Genetic basis of cardiovascular aging is at the core of human longevity

Abstract

Aging is an archetypical complex process influenced by genetic and environmental factors. Genetic variants impart a gradient of effect sizes, albeit the effect sizes seem to be skewed toward those with small effect sizes. On one end of the spectrum are the rare monogenic premature aging syndromes, such as Hutchinson Gilford Progeria Syndrome, whereby single nucleotide changes lead to rapidly progressive premature aging. On the end of the spectrum is the complex, slowly progressive process of living to an arbitrary-defined old age, i.e., longevity. Whereas the genetic basis of rare premature aging syndromes has been elucidated, only a small fraction of the genetic determinants of longevity and life span, time from birth to death, have been identified. The latter point to the complexity of the process and involvement of myriad of genetic and non-genetic factors and hence, the diluted effect of each determinant on longevity. The genetic discoveries point to the involvement of the DNA damage and activation of the DNA damage response pathway, particularly in the premature aging syndromes. Likewise, the insulin/insulin-like growth factor 1/mTOR/FOXO pathways have emerged as major regulators of life span. A notable fraction of the genetic variants that are associated with life span is also associated with age-related cardiovascular diseases, such as coronary artery disease and dyslipidemia, which places cardiovascular aging at the core of human life span. The clinical impact of the discoveries pertains to the identification of the pathways that are involved in life span, which might serve as targets of interventions to prevent, slow, and even possibly reverse aging.

Keywords

Longevity / life span / health span / genetics / progeria / APOE4 / FOXO3 / mTOR / DNA damage

References

[1] López-Otín C,Partridge L,Kroemer G.The hallmarks of aging.Cell2013;153:1194-217 PMCID:PMC3836174

[2] Erdmann J,Munoz Venegas L.A decade of genome-wide association studies for coronary artery disease: the challenges ahead.Cardiovasc Res2018;114:1241-57

[3] Young RD,Coles LS.Living and all-time world longevity record-holders over the age of 110.Rejuvenation Res2010;13:759-61

[4] Hennekam RC.Hutchinson-Gilford progeria syndrome: review of the phenotype.Am J Med Genet A2006;140:2603-24

[5] Merideth MA,Clauss S.Phenotype and course of Hutchinson-Gilford progeria syndrome.N Engl J Med2008;358:592-604 PMCID:PMC2940940

[6] Eriksson M,Gordon LB.Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome.Nature2003;423:293-8

[7] Bianchi A,Lucini F.Mechanotransduction, nuclear architecture and epigenetics in Emery Dreifuss Muscular Dystrophy: tous pour un, un pour tous.Nucleus2018;9:276-90 PMCID:PMC5973142

[8] Lin F.Structural organization of the human gene encoding nuclear lamin A and nuclear lamin C.J Biol Chem1993;268:16321-6

[9] Machiels BM,Endert JM.An alternative splicing product of the lamin A/C gene lacks exon 10.J Biol Chem1996;271:9249-53

[10] Nakajima N.Genomic structure of the mouse A-type lamin gene locus encoding somatic and germ cell-specific lamins.FEBS Letters1995;365:108-14

[11] De Sandre-Giovannoli A,Cau P.Lamin a truncation in Hutchinson-Gilford progeria.Science2003;300:2055

[12] Marian AJ.Non-syndromic cardiac progeria in a patient with the rare pathogenic p.Asp300Asn variant in the LMNA gene.BMC Med Genet2017;18:116 PMCID:PMC5648416

[13] Motegi S,Uchiyama A.First Japanese case of atypical progeroid syndrome/atypical Werner syndrome with heterozygous LMNA mutation.J Dermatol2014;41:1047-52

[14] Ragnauth CD,Liu Y.Prelamin A acts to accelerate smooth muscle cell senescence and is a novel biomarker of human vascular aging.Circulation2010;121:2200-10

[15] Scaffidi P.Lamin A-dependent nuclear defects in human aging.Science2006;312:1059-63 PMCID:PMC1855250

