Altersassoziierte Atherosklerose: Mechanismen der vaskulären Alterung, zelluläre Seneszenz und multimodale Minderung

Narrativer ÜbersichtsartikelEine narrative Übersichtsarbeit ist eine Art wissenschaftlicher Artikel, der die bestehende Forschung zu einem Thema durch die Auswahl und Interpretation von Experten zusammenfasst, anstatt durch eine vorab registrierte, erschöpfende Suche mit formaler Verzerrungsbewertung; im Gegensatz zu einer systematischen Übersichtsarbeit oder Meta-Analyse können ihre Schlussfolgerungen das redaktionelle Urteil der Autoren bei der Auswahl der zu betonenden Studien widerspiegeln.

Zusammenfassung

atherosklerotisch Herz-Kreislauf-ErkrankungHerz-Kreislauf-Erkrankungen sind der Oberbegriff für Probleme mit dem Herzen und den Blutgefäßen, einschließlich Herzinfarkten, Schlaganfällen und verstopften Beinarterien. steigt mit fortschreitendem Alter stark an, aber das chronologische Alter ist keine einzelne kausale Exposition. Diese narrative Übersichtsarbeit untersucht, wie kumulative ApolipoproteinEin Apolipoprotein ist ein Protein, das an ein fetttransportierendes Partikel in Ihrem Blut gebunden ist. Da Fett und Wasser sich nicht mischen, wirken diese Proteine wie eine Hülle, die es dem Fett ermöglicht, sicher durch den Blutkreislauf zu reisen. borhaltig LipoproteinEin Lipoprotein ist ein winziges Paket, das Fett und Cholesterin durch Ihren Blutkreislauf transportiert. Da sich Fett nicht in Wasser löst, benötigt es eine Proteinhülle, um zu reisen. Die Exposition interagiert mit dem altersbedingten Gefäßumbau, ZellseneszenzZelluläre Seneszenz ist ein Zustand, in dem geschädigte Zellen dauerhaft aufhören sich zu teilen, aber metabolisch aktiv bleiben und entzündliche Signale abgeben, die lokale Gewebeschäden begünstigen können; in alternden Arterien häufen sich seneszente Zellen an Plaque-Stellen an und tragen zu einer chronischen, geringgradigen Gefäßentzündung bei., mitochondriale Dysfunktion, gestörte mitochondriale Qualitätskontrolle und klonale Hämatopoese. Die Evidenz wird explizit in randomisierte humanbiologische, humane beobachtende/histologische/genetische sowie präklinische Ebenen unterteilt. Humandaten unterstützen altersassoziierte Umbauprozesse der extrazellulären Matrix, arterielle Versteifung, seneszenzbezogene Phänotypen und klonale Hämatopoese als Beitragfaktoren zum vaskulären Risiko, während mehrere mitochondriale und senotherapeutische Mechanismen überwiegend präklinisch bleiben. Die klinische Linderung bleibt multimodal: randomisierte Evidenz unterstützt lipidsenkendLipidsenkung bedeutet die Reduzierung der schädlichen, ApoB-haltigen Partikel in Ihrem Blut – durch Ernährung, Medikamente oder beides. in SekundärpräventionDie Sekundärprävention behandelt jemanden, der bereits einen Herzinfarkt, Schlaganfall oder Stent hatte, um den nächsten zu verhindern., blood-pressure control in older adults, and selected dietary and anti-inflammatory strategies in defined populations, while dedicated evidence for StatinEin Statin verlangsamt das Enzym, das Ihre Leber zur Bildung von Cholesterin nutzt. Ihre Leber reagiert darauf, indem sie mehr Cholesterin aus Ihrem Blut zieht, und genau daraus ergibt sich der eigentliche Nutzen. initiation in PrimärpräventionPrimäre Prävention ist die Behandlung von Personen, die noch nie einen Herzinfarkt oder Schlaganfall hatten, um das erste Auftreten zu verhindern. beyond age 75 remains limited. SenolyticsSenolytics are a class of drugs or compounds designed to selectively kill senescent cells; they are under investigation as potential anti-aging therapies but have not been tested in human trials for cardiovascular outcomes, and animal studies suggest they may worsen plaque stability in advanced disease., MitophagieMitophagy is the cellular process by which damaged or dysfunctional mitochondria are selectively identified and broken down, serving as a quality-control mechanism; impaired mitophagy has been proposed as a contributor to vascular aging, though the evidence in humans remains largely preclinical. enhancers, and other geroprotective strategies have not demonstrated clinical atherosclerotic outcome benefit in humans. Vaskuläre AlterungDie progressive strukturelle und funktionelle Verschlechterung von Arterien im Laufe der Zeit, gekennzeichnet durch Elastizitätsverlust, erhöhte Steifigkeit und die Ansammlung mikroskopischer Schäden, die die Arterienwände anfälliger für Lipidablagerungen und chronische Entzündungen machen. adds mechanisms to, rather than replaces, cumulative lipoprotein-mediated AtherogeneseAtherogenese ist der schrittweise Prozess der Plaquebildung., and evidence strength varies substantially across the proposed pathways.

