REFERENCES
1. Costantino S, Paneni F, Cosentino F. Ageing, metabolism and cardiovascular disease. J Physiol. 2016;594:2061-73.
2. Ferrucci L, Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol. 2018;15:505-22.
4. Sanfeliu-Redondo D, Gibert-Ramos A, Gracia-Sancho J. Cell senescence in liver diseases: pathological mechanism and theranostic opportunity. Nat Rev Gastroenterol Hepatol. 2024;21:477-92.
5. Abavisani M, Faraji S, Ebadpour N, Karav S, Sahebkar A. Beyond the hayflick limit: how microbes influence cellular aging. Ageing Res Rev. 2025;104:102657.
6. Ajoolabady A, Pratico D, Bahijri S, et al. Hallmarks and mechanisms of cellular senescence in aging and disease. Cell Death Discov. 2025;11:364.
7. Arif M, Matyas C, Mukhopadhyay P, et al. Data-driven transcriptomics analysis identifies PCSK9 as a novel key regulator in liver aging. Geroscience. 2023;45:3059-77.
8. Arif M, Zhang C, Li X, et al. iNetModels 2.0: an interactive visualization and database of multi-omics data. Nucleic Acids Res. 2021;49:W271-6.
9. Tan D, Yang X, Yang J, Fan G, Xiong G. PCSK9 in vascular aging and age-related diseases. Aging Dis. 2025;17:691-711.
10. Csiszar A, Tarantini S, Yabluchanskiy A, Ungvari Z. PCSK9: an emerging player in cardiometabolic aging and its potential as a therapeutic target and biomarker. Geroscience. 2024;46:257-63.
11. Seidah NG, Benjannet S, Wickham L, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci USA. 2003;100:928-33.
12. Abifadel M, Varret M, Rabès JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154-6.
13. Oleaga C, Hay J, Gurcan E, et al. Insights into the kinetics and dynamics of the furin-cleaved form of PCSK9. J Lipid Res. 2021;62:100003.
15. Ferri N, Tibolla G, Pirillo A, et al. Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels. Atherosclerosis. 2012;220:381-6.
16. Wang X, Liu L, Zhai L, Palade P, Wang X, Mehta JL. Direct impact of PCSK9 on SMC senescence and apoptosis: a new focus in cardiovascular diseases. Arterioscler Thromb Vasc Biol. 2024;44:1491-6.
17. Ajoolabady A, Pratico D, Mazidi M, et al. PCSK9 in metabolism and diseases. Metabolism. 2025;163:156064.
18. Cupido AJ, Reeskamp LF, Hingorani AD, et al. Joint genetic inhibition of PCSK9 and CETP and the association with coronary artery disease: a factorial mendelian randomization study. JAMA Cardiol. 2022;7:955-64.
19. Carreras A, Pane LS, Nitsch R, et al. In vivo genome and base editing of a human PCSK9 knock-in hypercholesterolemic mouse model. BMC Biol. 2019;17:4.
20. Nicholls SJ, Puri R, Anderson T, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. JAMA. 2016;316:2373-84.
21. Punch E, Klein J, Diaba-Nuhoho P, Morawietz H, Garelnabi M. Effects of PCSK9 targeting: alleviating oxidation, inflammation, and atherosclerosis. J Am Heart Assoc. 2022;11:e023328.
22. Kong N, Xu Q, Cui W, Feng X, Gao H. PCSK9 inhibitor inclisiran for treating atherosclerosis via regulation of endothelial cell pyroptosis. Ann Transl Med. 2022;10:1205.
23. Liu Y, Zhao Y, Feng P, Jiang H. PCSK9 inhibitor attenuates atherosclerosis by regulating SNHG16/EZH2/TRAF5-mediated VSMC proliferation, migration, and foam cell formation. Cell Biol Int. 2023;47:1267-80.
24. Langsted A, Nordestgaard BG, Benn M, Tybjærg-Hansen A, Kamstrup PR. PCSK9 R46L Loss-of-function mutation reduces lipoprotein(a), LDL cholesterol, and risk of aortic valve stenosis. J Clin Endocrinol Metab. 2016;101:3281-7.
25. Ostadal P, Steg PG, Poulouin Y, et al. Metabolic risk factors and effect of alirocumab on cardiovascular events after acute coronary syndrome: a post-hoc analysis of the ODYSSEY OUTCOMES randomised controlled trial. Lancet Diabetes Endocrinol. 2022;10:330-40.
26. Toulassi IA, Al Saedi UA, Gutlapalli SD, et al. A paradigm shift in the management of atherosclerosis: protective role of sirtuins in atherosclerosis. Cureus. 2021;13:e12735.
