Promoting healthy cardiovascular aging: emerging topics

Abstract

The development of age-related cardiovascular (CV) dysfunction increases the risk of CV disease as well as other chronic age-associated disorders, including chronic kidney disease, and Alzheimer’s disease and related dementias. Major manifestations of age-associated CV dysfunction that increase disease risk are vascular dysfunction, primarily vascular endothelial dysfunction and arterial stiffening, and elevated systolic blood pressure. Declines in nitric oxide bioavailability secondary to increased oxidative stress and inflammation are established mechanisms of CV dysfunction with aging. Moreover, fundamental mechanisms of aging, termed the “hallmarks of aging” extend to the CV system and, as such, may be considered “hallmarks of CV aging”. These mechanisms represent viable therapeutic targets for treating CV dysfunction with aging. Healthy lifestyle behaviors, such as regular aerobic exercise and certain dietary patterns, are considered “first-line” strategies to prevent and/or treat age-associated CV dysfunction. Despite the well-established benefits of these strategies, many older adults do not meet the recommended guidelines for exercise or consume a healthy diet. Therefore, it is important to establish alternative and/or complementary evidence-based approaches to prevent or reverse age-related CV dysfunction. Targeting fundamental mechanisms of CV aging with interventions such as time-efficient exercise training, food-derived molecules, termed nutraceuticals, or select synthetic pharmacological agents represents a promising approach. In the present review, we will highlight emerging topics in the field of healthy CV aging with a specific focus on how exercise, nutrition/dietary patterns, nutraceuticals and select synthetic pharmacological compounds may promote healthy CV aging, in part, by targeting the hallmarks of CV aging.

Keywords

Hallmarks of aging / exercise / nutrition / oxidative stress / inflammation / endothelial function / arterial stiffness

References

[1] Benjamin EJ,Callaway CW.Heart disease and stroke statistics-2018 update: a report from the american heart association.Circulation2018;137:e67-e492

[2] Forouzanfar MH,Anderson HR.Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.Lancet2015;386:2287-323

[3] Heidenreich PA,Khavjou OA.Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association.Circulation2011;123:933-44

[4] Bureau UC. Table 12: Projections of the populations by age and sex for the United States: 2010 to 2050 (NP2008-T12). Available from: https://www.census.gov/data/tables/2008/demo/popproj/2008-summary-tables.html [Last accessed on 29 Jul 2022].

[5] Lakatta EG.Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a “set up” for vascular disease.Circulation2003;107:139-46

[6] Najjar SS,Lakatta EG.Arterial aging: is it an immutable cardiovascular risk factor?.Hypertension2005;46:454-62

[7] Seals DR,Gioscia-Ryan RA.You’re only as old as your arteries: translational strategies for preserving vascular endothelial function with aging.Physiology (Bethesda)2014;29:250-64 PMCID:PMC4103060

[8] Fuchs FD.High blood pressure and cardiovascular disease.Hypertension2020;75:285-92

[9] Rossman MJ,Martens CR.Healthy lifestyle-based approaches for successful vascular aging.J Appl Physiol (1985)2018;125:1888-900 PMCID:PMC6842891

[10] Troiano RP,Dodd KW,Tilert T.Physical activity in the United States measured by accelerometer.Med Sci Sports Exerc2008;40:181-8

[11] Van Horn L,Appel LJ.Recommended dietary pattern to achieve adherence to the american heart association/american college of cardiology (AHA/ACC) guidelines: a scientific statement from the american heart association.Circulation2016;134:e505-29

[12] Kelly S,Kuhn I,Brayne C.Barriers and facilitators to the uptake and maintenance of healthy behaviours by people at mid-life: a rapid systematic review.PLoS One2016;11:e0145074 PMCID:PMC4731386

[13] Stutts WC.Physical activity determinants in adults: perceived benefits, barriers, and self efficacy.AAOHN J2002;50:499-507

[14] Babakus WS.Physical activity among South Asian women: a systematic, mixed-methods review.Int J Behav Nutr Phys Act2012;9:150 PMCID:PMC3542106

[15] Siddiqi Z,Shuval K.Understanding impediments and enablers to physical activity among African American adults: a systematic review of qualitative studies.Health Educ Res2011; 26:1010-24

[16] Yarwood J,Gagan MJ.Women maintaining physical activity at midlife: contextual complexities.Nurs Prax N Z21:24-37

[17] Leone LA.A mixed methods comparison of perceived benefits and barriers to exercise between obese and nonobese women.J Phys Act Health2013;10:461-9 PMCID:PMC3904548

[18] Steenman M.Cardiac aging and heart disease in humans.Biophys Rev2017;9:131-7 PMCID:PMC5418492

[19] Nowak KL,Chonchol M.Strategies for achieving healthy vascular aging.Hypertension2018;71:389-402 PMCID:PMC5812814

[20] LaRocca TJ,Seals DR.Nutrition and other lifestyle influences on arterial aging.Ageing Res Rev2017;39:106-19 PMCID:PMC5373983

[21] Ungvari Z,Donato AJ,Csiszar A.Mechanisms of vascular aging.Circ Res2018;123:849-67 PMCID:PMC6248882

[22] Ungvari Z,Sorond F,Csiszar A.Mechanisms of vascular aging, a geroscience perspective: JACC focus seminar.J Am Coll Cardiol2020;75:931-41 PMCID:PMC8559983

[23] Donato AJ,Lesniewski LA.Mechanisms of dysfunction in the aging vasculature and role in age-related disease.Circ Res2018;123:825-48 PMCID:PMC6207260

[24] Seals DR,Donato AJ.Aging and vascular endothelial function in humans.Clin Sci (Lond)2011;120:357-75 PMCID:PMC3482987

[25] Santos-Parker JR,Seals DR.Aerobic exercise and other healthy lifestyle factors that influence vascular aging.Adv Physiol Educ2014;38:296-307 PMCID:PMC4315444

[26] Wenceslau CF,Earley S.Guidelines for the measurement of vascular function and structure in isolated arteries and veins.Am J Physiol Heart Circ Physiol2021;321:H77-H111 PMCID:PMC8321813

[27] Donato AJ,Walker AE.Cellular and molecular biology of aging endothelial cells.J Mol Cell Cardiol2015;89:122-35 PMCID:PMC4522407

[28] Lind L,Larsson A.Endothelial function in resistance and conduit arteries and 5-year risk of cardiovascular disease.Circulation2011;123:1545-51