Schlüsselwörter AtheroskleroseAtherosklerose ist die Erkrankung, die den meisten Herzinfarkten und vielen Schlaganfällen zugrunde liegt. Cholesterinteilchen bleiben in der Wand einer Arterie stecken, der Körper schickt Immunzellen zur Beseitigung, und über Jahre hinweg verhärtet sich dieses Chaos zu Plaque.; vascular aging; cellular senescence; clonal hematopoiesis; mitochondrial dysfunction; older adults; cardiovascular prevention.

Review approach and evidence grading

This is a narrative rather than a systematische ÜbersichtsarbeitEine systematische Übersichtsarbeit sucht nach jeder Studie zu einer Fragestellung anhand einer zuvor festgelegten Methode und bewertet sie anschließend nach konsistenten Kriterien.. Sources were selected to represent the principal mechanistic and clinical literatures bearing on age-associated atherosclerosis, and quantitative claims were checked against primary publications when available rather than accepted from secondary or review-level citation.

Claims are drawn from three tiers, kept separable throughout: (i) randomized trial evidence in humans; (ii) human observational, histologic, and genetic-epidemiological evidence; and (iii) mechanistic and preclinical evidence in cell and animal models. Tier (iii) findings are labeled preclinical wherever they appear and are not clinically actionable. Human observational associations are not interpreted as establishing causal mediation unless supported by intervention, genetic, or convergent experimental evidence. Evidence-tier labels within tables refer to the sources cited in that row, not to the field generally.

This narrative review involved no original enrollment of human participants or animals and no generation of identifiable participant-level data.

1. Epidemiological kinetics and late-life disease burden

Atherosclerosis is a progressive inflammatory disease of the arterial wall that initiates early in life, and the incidence of clinically manifest atherosclerotic events rises steeply with advancing age [2]. Age-associated changes in the vessel wall — matrix remodeling, senescence, mitochondrial dysfunction and impaired mitochondrial quality control, and clonal hematopoiesis among them — have been implicated in atherogenesis and, in experimental models and human observational studies, in features associated with PlaquePlaque ist die Ansammlung von Cholesterin, Immunzellen, Narbengewebe und Kalzium in einer Arterienwand. vulnerability. This does not establish that the longitudinal rate of human plaque accumulation itself increases non-linearly with chronological age; that proposition has not been demonstrated, and clinically meaningful thresholds for coronary plaque progression remain unsettled.

Age is among the strongest contributors to absolute predicted ASCVD risk in contemporary risk models [32]. This is a statement about weight within risk models, not a demonstration that age outranks cumulative lipid exposure as a causal driver; the two are not commensurable, because age partly integrates exposure time. Fatty streaksA fatty streak is the earliest visible stage of atherosclerosis — a flat yellow smear of cholesterol-filled immune cells just under the artery lining. and diffuse IntimaverdickungIntimal thickening is an early adaptive or pathological increase in the thickness of the innermost layer of an artery (the intima), which can reflect either normal developmental changes or the accumulation of smooth muscle cells, lipids, and inflammatory cells that precede overt plaque formation. It is measurable non-invasively by carotid intima-media thickness ultrasound. develop in adolescence and early adulthood, whereas clinically obstructive, unstable, and calcified LäsionenIn der Kardiologie bezeichnet eine Läsion einen umschriebenen Bereich atherosklerotischer Plaque, der eine Koronararterie verengt und typischerweise durch den Prozentsatz der Lumenobstruktion beschrieben wird, die er verursacht. Der Artikel beschreibt vier Rests Läsionen, deren Gefäßdurchmesser zu gering ist, um nach der Behandlung der kritischsten Läsion einen Stent aufzunehmen. become increasingly prevalent beyond the sixth decade [2].

