REFERENCES
1. Kovacic JC, Moreno P, Nabel EG, Hachinski V, Fuster V. Cellular senescence, vascular disease, and aging: part 2 of a 2-part review: clinical vascular disease in the elderly. Circulation. 2011;123:1900-10.
2. Heidenreich PA, Trogdon JG, Khavjou OA, et al. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation. 2011;123:933-44.
3. Lutz W, Sanderson W, Scherbov S. The coming acceleration of global population ageing. Nature. 2008;451:716-9.
4. Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part II: the aging heart in health: links to heart disease. Circulation. 2003;107:346-54.
5. Gorbunova V, Seluanov A, Mita P, et al. The role of retrotransposable elements in ageing and age-associated diseases. Nature. 2021;596:43-53.
6. Peverill RE. Changes in left ventricular size, geometry, pump function and left heart pressures during healthy aging. Rev Cardiovasc Med. 2021;22:717.
7. Dai D, Chen T, Johnson SC, Szeto H, Rabinovitch PS. Cardiac aging: from molecular mechanisms to significance in human health and disease. Antioxid Redox Signal. 2012;16:1492-526.
8. Khouri MG, Maurer MS, Rumbarger LEK, King DL. Assessment of age‐related changes in left ventricular structure and function by freehand three‐dimensional echocardiography. Am J Geri Cardiol. 2007;14:118-25.
9. Lopaschuk GD, Folmes CD, Stanley WC. Cardiac energy metabolism in obesity. Circ Res. 2007;101:335-47.
10. Lopaschuk GD, Karwi QG, Tian R, Wende AR, Abel ED. Cardiac energy metabolism in heart failure. Circ Res. 2021;128:1487-513.
11. Benjamin EJ, Muntner P, Alonso A, et al. Heart disease and stroke statistics—2019 update: a report from the American Heart Association. Circulation. 2019;139:e56-528.
13. Lesnefsky EJ, Chen Q, Hoppel CL. Mitochondrial metabolism in aging heart. Circ Res. 2016;118:1593-611.
15. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev. 2005;85:1093-129.
16. Sawada M, Carlson JC. Changes in superoxide radical and lipid peroxide formation in the brain, heart and liver during the lifetime of the rat. Mech Ageing Dev. 1987;41:125-37.
17. Li Y, Ma Y, Song L, et al. SIRT3 deficiency exacerbates p53/Parkin-mediated mitophagy inhibition and promotes mitochondrial dysfunction: implication for aged hearts. Int J Mol Med. 2018;41:3517-26.
18. Kincaid B, Bossy-Wetzel E. Forever young: SIRT3 a shield against mitochondrial meltdown, aging, and neurodegeneration. Front Aging Neurosci. 2013;5:48.
19. Jamieson KL, Keshavarz-Bahaghighat H, Darwesh AM, Sosnowski DK, Seubert JM. Age and sex differences in hearts of soluble epoxide hydrolase null mice. Front Physiol. 2020;11:48.
20. Molina-Riquelme I, Barrientos G, Breitsprecher L, et al. Multiscale mitochondrial cristae remodeling links Opa1 downregulation to reduced OXPHOS capacity in aged hearts. Proc Natl Acad Sci USA. 2025;123:e2508911123.
21. Larsson N. Somatic mitochondrial DNA mutations in mammalian aging. Annu Rev Biochem. 2010;79:683-706.
22. Hu C, Zhang X, Teng T, Ma Z, Tang Q. Cellular senescence in cardiovascular diseases: a systematic review. Aging Dis. 2022;13:103.
23. Chen MS, Lee RT, Garbern JC. Senescence mechanisms and targets in the heart. Cardiovasc Res. 2022;118:1173-87.
24. Viña J, Gomez-cabrera MC, Borras C, et al. Mitochondrial biogenesis in exercise and in ageing. Adv Drug Delivery Rev. 2009;61:1369-74.
25. López-otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153:1194-217.
26. Zhu X, Shen W, Yao K, et al. Fine-tuning of PGC1α expression regulates cardiac function and longevity. Circ Res. 2019;125:707-19.