[29] Taddei S,Virdis A.Physical activity prevents age-related impairment in nitric oxide availability in elderly athletes.Circulation2000;101:2896-901

[30] Yeboah J,Hsu FC,Herrington DM.Brachial flow-mediated dilation predicts incident cardiovascular events in older adults: the Cardiovascular Health Study.Circulation2007;115:2390-7

[31] Yeboah J,Burke GL.Predictive value of brachial flow-mediated dilation for incident cardiovascular events in a population-based study: the multi-ethnic study of atherosclerosis.Circulation2009;120:502-9 PMCID:PMC2740975

[32] Donato AJ,Silver AE.Direct evidence of endothelial oxidative stress with aging in humans: relation to impaired endothelium-dependent dilation and upregulation of nuclear factor-kappaB.Circ Res2007;100:1659-66

[33] Eskurza I,Robinson JA.Effect of acute and chronic ascorbic acid on flow-mediated dilatation with sedentary and physically active human ageing.J Physiol2004;556:315-24 PMCID:PMC1664895

[34] Moreau KL,Plum AE.Ascorbic acid selectively improves large elastic artery compliance in postmenopausal women.Hypertension2005;45:1107-12

[35] Cosentino F,Brand MP.Reactive oxygen species mediate endothelium-dependent relaxations in tetrahydrobiopterin-deficient mice.Arterioscler Thromb Vasc Biol2001;21:496-502

[36] Landmesser U,Price SR.Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension.J Clin Invest2003;111:1201-9 PMCID:PMC152929

[37] Durrant JR,Connell ML.Voluntary wheel running restores endothelial function in conduit arteries of old mice: direct evidence for reduced oxidative stress, increased superoxide dismutase activity and down-regulation of NADPH oxidase.J Physiol2009;587:3271-85 PMCID:PMC2727036

[38] Rossman MJ,Clayton ZS,Seals DR.Targeting mitochondrial fitness as a strategy for healthy vascular aging.Clin Sci (Lond)2020;134:1491-519

[39] Brown KA,Andresen JJ.Effect of aging, MnSOD deficiency, and genetic background on endothelial function: evidence for MnSOD haploinsufficiency.Arterioscler Thromb Vasc Biol2007;27:1941-6

[40] Gioscia-Ryan RA,Sindler AL,Murphy MP.Mitochondria-targeted antioxidant (MitoQ) ameliorates age-related arterial endothelial dysfunction in mice.J Physiol2014;592:2549-61 PMCID:PMC4080937

[41] Wenzel P,Kienhöfer J.Manganese superoxide dismutase and aldehyde dehydrogenase deficiency increase mitochondrial oxidative stress and aggravate age-dependent vascular dysfunction.Cardiovasc Res2008;80:280-9 PMCID:PMC3937602

[42] Lakatta EG.Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part III: cellular and molecular clues to heart and arterial aging.Circulation2003;107:490-7

[43] Lesniewski LA,Connell ML,Donato AJ.Salicylate treatment improves age-associated vascular endothelial dysfunction: potential role of nuclear factor kappaB and forkhead Box O phosphorylation.J Gerontol A Biol Sci Med Sci2011;66:409-18 PMCID:PMC3055281

[44] Walker AE,Pierce GL,Seals DR.Prevention of age-related endothelial dysfunction by habitual aerobic exercise in healthy humans: possible role of nuclear factor κB.Clin Sci (Lond)2014;127:645-54 PMCID:PMC4408779

[45] Pierce GL,Lawson BR,Seals DR.Nuclear factor-{kappa}B activation contributes to vascular endothelial dysfunction via oxidative stress in overweight/obese middle-aged and older humans.Circulation2009;119:1284-92 PMCID:PMC2810548

[46] Jo EK,Shin DM.Molecular mechanisms regulating NLRP3 inflammasome activation.Cell Mol Immunol2016;13:148-59 PMCID:PMC4786634

[47] Mitchell GF.Effects of central arterial aging on the structure and function of the peripheral vasculature: implications for end-organ damage.J Appl Physiol (1985)2008;105:1652-60 PMCID:PMC2584844

[48] Seals DR.Edward F. Adolph distinguished lecture: the remarkable anti-aging effects of aerobic exercise on systemic arteries.J Appl Physiol (1985)2014;117:425-39

[49] Mitchell GF.Arterial stiffness and hypertension: chicken or egg?.Hypertension2014;64:210-4

[50] Franklin SS.Ageing and hypertension: the assessment of blood pressure indices in predicting coronary heart disease.J Hypertens Suppl1999;17:S29-36

[51] Chirinos JA,Hughes T.Large-artery stiffness in health and disease: JACC state-of-the-art review.J Am Coll Cardiol2019;74:1237-63 PMCID:PMC6719727

[52] Townsend RR,Schiffrin EL.Recommendations for improving and standardizing vascular research on arterial stiffness: a scientific statement from the American Heart Association.Hypertension2015;66:698-722 PMCID:PMC4587661

[53] Clayton ZS,Brunt VE.Apigenin restores endothelial function by ameliorating oxidative stress, reverses aortic stiffening, and mitigates vascular inflammation with aging.Am J Physiol Heart Circ Physiol2021;321:H185-96 PMCID:PMC8321807

[54] Gioscia-Ryan RA,Zigler MC.Lifelong voluntary aerobic exercise prevents age- and Western diet- induced vascular dysfunction, mitochondrial oxidative stress and inflammation in mice.J Physiol2021;599:911-25 PMCID:PMC7856030

[55] Mitchell GF,Vasan RS.Arterial stiffness and cardiovascular events: the Framingham Heart Study.Circulation2010;121:505-11 PMCID:PMC2836717

[56] Hughes TM,Lopez OL.Review of “the potential role of arterial stiffness in the pathogenesis of Alzheimer's disease”.Neurodegener Dis Manag2015;5:121-35 PMCID:PMC4423756

[57] Vasan RS,Xanthakis V.Arterial stiffness and long-term risk of health outcomes: the framingham heart study.Hypertension2022;79:1045-56 PMCID:PMC9009137

[58] Scuteri A,Gianni W,Volpe M.Arterial stiffness is an independent risk factor for cognitive impairment in the elderly: a pilot study.J Hypertens2005;23:1211-6