The contribution of additional age-associated mechanisms may become increasingly relevant across the lifespan [2]. In young and middle-aged adults, atherogenesis requires kumulative ExpositionKumulative Exposition ist die Gesamtmenge an schädlichen Cholesterinpartikeln, denen Ihre Arterien im Laufe Ihres gesamten Lebens ausgesetzt waren – wie hoch, multipliziert mit der Dauer. to apolipoprotein B-containing lipoproteins [6] and is driven importantly by that exposure together with RauchenRauchen schädigt die Innenauskleidung der Blutgefäße, erhöht den Blutdruck, lässt das Blut leichter gerinnen und beschleunigt das Plaque-Wachstum., BlutdruckBlutdruck ist die Kraft, mit der das Blut gegen Ihre Arterienwände drückt. Er wird als zwei Zahlen geschrieben, wie 120/80. Die obere Zahl ist der Druck, wenn sich Ihr Herz zusammenzieht, die untere, wenn es sich entspannt., DiabetesDiabetes ist eine Erkrankung, bei der der Blutzucker zu hoch bleibt, entweder weil der Körper zu wenig Insulin produziert oder weil er auf das produzierte Insulin nicht mehr reagiert., and other causal factors, against a background of relatively intact vascular repair [2]. The relative contribution of these exposures cannot be ranked from the data assembled here. In older adults, the lipid-driven process continues and is superimposed on cell-autonomous vascular senescence, hematopoietic somatic mutation, impaired autophagic quality control, and extracellular-matrix degradation [2]. The distinction is one of added mechanism, not substituted mechanism.

The age bands used in this review — 20-39, 40-59, 60-79, and 80 years and older — are an illustrative organizing framework rather than empirically derived biological thresholds. No inflection point in the mechanisms discussed has been mapped to a specific chronological age in humans; the bands are a device for exposition and correspond broadly to commonly reported surveillance strata.

1.0 What “acceleration” denotes in this review

Because the term is used inconsistently, accelerated atherosclerosis is defined operationally here as atherosclerotic burden, vascular dysfunction, a biological-aging signature, or clinical ASCVD occurring earlier, to a greater degree, or progressing more rapidly than expected for chronological age and measured conventional risk-factor exposure.

These are alternative operational phenotypes of accelerated vascular and atherosclerotic aging rather than manifestations of a single validated construct. They are not interchangeable, are measured by different instruments, and a person may satisfy one and not another. Vascular functional impairment and biological-aging signatures are not measures of atherosclerotic burden; they are grouped here only because the same terminology is applied to them in the literature. Throughout this review, vascular aging denotes age-associated structural and functional change in the ArterieEine Arterie ist ein Blutgefäß, das Blut vom Herzen weg in den Rest des Körpers transportiert. wall irrespective of plaque; atherosclerotic aging denotes the subset of that change bearing on plaque formation or composition; and accelerated atherosclerosis is reserved for the operational phenotypes defined above.

Table 1. Alternative operational phenotypes grouped under “accelerated atherosclerosis.” These are distinct constructs with distinct measurement bases; the table is not a staging system, and no threshold is clinically validated for individual decision-making.