27. Whitehead N, Gill JF, Brink M, Handschin C. Moderate modulation of cardiac PGC-1α expression partially affects age-associated transcriptional remodeling of the heart. Front Physiol. 2018;9:242.
28. Nàger M, Calvoli M, Larsen KB, Birgisdottir AB. The multifaceted role of autophagy and mitophagy in cardiovascular health and disease. Autophagy Rep. 2025;4:2572511.
29. Billia F, Hauck L, Konecny F, Rao V, Shen J, Mak TW. PTEN-inducible kinase 1 (PINK1)/Park6 is indispensable for normal heart function. Proc Natl Acad Sci USA. 2011;108:9572-7.
30. Ma L, Zhu J, Gao Q, Rebecchi MJ, Wang Q, Liu L. Restoring pharmacologic preconditioning in the aging heart: role of mitophagy/autophagy. J Gerontol Ser A. 2017;72:489-98.
31. Karwi QG, Uddin GM, Ho KL, Lopaschuk GD. Loss of metabolic flexibility in the failing heart. Front Cardiovasc Med. 2018;5:68.
32. Koonen DP, Febbraio M, Bonnet S, et al. CD36 expression contributes to age-induced cardiomyopathy in mice. Circulation. 2007;116:2139-47.
33. Ledee D, Portman MA, Kajimoto M, Isern N, Olson AK. Thyroid hormone reverses aging-induced myocardial fatty acid oxidation defects and improves the response to acutely increased afterload. PLoS ONE. 2013;8:e65532.
34. Sample J, Cleland JG, Seymour AL. Metabolic remodeling in the aging heart. J Mol Cell Cardiol. 2006;40:56-63.
35. Hyyti OM, Ledee D, Ning X, Ge M, Portman MA. Aging impairs myocardial fatty acid and ketone oxidation and modifies cardiac functional and metabolic responses to insulin in mice. Am J Physiol Heart Circ Physiol. 2010;299:H868-75.
36. Kates AM, Herrero P, Dence C, et al. Impact of aging on substrate metabolism by the human heart. J Am Coll Cardiol. 2003;41:293-9.
37. Herrero P, Soto PF, Dence CS, et al. Impact of hormone replacement on myocardial fatty acid metabolism: potential role of estrogen. J Nucl Cardiol. 2005;12:574-81.
38. Barger PM, Kelly DP. Fatty acid utilization in the hypertrophied and failing heart: molecular regulatory mechanisms. Am J Med Sci. 1999;318:36.
39. Lopaschuk GD, Ussher JR, Folmes CDL, Jaswal JS, Stanley WC. Myocardial fatty acid metabolism in health and disease. Physiol Rev. 2010;90:207-58.
40. Coughlin SS, Tefft MC, Rice JC, Gerone JL, Baughman KL. Epidemiology of idiopathic dilated cardiomyopathy in the elderly: pooled results from two case-control studies. Am J Epidemiol. 1996;143:881-8.
41. Dávila-Román VG, Vedala G, Herrero P, et al. Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 2002;40:271-7.
42. Funada J, Betts TR, Hodson L, et al. Substrate utilization by the failing human heart by direct quantification using arterio-venous blood sampling. PLoS ONE. 2009;4:e7533.
43. Chen L, Chen M, Yang X, et al. Energy metabolism in cardiovascular diseases: unlocking the hidden powerhouse of cardiac pathophysiology. Front Endocrinol. 2025;16:1617305.
44. Nakai N, Sato Y, Oshida Y, et al. Effects of aging on the activities of pyruvate dehydrogenase complex and its kinase in rat heart. Life Sci. 1997;60:2309-14.
45. Bhashyam S, Parikh P, Bolukoglu H, et al. Aging is associated with myocardial insulin resistance and mitochondrial dysfunction. Am J Physiol Heart Circ Physiol. 2007;293:H3063-71.
46. Ahiawodzi PD, Buzkova P, Djousse L, Ix JH, Kizer JR, Mukamal KJ. Nonesterified fatty acids and hospitalizations among older adults: the cardiovascular health study. J Gerontol Ser A. 2021;76:1326-32.