[16] Dreesen O.Towards delineating the chain of events that cause premature senescence in the accelerated aging syndrome Hutchinson-Gilford progeria (HGPS).Biochem Soc Trans2020;48:981-91 PMCID:PMC7329345

[17] Cenni V,Mattioli E.Lamin A involvement in ageing processes.Ageing Res Rev2020;62:101073

[18] Gordon LB,Massaro J.Clinical trial of the protein farnesylation inhibitors lonafarnib, pravastatin, and zoledronic acid in children with Hutchinson-Gilford progeria syndrome.Circulation2016;134:114-25 PMCID:PMC4943677

[19] Cheedipudi SM,Coarfa C.Genomic reorganization of Lamin-associated domains in cardiac myocytes is associated with differential gene expression and DNA methylation in human dilated cardiomyopathy.Circ Res2019;124:1198-213 PMCID:PMC6459729

[20] Liu B,Zhang L,Zheng H.Depleting the methyltransferase Suv39h1 improves DNA repair and extends lifespan in a progeria mouse model.Nat Commun2013;4:1868 PMCID:PMC3674265

[21] Zullo JM,Piqué-Regi R.DNA sequence-dependent compartmentalization and silencing of chromatin at the nuclear lamina.Cell2012;149:1474-87

[22] Fajas L,Reiter R.The retinoblastoma-histone deacetylase 3 complex inhibits PPARγ and adipocyte differentiation.Developmental Cell2002;3:903-10

[23] Auguste G,Lombardi R,Willerson JT.Suppression of activated FOXO transcription factors in the heart prolongs survival in a mouse model of laminopathies.Circ Res2018;122:678-92 PMCID:PMC5834384

[24] Melcer S,Rand E.Histone modifications and lamin A regulate chromatin protein dynamics in early embryonic stem cell differentiation.Nat Commun2012;3:910 PMCID:PMC3564597

[25] Shamma A,Hayashi N.ATM mediates pRB function to control DNMT1 protein stability and DNA methylation.Mol Cell Biol2013;33:3113-24 PMCID:PMC3753918

[26] Burla R,Merigliano C,Saggio I.Genomic instability and DNA replication defects in progeroid syndromes.Nucleus2018;9:368-79 PMCID:PMC7000143

[27] Graziano S,Coll-Bonfill N.Causes and consequences of genomic instability in laminopathies: replication stress and interferon response.Nucleus2018;9:258-75 PMCID:PMC5973265

[28] Komari CJ,Carr SR.Alteration of genetic recombination and double-strand break repair in human cells by progerin expression.DNA Repair (Amst)2020;96:102975 PMCID:PMC7669652

[29] Liu Y,Rusinol AE.Involvement of xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A.FASEB J2008;22:603-11 PMCID:PMC3116236

[30] Hilton BA,Cartwright BM.Progerin sequestration of PCNA promotes replication fork collapse and mislocalization of XPA in laminopathy-related progeroid syndromes.FASEB J2017;31:3882-93 PMCID:PMC5572696

[31] Higo T,Sumida T.DNA single-strand break-induced DNA damage response causes heart failure.Nat Commun2017;8:15104 PMCID:PMC5413978

[32] Chen SN,Karmouch J.DNA damage response/TP53 pathway is activated and contributes to the pathogenesis of dilated cardiomyopathy associated with LMNA (Lamin A/C) mutations.Circ Res2019;124:856-73 PMCID:PMC6460911

[33] Pilié PG,Mills GB.State-of-the-art strategies for targeting the DNA damage response in cancer.Nat Rev Clin Oncol2019;16:81-104 PMCID:PMC8327299

[34] Blackford AN.ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response.Mol Cell2017;66:801-17

[35] Kudlow BA,Burtner CR,Kennedy BK.Suppression of proliferative defects associated with processing-defective lamin A mutants by hTERT or inactivation of p53.Mol Biol Cell2008;19:5238-48 PMCID:PMC2592682

[36] Liu Y,Sinensky M,Zou Y.DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A.J Cell Sci2006;119:4644-9 PMCID:PMC3105909

[37] Maurer M.The driving force: nuclear mechanotransduction in cellular function, fate, and disease.Annu Rev Biomed Eng2019;21:443-68 PMCID:PMC6815102