Phänotyp	Typical measurement basis	What an abnormal result establishes	Principal limitation
Excess anatomic burden for age	Coronary artery calcium scoreEin Calcium-Score der Herzkranzgefäße, oder CAC-Score, stammt von einem schnellen CT-Scan, der misst, wie viel verkalkte Plaque sich in den Arterien Ihres Herzens befindet. Keine Kontrastmittel, keine Nadeln, etwa zehn Minuten., carotid plaque area or number, CCTA PlaquevolumenPlaque-Volumen ist die gesamte physische Menge an Plaque in einem Arterienabschnitt, gemessen in Kubikmillimetern.	Burden exceeds an age- and sex-referenced distribution; some reference sets are additionally stratified by race or ethnicity	Percentile position is not a progression rate; reference distributions are cohort-specific
Accelerated structural progression	Serial IMT, serial CAC, serial CCTA plaque volume, primarily in research settings	Change over time exceeds that observed in an appropriate reference population or a prespecified research threshold	Requires two standardized measurements; change may approach or fall below the resolution of an individual examination
Vascular functional impairment	Pulse wave velocityDie Pulswelle misst, wie schnell die Druckwelle jedes Herzschlags durch Ihre Arterien wandert. Steifere Arterien leiten sie schneller weiter., flow-mediated dilation, central pressure augmentation	Arterial stiffening or Endotheliale DysfunktionEndotheliale Dysfunktion liegt vor, wenn diese dünne Auskleidung ihre Aufgabe nicht mehr gut erfüllt. Die Blutgefäße weiten sich nicht richtig und die Barriere wird durchlässiger. exceeding an age reference	Functional measures correlate imperfectly with PlaquebelastungPlaque-Last ist die Gesamtmenge an Plaque in Ihren Arterien, und zwar überall – nicht nur an der schlimmsten Einzelstelle.
Biological-aging signature	Epigenetic and proteomic age estimators, telomere length, senescence markers	A biological-aging estimator indicates greater age-associated molecular change than expected for chronological age	Research measures; no validated treatment threshold
Premature clinical ASCVD	Event occurring at an unusually young age according to the study or guideline definition used	Clinical disease earlier than population expectation	An event is a discrete endpoint, not a rate

1.1 Prevalence and incidence — with attention to case definition

Prevalence figures for “cardiovascular disease” in older adults are routinely quoted without the definitional caveat that drives them. In American Heart Association surveillance, the composite CVD category includes BluthochdruckBluthochdruck ist der medizinische Begriff für hohe Blutdruckwerte.. Using NHANES 2015-2018 data as reported in AHA surveillance, CVD prevalence at ages 60-79 years is 77.5% in males and 75.4% in females, rising to 89.4% and 90.8%, respectively, at age 80 years and older [3]. Narrowing the case definition to koronare HerzkrankheitDie koronare Herzkrankheit ist die Verengung oder Verstopfung der Arterien, die den Herzmuskel mit Blut versorgen, verursacht durch die Anlagerung von atherosklerotischer Plaque; sie ist weltweit die häufigste Ursache für Herzinfarkt und Herztod. in the same data yields substantially lower figures: 22.0% of males and 13.4% of females at ages 60-79, and 33.9% and 21.6% at age 80 and older [3]. Because this review concerns atherosclerosis rather than blood pressure, the coronary heart disease figures are more directly relevant; widely circulated estimates near 86-90% should be understood as hypertension-inclusive.

The 2015-2018 NHANES cycle is used because it provides the sex- and age-stratified comparison required here. More recent surveillance is available in the 2026 Statistical Update [4]. Age-specific rates of first cardiovascular events likewise rise markedly across later decades of life [4]. Absolute rates are sex-, calendar-period-, ascertainment-, and case-definition-specific, so no single set of point estimates is quoted here.

1.2 The “lipid paradox” in the very old

An epidemiological nuance in octogenarians and nonagenarians is attenuation, and sometimes inversion, of traditional risk-factor associations — the so-called Lipid-ParadoxonThe lipid paradox refers to the observation in people in their 80s and 90s that the usual positive association between LDL cholesterol and heart disease weakens or even reverses, an apparent anomaly explained by reverse causation from illness lowering cholesterol, survivorship selection, and competing causes of death rather than any change in LDL's underlying biology., described in early form three decades ago [5] and still debated [34]. Three explanations dominate and are not mutually exclusive: umgekehrte KausalitätUmgekehrte Kausalität liegt vor, wenn der Pfeil in die andere Richtung zeigt – die Krankheit hat die Exposition verursacht, anstatt dass die Exposition die Krankheit verursacht hat. und verwirrendEine Störgröße liegt vor, wenn ein versteckter dritter Faktor zwei ansonsten unverbundene Dinge miteinander verknüpft erscheinen lässt. by illness, because frailty, occult malignancy, chronic infection, HerzinsuffizienzHerzinsuffizienz bedeutet, dass das Herz nicht mehr gut genug pumpt, um den Bedarf des Körpers zu decken. Der Name ist irreführend – er bedeutet nicht, dass das Herz stehen geblieben ist., and protein-energy wasting can lower CholesterinCholesterin ist eine wachsartige Substanz, die Ihr Körper braucht. Es fließt in Zellwände, Hormone, Vitamin D und die Galle ein, die Ihre Nahrung verdaut. Ohne es würden Sie sterben. [5]; survivorship selection, because those most susceptible to LDL-driven atherogenesis may disproportionately have experienced events or died before the ninth decade; and competing risk, because a rising hazard of non-atherosclerotic death changes observed cause-specific and cumulative-incidence relationships.