47. Jouven X, Charles M, Desnos M, Ducimetière P. Circulating nonesterified fatty acid level as a predictive risk factor for sudden death in the population. Circulation. 2001;104:756-61.
48. Djoussé L, Biggs ML, Ix JH, et al. Nonesterified fatty acids and risk of sudden cardiac death in older adults. Circ Arrhythm Electrophysiol. 2012;5:273-8.
49. Reaven GM. Effect of age and sex on triglyceride metabolism in the rat. J Gerontol. 1978;33:368-71.
50. Houtkooper RH, Argmann C, Houten SM, et al. The metabolic footprint of aging in mice. Sci Rep. 2011;1:134.
51. Wisneski JA, Gertz EW, Neese RA, Mayr M. Myocardial metabolism of free fatty acids. Studies with 14C-labeled substrates in humans. J Clin Investig. 1987;79:359-66.
52. Zhao L, Zou X, Feng Z, et al. Evidence for association of mitochondrial metabolism alteration with lipid accumulation in aging rats. Exp Gerontol. 2014;56:3-12.
53. Van Der Meer RW, Rijzewijk LJ, Diamant M, et al. The ageing male heart: myocardial triglyceride content as independent predictor of diastolic function. Eur Heart J. 2008;29:1516-22.
54. Luiken JJFP, Turcotte LP, Bonen A. Protein-mediated palmitate uptake and expression of fatty acid transport proteins in heart giant vesicles. J Lipid Res. 1999;40:1007-16.
55. Cai Y, Liu H, Song E, et al. Deficiency of telomere-associated repressor activator protein 1 precipitates cardiac aging in mice via p53/PPARα signaling. Theranostics. 2021;11:4710-27.
56. Mcmillin JB, Taffet GE, Taegtmeyer H, Hudson EK, Tate CA. Mitochondrial metabolism and substrate competition in the aging Fischer rat heart. Cardiovasc Res. 1993;27:2222-8.
57. Odiet JA, Boerrigter ME, Wei JY. Carnitine palmitoyl transferase-I activity in the aging mouse heart. Mech Ageing Dev. 1995;79:127-36.
58. Gómez LA, Heath SD, Hagen TM. Acetyl-l-carnitine supplementation reverses the age-related decline in carnitine palmitoyltransferase 1 (CPT1) activity in interfibrillar mitochondria without changing the l-carnitine content in the rat heart. Mech Ageing Dev. 2012;133:99-106.
59. Iemitsu M, Miyauchi T, Maeda S, et al. Aging-induced decrease in the PPAR-α level in hearts is improved by exercise training. Am J Physiol Heart Circ Physiol. 2002;283:H1750-60.
60. Poynter ME, Daynes RA. Peroxisome proliferator-activated receptor α activation modulates cellular redox status, represses nuclear factor-κB signaling, and reduces inflammatory cytokine production in aging. J Biol Chem. 1998;273:32833-41.
61. Watanabe K, Fujii H, Takahashi T, et al. Constitutive regulation of cardiac fatty acid metabolism through peroxisome proliferator-activated receptor α associated with age-dependent cardiac toxicity. J Biol Chem. 2000;275:22293-9.
62. Howroyd P, Swanson C, Dunn C, Cattley RC, Corton JC. Decreased longevity and enhancement of age-dependent lesions in mice lacking the nuclear receptor peroxisome proliferator-activated receptor α (PPARα). Toxicol Pathol. 2004;32:591-9.
63. Son N, Ananthakrishnan R, Yu S, et al. Cardiomyocyte aldose reductase causes heart failure and impairs recovery from ischemia. PLoS ONE. 2012;7:e46549.
64. Thiagarajan D, Ananthakrishnan R, Zhang J, et al. Aldose reductase acts as a selective derepressor of PPARγ and the retinoic acid receptor. Cell Rep. 2016;15:181-96.
65. Drosatos K, Schulze PC. Cardiac lipotoxicity: molecular pathways and therapeutic implications. Curr Heart Fail Rep. 2013;10:109-21.
66. Rodriguez-calvo R, Serrano L, Barroso E, et al. Peroxisome proliferator-activated receptor down-regulation is associated with enhanced ceramide levels in age-associated cardiac hypertrophy. J Gerontol Ser A Biol Sci Med Sci. 2007;62:1326-36.
67. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963;281:785-9.
68. Nyberg M, Jones AM. Matching of O2 utilization and O2 delivery in contracting skeletal muscle in health, aging, and heart failure. Front Physiol. 2022;13:898395.
69. Lakatta EG, Yin FC. Myocardial aging: functional alterations and related cellular mechanisms. Am J Physiol Heart Circ Physiol. 1982;242:H927-41.
70. Abu-Erreish GM, Neely JR, Whitmer JT, Whitman V, Sanadi DR. Fatty acid oxidation by isolated perfused working hearts of aged rats. Am J Physiol Endocrinol Metab. 1977;232:E258.
71. Ji LL, Dillon D, Wu E. Myocardial aging: antioxidant enzyme systems and related biochemical properties. Am J Physiol Regul Integr Comp Physiol. 1991;261:R386-92.
72. Soto PF, Herrero P, Kates AM, et al. Impact of aging on myocardial metabolic response to dobutamine. Am J Physiol Heart Circ Physiol. 2003;285:H2158-64.
73. El Khoudary SR, Aggarwal B, Beckie TM, et al. Menopause transition and cardiovascular disease risk: implications for timing of early prevention: a scientific statement from the American Heart Association. Circulation. 2020;142:25.
74. Goodwin GW, Ahmad F, Doenst T, Taegtmeyer H. Energy provision from glycogen, glucose, and fatty acids on adrenergic stimulation of isolated working rat hearts. Am J Physiol Heart Circ Physiol. 1998;274:H1239-47.
75. Hall JL, Stanley WC, Lopaschuk GD, et al. Impaired pyruvate oxidation but normal glucose uptake in diabetic pig heart during dobutamine-induced work. Am J Physiol Heart Circ Physiol. 1996;271:H2320-9.
77. Faakye A, Harold KM, Matsuzaki S, et al. The effect of enhanced glycolysis on cardiac aging. GeroScience. 2025;47:6455-72.
78. Hall JL, Mazzeo RS, Podolin DA, Cartee GD, Stanley WC. Exercise training does not compensate for age-related decrease in myocardial GLUT-4 content. J Appl Physiol. 1994;76:328-32.
79. Mooradian AD, Chehade JM, Kim J. Age-related changes in thyroid hormone effects on glucose transporter isoforms of rat heart. Life Sci. 1999;65:981-9.
80. Martineau LC, Chadan SG, Parkhouse WS. Age-associated alterations in cardiac and skeletal muscle glucose transporters, insulin and IGF-1 receptors, and PI3-kinase protein contents in the C57BL/6 mouse. Mech Ageing Dev. 1999;106:217-32.
81. Ozaki N, Sato E, Kurokawa T, Ishibashi S. Early changes in the expression of GLUT4 protein in the heart of senescence-accelerated mouse. Mech Ageing Dev. 1996;88:149-58.
82. Luptak I, Yan J, Cui L, Jain M, Liao R, Tian R. Long-term effects of increased glucose entry on mouse hearts during normal aging and ischemic stress. Circulation. 2007;116:901-9.
83. Patel MS, Nemeria NS, Furey W, Jordan F. The pyruvate dehydrogenase complexes: structure-based function and regulation. J Biol Chem. 2014;289:16615-23.
84. Sugden MC, Holness MJ. Interactive regulation of the pyruvate dehydrogenase complex and the carnitine palmitoyltransferase system. FASEB J. 1994;8:54-61.
85. Moreau R, Heath SHD, Doneanu CE, Harris RA, Hagen TM. Age-related compensatory activation of pyruvate dehydrogenase complex in rat heart. Biochem Biophys Res Commun. 2004;325:48-58.
86. Chuffa LG, Seiva FR. Combined effects of age and diet-induced obesity on biochemical parameters and cardiac energy metabolism in rats. Ind J Biochem Biophys. 2013;50:40-7.
87. Puchalska P, Crawford PA. Multi-dimensional roles of Ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab. 2017;25:262-84.