[59] Waldstein SR,Thayer JF,Scuteri A.Pulse pressure and pulse wave velocity are related to cognitive decline in the Baltimore Longitudinal Study of Aging.Hypertension2008;51:99-104

[60] Liu Q,Cui C.Association of aortic stiffness and cognitive decline: a systematic review and meta-analysis.Front Aging Neurosci2021;13:680205 PMCID:PMC8261283

[61] Matsuda N,Fujiu A,Nitta K.Arterial stiffness in patients with non-diabetic chronic kidney disease (CKD).J Atheroscler Thromb2009;16:57-62

[62] Wang MC,Chen JY.Stepwise increase in arterial stiffness corresponding with the stages of chronic kidney disease.Am J Kidney Dis2005;45:494-501

[63] Townsend RR.Arterial stiffness in CKD: a review.Am J Kidney Dis2019;73:240-7 PMCID:PMC6450550

[64] Zheng M,Chen S.Arterial stiffness preceding diabetes: a longitudinal study.Circ Res2020;127:1491-8

[65] Tian X,Chen S.Hypertension, arterial stiffness, and diabetes: a prospective cohort study.Hypertension2022;79:1487-96 PMCID:PMC9172905

[66] Moreau K.Regular exercise, hormone replacement therapy and the age-related decline in carotid arterial compliance in healthy women.Cardiovasc Res2003;57:861-8

[67] Tanaka H,Monahan KD,DeSouza CA.Aging, habitual exercise, and dynamic arterial compliance.Circulation2000;102:1270-5

[68] van Sloten TT,Laurent S.Carotid stiffness is associated with incident stroke: a systematic review and individual participant data meta-analysis.J Am Coll Cardiol2015;66:2116-25

[69] Fleenor BS.Large elastic artery stiffness with aging: novel translational mechanisms and interventions.Aging Dis2013;4:76-83 PMCID:PMC3659253

[70] Lakatta EG.Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part II: the aging heart in health: links to heart disease.Circulation2003;107:346-54

[71] Fleenor BS,Zigler ML.Superoxide-lowering therapy with TEMPOL reverses arterial dysfunction with aging in mice.Aging Cell2012;11:269-76 PMCID:PMC3409251

[72] Wilkinson IB,Cockcroft JR.Nitric oxide and the regulation of large artery stiffness: from physiology to pharmacology.Hypertension2004;44:112-6

[73] Lyle AN.Killing Me unsoftly: causes and mechanisms of arterial stiffness.Arterioscler Thromb Vasc Biol2017;37:e1-e11 PMCID:PMC5308873

[74] Okada Y,Shibata S.Relationship between sympathetic baroreflex sensitivity and arterial stiffness in elderly men and women.Hypertension2012;59:98-104 PMCID:PMC3241909

[75] Stauffer BL,DeSouza CA.Endothelin-1, aging and hypertension.Curr Opin Cardiol2008;23:350-5 PMCID:PMC2430763

[76] Qiu H,Sun Z.Short communication: vascular smooth muscle cell stiffness as a mechanism for increased aortic stiffness with aging.Circ Res2010;107:615-9 PMCID:PMC2936100

[77] Miura K,Dyer AR.Relationship of blood pressure to 25-year mortality due to coronary heart disease, cardiovascular diseases, and all causes in young adult men: the Chicago Heart Association Detection Project in Industry.Arch Intern Med2001;161:1501-8

[78] Franco OH,Bonneux L.Blood pressure in adulthood and life expectancy with cardiovascular disease in men and women: life course analysis.Hypertension2005;46:280-6

[79] AlGhatrif M,Morrell CH.Longitudinal trajectories of arterial stiffness and the role of blood pressure: the baltimore longitudinal study of aging.Hypertension2013;62:934-41 PMCID:PMC3880832

[80] Laddu DR,Haring B.Longitudinal physical performance and blood pressure changes in older women: findings form the women’s health initiative.Arch Gerontol Geriatr2022;98:104576 PMCID:PMC8649052

[81] Weber MA,Cheung DG.Hypertension in the aged: a pathophysiologic basis for treatment.Am J Cardiol1989;63:25-32

[82] Guzik TJ.Oxidative stress, inflammation, and vascular aging in hypertension.Hypertension2017;70:660-7

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

[84] Kennedy BK,Brunet A.Geroscience: linking aging to chronic disease.Cell2014;159:709-13 PMCID:PMC4852871

[85] Gems D.The hoverfly and the wasp: a critique of the hallmarks of aging as a paradigm.Ageing Res Rev2021;70:101407 PMCID:PMC7611451

[86] Gioscia-Ryan RA,Cuevas LM,Sindler AL.Voluntary aerobic exercise increases arterial resilience and mitochondrial health with aging in mice.Aging (Albany NY)2016;8:2897-914 PMCID:PMC5191877

[87] Foote K,Yu EPK.Restoring mitochondrial DNA copy number preserves mitochondrial function and delays vascular aging in mice.Aging Cell2018;17:e12773 PMCID:PMC6052475

[88] Pierce GL,LaRocca TJ,Silver AE.Habitually exercising older men do not demonstrate age-associated vascular endothelial oxidative stress.Aging Cell2011;10:1032-7

[89] Gioscia-Ryan RA,Cuevas LM,Murphy MP.Mitochondria-targeted antioxidant therapy with MitoQ ameliorates aortic stiffening in old mice.J Appl Physiol (1985)2018;124:1194-202 PMCID:PMC6008077

[90] LaRocca TJ,Henson GD.Mitochondrial quality control and age-associated arterial stiffening.Exp Gerontol2014;58:78-82 PMCID:PMC4252265

[91] Mizushima N.Autophagy: process and function.Genes Dev2007;21:2861-73

[92] LaRocca TJ,Thorburn A,Pierce GL.Translational evidence that impaired autophagy contributes to arterial ageing.J Physiol2012;590:3305-16 PMCID:PMC3459044

[93] Demaria M,Youssef SA.An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA.Dev Cell2014;31:722-33 PMCID:PMC4349629

[94] Demaria M,Chang J.Cellular senescence promotes adverse effects of chemotherapy and cancer relapse.Cancer Discov2017;7:165-76 PMCID:PMC5296251

[95] Zhang L,Prahalad V,Robbins PD.Targeting cellular senescence with senotherapeutics: senolytics and senomorphics.FEBS J2022;

