Cancer treatment-induced NAD⁺ depletion in premature senescence and late cardiovascular complications

Abstract

Numerous studies have revealed the critical role of premature senescence induced by various cancer treatment modalities in the pathogenesis of aging-related diseases. Senescence-associated secretory phenotype (SASP) can be induced by telomere dysfunction. Telomeric DNA damage response induced by some cancer treatments can persist for months, possibly accounting for long-term sequelae of cancer treatments. Telomeric DNA damage-induced mitochondrial dysfunction and increased reactive oxygen species production are hallmarks of premature senescence. Recently, we reported that the nucleus-mitochondria positive feedback loop formed by p90 ribosomal S6 kinase (p90RSK) and phosphorylation of S496 on ERK5 (a unique member of the mitogen-activated protein kinase family that is not only a kinase but also a transcriptional co-activator) were vital signaling events that played crucial roles in linking mitochondrial dysfunction, nuclear telomere dysfunction, persistent SASP induction, and atherosclerosis. In this review, we will discuss the role of NAD⁺ depletion in instigating SASP and its downstream signaling and regulatory mechanisms that lead to the premature onset of atherosclerotic cardiovascular diseases in cancer survivors.

Keywords

NAD⁺ / senescence-associated secretory phenotype (SASP) / cardiovascular diseases / p90RSK / ERK5

References

[1] Bhakta N,Yeo F.Cumulative burden of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin’s lymphoma: an analysis from the St Jude lifetime cohort study.The Lancet Oncology2016;17:1325-34 PMCID:PMC5029267

[2] Iconaru EI,Georgescu L.Hand grip strength as a physical biomarker of aging from the perspective of a Fibonacci mathematical modeling.BMC Geriatr2018;18:296 PMCID:PMC6267814

[3] Huang S,Waisman J.Cutaneous metastasectomy: is there a role in breast cancer?.J Surg Oncol2022;

[4] Stec R,Smoter M,Szczylik C.Metastatic colorectal cancer in the elderly: an overview of the systemic treatment modalities (Review).Oncol Lett2011;2:3-11 PMCID:PMC3412521

[5] Syrigos KN,Karapanagiotou EM,Manolopoulos L.Head and neck cancer in the elderly: an overview on the treatment modalities.Cancer Treat Rev2009;35:237-45

[6] Cupit-Link MC,Ness KK.Biology of premature ageing in survivors of cancer.ESMO Open2017;2:e000250 PMCID:PMC5757468

[7] Sung H,Siegel RL.Global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin2021;71:209-49

[8] Qin S,Wang GY.Role of senescence induction in cancer treatment.World J Clin Oncol2018;9:180-7 PMCID:PMC6314866

[9] Luo H,Lang H.Activation of p53 with Nutlin-3a radiosensitizes lung cancer cells via enhancing radiation-induced premature senescence.Lung Cancer2013;81:167-73 PMCID:PMC3739976

[10] Sherr CJ,Shapiro GI.Targeting CDK4 and CDK6: from discovery to therapy.Cancer Discov2016;6:353-67 PMCID:PMC4821753

[11] Rader J,Hart LS.Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma.Clin Cancer Res2013;19:6173-82 PMCID:PMC3844928

[12] Yoshida A,Diehl JA.Induction of therapeutic senescence in vemurafenib-resistant melanoma by extended inhibition of CDK4/6.Cancer Res2016;76:2990-3002 PMCID:PMC4873417

[13] Klein ME,Antonescu C.PDLIM7 and CDH18 regulate the turnover of MDM2 during CDK4/6 inhibitor therapy-induced senescence.Oncogene2018;37:5066-78 PMCID:PMC6137027

[14] Manfredi MG,Meetze KA.Antitumor activity of MLN8054, an orally active small-molecule inhibitor of Aurora A kinase.Proc Natl Acad Sci U S A2007;104:4106-11 PMCID:PMC1820716

[15] Liu Y,Su Y,Sobolik T.Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-kappaB impairs this drug-induced senescence.EMBO Mol Med2013;5:149-66 PMCID:PMC3569660

[16] Liu Y,Su Y.Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-κB impairs this drug-induced senescence.EMBO Mol Med2013;5:149-66 PMCID:PMC3569660

[17] Wysong DR,Hoar K.The inhibition of Aurora A abrogates the mitotic delay induced by microtubule perturbing agents.Cell Cycle2009;8:876-88

[18] Dobrzanski MJ,Quinlin IS.Autologous MUC1-specific Th1 effector cell immunotherapy induces differential levels of systemic TReg cell subpopulations that result in increased ovarian cancer patient survival.Clin Immunol2009;133:333-52 PMCID:PMC2805085