Attenuation of an observational association in the very old is not evidence against LDLLDL oder Low-Density-Lipoprotein ist das Hauptpartikel, das Cholesterin durch Ihr Blut transportiert – und das Hauptpartikel, das in den Arterienwänden stecken bleibt. causality. Genetic evidence supports LDL causality across the life course, and randomized statin evidence demonstrates reduction in major vascular events among older adults, particularly those with established vascular disease [6,7]. Absolute ASCVD burden remains highest in older adults [3,4], reflecting age-associated vascular remodeling superimposed on decades of lipoprotein exposure [2].

1.3 Risk models and biological thresholds

Contemporary prediction frameworks incorporate age as a continuous covariate and do not specify a discrete biological age threshold. This is a property of model structure rather than a finding about vascular biology: the absence of a threshold term in a prediction equation is not evidence that no biological inflection exists, and a strong age coefficient is not evidence that one does.

Table 2. Age-stratified disease burden and illustrative mechanisms. Prevalence values are drawn from AHA surveillance [3] and are shown only for the strata that source reports directly; an em dash indicates that no directly reported age- and sex-stratified value was available. Age assignments are illustrative and do not indicate biological onset, exclusivity, or a validated staging system.

Age cohort (years)	CVD prevalence, hypertension-inclusive [3]	CHD prevalence [3]	Mechanisms highlighted in this age band (Sec.)	Common ASCVD manifestations
20-39	—	—	Endothelial dysfunction, diffuse intimal thickening, early lipid retention (2.1)	Silent fatty streaks, early lipid-rich lesions
40-59	—	—	The above, plus cumulative ApoBApoB ist ein Protein, das sich auf der Außenseite jedes Cholesterinteilchens befindet, das in Ihrer Arterienwand stecken bleiben und Plaque verursachen kann. Jedes dieser Teilchen trägt genau ein ApoB. exposure, VSMC migration and phenotype switching (1, 2.2)	Stable AnginaAngina is chest discomfort that happens when the heart muscle isn't getting enough oxygen. People describe it as pressure, tightness, squeezing, or burning, and it can spread to the arm, neck, or jaw., akute KoronarsyndromeAkutes Koronarsyndrom (AKS) ist der Oberbegriff für jeden plötzlichen Abfall der Blutversorgung des Herzens – von instabiler Angina pectoris bis hin zu einem vollständigen Herzinfarkt –, der durch das plötzliche Aufreißen oder die Erosion einer Plaque verursacht wird.
60-79	77.5% M / 75.4% F	22.0% M / 13.4% F	The above, plus vascular senescence, stiffening, mitochondrial ROS, VerkalkungVerkalkung tritt auf, wenn sich Kalzium in einer Plaque ablagert, wodurch diese teilweise hart und knöchern wird. (2.1-2.4)	Myocardial infarctionSiehe Herzinfarkt für den vollständigen Eintrag., ischämischer SchlaganfallEin ischämischer Schlaganfall tritt auf, wenn die Blutzufuhr zu einem Teil des Gehirns unterbrochen wird und das Gehirngewebe abstirbt., claudication
80+	89.4% M / 90.8% F	33.9% M / 21.6% F	The above, plus rising CHIP prevalence, cumulative ElastinElastin ist ein Strukturprotein in der Arterienwand, das es den Blutgefäßen ermöglicht, sich bei jedem Herzschlag zu dehnen und wieder zusammenzuziehen; mit zunehmendem Alter baut es sich ab und wird durch steiferes Kollagen ersetzt, was zur Arterienversteifung und einem Anstieg des systolischen Blutdrucks beiträgt. and matrix remodeling, and age-associated impairment of vascular repair (2.5-2.6)	Complex multivessel CAD; ischemic SchlaganfallEin Schlaganfall tritt auf, wenn die Blutversorgung eines Teils des Gehirns unterbrochen wird, entweder durch einen Verschluss oder durch eine Blutung.; peripheral or multiterritory atherosclerotic disease

