[43]  R. Plomin,et al.  Common disorders are quantitative traits , 2009, Nature Reviews Genetics.

[44]  A. Yashin,et al.  Date of eclosion modulates longevity: Insights across dietary-restriction gradients and female reproduction in the mexfly Anastrepha ludens , 2009, Experimental Gerontology.

[45]  Judy H. Cho,et al.  Finding the missing heritability of complex diseases , 2009, Nature.

[46]  A. Chakravarti,et al.  Understanding cardiovascular disease through the lens of genome-wide association studies. , 2009, Trends in genetics : TIG.

[47]  K. Frazer,et al.  Common vs. rare allele hypotheses for complex diseases. , 2009, Current opinion in genetics & development.

[48]  Gabrielle Osborne,et al.  Changing course in ageing research: The healthy ageing phenotype. , 2009, Maturitas.

[49]  K. Frazer,et al.  Human genetic variation and its contribution to complex traits , 2009, Nature Reviews Genetics.

[50]  R. Suzman,et al.  Prospects for life span extension. , 2009, Annual review of medicine.

[51]  A. Yashin,et al.  Trade-off between cancer and aging: What role do other diseases play? Evidence from experimental and human population studies , 2009, Mechanisms of Ageing and Development.

[52]  D. Willcox,et al.  Genetic and Environmental Determinants of Healthy Aging Life at the Extreme Limit : Phenotypic Characteristics of Supercentenarians in Okinawa , 2008 .

[53]  A. Yashin,et al.  Cumulative deficits and physiological indices as predictors of mortality and long life. , 2008, The journals of gerontology. Series A, Biological sciences and medical sciences.

[54]  Katsuhiko Yano,et al.  FOXO3A genotype is strongly associated with human longevity , 2008, Proceedings of the National Academy of Sciences.

[55]  K. Weiss Tilting at Quixotic Trait Loci (QTL): An Evolutionary Perspective on Genetic Causation , 2008, Genetics.

[56]  Jane-ling Wang,et al.  Longevity–fertility trade‐offs in the tephritid fruit fly, Anastrepha ludens, across dietary‐restriction gradients , 2008, Aging cell.

[57]  W. Bodmer,et al.  Common and rare variants in multifactorial susceptibility to common diseases , 2008, Nature Genetics.

[58]  M. McCarthy,et al.  Genome-wide association studies for complex traits: consensus, uncertainty and challenges , 2008, Nature Reviews Genetics.

[59]  A. Yashin,et al.  Health‐Protective and Adverse Effects of the Apolipoprotein E ɛ2 Allele in Older Men , 2008, Journal of the American Geriatrics Society.

[60]  S. Olshansky,et al.  Pursuing the Longevity Dividend , 2007, Annals of the New York Academy of Sciences.

[61]  J. M. Gatt,et al.  The contribution of apolipoprotein E alleles on cognitive performance and dynamic neural activity over six decades , 2007, Biological Psychology.

[62]  A. Bergman,et al.  Genetic Determinants of Human Health Span and Life Span: Progress and New Opportunities , 2007, PLoS genetics.

[63]  A. Barabasi,et al.  The human disease network , 2007, Proceedings of the National Academy of Sciences.

[64]  George M. Martin Modalities of Gene Action Predicted by the Classical Evolutionary Biological Theory of Aging , 2007, Annals of the New York Academy of Sciences.

[65]  A. Yashin,et al.  Insights on aging and exceptional longevity from longitudinal data: novel findings from the Framingham Heart Study , 2006, AGE.

[66]  Michael J. Pencina,et al.  Trends in the Incidence of Type 2 Diabetes Mellitus From the 1970s to the 1990s: The Framingham Heart Study , 2006, Circulation.

[67]  Steven P R Rose,et al.  Commentary: heritability estimates--long past their sell-by date. , 2006, International journal of epidemiology.

[68]  T. Perls The different paths to 100. , 2006, The American journal of clinical nutrition.

[69]  André Scheen Diabetes mellitus in the elderly: insulin resistance and/or impaired insulin secretion? , 2005, Diabetes & metabolism.

[70]  G. Church,et al.  Genomes optimize reproduction: aging as a consequence of the developmental program. , 2005, Physiology.

[71]  Bernd W. Brandt,et al.  Variation in the human TP53 gene affects old age survival and cancer mortality1 , 2005, Experimental Gerontology.