[19] Rosemblit C,Lowenfeld L.Oncodriver inhibition and CD4⁺ Th1 cytokines cooperate through Stat1 activation to induce tumor senescence and apoptosis in HER2+ and triple negative breast cancer: implications for combining immune and targeted therapies.Oncotarget2018;9:23058-77 PMCID:PMC5955413

[20] Luheshi N,Poon E,McCourt M.Th1 cytokines are more effective than Th2 cytokines at licensing anti-tumour functions in CD40-activated human macrophages in vitro.Eur J Immunol2014;44:162-72

[21] Iconaru EI.Hand grip strength variability during serial testing as an entropic biomarker of aging: a Poincaré plot analysis.BMC Geriatr2020;20:12 PMCID:PMC6958685

[22] Cooper R,Hardy R.Mortality Review GroupFALCon and HALCyon Study TeamsObjectively measured physical capability levels and mortality: systematic review and meta-analysis.BMJ2010;341:c4467 PMCID:PMC2938886

[23] Celis-Morales CA,Lyall DM.Associations of grip strength with cardiovascular, respiratory, and cancer outcomes and all cause mortality: prospective cohort study of half a million UK Biobank participants.BMJ2018;361:k1651 PMCID:PMC5939721

[24] Uziel O,Shargian L.Premature ageing following allogeneic hematopoietic stem cell transplantation.Bone Marrow Transplant2020;55:1438-46

[25] Uziel O,Shargian L.Correction: Premature ageing following allogeneic hematopoietic stem cell transplantation.Bone Marrow Transplant2020;55:1519

[26] Arora M,Ness KK.Physiologic Frailty in nonelderly hematopoietic cell transplantation patients: results from the bone marrow transplant survivor study.JAMA Oncol2016;2:1277-86 PMCID:PMC5078990

[27] Kim DK,Park JY.Risk of cardiovascular intervention after androgen deprivation therapy in prostate cancer patients with a prior history of ischemic cardiovascular and cerebrovascular disease: a nationwide population-based cohort study.Urol Oncol2022;40:6.e11-9

[28] Leer P. The risk of cardiovascular disease, fracture, dementia, and cancer after long-term hormone therapy in perimenopausal and postmenopausal women.Am Fam Physician2018;98:117-8

[29] Aleman BM,Nuver J.Cardiovascular disease after cancer therapy.EJC Suppl2014;12:18-28 PMCID:PMC4250533

[30] O’Farrell S,Holmberg L,Stattin P.Risk and timing of cardiovascular disease after androgen-deprivation therapy in men with prostate cancer.J Clin Oncol2015;33:1243-51

[31] Scott JM,Hornsby WE.Exercise therapy as treatment for cardiovascular and oncologic disease after a diagnosis of early-stage cancer.Semin Oncol2013;40:218-28

[32] Lipshultz SE,Lopez-Mitnik G.Cardiovascular status of childhood cancer survivors exposed and unexposed to cardiotoxic therapy.J Clin Oncol2012;30:1050-7 PMCID:PMC3341149

[33] Hudson MM,Gurney JG.Clinical ascertainment of health outcomes among adults treated for childhood cancer.JAMA2013;309:2371-81 PMCID:PMC3771083

[34] Robinson PD,Beauchemin M.Identifying clinical practice guidelines for symptom control in pediatric oncology.Support Care Cancer2021;29:7049-55

[35] Signorelli C,McLoone JK.ANZCHOG Survivorship Study GroupModels of childhood cancer survivorship care in Australia and New Zealand: strengths and challenges.Asia Pac J Clin Oncol2017;13:407-15

[36] Campisi J.The biology of replicative senescence.European Journal of Cancer1997;33:703-9

[37] Hayflick L.The serial cultivation of human diploid cell strains.Experimental Cell Research1961;25:585-621

[38] Banerjee P,Reddy Velatooru L.Senescence-associated secretory phenotype as a hinge between cardiovascular diseases and cancer.Front Cardiovasc Med2021;8:763930 PMCID:PMC8563837

[39] Dominic A,Hamilton DJ,Abe JI.Time-dependent replicative senescence vs. disturbed flow-induced pre-mature aging in atherosclerosis.Redox Biol2020;37:101614 PMCID:PMC7767754

[40] Liu J,Wang Z.Roles of telomere biology in cell senescence, replicative and chronological ageing.Cells2019;8:54 PMCID:PMC6356700

[41] Chuenwisad K,Tubsaeng P.Premature senescence and telomere shortening induced by oxidative stress from oxalate, calcium oxalate monohydrate, and urine from patients with calcium oxalate nephrolithiasis.Front Immunol2021;12:696486 PMCID:PMC8566732

[42] Magalhães JP, Chainiaux F, Remacle J, Toussaint O. Stress-induced premature senescence in BJ and hTERT-BJ1 human foreskin fibroblasts.FEBS Letters2002;523:157-62