27. Chen H, Zhou X, Hu J, et al. Genetic insights into the association of statin and newer nonstatin drug target genes with human longevity: a Mendelian randomization analysis. Lipids Health Dis. 2023;22:220.
28. Gusev E, Sarapultsev A. Atherosclerosis and inflammation: insights from the theory of general pathological processes. Int J Mol Sci. 2023;24:7910.
29. Shin D, Kim S, Lee H, et al. PCSK9 stimulates Syk, PKCδ, and NF-κB, leading to atherosclerosis progression independently of LDL receptor. Nat Commun. 2024;15:2789.
30. Kataoka Y, Harada-Shiba M, Hori M, et al. Circulating furin-cleaved proprotein convertase subtilisin/kexin type 9 concentration predicts future coronary events in Japanese subjects. JACC Asia. 2021;1:360-8.
31. College of Cardiovascular Physicians. Chinese expert consensus on anti-thrombotic therapy for pan-vascular diseases (2023 edition). Cardiol Plus. 2024;9:49-69.
32. Matyas C, Trojnar E, Zhao S, et al. PCSK9, A promising novel target for age-related cardiovascular dysfunction. JACC Basic Transl Sci. 2023;8:1334-53.
33. Qi Z, Hu L, Zhang J, et al. PCSK9 (proprotein convertase subtilisin/Kexin 9) enhances platelet activation, thrombosis, and myocardial infarct expansion by binding to platelet CD36. Circulation. 2021;143:45-61.
34. Abdellatif M, Schmid ST, Fuerlinger A, Kroemer G. Anti-ageing interventions for the treatment of cardiovascular disease. Cardiovasc Res. 2025;121:1524-36.
35. Guo Y, Tang Z, Yan B, et al. PCSK9 (proprotein convertase subtilisin/kexin type 9) triggers vascular smooth muscle cell senescence and apoptosis: implication of its direct role in degenerative vascular disease. Arterioscler, Thromb, Vasc Biol. 2022;42:67-86.
36. Ajoolabady A, Pratico D, Bahijri S, Tuomilehto J, Uversky VN, Ren J. Hallmarks of cellular senescence: biology, mechanisms, regulations. Exp Mol Med. 2025;57:1482-91.
37. Wang Y, Cao S, Wang Z, et al. PCSK9 affects vascular senescence through the SIRT1 pathway. Exp Gerontol. 2025;201:112701.
38. Ungvari Z, Tarantini S, Sorond F, Merkely B, Csiszar A. Mechanisms of vascular aging, a geroscience perspective: JACC focus seminar. J Am Coll Cardiol. 2020;75:931-41.
39. Lee RG, Mazzola AM, Braun MC, et al. Efficacy and safety of an investigational single-course CRISPR base-editing therapy targeting PCSK9 in nonhuman primate and mouse models. Circulation. 2023;147:242-53.
40. Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV. Blood-brain barrier: from physiology to disease and back. Physiol Rev. 2019;99:21-78.
41. Jaafar AK, Techer R, Chemello K, Lambert G, Bourane S. PCSK9 and the nervous system: a no-brainer? J Lipid Res. 2023;64:100426.
42. Montagne A, Barnes SR, Sweeney MD, et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron. 2015;85:296-302.
43. Poirier S, Prat A, Marcinkiewicz E, et al. Implication of the proprotein convertase NARC-1/PCSK9 in the development of the nervous system. J Neurochem. 2006;98:838-50.
44. Papotti B, Adorni MP, Marchi C, et al. PCSK9 affects astrocyte cholesterol metabolism and reduces neuron cholesterol supplying in vitro: potential implications in Alzheimer's disease. Int J Mol Sci. 2022:23.
45. Piao MX, Bai JW, Zhang PF, Zhang YZ. PCSK9 regulates apoptosis in human neuroglioma u251 cells via mitochondrial signaling pathways. Int J Clin Exp Pathol. 2015;8:2787-94.
46. Zhao XS, Wu Q, Peng J, et al. Hyperlipidemia-induced apoptosis of hippocampal neurons in apoE-/- mice may be associated with increased PCSK9 expression. Mol Med Rep. 2017;15:712-8.
47. Vilella A, Bodria M, Papotti B, et al. PCSK9 ablation attenuates Aβ pathology, neuroinflammation and cognitive dysfunctions in 5XFAD mice. Brain Behav Immun. 2024;115:517-34.
48. Papotti B, Palumbo M, Adorni MP, et al. Influence of APOE4 genotype on PCSK9-lipids association in cerebrospinal fluid and serum of patients in the Alzheimer's disease continuum. J Alzheimers Dis. 2024;102:162-72.