[96] Hu C,Teng T,Tang QZ.Cellular senescence in cardiovascular diseases: a systematic review.Aging Dis2022;13:103-28 PMCID:PMC8782554

[97] Rossman MJ,Hill SD.Endothelial cell senescence with aging in healthy humans: prevention by habitual exercise and relation to vascular endothelial function.Am J Physiol Heart Circ Physiol2017;313:H890-5 PMCID:PMC5792201

[98] Mahoney S,Rossman M.Late-life treatment with the senolytic ABT-263 reverses aortic stiffening and improves endothelial function with aging.FASEB J2021;35

[99] Venkatasubramanian R,Rossman MJ.Cellular senescence and the associated secretome contribute to age-related vascular dysfunction.FASEB J2022;36:fasebj.2022.36.S1.R2053

[100] Chen C,Ge Y.SIRT1 and aging related signaling pathways.Mech Ageing Dev2020;187:111215

[101] Donato AJ,Lawson BR,Lesniewski LA.SIRT-1 and vascular endothelial dysfunction with ageing in mice and humans.J Physiol2011;589:4545-54 PMCID:PMC3208223

[102] Gano LB,Pasha HM,Sindler AL.The SIRT1 activator SRT1720 reverses vascular endothelial dysfunction, excessive superoxide production, and inflammation with aging in mice.Am J Physiol Heart Circ Physiol2014;307:H1754-63 PMCID:PMC4269699

[103] Zapata-Pérez R,van Karnebeek CDM.NAD⁺ homeostasis in human health and disease.EMBO Mol Med2021;13:e13943 PMCID:PMC8261484

[104] Strømland Ø,Ferrario E,Ziegler M.The balance between NAD⁺ biosynthesis and consumption in ageing.Mech Ageing Dev2021;199:111569

[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] 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

[107] Hall MN.mTOR-what does it do?.Transplant Proc2008;40:S5-8

[108] Lesniewski LA,Walker AE.Dietary rapamycin supplementation reverses age-related vascular dysfunction and oxidative stress, while modulating nutrient-sensing, cell cycle, and senescence pathways.Aging Cell2017;16:17-26 PMCID:PMC5242306

[109] Salminen A.AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network.Ageing Res Rev2012;11:230-41

[110] Lesniewski LA,Durrant JR,Seals DR.Sustained activation of AMPK ameliorates age-associated vascular endothelial dysfunction via a nitric oxide-independent mechanism.Mech Ageing Dev2012;133:368-71 PMCID:PMC3359767

[111] Finerty JC.Parabiosis in physiological studies.Physiol Rev1952;32:277-302

[112] Wright DE,Gulati AP,Weissman IL.Physiological migration of hematopoietic stem and progenitor cells.Science2001;294:1933-6

[113] Loffredo FS,Jay SM.Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy.Cell2013;153:828-39 PMCID:PMC3677132

[114] Villeda SA,Mosher KI.The ageing systemic milieu negatively regulates neurogenesis and cognitive function.Nature2011;477:90-4 PMCID:PMC3170097

[115] Kiss T,Csipo T.Circulating anti-geronic factors from heterochonic parabionts promote vascular rejuvenation in aged mice: transcriptional footprint of mitochondrial protection, attenuation of oxidative stress, and rescue of endothelial function by young blood.Geroscience2020;42:727-48 PMCID:PMC7205954

[116] Santos-Parker JR,McQueen MB,Seals DR.Habitual aerobic exercise and circulating proteomic patterns in healthy adults: relation to indicators of healthspan.J Appl Physiol (1985)2018;125:1646-59 PMCID:PMC6295489

[117] Johnson LC,Aguirre BF.The plasma metabolome as a predictor of biological aging in humans.Geroscience2019;41:895-906 PMCID:PMC6925078

[118] Johnson LC,Santos-Parker JR.Amino acid and lipid associated plasma metabolomic patterns are related to healthspan indicators with ageing.Clin Sci (Lond)2018;132:1765-77

[119] DeVan AE,Brooks FA.Effects of sodium nitrite supplementation on vascular function and related small metabolite signatures in middle-aged and older adults.J Appl Physiol (1985)2016;120:416-25 PMCID:PMC4754621

[120] Ballak DB,Sapinsley ZJ.Short-term interleukin-37 treatment improves vascular endothelial function, endurance exercise capacity, and whole-body glucose metabolism in old mice.Aging Cell2020;19:e13074 PMCID:PMC6974720

[121] Rossman MJ,Santos-Parker JR.Inorganic nitrite supplementation improves endothelial function with aging: translational evidence for suppression of mitochondria-derived oxidative stress.Hypertension2021;77:1212-22 PMCID:PMC7946806

[122] Craighead DH,Freeberg KA.Time-efficient inspiratory muscle strength training lowers blood pressure and improves endothelial function, no bioavailability, and oxidative stress in midlife/older adults with above-normal blood pressure.J Am Heart Assoc2021;10:e020980 PMCID:PMC8403283

[123] McCarthy CG,Goulopoulou S.Circulating mitochondrial DNA and Toll-like receptor 9 are associated with vascular dysfunction in spontaneously hypertensive rats.Cardiovasc Res2015;107:119-30 PMCID:PMC4560046

[124] Zhou SS,Wang JQ.miRNAS in cardiovascular diseases: potential biomarkers, therapeutic targets and challenges.Acta Pharmacol Sin2018;39:1073-84 PMCID:PMC6289363

[125] Li M,Li Y.Long noncoding RNA/circular noncoding RNA-miRNA-mRNA axes in cardiovascular diseases.Life Sci2019;233:116440

[126] Negishi K,Shimpo M,Kario K.Growth differentiation Factor-15 predicts death and stroke event in outpatients with cardiovascular risk factors: the j-hop study.J Am Heart Assoc2021;10:e022601 PMCID:PMC9075247

[127] Wollert KC,Wallentin L.Growth differentiation factor 15 as a biomarker in cardiovascular disease.Clin Chem2017;63:140-51

[128] Avan A,Ghayour-Mobarhan M,Tajfard M.Serum C-reactive protein in the prediction of cardiovascular diseases: Overview of the latest clinical studies and public health practice.J Cell Physiol2018;233:8508-25

[129] Williams JW,Randolph GJ.Cytokine circuits in cardiovascular disease.Immunity2019;50:941-54 PMCID:PMC6924925