[43] Hewitt G,Marques FD.Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence.Nat Commun2012;3:708 PMCID:PMC3292717

[44] Naka K,Ikeda K.Stress-induced premature senescence in hTERT-expressing ataxia telangiectasia fibroblasts.J Biol Chem2004;279:2030-7

[45] Nakamura AJ,Hathcock KS.Both telomeric and non-telomeric DNA damage are determinants of mammalian cellular senescence.Epigenetics Chromatin2008;1:6 PMCID:PMC2584625

[46] Gioia U,Cabrini M.Pharmacological boost of DNA damage response and repair by enhanced biogenesis of DNA damage response RNAs.Sci Rep2019;9:6460 PMCID:PMC6478851

[47] Schumann S,Pfestroff K.DNA damage and repair in peripheral blood mononuclear cells after internal ex vivo irradiation of patient blood with ¹³¹ I.Eur J Nucl Med Mol Imaging2022;49:1447-55 PMCID:PMC8940852

[48] Fumagalli M,Clerici M.Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation.Nat Cell Biol2012;14:355-65 PMCID:PMC3717580

[49] Vaiserman A.Telomere length as a marker of biological age: state-of-the-art, open issues, and future perspectives.Front Genet2020;11:630186 PMCID:PMC7859450

[50] Jiang H,Rudolph KL.Telomere shortening and ageing.Z Gerontol Geriatr2007;40:314-24

[51] Li P,Lou F,Xu D.Telomere dysfunction induced by chemotherapeutic agents and radiation in normal human cells.Int J Biochem Cell Biol2012;44:1531-40

[52] Wong KK,Bachoo RM.Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing.Nature2003;421:643-8

[53] Armanios M,Parry EM,Strong MA.Short telomeres are sufficient to cause the degenerative defects associated with aging.Am J Hum Genet2009;85:823-32 PMCID:PMC2790562

[54] Armanios M,Parry EM,Strong MA.Short telomeres are sufficient to cause the degenerative defects associated with aging.Am J Hum Genet2009;85:823-32 PMCID:PMC2790562

[55] Rolles B,Tometten M.Telomere shortening in peripheral leukocytes is associated with poor survival in cancer patients treated with immune checkpoint inhibitor therapy.Front Oncol2021;11:729207 PMCID:PMC8417059

[56] Bianchi A,Chong L,de Lange T.TRF1 is a dimer and bends telomeric DNA.EMBO J1997;16:1785-94 PMCID:PMC1169781

[57] Ilicheva NV,Voronin AP.Telomere repeat-binding factor 2 is responsible for the telomere attachment to the nuclear membrane. Elsevier; 2015. pp. 67-96.

[58] Kotla S,Ko KA.Endothelial senescence is induced by phosphorylation and nuclear export of telomeric repeat binding factor 2-interacting protein.JCI Insight2019;4:124867 PMCID:PMC6538340

[59] Gu P,Takasugi T.Distinct functions of POT1 proteins contribute to the regulation of telomerase recruitment to telomeres.Nat Commun2021;12:5514 PMCID:PMC8448735

[60] Liu B,Wang Y,Zhou ZH.Structure of active human telomerase with telomere shelterin protein TPP1.Nature2022;604:578-83

[61] Abe J,Yeh ET.The future of onco-cardiology: we are not just ‘side effect hunters’.Circ Res2016;119:896-9 PMCID:PMC5147506

[62] Kim SH,Campisi J.TIN2, a new regulator of telomere length in human cells.Nat Genet1999;23:405-12 PMCID:PMC4940194

[63] Rossiello F,Sepe S.DNA damage response inhibition at dysfunctional telomeres by modulation of telomeric DNA damage response RNAs.Nat Commun2017;8:13980 PMCID:PMC5473644

[64] Cipressa F.DNA damage response, checkpoint activation and dysfunctional telomeres: face to face between mammalian cells and Drosophila.Tsitologiia2013;55:211-7.

[65] Guo X,Lin Y.Dysfunctional telomeres activate an ATM-ATR-dependent DNA damage response to suppress tumorigenesis.EMBO J2007;26:4709-19 PMCID:PMC2080807

[66] Longhese MP.DNA damage response at functional and dysfunctional telomeres.Genes Dev2008;22:125-40 PMCID:PMC2731633

[67] Muraki K.The DNA damage response at dysfunctional telomeres, and at interstitial and subtelomeric DNA double-strand breaks.Genes Genet Syst2018;92:135-52

[68] Rai R.Monitoring the DNA damage response at dysfunctional telomeres.