[38] Osmanagic-Myers S,Foisner R.Lamins at the crossroads of mechanosignaling.Genes Dev2015;29:225-37 PMCID:PMC4318140

[39] Selman C,Wieser D.Ribosomal protein S6 kinase 1 signaling regulates mammalian life span.Science2009;326:140-4 PMCID:PMC4954603

[40] Cabral WA,Beeram I.Genetic reduction of mTOR extends lifespan in a mouse model of Hutchinson-Gilford Progeria syndrome.Aging Cell2021;20:e13457 PMCID:PMC8441492

[41] Richardson NE,Schuster HS.Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and lifespan in mice.Nat Aging2021;1:73-86 PMCID:PMC8009080

[42] Sciarretta S,Sadoshima J.Boosting circadian autophagy by means of intermittent time-restricted feeding: a novel anti-ageing strategy?.J Cardiovasc Aging2022;2:5 PMCID:PMC8785976

[43] Gao C,Wang Y.The coming of age for branched-chain amino acids.J Cardiovasc Aging2021;1:10.20517/jca.2021.02 PMCID:PMC8459750

[44] Decker ML,Vulto I.Telomere length in Hutchinson-Gilford progeria syndrome.Mech Ageing Dev2009;130:377-83

[45] Doksani Y,de Lange T.Super-resolution fluorescence imaging of telomeres reveals TRF2-dependent T-loop formation.Cell2013;155:345-56 PMCID:PMC4062873

[46] Wood AM,Lucas CA.TRF2 and lamin A/C interact to facilitate the functional organization of chromosome ends.Nat Commun2014;5:5467 PMCID:PMC4235626

[47] Huang S,Martin GM,Oshima J.Accelerated telomere shortening and replicative senescence in human fibroblasts overexpressing mutant and wild-type lamin A.Exp Cell Res2008;314:82-91 PMCID:PMC2228272

[48] Anderson R,Maggiorani D.Length-independent telomere damage drives post-mitotic cardiomyocyte senescence.EMBO J2019;38:e100492 PMCID:PMC6396144

[49] Dobrzynska A,Shanahan C.The nuclear lamina in health and disease.Nucleus2016;7:233-48 PMCID:PMC4991244

[50] Worman HJ.“Laminopathies”: a wide spectrum of human diseases.Exp Cell Res2007;313:2121-33 PMCID:PMC2964355

[51] Cattin ME,Bonne G.‘State-of-the-heart’ of cardiac laminopathies.Curr Opin Cardiol2013;28:297-304

[52] Oshima J,Monnat RJ Jr.Werner syndrome: clinical features, pathogenesis and potential therapeutic interventions.Ageing Res Rev2017;33:105-14 PMCID:PMC5025328

[53] Yu CE,Fu YH.Positional cloning of the Werner’s syndrome gene.Science1996;272:258-62

[54] Lachapelle S,Garand C.Proteome-wide identification of WRN-interacting proteins in untreated and nuclease-treated samples.J Proteome Res2011;10:1216-27 PMCID:PMC4586248

[55] Kusumoto R,Marchetti C.Werner protein cooperates with the XRCC4-DNA ligase IV complex in end-processing.Biochemistry2008;47:7548-56 PMCID:PMC2572716

[56] Ishikawa N,Izumiyama-Shimomura N.Accelerated in vivo epidermal telomere loss in Werner syndrome.Aging (Albany NY)2011;3:417-29 PMCID:PMC3117457

[57] Li B,Chen LY.Downregulation of the Werner syndrome protein induces a metabolic shift that compromises redox homeostasis and limits proliferation of cancer cells.Aging Cell2014;13:367-78 PMCID:PMC3999508

[58] Marian AJ.Clinical interpretation and management of genetic variants.JACC Basic Transl Sci2020;5:1029-42 PMCID:PMC7591931

[59] Yap KL,Muñoz-Cabello AM.Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a.Mol Cell2010;38:662-74 PMCID:PMC2886305