49. Halliday MR, Rege SV, Ma Q, et al. Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease. J Cereb Blood Flow Metab. 2016;36:216-27.
50. Courtemanche H, Bigot E, Pichelin M, et al. PCSK9 concentrations in cerebrospinal fluid are not specifically increased in Alzheimer's disease. J Alzheimers Dis. 2018;62:1519-25.
51. Teleanu DM, Niculescu AG, Lungu II, et al. An overview of oxidative stress, neuroinflammation, and neurodegenerative diseases. Int J Mol Sci. 2022;23:5938.
52. Park LM, Pacher P, Lohoff FW. Targeting oxidative stress in neurodegenerative disorders: a novel role for PCSK9 inhibition? ACS Chem Neurosci. 2024;15:2662-4.
53. Rosoff DB, Bell AS, Jung J, Wagner J, Mavromatis LA, Lohoff FW. Mendelian randomization study of PCSK9 and HMG-CoA reductase inhibition and cognitive function. J Am Coll Cardiol. 2022;80:653-62.
54. Huang Q, Zhang Q, Cao B. Causal relationship between PCSK9 inhibitor and common neurodegenerative diseases: A drug target Mendelian randomization study. Brain Behav. 2024;14:e3543.
55. Xia K, Huang N, Wang Y, et al. Shared genetic link and causal inference between blood lipids, lipid-lowering drugs and amyotrophic lateral sclerosis. Neural Regen Res. 2025.
56. Kysenius K, Muggalla P, Mätlik K, Arumäe U, Huttunen HJ. PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling. Cell Mol Life Sci. 2012;69:1903-16.
57. Wang L, Wang Z, Shi J, et al. Inhibition of proprotein convertase subtilisin/kexin type 9 attenuates neuronal apoptosis following focal cerebral ischemia via apolipoprotein E receptor 2 downregulation in hyperlipidemic mice. Int J Mol Med. 2018;42:2098-106.
58. Jahed MR, Habibi SAH, Vaseghi G, Amiri H, Montazeri H, Eshraghi A. Association between plasma PCSK9 levels and lipid profile in patients with Parkinson's disease and comparison with healthy subjects. Curr J Neurol. 2022;21:236-43.
59. Xu X, Pang Y, Fan X. Mitochondria in oxidative stress, inflammation and aging: from mechanisms to therapeutic advances. Signal Transduct Target Ther. 2025;10:190.
60. Li X, Li C, Zhang W, Wang Y, Qian P, Huang H. Inflammation and aging: signaling pathways and intervention therapies. Signal Transduct Target Ther. 2023;8:239.
61. Mohammed S, Thadathil N, Selvarani R, et al. Necroptosis contributes to chronic inflammation and fibrosis in aging liver. Aging Cell. 2021;20:e13512.
62. Ding Z, Liu S, Wang X, et al. PCSK9 regulates expression of scavenger receptors and ox-LDL uptake in macrophages. Cardiovasc Res. 2018;114:1145-53.
63. Ding Z, Liu S, Wang X, et al. Hemodynamic shear stress via ROS modulates PCSK9 expression in human vascular endothelial and smooth muscle cells and along the mouse aorta. Antioxid Redox Signaling. 2015;22:760-71.
64. Xu R, Li T, Luo J, et al. PCSK9 increases vulnerability of carotid plaque by promoting mitochondrial dysfunction and apoptosis of vascular smooth muscle cells. CNS Neurosci Ther. 2024;30:e14640.
65. Barale C, Tempesta G, Melchionda E, et al. PCSK9 expression in vascular smooth muscle cells: role of insulin resistance and high glucose. Int J Mol Sci. 2025;26:1003.
66. Levenson AE, Shah AS, Khoury PR, et al. Obesity and type 2 diabetes are associated with elevated PCSK9 levels in young women. Pediatr Diabetes. 2017;18:755-60.
67. Levenson AE, Wadwa RP, Shah AS, et al. PCSK9 is increased in youth with type 1 diabetes. Diabetes Care. 2017;40:e85-7.
68. Shi J, Zhang W, Niu Y, et al. Association of circulating proprotein convertase subtilisin/kexin type 9 levels and the risk of incident type 2 diabetes in subjects with prediabetes: a population-based cohort study. Cardiovasc Diabetol. 2020;19:209.
69. Shu X, Wu J, Zhang T, et al. Statin-induced geranylgeranyl pyrophosphate depletion promotes PCSK9-dependent adipose insulin resistance. Nutrients. 2022;14:5314.
70. O'Donoghue ML, Giugliano RP, Wiviott SD, et al. Long-term evolocumab in patients with established atherosclerotic cardiovascular disease. Circulation. 2022;146:1109-19.