[69] Passos JF,Wang C.Feedback between p21 and reactive oxygen production is necessary for cell senescence.Mol Syst Biol2010;6:347 PMCID:PMC2835567

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

[71] Brand T.Length doesn’t matter-telomere damage triggers cellular senescence in the ageing heart.EMBO J2019;38:e101571 PMCID:PMC6396151

[72] Li A,Jiang W,Gong G.Mitochondrial dynamics in adult cardiomyocytes and heart diseases.Front Cell Dev Biol2020;8:584800 PMCID:PMC7773778

[73] Livingston K,Puckett LL.The role of mitochondrial dysfunction in radiation-induced heart disease: from bench to bedside.Front Cardiovasc Med2020;7:20 PMCID:PMC7047199

[74] Gorini S,Berrino L,Rosano G.Chemotherapeutic drugs and mitochondrial dysfunction: focus on doxorubicin, trastuzumab, and sunitinib.Oxidative Medicine and Cellular Longevity2018;2018:1-15 PMCID:PMC5878876

[75] Wang B,Demaria M.Senescent cells in cancer therapy: friends or foes?.Trends Cancer2020;6:838-57

[76] Wang Y,Zhou D.Ionizing radiation-induced endothelial cell senescence and cardiovascular diseases.Radiat Res2016;186:153-61 PMCID:PMC4997805

[77] Kotla S,Imanishi M.Nucleus-mitochondria positive feedback loop formed by ERK5 S496 phosphorylation-mediated poly (ADP-ribose) polymerase activation provokes persistent pro-inflammatory senescent phenotype and accelerates coronary atherosclerosis after chemo-radiation.Redox Biol2021;47:102132 PMCID:PMC8502954

[78] Hodjat M,Dumler I.Urokinase receptor mediates doxorubicin-induced vascular smooth muscle cell senescence via proteasomal degradation of TRF2.J Vasc Res2013;50:109-23

[79] Piegari E,Cappetta D.Doxorubicin induces senescence and impairs function of human cardiac progenitor cells.Basic Res Cardiol2013;108:334

[80] Chagastelles PC.Biology of stem cells: an overview.Kidney Int Suppl (2011)2011;1:63-7 PMCID:PMC4089750

[81] Rebelo-Marques A,Andrade R.Aging hallmarks: the benefits of physical exercise.Front Endocrinol (Lausanne)2018;9:258 PMCID:PMC5980968

[82] Rossi DJ,Weissman IL.Stems cells and the pathways to aging and cancer.Cell2008;132:681-96

[83] Kollman C,Anasetti C.Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age.Blood2001;98:2043-51

[84] Cupit-Link MC,Wood WA.Relationship between Aging and Hematopoietic Cell Transplantation.Biol Blood Marrow Transplant2018;24:1965-70

[85] Lahav M,Kestenbaum M.Nonmyeloablative conditioning does not prevent telomere shortening after allogeneic stem cell transplantation.Transplantation2005;80:969-76

[86] Beauséjour C.Bone marrow-derived cells: the influence of aging and cellular senescence.Handb Exp Pharmacol2007;180:67-88

[87] Biran A.Senescent cells talk frankly with their neighbors.Cell Cycle2015;14:2181-2 PMCID:PMC4613544

[88] Gorgoulis V,Alimonti A.Cellular senescence: defining a path forward.Cell2019;179:813-27

[89] Kuilman T.Senescence-messaging secretome: SMS-ing cellular stress.Nat Rev Cancer2009;9:81-94

[90] Coppé JP,Rodier F.Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.PLoS Biol2008;6:2853-68 PMCID:PMC2592359

[91] Wiley CD.The metabolic roots of senescence: mechanisms and opportunities for intervention.Nat Metab2021;3:1290-301 PMCID:PMC8889622

[92] Sabbatinelli J,Olivieri F,Rippo MR.Where metabolism meets senescence: focus on endothelial cells.Front Physiol2019;10:1523 PMCID:PMC6930181

[93] James EL,Pitiyage GN.Senescent human fibroblasts show increased glycolysis and redox homeostasis with extracellular metabolomes that overlap with those of irreparable DNA damage, aging, and disease.J Proteome Res2015;14:1854-71

[94] Chen JH.Deep senescent human fibroblasts show diminished DNA damage foci but retain checkpoint capacity to oxidative stress.FEBS Lett2006;580:6669-73

[95] Zwerschke W,Stöckl P,Eigenbrodt E.Metabolic analysis of senescent human fibroblasts reveals a role for AMP in cellular senescence.Biochem J2003;376:403-11 PMCID:PMC1223775

[96] Xie N,Gao W.NAD⁺ metabolism: pathophysiologic mechanisms and therapeutic potential.Signal Transduct Target Ther2020;5:227 PMCID:PMC7539288

[97] Xiao W,Handy DE.NAD(H) and NADP(H) redox couples and cellular energy metabolism.Antioxid Redox Signal2018;28:251-72 PMCID:PMC5737637