88. Cotter DG, Schugar RC, Crawford PA. Ketone body metabolism and cardiovascular disease. Am J Physiol Heart Circ Physiol. 2013;304:H1060-76.
89. Aubert G, Martin OJ, Horton JL, et al. The failing heart relies on ketone bodies as a fuel. Circulation. 2016;133:698-705.
90. Takahara S, Soni S, Maayah ZH, Ferdaoussi M, Dyck JRB. Ketone therapy for heart failure: current evidence for clinical use. Cardiovasc Res. 2022;118:977-87.
91. Hernandez A, Truckenbrod L, Federico Q, et al. Metabolic switching is impaired by aging and facilitated by ketosis independent of glycogen. Aging. 2020;12:7963-84.
92. Okuda Y, Kawai K, Yamashita K. Age-related change in ketone body metabolism: diminished glucagon effect on ketogenesis in adult rats. Endocrinology. 1987;120:2152-7.
93. Hernandez AR, Hernandez CM, Campos KT, et al. The antiepileptic ketogenic diet alters hippocampal transporter levels and reduces adiposity in aged rats. J Gerontol Ser A. 2018;73:450-8.
94. Eap B, Nomura M, Panda O, et al. Ketone body metabolism declines with age in mice in a sex-dependent manner. bioRxiv. 2022. [Preprint].
95. Niezen S, Connelly MA, Hirsch C, et al. Elevated plasma levels of ketone bodies are associated with all‐cause mortality and incidence of heart failure in older adults: the CHS. J Am Heart Assoc. 2023;12:e029960.
96. Edwards C, Canfield J, Copes N, Rehan M, Lipps D, Bradshaw PC. D-beta-hydroxybutyrate extends lifespan in C. elegans. Aging. 2014;6:621-44.
97. Roberts MN, Wallace MA, Tomilov AA, et al. A ketogenic diet extends longevity and healthspan in adult mice. Cell Metab. 2017;26:539-46.e5.
98. Yu Y, Wang F, Wang J, Zhang D, Zhao X. Ketogenic diet attenuates aging-associated myocardial remodeling and dysfunction in mice. Exp Gerontol. 2020;140:111058.
99. Han Y, Ramprasath T, Zou M. β-hydroxybutyrate and its metabolic effects on age-associated pathology. Exp Mol Med. 2020;52:548-55.
100. Wei S, Schell JR, Chocron ES, et al. Ketogenic diet induces p53-dependent cellular senescence in multiple organs. Sci Adv. 2024;10:eado1463.
101. Greenwell AA, Saed CT, Tabatabaei Dakhili SA, et al. An isoproteic cocoa butter-based ketogenic diet fails to improve glucose homeostasis and promote weight loss in obese mice. Am J Physiol Endocrinol Metab. 2022;323:E8-20.
102. Keller MA, Nakamura M. Ketone catabolism is essential for maintaining normal heart function during aging. bioRxiv. 2025. [Preprint].
103. Lopaschuk GD, Dyck JRB. Ketones and the cardiovascular system. Nat Cardiovasc Res. 2023;2:425-37.
104. Rebrin I, Brégère C, Kamzalov S, Gallaher TK, Sohal RS. Nitration of tryptophan 372 in succinyl-CoA:3-ketoacid CoA transferase during aging in rat heart mitochondria. Biochemistry. 2007;46:10130-44.
105. Huang Y, Zhou M, Sun H, Wang Y. Branched-chain amino acid metabolism in heart disease: an epiphenomenon or a real culprit? Cardiovasc Res. 2011;90:220-3.
106. Harper AE, Miller RH, Block KP. Branched-chain amino acid metabolism. Annu Rev Nutr. 1984;4:409-54.
107. D'antona G, Ragni M, Cardile A, et al. Branched-chain amino acid supplementation promotes survival and supports cardiac and skeletal muscle mitochondrial biogenesis in middle-aged mice. Cell Metab. 2010;12:362-72.
108. Kovalik J, Zhao X, Gao F, et al. Amino acid differences between diabetic older adults and non-diabetic older adults and their associations with cardiovascular function. J Mol Cell Cardiol. 2021;158:63-71.