2. Intrinsic and extrinsic mechanisms of vascular aging

2.1 Extracellular matrix remodeling, glycation, and hemodynamic shear stress

Aging alters the mechanical properties of central elastic arteries, establishing a biophysical feedback loop proposed to promote atherogenesis [8]. Chronic pulsatile stress triggers elastolysis, elastase up-regulation, and fraying of elastin fibrils, with compensatory collagen deposition and cross-linking [8]. Cumulative glycemic exposure contributes to formation and accumulation of advanced glycation end-products (AGEs)AGEs sind Verbindungen, die entstehen, wenn Proteine oder Fette Zucker oder hohen Kochtemperaturen ausgesetzt werden; in bei starker Hitze gegartem Fleisch binden sie an einen Rezeptor namens RAGE auf Blutgefäßzellen, wodurch eine Entzündungskaskade ausgelöst wird. Der Artikel führt sie als eine von mehreren Komponenten von rotem Fleisch auf – neben gesättigten Fetten und Häm-Eisen –, die unabhängig von TMAO die kardiovaskuläre Gesundheit schädigen können. on long-lived structural ProteineProtein ist der Nährstoff, den Ihr Körper zum Aufbau und zur Reparatur von Muskeln und Gewebe verwendet.; these modifications are subject to slow turnover rather than being strictly irreversible [8]. AGE cross-linking of collagen impairs compliance [8], while AGE-RAGE engagement activates endothelial NF-kB signaling and amplifies inflammatory and adhesion-molecule expression [61]. AGE accumulation is one contributor among several to age-related arterial stiffening.

The hemodynamic consequence is stiffening, manifest as rising carotid-femoral pulse wave velocity and central systolic pressure, with diastolic pressure typically falling at the population level after the sixth decade and pulse pressure widening [8].

Regions exposed to low or oscillatory endothelial shear stress (ESS) — the tangential frictional force of flowing blood, expressed in dyn/cm2 — are preferentially atheroprone [9]. Reported physiological and low-ESS ranges vary by vessel, methodology, species, and temporal averaging and should be treated as experimental reference ranges rather than universal thresholds. Values of roughly 15-70 dyn/cm2 have been reported for relatively straight segments under pulsatile unidirectional flow, whereas disturbed-flow regions at bifurcations, curvatures, and outer branch walls may show time-averaged magnitudes below approximately 10-12 dyn/cm2 or oscillatory ESS with a near-zero time average [9]. Low ESS down-regulates eNOS, up-regulates VCAM-1VCAM-1 is a sticky molecule that appears on an inflamed vessel lining and grabs passing white blood cells so they can burrow into the wall. und ICAM-1ICAM-1 is a molecule that appears on the surface of the blood vessel lining and acts like Velcro, catching passing immune cells., and facilitates lipoprotein retention and monocyte transendothelial migration [9].

An aging-specific qualification is important. Aging dilates and stiffens arteries [8], and low-ESS regions are atheroprone [9], but the composite claim that aging enlarges low-ESS territory has not been clearly demonstrated in aging-specific human hemodynamic studies. Age-related geometric and mechanical change may expand low-ESS zones; testing this directly in age-stratified Koronare CT-AngiographieDie Koronar-CT-Angiographie, kurz CCTA, ist eine CT-Untersuchung mit Kontrastmittel in den Venen, die detaillierte Bilder der Herzkranzgefäße liefert. cohorts with computational fluid dynamics would be informative.

2.2 Local renin-angiotensin signaling in the aged arterial wall

Two facts are commonly conflated in secondary literature and are separated here. First, arterial-wall angiotensin II (Ang-II) is locally regulated and can differ substantially from circulating levels [10]. Tissue and plasma measurements are not methodologically equivalent, so this should be understood as compartmental separation rather than as a simple concentration ratio. That separation is present across adult life and is not itself an age-related increase.

Second, multiple components of the local renin-angiotensin system — including angiotensinogen, ACE and chymase activity, Ang-II abundance, and AT1-receptor signaling — have been reported to increase in aged arterial tissue across animal models and human tissue studies, whereas plasma renin activity and circulating Ang-II tend to fall with age [10,11]. The intramural age-associated increase should not be conflated with the tissue-to-plasma compartmental difference.

Local Ang-II acts as a mitogen and pressor agent, driving vascular smooth-muscle cell (VSMC) hypertrophy, synthetic phenotype switching, migration, and Matrix-MetalloproteinaseMatrix metalloproteinases are enzymes that cut through the collagen scaffolding of tissue. Immune cells inside plaques release them. secretion, particularly MMP-2 [10,11].