[130] Poznyak AV,Markin AM.Overview of OxLDL and its impact on cardiovascular health: focus on atherosclerosis.Front Pharmacol2020;11:613780 PMCID:PMC7836017

[131] Brunt VE,Casso AG.Trimethylamine-N-oxide promotes age-related vascular oxidative stress and endothelial dysfunction in mice and healthy humans.Hypertension2020;76:101-12 PMCID:PMC7295014

[132] Brunt VE,Gioscia-Ryan RA.Gut microbiome-derived metabolite trimethylamine N-oxide induces aortic stiffening and increases systolic blood pressure with aging in mice and humans.Hypertension2021;78:499-511 PMCID:PMC8266738

[133] Iglesias MJ,Sanchez-Rivera L.Identification of endothelial proteins in plasma associated with cardiovascular risk factors.Arterioscler Thromb Vasc Biol2021;41:2990-3004 PMCID:PMC8608011

[134] Childs BG,van Deursen JM.Senescent cells: a therapeutic target for cardiovascular disease.J Clin Invest2018;128:1217-28 PMCID:PMC5873883

[135] Craighead DH,Hamilton MN.Time-efficient physical training for enhancing cardiovascular function in midlife and older adults: promise and current research gaps.J Appl Physiol (1985)2019;127:1427-40

[136] Seals DR,Rossman MJ.Keynote lecture: strategies for optimal cardiovascular aging.Am J Physiol Heart Circ Physiol2018;315:H183-8 PMCID:PMC6139621

[137] DeSouza CA,Clevenger CM.Regular aerobic exercise prevents and restores age-related declines in endothelium-dependent vasodilation in healthy men.Circulation2000;102:1351-7

[138] Jablonski KL,Fleenor BS.Reduced large elastic artery stiffness with regular aerobic exercise in middle-aged and older adults: potential role of suppressed nuclear factor κ B signalling.J Hypertens2015;33:2477-82 PMCID:PMC4657448

[139] Pierce GL,Walker AE,Seals DR.Sex-specific effects of habitual aerobic exercise on brachial artery flow-mediated dilation in middle-aged and older adults.Clin Sci (Lond)2011;120:13-23 PMCID:PMC3809822

[140] Lesniewski LA,Durrant JR.Aging compounds western diet-associated large artery endothelial dysfunction in mice: prevention by voluntary aerobic exercise.Exp Gerontol2013;48:1218-25 PMCID:PMC3840721

[141] Seals DR,Moreau KL.Aerobic exercise training and vascular function with ageing in healthy men and women.J Physiol2019;597:4901-14 PMCID:PMC6773490

[142] Connelly MT,Platt R.Prevalence and duration of postmenopausal hormone replacement therapy use in a managed care organization, 1990-1995.J Gen Intern Med2000;15:542-50 PMCID:PMC1495583

[143] Moreau KL,Kohrt WM.Essential role of estrogen for improvements in vascular endothelial function with endurance exercise in postmenopausal women.J Clin Endocrinol Metab2013;98:4507-15 PMCID:PMC3816259

[144] Casey DP,Howe KS,Braith RW.Effect of resistance training on arterial wave reflection and brachial artery reactivity in normotensive postmenopausal women.Eur J Appl Physiol2007;100:403-8

[145] Swift DL,Patrie JT.Predictors of improvement in endothelial function after exercise training in a diverse sample of postmenopausal women.J Womens Health (Larchmt)2014;23:260-6 PMCID:PMC3952526

[146] Santos-Parker JR,Vorwald VM,Seals DR.Habitual aerobic exercise does not protect against micro- or macrovascular endothelial dysfunction in healthy estrogen-deficient postmenopausal women.J Appl Physiol (1985)2017;122:11-9

[147] Brooks HL,Hoyer PB.The VCD Mouse model of menopause and perimenopause for the study of sex differences in cardiovascular disease and the metabolic syndrome.Physiology (Bethesda)2016;31:250-7 PMCID:PMC5504385

[148] Stice JP,Knowlton AA.Role of aging versus the loss of estrogens in the reduction in vascular function in female rats.Endocrinology2009;150:212-9 PMCID:PMC2630896

[149] Pierce GL.Aortic stiffness in aging and hypertension: prevention and treatment with habitual aerobic exercise.Curr Hypertens Rep2017;19:90

[150] Pierce GL.Initiating life-long aerobic exercise 4-5 days per week before or near age 50 years: is this the 'holy-grail' of preventing age-related central artery stiffness?.J Physiol2018;596:2635-6 PMCID:PMC6046078

[151] Laurent P,Castagna O,Blacher J.Differences in central systolic blood pressure and aortic stiffness between aerobically trained and sedentary individuals.J Am Soc Hypertens2011;5:85-93

[152] Vlachopoulos C,Stefanadis C.Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis.J Am Coll Cardiol2010;55:1318-27

[153] Tanaka H,Seals DR.Absence of age-related increase in central arterial stiffness in physically active women.Arterioscler Thromb Vasc Biol1998;18:127-32

[154] Matsubara T,Akazawa N.Aerobic exercise training increases plasma Klotho levels and reduces arterial stiffness in postmenopausal women.Am J Physiol Heart Circ Physiol2014;306:H348-55

[155] Tanahashi K,Miyaki A.Aerobic exercise training decreases plasma asymmetric dimethylarginine concentrations with increase in arterial compliance in postmenopausal women.Am J Hypertens2014;27:415-21

[156] Shibata S,Hastings JL.The effect of lifelong exercise frequency on arterial stiffness.J Physiol2018;596:2783-95 PMCID:PMC6046080

[157] Gioscia-Ryan RA,Fleenor BS.Late-life voluntary wheel running reverses age-related aortic stiffness in mice: a translational model for studying mechanisms of exercise-mediated arterial de-stiffening.Geroscience2021;43:423-32 PMCID:PMC8050175

[158] Whelton SP,Xin X.Effect of aerobic exercise on blood pressure: a meta-analysis of randomized, controlled trials.Ann Intern Med2002;136:493-503

[159] Whelton PK,Aronow WS.2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the american college of cardiology/american heart association task force on clinical practice guidelines.Circulation2018;138:e426-83

[160] Chodzko-Zajko WJ,Fiatarone Singh MA.American college of sports medicine position stand. exercise and physical activity for older adults.Med Sci Sports Exerc2009;41:1510-30

[161] Piercy KL,Ballard RM.The Physical activity guidelines for americans.JAMA2018;320:2020-8