71. Schmidt AF, Swerdlow DI, Holmes MV, et al. PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study. Lancet Diabetes Endocrinol. 2017;5:97-105.
72. Lotta LA, Sharp SJ, Burgess S, et al. Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: a meta-analysis. JAMA. 2016;316:1383-91.
73. Liu S, Wan J, Wang D, et al. Effect of the PCSK9 R46L genetic variant on plasma insulin and glucose levels, risk of diabetes mellitus and cardiovascular disease: a meta-analysis. Nutr Metab Cardiovasc Dis. 2024;34:1339-51.
74. Da Dalt L, Ruscica M, Bonacina F, et al. PCSK9 deficiency reduces insulin secretion and promotes glucose intolerance: the role of the low-density lipoprotein receptor. Eur Heart J. 2019;40:357-68.
75. Ajoolabady A, Pratico D, Vinciguerra M, Lip GYH, Franceschi C, Ren J. Inflammaging: mechanisms and role in the cardiac and vasculature. Trends Endocrinol Metab. 2023;34:373-87.
76. Franceschi C, Bonafè M, Valensin S, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000;908:244-54.
77. Ajoolabady A, Pratico D, Tang D, Zhou S, Franceschi C, Ren J. Immunosenescence and inflammaging: mechanisms and role in diseases. Ageing Res Rev. 2024;101:102540.
78. Luan C, He Y, Liu W, et al. PCSK9 inhibition interrupts the cross-talk between keratinocytes and macrophages and prevents UVB-induced skin damage. J Biol Chem. 2023;299:104895.
79. Chan WC, Liu L, Bouras E, et al. Associations of blood lipids and LDL cholesterol lowering drug-targets with colorectal cancer risk: a Mendelian randomisation study. Br J Cancer. 2025;132:103-10.
80. Wang L, Li S, Luo H, Lu Q, Yu S. PCSK9 promotes the progression and metastasis of colon cancer cells through regulation of EMT and PI3K/AKT signaling in tumor cells and phenotypic polarization of macrophages. J Exp Clin Cancer Res. 2022;41:303.
81. Martin A, Gerovska D, Arauzo-Bravo MJ, et al. Inhibition of PCSK9 Attenuates liver endothelial cell activation induced by colorectal cancer stem cells during liver metastasis. Cancers. 2025;17:1977.
82. Ungvari Z, Menyhart O, Lehoczki A, Fekete M, Bianchini G, Győrffy B. PCSK9 expression and cancer survival: a prognostic biomarker at the intersection of oncology and geroscience. Geroscience. 2026;48:435-49.
83. Li T, Wu R, Luo KQ. PCSK9 promotes the malignancy of triple-negative breast cancer cells by reducing cholesterol levels at the plasma membrane to activate EGFR and HER3. Adv Sci. 2025;12:e2408514.
84. Liu X, Bao X, Hu M, et al. Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer. Nature. 2020;588:693-8.
85. Xu W, Hu M, Lu X, et al. Inhibition of PCSK9 enhances the anti-hepatocellular carcinoma effects of TCR-T cells and anti-PD-1 immunotherapy. Int J Biol Sci. 2024;20:3942-55.
86. Gulej R, Patai R, Ungvari A, et al. Impacts of systemic milieu on cerebrovascular and brain aging: insights from heterochronic parabiosis, blood exchange, and plasma transfer experiments. Geroscience. 2025;47:6207-376.
87. Ximerakis M, Holton KM, Giadone RM, et al. Heterochronic parabiosis reprograms the mouse brain transcriptome by shifting aging signatures in multiple cell types. Nat Aging. 2023;3:327-45.
88. Kiss T, Tarantini S, Csipo T, et al. 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. Geroscience. 2020;42:727-48.
89. Kiss T, Nyúl-Tóth Á, Gulej R, et al. Old blood from heterochronic parabionts accelerates vascular aging in young mice: transcriptomic signature of pathologic smooth muscle remodeling. Geroscience. 2022;44:953-81.
90. Tang ZH, Peng J, Ren Z, et al. New role of PCSK9 in atherosclerotic inflammation promotion involving the TLR4/NF-κB pathway. Atherosclerosis. 2017;262:113-22.
91. Yan X, Ding JY, Zhang RJ, et al. FSTL1 accelerates nucleus pulposus cell senescence and intervertebral disc degeneration through TLR4/NF-κB pathway. Inflammation. 2024;47:1229-47.
92. Sweeney MD, Sagare AP, Zlokovic BV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. 2018;14:133-50.
93. Zhang G, Chang S, Zhao F, et al. The benefits of PCSK9 inhibitors in patients with acute coronary syndrome: a systematic review and meta-analysis. Emerg Crit Care Med. 2024;4:28-34.