[72]  D. Barker The developmental origins of well-being. , 2004, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[73]  P. Sham,et al.  The future of association studies: gene-based analysis and replication. , 2004, American journal of human genetics.

[74]  E. Lange,et al.  Age-stratified heritability estimation in the Framingham Heart Study families , 2003, BMC Genetics.

[75]  R. Lipton,et al.  Unique lipoprotein phenotype and genotype associated with exceptional longevity. , 2003, JAMA.

[76]  T. Day,et al.  ANTAGONISTIC PLEIOTROPY, MORTALITY SOURCE INTERACTIONS, AND THE EVOLUTIONARY THEORY OF SENESCENCE , 2003, Evolution; international journal of organic evolution.

[77]  T. Perls,et al.  Morbidity profiles of centenarians: survivors, delayers, and escapers. , 2003, The journals of gerontology. Series A, Biological sciences and medical sciences.

[78]  Carol Jagger,et al.  Determining health expectancies. , 2002 .

[79]  S. Jazwinski Biological aging research today: potential, peeves, and problems , 2002, Experimental Gerontology.

[80]  E. Stallard Underlying and Multiple Case Mortality Advanced Ages: United States 1980-1998 , 2002 .

[81]  J. Vaupel,et al.  Broken Limits to Life Expectancy , 2002, Science.

[82]  K. Toyka,et al.  Does Down’s Syndrome Protect against Multiple Sclerosis? , 2002, European Neurology.

[83]  A. Yashin,et al.  The new trends in survival improvement require a revision of traditional gerontological concepts , 2001, Experimental Gerontology.

[84]  D. Dix,et al.  Expression of inducible Hsp70 enhances the proliferation of MCF-7 breast cancer cells and protects against the cytotoxic effects of hyperthermia , 2001, Cell stress & chaperones.

[85]  Dmitri A. Jdanov,et al.  Have the oldest old adults ever been frail in the past? A hypothesis that explains modern trends in survival. , 2001, The journals of gerontology. Series A, Biological sciences and medical sciences.

[86]  T. Kirkwood,et al.  If you would live long, choose your parents well. , 2001, Trends in genetics : TIG.

[87]  Steven N. Austad,et al.  Why do we age? , 2000, Nature.

[88]  M. Aronson,et al.  Confidential clinician-reported surveillance of adverse events among medical inpatients , 2000, Journal of General Internal Medicine.

[89]  T. Lehtimäki,et al.  Age-dependent association of apolipoprotein E genotype with coronary and aortic atherosclerosis in middle-aged men: an autopsy study. , 1999, Circulation.

[90]  G. Martin APOE alleles and lipophylic pathogens , 1999, Neurobiology of Aging.

[91]  A. Yashin,et al.  How heritable is individual susceptibility to death? The results of an analysis of survival data on Danish, Swedish and Finnish twins , 1998, Twin Research.

[92]  D. Levy,et al.  Prediction of coronary heart disease using risk factor categories. , 1998, Circulation.

[93]  E. Charnov,et al.  Grandmothering, menopause, and the evolution of human life histories. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[94]  C. Finch,et al.  Genetics of aging. , 1997, Science.

[95]  G. Schellenberg,et al.  Evidence that the apolipoprotein E-genotype effects on lipid levels can change with age in males: a longitudinal analysis. , 1997, American journal of human genetics.

[96]  James W. Vaupel,et al.  The heritability of human longevity: A population-based study of 2872 Danish twin pairs born 1870–1900 , 1996, Human Genetics.

[97]  B. Charlesworth Evolution of senescence: Alzheimer's disease and evolution , 1996, Current Biology.

[98]  Momiao Xiong,et al.  Gene and pathway-based second-wave analysis of genome-wide association studies , 2010, European Journal of Human Genetics.

[99]  J. Vijg,et al.  Genetics of longevity and aging. , 2005, Annual review of medicine.

[100]  J. Tobin,et al.  Longitudinal changes in serum cholesterol in man: an epidemiologic search for an etiology. , 1982, Journal of chronic diseases.

[101]  S. Wright GENETICS OF ABNORMAL GROWTH IN THE GUINEA PIG , 1934 .

[102]  R. Fisher XV.—The Correlation between Relatives on the Supposition of Mendelian Inheritance. , 1919, Transactions of the Royal Society of Edinburgh.

[103]  P. Sebastiani,et al.  American Journal of Epidemiology Practice of Epidemiology a Family Longevity Selection Score: Ranking Sibships by Their Longevity, Size, and Availability for Study , 2022 .