[162] Miyachi M,Yamamoto K.Greater age-related reductions in central arterial compliance in resistance-trained men.Hypertension2003;41:130-5

[163] Nascimento Dda C,Benik FM.Sustained effect of resistance training on blood pressure and hand grip strength following a detraining period in elderly hypertensive women: a pilot study.Clin Interv Aging2014;9:219-25 PMCID:PMC3901741

[164] Cook JN,Schleifer JL,Cortez-Cooper MY.Arterial compliance of rowers: implications for combined aerobic and strength training on arterial elasticity.Am J Physiol Heart Circ Physiol2006;290:H1596-600

[165] Shiotsu Y,Tujii S.Effect of exercise order of combined aerobic and resistance training on arterial stiffness in older men.Exp Gerontol2018;111:27-34

[166] Silva JKTNF,Parmenter BJ,Farah BQ.Effects of resistance training on endothelial function: A systematic review and meta-analysis.Atherosclerosis2021;333:91-9

[167] Ansari W, Lovell G. Barriers to exercise in younger and older non-exercising adult women: a cross sectional study in London, United Kingdom.Int J Environ Res Public Health2009;6:1443-55 PMCID:PMC2681199

[168] Islam H,Little JP.Exercise snacks: a novel strategy to improve cardiometabolic health.Exerc Sport Sci Rev2022;50:31-7

[169] Stamatakis E,Maher C.Untapping the Health enhancing potential of vigorous intermittent lifestyle physical activity (vilpa): rationale, scoping review, and a 4-pillar research framework.Sports Med2021;51:1-10 PMCID:PMC7806564

[170] Craighead DH,McCarty NP.Time-efficient, high-resistance inspiratory muscle strength training for cardiovascular aging.Exp Gerontol2021;154:111515 PMCID:PMC9150656

[171] Craighead DH,Maurer GS,Seals DR.Translational potential of high-resistance inspiratory muscle strength training.Exerc Sport Sci Rev2022;50:107-17 PMCID:PMC9203907

[172] Tavoian D,Craighead DH.Six months of inspiratory muscle training to lower blood pressure and improve endothelial function in middle-aged and older adults with above-normal blood pressure and obstructive sleep apnea: protocol for the chart clinical trial.Front Cardiovasc Med2021;8:760203 PMCID:PMC8652071

[173] Brunt VE.Heat therapy: mechanistic underpinnings and applications to cardiovascular health.J Appl Physiol (1985)2021;130:1684-704 PMCID:PMC8285605

[174] Brunt VE,Francisco MA,Minson CT.Passive heat therapy improves cutaneous microvascular function in sedentary humans via improved nitric oxide-dependent dilation.J Appl Physiol (1985)2016;121:716-23 PMCID:PMC6195670

[175] Brunt VE,Francisco MA,Minson CT.Passive heat therapy improves endothelial function, arterial stiffness and blood pressure in sedentary humans.J Physiol2016;594:5329-42 PMCID:PMC5023696

[176] Brunt VE,Comrada LN.Passive heat therapy protects against endothelial cell hypoxia-reoxygenation via effects of elevations in temperature and circulating factors.J Physiol2018;596:4831-45 PMCID:PMC6187037

[177] Brunt VE,Bazzoni AE.Passive heat therapy lowers systolic blood pressure and improves vascular endothelial function in healthy older adults.FASEB J2019;33

[178] Brunt VE,Comrada LN,Eymann TM.Serum from young, sedentary adults who underwent passive heat therapy improves endothelial cell angiogenesis via improved nitric oxide bioavailability.Temperature (Austin)2019;6:169-78 PMCID:PMC6601412

[179] Ely BR,Halliwill JR.Heat therapy reduces sympathetic activity and improves cardiovascular risk profile in women who are obese with polycystic ovary syndrome.Am J Physiol Regul Integr Comp Physiol2019;317:R630-40 PMCID:PMC8424543

[180] Akasaki Y,Eto H.Repeated thermal therapy up-regulates endothelial nitric oxide synthase and augments angiogenesis in a mouse model of hindlimb ischemia.Circ J2006;70:463-70

[181] Weiss EP.Caloric restriction: powerful protection for the aging heart and vasculature.Am J Physiol Heart Circ Physiol2011;301:H1205-19 PMCID:PMC3197347

[182] Rippe C,Connell M,Donato A.Short-term calorie restriction reverses vascular endothelial dysfunction in old mice by increasing nitric oxide and reducing oxidative stress.Aging Cell2010;9:304-12 PMCID:PMC2894368

[183] Donato AJ,Magerko KA.Life-long caloric restriction reduces oxidative stress and preserves nitric oxide bioavailability and function in arteries of old mice.Aging Cell2013;12:772-83 PMCID:PMC3772986

[184] Wohlgemuth SE,Akin DE.Autophagy in the heart and liver during normal aging and calorie restriction.Rejuvenation Res2007;10:281-92

[185] Pierce GL,Lawson BR.Weight loss alone improves conduit and resistance artery endothelial function in young and older overweight/obese adults.Hypertension2008;52:72-9 PMCID:PMC2913284

[186] Dengo AL,Orr JS.Arterial destiffening with weight loss in overweight and obese middle-aged and older adults.Hypertension2010;55:855-61 PMCID:PMC2859827

[187] Brinkley TE,Bailey MJ.Effects of exercise and weight loss on proximal aortic stiffness in older adults with obesity.Circulation2021;144:684-93 PMCID:PMC8405553

[188] Villareal DT,Das SK.Effect of two-year caloric restriction on bone metabolism and bone mineral density in non-obese younger adults: a randomized clinical trial.J Bone Miner Res2016;31:40-51 PMCID:PMC4834845

[189] Miller SL.The danger of weight loss in the elderly.J Nutr Health Aging2008;12:487-91

[190] Martens CR.Practical alternatives to chronic caloric restriction for optimizing vascular function with ageing.J Physiol2016;594:7177-95 PMCID:PMC5157076

[191] Martens CR,Mazzo MR.Short-term time-restricted feeding is safe and feasible in non-obese healthy midlife and older adults.Geroscience2020;42:667-86 PMCID:PMC7206473

[192] Lowe DA,Rohdin-Bibby L.Effects of Time-restricted eating on weight loss and other metabolic parameters in women and men with overweight and obesity: the treat randomized clinical trial.JAMA Intern Med2020;180:1491-9 PMCID:PMC7522780