[98] Nacarelli T,Fukumoto T.NAD⁺ metabolism governs the proinflammatory senescence-associated secretome.Nat Cell Biol2019;21:397-407 PMCID:PMC6448588

[99] Covarrubias AJ,Grozio A.NAD⁺ metabolism and its roles in cellular processes during ageing.Nat Rev Mol Cell Biol2021;22:119-41 PMCID:PMC7963035

[100] Lin Q,Liu Y,Liu Q.NAD⁺ and cardiovascular diseases.Clin Chim Acta2021;515:104-10

[101] Luongo TS,Lu MJ.SLC25A51 is a mammalian mitochondrial NAD⁺ transporter.Nature2020;588:174-9 PMCID:PMC7718333

[102] Leverve XM,Groen AK,Tager JM.The malate/aspartate shuttle and pyruvate kinase as targets involved in the stimulation of gluconeogenesis by phenylephrine.Eur J Biochem1986;155:551-6

[103] Lautrup S,Mattson MP.NAD⁺ in Brain Aging and Neurodegenerative Disorders.Cell Metab2019;30:630-55 PMCID:PMC6787556

[104] Braidy N,Mansour H,Poljak A.Age related changes in NAD⁺ metabolism oxidative stress and Sirt1 activity in wistar rats.PLoS One2011;6:e19194 PMCID:PMC3082551

[105] Camacho-Pereira J,Chini CCS.CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism.Cell Metab2016;23:1127-39 PMCID:PMC4911708

[106] Mouchiroud L,Moullan N.The NAD(⁺)/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling.Cell2013;154:430-41 PMCID:PMC3753670

[107] Zhu XH,Lee BY,Chen W.In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences.Proc Natl Acad Sci U S A2015;112:2876-81 PMCID:PMC4352772

[108] Verdin E.NAD⁺ in aging, metabolism, and neurodegeneration.Science2015;350:1208-13

[109] Zhang H,Wu Y.NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice.Science2016;352:1436-43

[110] Frederick DW,Liu L.Loss of NAD homeostasis leads to progressive and reversible degeneration of skeletal muscle.Cell Metab2016;24:269-82 PMCID:PMC4985182

[111] Stein LR.Specific ablation of Nampt in adult neural stem cells recapitulates their functional defects during aging.EMBO J2014;33:1321-40 PMCID:PMC4194122

[112] van der Veer E,O’Neil C.Extension of human cell lifespan by nicotinamide phosphoribosyltransferase.J Biol Chem2007;282:10841-5

[113] Chang HC.SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging.Cell2013;153:1448-60 PMCID:PMC3748806

[114] Zeidler JD,Agorrody G.The CD38 glycohydrolase and the NAD sink: implications for pathological conditions.Am J Physiol Cell Physiol2022;322:C521-45 PMCID:PMC8917930

[115] Chini CCS,Kashyap S,Chini EN.Evolving concepts in NAD⁺ metabolism.Cell Metab2021;33:1076-87 PMCID:PMC8172449

[116] Feldman JL,Denu JM.Sirtuin catalysis and regulation.J Biol Chem2012;287:42419-27 PMCID:PMC3522242

[117] Pehar M,Killoy KM.Nicotinamide adenine dinucleotide metabolism and neurodegeneration.Antioxid Redox Signal2018;28:1652-68 PMCID:PMC5962335

[118] Hayakawa T,Aoki S.SIRT1 suppresses the senescence-associated secretory phenotype through epigenetic gene regulation.PLoS One2015;10:e0116480 PMCID:PMC4312089

[119] Lee S,Lee H.Sirtuin signaling in cellular senescence and aging.BMB Rep2019;52:24-34 PMCID:PMC6386230

[120] Mostoslavsky R,Lombard DB.Genomic instability and aging-like phenotype in the absence of mammalian SIRT6.Cell2006;124:315-29

[121] Ota H,Eto M,Kaneki M.Sirt1 modulates premature senescence-like phenotype in human endothelial cells.J Mol Cell Cardiol2007;43:571-9

[122] Kane AE.Sirtuins and NAD⁺ in the Development and treatment of metabolic and cardiovascular diseases.Circ Res2018;123:868-85 PMCID:PMC6206880

[123] Murata MM,Moncada E.NAD+ consumption by PARP1 in response to DNA damage triggers metabolic shift critical for damaged cell survival.Mol Biol Cell2019;30:2584-97 PMCID:PMC6740200

[124] Poltronieri P,Palazzo L.Mono(ADP-ribosyl)ation enzymes and NAD⁺ metabolism: a focus on diseases and therapeutic perspectives.Cells2021;10:128 PMCID:PMC7827148