109. Chaleckis R, Murakami I, Takada J, Kondoh H, Yanagida M. Individual variability in human blood metabolites identifies age-related differences. Proc Natl Acad Sci USA. 2016;113:4252-9.
110. Kouchiwa T, Wada K, Uchiyama M, et al. Age-related changes in serum amino acids concentrations in healthy individuals. Clin Chem Lab Med. 2012;50:861-70.
111. Xia J, Nong Y, Teng J, et al. Unlocking metabolic flexibility in heart failure with preserved ejection fraction: Bridging fundamental mechanisms to clinical innovation. iScience. 2025;28:113471.
112. Alfaras I, Di Germanio C, Bernier M, et al. Pharmacological strategies to retard cardiovascular aging. Circ Res. 2016;118:1626-42.
113. Ye M, Feng S, Xu Z, He W, Liu C, Zhu W. Aging and metabolism in HFpEF: pathophysiology and therapeutic implications. Metabolism. 2026;176:156460.
114. Weiss EP, Fontana L. Caloric restriction: powerful protection for the aging heart and vasculature. Am J Physiol Heart Circ Physiol. 2011;301:H1205-19.
115. Racette SB, Silver RE, Barry VG, et al. Diet quality and nutritional adequacy during a 2-year calorie restriction intervention: the comprehensive assessment of long-term effects of reducing intake of energy 2 trial. Am J Clin Nutr. 2026;123:101182.
116. Ravussin E, Redman LM, Rochon J, et al. A 2-year randomized controlled trial of human caloric restriction: feasibility and effects on predictors of health span and longevity. J Gerontol Ser A. 2015;70:1097-104.
117. Marzetti E, Wohlgemuth SE, Anton SD, Bernabei R, Carter CS, Leeuwenburgh C. Cellular mechanisms of cardioprotection by calorie restriction: state of the science and future perspectives. Clin Geriatr Med. 2009;25:715-32.
118. Lechner K, Scherr J, Lorenz E, et al. Omega-3 fatty acid blood levels are inversely associated with cardiometabolic risk factors in HFpEF patients: the Aldo-DHF randomized controlled trial. Clin Res Cardiol. 2021;111:308-21.
119. Carbone S, Billingsley HE, Canada JM, et al. Unsaturated fatty acids to improve cardiorespiratory fitness in patients with obesity and HFpEF. JACC. 2019;4:563-5.
120. Selvaraj S, Karaj A, Chirinos JA, et al. Crossover trial of exogenous ketones on cardiometabolic endpoints in heart failure with preserved ejection fraction. JACC. 2025;13:102435.
121. Eggebeen J, Kim-Shapiro DB, Haykowsky M, et al. One week of daily dosing with beetroot juice improves submaximal endurance and blood pressure in older patients with heart failure and preserved ejection fraction. JACC. 2016;4:428-37.
122. Brubaker PH, Avis T, Rejeski WJ, Mihalko SE, Tucker WJ, Kitzman DW. Exercise training effects on the relationship of physical function and health-related quality of life among older heart failure patients with preserved ejection fraction. J Cardiopulm Rehabil Prev. 2020;40:427-33.
123. Gary R, Lee SY. Physical function and quality of life in older women with diastolic heart failure: effects of a progressive walking program on sleep patterns. Prog Cardiovasc Nurs. 2007;22:72-80.
124. Lopaschuk GD, Verma S. Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: a state-of-the-art review. JACC. 2020;5:632-44.
125. Verma S, Rawat S, Ho KL, et al. Empagliflozin Increases cardiac energy production in diabetes: novel translational insights into the heart failure benefits of SGLT2 inhibitors. JACC. 2018;3:575-87.
126. Marx N, Husain M, Lehrke M, Verma S, Sattar N. GLP-1 receptor agonists for the reduction of atherosclerotic cardiovascular risk in patients with type 2 diabetes. Circulation. 2022;146:1882-94.
127. Huang J, Kwok AJ, Li JCY, et al. Body-wide multi-omic counteraction of aging with GLP-1R agonism. Cell Metab. 2025;37:2362-80.e8.
128. Martin-montalvo A, Mercken EM, Mitchell SJ, et al. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;4:2192.