[193] Liu D,Huang C.Calorie restriction with or without time-restricted eating in weight loss.N Engl J Med2022;386:1495-504

[194] Kitada M,Monno I,Koya D.Effect of methionine restriction on aging: its relationship to oxidative stress.Biomedicines2021;9:130 PMCID:PMC7911310

[195] Simpson SJ,Raubenheimer D.Dietary protein, aging and nutritional geometry.Ageing Res Rev2017;39:78-86

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

[197] Newman JC,Zhao M.Ketogenic diet reduces midlife mortality and improves memory in aging mice.Cell Metab2017;26:547-557.e8 PMCID:PMC5605815

[198] O'Donnell M,Yusuf S.Sodium intake and cardiovascular health.Circ Res2015;116:1046-57

[199] Sacks FM,Vollmer WM.Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group.N Engl J Med2001;344:3-10

[200] Boegehold MA.Effect of dietary salt on arteriolar nitric oxide in striated muscle of normotensive rats.Am J Physiol1993;264:H1810-6

[201] Nurkiewicz TR.High salt intake reduces endothelium-dependent dilation of mouse arterioles via superoxide anion generated from nitric oxide synthase.Am J Physiol Regul Integr Comp Physiol2007;292:R1550-6

[202] Jablonski KL,Pierce GL.Low dietary sodium intake is associated with enhanced vascular endothelial function in middle-aged and older adults with elevated systolic blood pressure.Ther Adv Cardiovasc Dis2009;3:347-56 PMCID:PMC3480332

[203] Vaudin A,Moshfegh AJ.Sodium and potassium intake, the sodium to potassium ratio, and associated characteristics in older adults, NHANES 2011-2016.J Acad Nutr Diet2022;122:64-77

[204] Jablonski KL,Geolfos CJ.Dietary sodium restriction reverses vascular endothelial dysfunction in middle-aged/older adults with moderately elevated systolic blood pressure.J Am Coll Cardiol2013;61:335-43 PMCID:PMC3549053

[205] Jablonski KL,Racine ML.Dietary sodium restriction and association with urinary marinobufagenin, blood pressure, and aortic stiffness.Clin J Am Soc Nephrol2013;8:1952-9 PMCID:PMC3817896

[206] Gates PE,Hiatt WR.Dietary sodium restriction rapidly improves large elastic artery compliance in older adults with systolic hypertension.Hypertension2004;44:35-41

[207] Kidambi S,Yang C.Dietary Sodium restriction results in tissue-specific changes in DNA methylation in humans.Hypertension2021;78:434-46 PMCID:PMC9299531

[208] Maddock J,Ambrosini GL,Hardy R.Adherence to a Dietary Approaches to Stop Hypertension (DASH)-type diet over the life course and associated vascular function: a study based on the MRC 1946 British birth cohort.Br J Nutr2018;119:581-9 PMCID:PMC5848753

[209] Hodson L,Roberts R,Frayn KN.Does the DASH diet lower blood pressure by altering peripheral vascular function?.J Hum Hypertens2010;24:312-9

[210] Couch SC,Khoury PR.Dietary approaches to stop hypertension dietary intervention improves blood pressure and vascular health in youth with elevated blood pressure.Hypertension2021;77:241-51 PMCID:PMC7725858

[211] Torres-Peña JD,Alcala-Diaz JF,Delgado-Lista J.Mediterranean Diet and endothelial function: a review of its effects at different vascular bed levels.Nutrients2020;12:2212 PMCID:PMC7469011

[212] Jennings A,de Groot LCPGM.Mediterranean-style diet improves systolic blood pressure and arterial stiffness in older adults.Hypertension2019;73:578-86 PMCID:PMC6380440

[213] Estruch R,Salas-Salvadó J.Primary prevention of cardiovascular disease with a Mediterranean diet.N Engl J Med2013;368:1279-90

[214] Park Y,Hollenbeck A.Dietary fiber intake and mortality in the NIH-AARP diet and health study.Arch Intern Med2011;171:1061-8 PMCID:PMC3513325

[215] Todd S,Tunstall-Pedoe H.Dietary antioxidant vitamins and fiber in the etiology of cardiovascular disease and all-causes mortality: results from the Scottish Heart Health Study.Am J Epidemiol1999;150:1073-80

[216] Streppel MT,Boshuizen HC,Kromhout D.Dietary fiber intake in relation to coronary heart disease and all-cause mortality over 40 y: the zutphen study.Am J Clin Nutr2008;88:1119-25

[217] Lubin F,Chetrit A.Lifestyle and ethnicity play a role in all-cause mortality.J Nutr2003;133:1180-5

[218] Grooms KN,Pham DQ,Clark CR.Dietary fiber intake and cardiometabolic risks among US adults, NHANES 1999-2010.Am J Med2013;126:1059-67.e1 PMCID:PMC3865784

[219] Casso AG,Lubieniecki KL.Consumption of a high-fiber diet improves systolic blood pressure and vascular endothelial function and may reduce oxidative stress in middle-aged to older adults.FASEB J2022;36:fasebj.2022.36.S1.R4104

[220] Seals DR,LaRocca TJ.Physiological geroscience: targeting function to increase healthspan and achieve optimal longevity.J Physiol2016;594:2001-24 PMCID:PMC4933122

[221] Mozaffarian D,Van Horn L.Components of a cardioprotective diet: new insights.Circulation2011;123:2870-91 PMCID:PMC6261290

[222] Hayashi K,Sato K,Dohi Y.Temocapril, an Angiotensin converting enzyme inhibitor, ameliorates age-related increase in carotid arterial stiffness in normotensive subjects.Cardiology2006;106:190-4

[223] Zuchi C,Lüscher TF.Nutraceuticals in cardiovascular prevention: lessons from studies on endothelial function.Cardiovasc Ther2010;28:187-201

[224] Gates PE,Silver AE,Seals DR.Impaired flow-mediated dilation with age is not explained by L-arginine bioavailability or endothelial asymmetric dimethylarginine protein expression.J Appl Physiol (1985)2007;102:63-71

[225] Sindler AL,Fleenor BS.Inorganic nitrite supplementation for healthy arterial aging.J Appl Physiol (1985)2014;116:463-77 PMCID:PMC3949212