[125] Jubin T,Jariwala M.The PARP family: insights into functional aspects of poly (ADP-ribose) polymerase-1 in cell growth and survival.Cell Prolif2016;49:421-37 PMCID:PMC6496725

[126] Savelyev NV,Lavrik OI,Dontsova OA.PARP1 regulates the biogenesis and activity of telomerase complex through modification of H/ACA-proteins.Front Cell Dev Biol2021;9:621134 PMCID:PMC8170401

[127] Gomez M,Schreiber V.PARP1 Is a TRF2-associated poly(ADP-ribose)polymerase and protects eroded telomeres.Mol Biol Cell2006;17:1686-96 PMCID:PMC1415310

[128] Gupte R,Kraus WL.PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes.Genes Dev2017;31:101-26 PMCID:PMC5322727

[129] Slade D.PARP and PARG inhibitors in cancer treatment.Genes Dev2020;34:360-94 PMCID:PMC7050487

[130] Ohanna M,Bonet C.Senescent cells develop a PARP-1 and nuclear factor-{kappa}B-associated secretome (PNAS).Genes Dev2011;25:1245-61 PMCID:PMC3127427

[131] Lv ZC,Wang L.Impact of parthanatos on the increased risk of onset and mortality in male patients with pulmonary hypertension.Am J Mens Health2021;15:15579883211029458 PMCID:PMC8256257

[132] Malyuchenko NV,Kulaeva OI,Studitskiy VM.PARP1 inhibitors: antitumor drug design.Acta Naturae2015;7:27-37 PMCID:PMC4610162

[133] Quarona V,Chillemi A.CD38 and CD157: a long journey from activation markers to multifunctional molecules.Cytometry B Clin Cytom2013;84:207-17

[134] Hogan KA,Chini EN.The multi-faceted ecto-enzyme CD38: Roles in immunomodulation, cancer, aging, and metabolic diseases.Front Immunol2019;10:1187 PMCID:PMC6555258

[135] Preugschat F,Boros EE,Stewart EL.A pre-steady state and steady state kinetic analysis of the N-ribosyl hydrolase activity of hCD157.Arch Biochem Biophys2014;564:156-63

[136] Chini CCS,Warner GM.CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD⁺ and NMN levels.Nat Metab2020;2:1284-304 PMCID:PMC8752031

[137] Tarragó MG,Kanamori KS.A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD⁺ Decline.Cell Metab2018;27:1081-1095.e10 PMCID:PMC5935140

[138] Covarrubias AJ,Perrone R.Senescent cells promote tissue NAD⁺ decline during ageing via the activation of CD38⁺ macrophages.Nat Metab2020;2:1265-83 PMCID:PMC7908681

[139] Boslett J,Christofi FL.Characterization of CD38 in the major cell types of the heart: endothelial cells highly express CD38 with activation by hypoxia-reoxygenation triggering NAD(P)H depletion.Am J Physiol Cell Physiol2018;314:C297-309 PMCID:PMC6335017

[140] Agorrody G,Peluso G.Benefits in cardiac function by CD38 suppression: Improvement in NAD⁺ levels, exercise capacity, heart rate variability and protection against catecholamine-induced ventricular arrhythmias.J Mol Cell Cardiol2022;166:11-22

[141] Boslett J,Zhao YJ,Zweier JL.Luteolinidin protects the postischemic heart through CD38 Inhibition with preservation of NAD(P)(H).J Pharmacol Exp Ther2017;361:99-108 PMCID:PMC5363772

[142] Boslett J,Alzarie YA.Inhibition of CD38 with the Thiazoloquin(az)olin(on)e 78c Protects the heart against postischemic injury.J Pharmacol Exp Ther2019;369:55-64 PMCID:PMC6413770

[143] Hopkins EL,Kobe B.A Novel NAD Signaling Mechanism in Axon Degeneration and its Relationship to Innate Immunity.Front Mol Biosci2021;8:703532 PMCID:PMC8295901

[144] Gerdts J,Sasaki Y,Milbrandt J.SARM1 activation triggers axon degeneration locally via NAD⁺ destruction.Science2015;348:453-7 PMCID:PMC4513950

[145] Wang Q,Liu T.Sarm1/Myd88-5 regulates neuronal intrinsic immune response to traumatic axonal injuries.Cell Rep2018;23:716-24

[146] Murata H,Nishikawa A,Kinoshita R.c-Jun N-terminal kinase (JNK)-mediated phosphorylation of SARM1 regulates NAD⁺ cleavage activity to inhibit mitochondrial respiration.J Biol Chem2018;293:18933-43 PMCID:PMC6295714

[147] Gilley J,Coleman MP.Sarm1 deletion, but not Wld^S, confers lifelong rescue in a mouse model of severe axonopathy.Cell Rep2017;21:10-6 PMCID:PMC5640801