[60] Kong Y,Alonso LC.ANRIL: A lncRNA at the CDKN2A/B locus with roles in cancer and metabolic disease.Front Endocrinol (Lausanne) 2018;9:405 PMCID:PMC6066557

[61] McDaid AF,Porcu E.Bayesian association scan reveals loci associated with human lifespan and linked biomarkers.Nat Commun2017;8:15842 PMCID:PMC5537485

[62] Deelen J,Arking DE.A meta-analysis of genome-wide association studies identifies multiple longevity genes.Nat Commun2019;10:3669 PMCID:PMC6694136

[63] Visel A,May D.Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice.Nature2010;464:409-12 PMCID:PMC2938076

[64] Harismendy O,Song X.9p21 DNA variants associated with coronary artery disease impair interferon-γ signalling response.Nature2011;470:264-8 PMCID:PMC3079517

[65] Helgadottir A,Manolescu A.A common variant on chromosome 9p21 affects the risk of myocardial infarction.Science2007;316:1491-3

[66] Helgadottir A,Magnusson KP.The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm.Nat Genet2008;40:217-24

[67] Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.Nature2007;447:661-78

[68] Milan G,Pescatore F.Regulation of autophagy and the ubiquitin-proteasome system by the FoxO transcriptional network during muscle atrophy.Nat Commun2015;6:6670 PMCID:PMC4403316

[69] Eijkelenboom A.FOXOs: signalling integrators for homeostasis maintenance.Nat Rev Mol Cell Biol2013;14:83-97

[70] Kimura KD,Liu Y.daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans.Science1997;277:942-6

[71] Kenyon C.The plasticity of aging: insights from long-lived mutants.Cell2005;120:449-60

[72] Green CL,Fontana L.Molecular mechanisms of dietary restriction promoting health and longevity.Nat Rev Mol Cell Biol2022;23:56-73 PMCID:PMC8692439

[73] Brunet A,Zigmond MJ.Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor.Cell1999;96:857-68

[74] Willcox BJ,He Q.FOXO3A genotype is strongly associated with human longevity.Proc Natl Acad Sci U S A2008;105:13987-92 PMCID:PMC2544566

[75] Broer L,Deelen J.GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy.J Gerontol A Biol Sci Med Sci2015;70:110-8 PMCID:PMC4296168

[76] Joshi PK,Kentistou KA.Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity.Nat Commun2017;8:910 PMCID:PMC5715013

[77] Joshi PK,Schraut KE,Esko T.Variants near CHRNA3/5 and APOE have age- and sex-related effects on human lifespan.Nat Commun2016;7:11174 PMCID:PMC5438072

[78] Boerwinkle E.Simultaneous effects of the apolipoprotein E polymorphism on apolipoprotein E, apolipoprotein B, and cholesterol metabolism.Am J Hum Genet1988;42:104-12 PMCID:PMC1715322

[79] Corder EH,Strittmatter WJ.Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families.Science1993;261:921-3

[80] Rasmussen I, Rasmussen KL, Nordestgaard BG, Tybjærg-Hansen A, Frikke-Schmidt R. Impact of cardiovascular risk factors and genetics on 10-year absolute risk of dementia: risk charts for targeted prevention.Eur Heart J2020;41:4024-33 PMCID:PMC7672536

[81] Schächter F,Guénot F.Genetic associations with human longevity at the APOE and ACE loci.Nat Genet1994;6:29-32

[82] Wright KM,Kermany A.A prospective analysis of genetic variants associated with human lifespan.G3 (Bethesda)2019;9:2863-78 PMCID:PMC6723124

[83] McLean JW,Kuang WJ.cDNA sequence of human apolipoprotein(a) is homologous to plasminogen.Nature1987;330:132-7

[84] Lackner C,Hobbs HH.Molecular definition of the extreme size polymorphism in apolipoprotein(a).Hum Mol Genet1993;2:933-40

[85] Clarke R,Hopewell JC.PROCARDIS ConsortiumGenetic variants associated with Lp(a) lipoprotein level and coronary disease.N Engl J Med2009;361:2518-28