[226] Sindler AL,Calvert JW.Nitrite supplementation reverses vascular endothelial dysfunction and large elastic artery stiffness with aging.Aging Cell2011;10:429-37 PMCID:PMC3094511

[227] Fleenor BS,Eng JS,Dodson RB.Sodium nitrite de-stiffening of large elastic arteries with aging: role of normalization of advanced glycation end-products.Exp Gerontol2012;47:588-94 PMCID:PMC3389216

[228] Jankowski J,Fliser D,Marx N.Cardiovascular disease in chronic kidney disease: pathophysiological insights and therapeutic options.Circulation2021;143:1157-72 PMCID:PMC7969169

[229] Rossman MJ,Steward CAC.Chronic supplementation with a mitochondrial antioxidant (MitoQ) improves vascular function in healthy older adults.Hypertension2018;71:1056-63 PMCID:PMC5945293

[230] Kaplon RE,Bispham NZ.Oral trehalose supplementation improves resistance artery endothelial function in healthy middle-aged and older adults.Aging (Albany NY)2016;8:1167-83 PMCID:PMC4931825

[231] LaRocca TJ,Hearon CM Jr.The autophagy enhancer spermidine reverses arterial aging.Mech Ageing Dev2013;134:314-20 PMCID:PMC3700669

[232] Eisenberg T,Schroeder S.Cardioprotection and lifespan extension by the natural polyamine spermidine.Nat Med2016;22:1428-38 PMCID:PMC5806691

[233] Schwarz C,Wirth M.Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline.Aging (Albany NY)2018;10:19-33 PMCID:PMC5807086

[234] Fleenor BS,Marvi NK.Curcumin ameliorates arterial dysfunction and oxidative stress with aging.Exp Gerontol2013;48:269-76 PMCID:PMC3557759

[235] Santos-Parker JR,Bassett CJ,Chonchol MB.Curcumin supplementation improves vascular endothelial function in healthy middle-aged and older adults by increasing nitric oxide bioavailability and reducing oxidative stress.Aging (Albany NY)2017;9:187-208 PMCID:PMC5310664

[236] Nowak KL,Wang W.Curcumin therapy to treat vascular dysfunction in children and young adults with adpkd: a randomized controlled trial.Clin J Am Soc Nephrol2022;17:240-50

[237] de Picciotto NE,Johnson LC.Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice.Aging Cell2016;15:522-30 PMCID:PMC4854911

[238] Martens CR,Mazzo MR.Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD⁺ in healthy middle-aged and older adults.Nat Commun2018;9:1286 PMCID:PMC5876407

[239] Freeberg KA,Martens CR,Chonchol M.Nicotinamide riboside supplementation for treating elevated systolic blood pressure and arterial stiffness in midlife and older adults.Front Cardiovasc Med2022;9:881703 PMCID:PMC9127073

[240] Childs BG,Baker DJ.Cellular senescence in aging and age-related disease: from mechanisms to therapy.Nat Med2015;21:1424-35 PMCID:PMC4748967

[241] Roos CM,Palmer AK.Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice.Aging Cell2016;15:973-7

[242] Hickson LJ,Bobart SA.Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease.EBioMedicine2019;47:446-56 PMCID:PMC6796530

[243] Justice JN,Tchkonia T.Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study.EBioMedicine2019;40:554-63 PMCID:PMC6412088

[244] Yousefzadeh MJ,McGowan SJ.Fisetin is a senotherapeutic that extends health and lifespan.EBioMedicine2018;36:18-28 PMCID:PMC6197652

[245] Mahoney SA,Rossman M.Fisetin supplementation improves age-related vascular endothelial function by suppressing cellular senescence and mitochondrial oxidative stress.FASEB J2022;36:fasebj.2022.36.S1.R1931

[246] Xu Q,Li Z.The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice.Nat Metab2021;3:1706-26 PMCID:PMC8688144

[247] Lim JS,Kim HS.Identification of a novel senomorphic agent, avenanthramide C, via the suppression of the senescence-associated secretory phenotype.Mech Ageing Dev2020;192:111355

[248] Wang Y,Liu X.Discovery of piperlongumine as a potential novel lead for the development of senolytic agents.Aging (Albany NY)2016;8:2915-26 PMCID:PMC5191878

[249] Moaddel R,Rodriguez S.Identification of gingerenone A as a novel senolytic compound.PLoS One2022;17:e0266135 PMCID:PMC8963586

[250] Li W,Zhang R,Zhou D.The curcumin analog EF24 is a novel senolytic agent.Aging (Albany NY)2019;11:771-82 PMCID:PMC6366974

[251] Limbad C,McGirr J.Senolysis induced by 25-hydroxycholesterol targets CRYAB in multiple cell types.iScience2022;25:103848 PMCID:PMC8851282

[252] Streed CG Jr,Caceres BA.Assessing and addressing cardiovascular health in people who are transgender and gender diverse: a scientific statement from the american heart association.Circulation2021;144:e136-48 PMCID:PMC8638087

[253] Stachenfeld NS.Precision medicine requires understanding how both sex and gender influence health.Cell2022;185:1619-22

[254] Wissler Gerdes EO,Verdoorn BP.Role of senescence in the chronic health consequences of COVID-19.Transl Res2022;241:96-108 PMCID:PMC8532377

[255] Verdoorn BP,Hanson GJ.Fisetin for COVID-19 in skilled nursing facilities: senolytic trials in the COVID era.J Am Geriatr Soc2021;69:3023-33 PMCID:PMC8447437

[256] Zheng M,Sinclair DA.NAD⁺ in COVID-19 and viral infections.Trends Immunol2022;43:283-95 PMCID:PMC8831132

[257] Zeidler JD,Hogan KA.Implications of the NADase CD38 in COVID pathophysiology.Physiol Rev2022;102:339-41 PMCID:PMC8805734

[258] Clayton ZS,Mahoney SA.Anthracycline chemotherapy-mediated vascular dysfunction as a model of accelerated vascular aging.Aging Cancer2021;2:45-69 PMCID:PMC8240486

[259] Kovacs L,Belin de Chantemèle EJ.HIV, combination antiretroviral therapy, and vascular diseases in men and women.JACC Basic Transl Sci2022;7:410-21 PMCID:PMC9079796

[260] Pase MP,Himali JJ.Aortic Stiffness and the risk of incident mild cognitive impairment and dementia.Stroke2016;47:2256-61 PMCID:PMC4995162