[148] Sur M,Sarkar A.Sarm1 induction and accompanying inflammatory response mediates age-dependent susceptibility to rotenone-induced neurotoxicity.Cell Death Discov2018;4:114 PMCID:PMC6289984

[149] Liu HW,Schmidt MS.Pharmacological bypass of NAD⁺ salvage pathway protects neurons from chemotherapy-induced degeneration.Proc Natl Acad Sci U S A2018;115:10654-9 PMCID:PMC6196523

[150] Mukherjee P,Moore RA.Activation of the innate signaling molecule MAVS by bunyavirus infection upregulates the adaptor protein SARM1, leading to neuronal death.Immunity2013;38:705-16 PMCID:PMC4783152

[151] Osterloh JM,Rooney TM.dSarm/Sarm1 is required for activation of an injury-induced axon death pathway.Science2012;337:481-4 PMCID:PMC5225956

[152] Lin CW,Chen CY.Neuronally-expressed Sarm1 regulates expression of inflammatory and antiviral cytokines in brains.Innate Immun2014;20:161-72

[153] Yoo KH,Rashid MA.Nicotinamide mononucleotide prevents cisplatin-induced cognitive impairments.Cancer Res2021;81:3727-37 PMCID:PMC8277702

[154] Navas LE.NAD⁺ metabolism, stemness, the immune response, and cancer.Signal Transduct Target Ther2021;6:2 PMCID:PMC7775471

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

[156] Franceschi C,Valensin S.Inflamm-aging. An evolutionary perspective on immunosenescence.Ann N Y Acad Sci2000;908:244-54

[157] Chini C,Warner GM.The NADase CD38 is induced by factors secreted from senescent cells providing a potential link between senescence and age-related cellular NAD⁺ decline.Biochem Biophys Res Commun2019;513:486-93 PMCID:PMC6486859

[158] Cameron AM,Sanin DE.Inflammatory macrophage dependence on NAD⁺ salvage is a consequence of reactive oxygen species-mediated DNA damage.Nat Immunol2019;20:420-32

[159] Muris Consortium, Overall coordination, Logistical coordination, Organ collection and processing, Library preparation and sequencing, Computational data analysis, Cell type annotation, Writing group, Supplemental text writing group, Principal investigators. Single-cell transcriptomics of 20 mouse organs creates a tabula Muris.Nature2018;562:367-72 PMCID:PMC6642641

[160] Youm YH,McCabe LR.Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging.Cell Metab2013;18:519-32 PMCID:PMC4017327

[161] Jeng MY,Fei M.Metabolic reprogramming of human CD8⁺ memory T cells through loss of SIRT1.J Exp Med2018;215:51-62 PMCID:PMC5748845

[162] Chatterjee S,Chakraborty P.CD38-NAD⁺axis regulates immunotherapeutic anti-tumor T cell response.Cell Metab2018;27:85-100.e8 PMCID:PMC5837048

[163] Lee KA,Kim GY.Characterization of age-associated exhausted CD8⁺ T cells defined by increased expression of Tim-3 and PD-1.Aging Cell2016;15:291-300 PMCID:PMC4783346

[164] Shimada Y,Nagasaka Y,Inomata M.Age-associated up-regulation of a negative co-stimulatory receptor PD-1 in mouse CD4⁺ T cells.Exp Gerontol2009;44:517-22

[165] Lages CS,Sproles A,Chougnet C.Partial restoration of T-cell function in aged mice by in vitro blockade of the PD-1/ PD-L1 pathway.Aging Cell2010;9:785-98 PMCID:PMC2941565

[166] Wang Y,Wang L.NAD⁺ supplement potentiates tumor-killing function by rescuing defective TUB-mediated NAMPT transcription in tumor-infiltrated T cells.Cell Rep2021;36:109516

[167] Verma V,Ahmad S.PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1⁺ CD38^hi cells and anti-PD-1 resistance.Nat Immunol2019;20:1231-43 PMCID:PMC7472661

[168] Chen L,Yang Y.CD38-Mediated immunosuppression as a mechanism of tumor cell escape from PD-1/PD-L1 blockade.Cancer Discov2018;8:1156-75 PMCID:PMC6205194

[169] Kumar N,Van Houten B.Sick mitochondria cause telomere damage: implications for disease.Mol Cell Oncol2020;7:1678362 PMCID:PMC6961657

[170] Bai P.Biology of poly(ADP-Ribose) polymerases: the factotums of cell maintenance.Mol Cell2015;58:947-58

[171] Alano CC,Ying W,Kauppinen TM.NAD⁺ depletion is necessary and sufficient for poly(ADP-ribose) polymerase-1-mediated neuronal death.J Neurosci2010;30:2967-78 PMCID:PMC2864043