In 16-year longitudinal follow-up of the Malmö Diet and Cancer cohort, mean common carotid Intima-Media-DickeDie Intima-Media-Dicke, kurz IMT, ist ein Maß dafür, wie dick die inneren Schichten einer Arterie geworden sind, was normalerweise am Hals mittels Ultraschall gemessen wird. progressed at 0.011 mm/year in men and 0.010 mm/year in women, with faster progression at the bifurcation (0.036 and 0.030 mm/year, respectively) [12]. Approximately 0.01 mm/year, or 0.1 mm per decade for the common carotid, is therefore a reasonable summary of these longitudinal data. Cross-sectional age-reference studies report larger between-age differences [8,13], but cross-sectional and longitudinal quantities should not be arithmetically converted into one another. Carotid IMT also incorporates non-atherosclerotic medial hypertrophy and adaptive wall thickening and is therefore a structural readout rather than a direct measure of plaque accumulation.

2.3 Cellular senescence and the senescence-associated secretory phenotype

DNA damage, telomere attrition, and chronic oxidativer StressOxidative stress is an imbalance between damaging reactive molecules and the body's ability to neutralize them. up-regulate the cyclin-dependent kinase inhibitors p16INK4a and p21CIP1/WAF1, producing durable replicative arrest in vascular EndothelzellenThe thin layer of cells lining the inner surface of all blood vessels; they regulate vascular tone, prevent clotting, and control the passage of substances into the artery wall — and their dysfunction is an early, critical step in atherosclerosis. and VSMCs [1,14]. In human atherectomy and endarterectomy specimens, cells displaying senescence-associated beta-galactosidase positivity together with shortened telomeres concentrate at atherosclerotic sites and are largely absent from adjacent non-diseased tissue [14]. Neither marker is individually specific for senescence, so these findings identify a senescence-associated phenotype rather than definitively identifying seneszente ZellenCells that have permanently stopped dividing in response to stress or damage and instead secrete a cocktail of inflammatory cytokines, proteases, and growth factors; in the arterial wall, their accumulation with age drives chronic inflammation and accelerates plaque growth..

Senescent cells develop a pro-inflammatory senescence-associated secretory phenotype (SASP), including secretion of IL-6Interleukin-6 oder IL-6 ist ein Signalmolekül, das das Immunsystem nutzt, um eine entzündliche Botschaft im Körper zu verbreiten., IL-1beta, TNF-alpha, MCP-1/CCL2, and matrix-degrading enzymes such as MMP-2 and MMP-9 [1,15]. Human observational data show senescence-associated markers co-localizing with advanced lesion regions and intraplaque calcification [14-16]. Animal studies show that genetic or pharmacological senescent-cell targeting can reduce SASP-related signaling, matrix degradation, calcification, or vascular dysfunction [15,45]. Fibrous-cap thinning and impaired re-endothelialization are mechanistically coherent consequences, but causal sequences are not established in humans [15].

Senescence in plaque is not uniformly deleterious. VSMCs are essential for fibrous-cap matrix and stability, whereas VSMC senescence impairs proliferative and matrix-producing repair [15]. Accordingly, effects of senescent-cell clearance are stage- and model-dependent. In Ldlr-/- mice, p16-directed genetic clearance reduced plaque burden and increased cap thickness, while NavitoclaxNavitoclax is an experimental senolytic drug that promotes apoptosis in senescent cells; in animal studies of advanced atherosclerosis it reduced the cells maintaining the fibrous cap, leading to thinner caps and increased mortality — an outcome opposite to its intended benefit. reduced aortic plaque burden [57]. In Apoe-/- mice, p16-driven clearance did not reduce plaque burden, cap thickness, or nekrotischer KernDer nekrotische Kern ist das tote, breiige Zentrum einer fortgeschrittenen Plaque, das aus Immunzellen besteht, die eingeschlossenes Cholesterin gefressen haben und dann an Ort und Stelle starben. area and increased apoptotic cells and EntzündungEntzündungen sind die Reaktion Ihres Immunsystems auf eine Verletzung oder etwas, das es als Eindringling behandelt. Sie verursachen Schwellungen, Hitze und Aufräumzellen., while navitoclax reduced lesion size without increasing cap thickness [58]. In Apoe-/- mice with advanced lesions and persistent hyperlipidemia, navitoclax reduced smooth-muscle-derived cells within the faserige KappeDie fibröse Kappe ist die zähe Gewebeschicht, die eine Plaque bedeckt und ihren fettigen Kern vom Blutstrom trennt., decreased cap thickness, and increased mortality [59]. Thus, pharmacological senolysis in advanced experimental atherosclerosis can deplete reparative cap cells and compromise plaque stability, materially qualifying therapeutic inference.