[86] Kamstrup PR,Steffensen R.Genetically elevated lipoprotein(a) and increased risk of myocardial infarction.JAMA2009;301:2331-9

[87] Kaltoft M,Afzal S.Elevated lipoprotein(a) in mitral and aortic valve calcification and disease: The Copenhagen General Population Study.Atherosclerosis2021;

[88] Arsenault BJ,Kaiser Y.Association of long-term exposure to elevated lipoprotein(a) levels with parental life span, chronic disease-free survival, and mortality risk: a Mendelian randomization analysis.JAMA Netw Open2020;3:e200129 PMCID:PMC7049087

[89] Weinstock PH,Aalto-Setälä K.Severe hypertriglyceridemia, reduced high density lipoprotein, and neonatal death in lipoprotein lipase knockout mice. Mild hypertriglyceridemia with impaired very low density lipoprotein clearance in heterozygotes.J Clin Invest1995;96:2555-68 PMCID:PMC185959

[90] Kathiresan S,Guiducci C.Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans.Nat Genet2008;40:189-97 PMCID:PMC2682493

[91] Thorgeirsson TE,Sulem P.A variant associated with nicotine dependence, lung cancer and peripheral arterial disease.Nature2008;452:638-42 PMCID:PMC4539558

[92] Laffita-Mesa JM,Svenningsson P.Ataxin-2 gene: a powerful modulator of neurological disorders.Curr Opin Neurol2021;34:578-88 PMCID:PMC8279897

[93] Newman JW,Harris TR.The soluble epoxide hydrolase encoded by EPXH2 is a bifunctional enzyme with novel lipid phosphate phosphatase activity.Proc Natl Acad Sci U S A2003;100:1558-63 PMCID:PMC149871

[94] Poon S,Rybchyn MS,Wilson MR.Clusterin is an ATP-independent chaperone with very broad substrate specificity that stabilizes stressed proteins in a folding-competent state.Biochemistry2000;39:15953-60

[95] Qu X,Zhai Y.Identification, characterization, and functional study of the two novel human members of the semaphorin gene family.J Biol Chem2002;277:35574-85

[96] Streb H,Berridge MJ.Release of Ca²⁺ from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol-1,4,5-trisphosphate.Nature1983;306:67-9

[97] Ruby JG,Rand KA.Estimates of the heritability of human longevity are substantially inflated due to assortative mating.Genetics2018;210:1109-24 PMCID:PMC6218226

[98] Sebastiani P.The genetics of extreme longevity: lessons from the new England centenarian study.Front Genet2012;3:277 PMCID:PMC3510428

[99] Herskind AM,Holm NV,Harvald B.The heritability of human longevity: a population-based study of 2872 Danish twin pairs born 1870-1900.Hum Genet1996;97:319-23

[100] Evans A,McCarron P.The genetics of coronary heart disease: the contribution of twin studies.Twin Res2003;6:432-41

[101] Papadopoli D,Kazak L.mTOR as a central regulator of lifespan and aging.F1000Res2019;8:998 PMCID:PMC6611156

[102] Martins R,Link W.Long live FOXO: unraveling the role of FOXO proteins in aging and longevity.Aging Cell2016;15:196-207 PMCID:PMC4783344

[103] Arantes-Oliveira N,Kenyon C.Healthy animals with extreme longevity.Science2003;302:611

[104] Hsin H.Signals from the reproductive system regulate the lifespan of C. elegans.Nature1999;399:362-6

[105] Willer CJ,Jackson AU.Newly identified loci that influence lipid concentrations and risk of coronary artery disease.Nat Genet2008;40:161-9 PMCID:PMC5206900

[106] Willer CJ,Sengupta S.Global Lipids Genetics ConsortiumDiscovery and refinement of loci associated with lipid levels.Nat Genet2013;45:1274-83 PMCID:PMC3838666

[107] Kathiresan S,Peloso GM.Common variants at 30 loci contribute to polygenic dyslipidemia.Nat Genet2009;41:56-65 PMCID:PMC2881676

[108] Lee MB,Bitto A.Antiaging diets: separating fact from fiction.Science2021;374:eabe7365 PMCID:PMC8841109