[172] Tang KS,Alano CC.Astrocytic poly(ADP-ribose) polymerase-1 activation leads to bioenergetic depletion and inhibition of glutamate uptake capacity.Glia2010;58:446-57

[173] Bai P,Oudart H.PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation.Cell Metab2011;13:461-8 PMCID:PMC3086520

[174] Virag L,Szabo C.Poly(ADP-ribose) synthetase activation mediates mitochondrial injury during oxidant-induced cell death.J Immunol1998;161:3753-9

[175] Bai P,Fodor T,Pacher P.Poly(ADP-ribose) polymerases as modulators of mitochondrial activity.Trends Endocrinol Metab2015;26:75-83

[176] Singh MV,Le NT.Senescent phenotype induced by p90RSK-NRF2 signaling sensitizes monocytes and macrophages to oxidative stress in HIV-positive individuals.Circulation2019;139:1199-216 PMCID:PMC6957233

[177] Albadawi H,Atkins MD.Role of poly(ADP-ribose) polymerase during vascular reconstruction.Vascular2006;14:362-5

[178] Yeh JM,Chaudhry A.Life expectancy of adult survivors of childhood cancer over 3 decades.JAMA Oncol2020;6:350-7 PMCID:PMC6990848

[179] Miller KD,Mariotto AB.Cancer treatment and survivorship statistics, 2019.CA Cancer J Clin2019;69:363-85

[180] Bluethmann SM,Rowland JH.Anticipating the “Silver Tsunami”: prevalence trajectories and comorbidity burden among older cancer survivors in the United States.Cancer Epidemiol Biomarkers Prev2016;25:1029-36 PMCID:PMC4933329

[181] Sedrak MS,Tchkonia T.Accelerated aging in older cancer survivors.J Am Geriatr Soc2021;69:3077-80 PMCID:PMC8595814

[182] Kannel WB,Kagan A,Stokes J 3rd.Factors of risk in the development of coronary heart disease--six year follow-up experience. The Framingham Study.Ann Intern Med1961;55:33-50

[183] Stern S,Gottlieb S.Cardiology patient pages. Aging and diseases of the heart.Circulation2003;108:e99-101

[184] Kincaid JW.NAD metabolism in aging and cancer.Exp Biol Med (Maywood)2020;245:1594-614 PMCID:PMC7787546

[185] Oeffinger KC,Sklar CA.Childhood Cancer Survivor StudyChronic health conditions in adult survivors of childhood cancer.N Engl J Med2006;355:1572-82

[186] Khanna A,Gupta S.Increased risk of all cardiovascular disease subtypes among childhood cancer survivors: population-based matched cohort study.Circulation2019;140:1041-3

[187] von Korn P,Quell C.Health-related physical fitness and arterial stiffness in childhood cancer survivors.Front Cardiovasc Med2019;6:63 PMCID:PMC6530416

[188] Vatanen A,Huang T.Clinical and biological markers of premature aging after autologous SCT in childhood cancer.Bone Marrow Transplant2017;52:600-5

[189] Guida JL,Belsky D.Measuring aging and identifying aging phenotypes in cancer survivors.J Natl Cancer Inst2019;111:1245-54 PMCID:PMC7962788

[190] Gold K,Jain A.Emerging trends in multiscale modeling of vascular pathophysiology: Organ-on-a-chip and 3D printing.Biomaterials2019;196:2-17 PMCID:PMC6344330

[191] Walther BK,Gold KA.Mechanotransduction-on-chip: vessel-chip model of endothelial YAP mechanobiology reveals matrix stiffness impedes shear response.Lab Chip2021;21:1738-51

[192] Saha B,Tronolone JJ.Human tumor microenvironment chip evaluates the consequences of platelet extravasation and combinatorial antitumor-antiplatelet therapy in ovarian cancer.Sci Adv2021;7:eabg5283 PMCID:PMC8294767

[193] Mathur T,Jain A.Tripartite collaboration of blood-derived endothelial cells, next generation RNA sequencing and bioengineered vessel-chip may distinguish vasculopathy and thrombosis among sickle cell disease patients.Bioeng Transl Med2021;6:e10211 PMCID:PMC8459595

[194] Gold KA,Rajeeva Pandian NK.3D bioprinted multicellular vascular models.Adv Healthc Mater2021;10:e2101141

[195] Pandian NK, Walther BK, Suresh R, Cooke JP, Jain A. Microengineered human vein-chip recreates venous valve architecture and its contribution to thrombosis.Small2020;16:e2003401 PMCID:PMC7791597

[196] Connell NJ,Fealy CE.3 NAD⁺-precursor supplementation with L-tryptophan, nicotinic acid, and nicotinamide does not affect mitochondrial function or skeletal muscle function in physically compromised older adults..J Nutr2021;151:2917-31