2.4 Mitochondrial dysfunction, mitophagy, and vascular inflammaging

In murine vascular-aging models, aged arterial tissue exhibits declining mtDNA copy number and reduced expression of the copy-number regulators TFAM, PGC-1alpha, and the mtDNA helicase Twinkle [17]. These changes track with reduced mitochondrial respiration, decreased carotid compliance and distensibility, and rising aortic pulse wave velocity [17]. Transgenic Twinkle overexpression increases mtDNA copy number, improves arterial respiration, and delays vascular aging in that model, whereas polymerase-gamma-mutant mice with degraded mtDNA integrity age faster [17]. In ApoE-/- mice, related mitochondrial rescue reduces necrotic-core area and increases relative fibrous-cap thickness [18]. This evidence base is predominantly murine; equivalent longitudinal human vascular Twinkle data do not exist.

Damaged mitochondria are cleared through mitophagy. In the canonical PINK1/Parkin pathway, depolarization stabilizes PINK1 on the outer membrane and recruits Parkin, which ubiquitylates outer-membrane proteins including MFN1, MFN2, and VDAC1 and targets the organelle for autophagic-lysosomal degradation [19]. Parkin-independent pathways also exist.

The relationship between aging and mitophagic flux in the vessel wall is more complicated than a simple decline. In aged murine AortaDie Aorta ist die größte Arterie in Ihrem Körper. Sie transportiert Blut aus dem Herzen heraus und durch die Brust und den Bauch nach unten, wobei sie überall Abzweigungen abgibt., Parkin protein and mitophagy markers are increased alongside elevated IL-6 and impaired respiration, consistent with compensatory or stalled mitophagy responding to a rising burden of damaged organelles rather than simple pathway loss [19]. Increased pathway markers do not establish increased successful flux. Global autophagic capacity declines with age in many tissues, and available data are consistent with clearance becoming insufficient relative to damaged-organelle burden in the aged artery [50]. Persistent damaged mitochondria can generate mitochondrial Reaktive SauerstoffspeziesReactive oxygen species are unstable oxygen-containing molecules produced as a by-product of normal metabolism. and release mitochondrial damage-associated molecular patterns, including unmethylated CpG mtDNA, into the cytosol [19].

Cytosolic mitochondrial damage-associated molecular patterns engage NLRP3-InflammasomThe NLRP3 inflammasome is an intracellular protein complex in immune cells that, when activated by cholesterol crystals, oxidized lipids, or other danger signals within an atherosclerotic plaque, triggers the release of the inflammatory cytokines interleukin-1β and interleukin-6, accelerating plaque growth and instability. and TLR9/MyD88 signaling. In the murine model in which this pathway was demonstrated, this signaling contributes to a feed-forward IL-6-associated inflammatory loop linking mitochondrial dysfunction to increased atherogenesis [19]. An equivalent longitudinal causal sequence has not been demonstrated in humans.

2.5 Clonal hematopoiesis of indeterminate potential (CHIP)

Clonal hematopoiesis of indeterminate potential (CHIP) denotes age-related acquisition of somatic mutations in leukemia-associated driver genes within hematopoietic stem and progenitor cells, traditionally operationalized by detection of a driver mutation at variant allele fraction (VAF) >=2% in the absence of persistent unexplained cytopenia and without a diagnosable hematologic neoplasm [20]. When persistent otherwise unexplained cytopenia coexists with clonality, current classifications designate clonal cytopenia of undetermined significance (CCUS), which carries a different malignant-progression risk [21]. The cardiovascular literature summarized here concerns CHIP, not CCUS. Prevalence rises from <1% below age 40 to approximately 10% among adults older than 70 in early sequencing cohorts, with higher estimates when deep sequencing detects clones below the 2% threshold [20]. The 2% VAF cutoff is an assay and reporting convention, not a biological boundary.

Dominant drivers include DNMT3A, TET2, and ASXL1, with JAK2 V617F less common but functionally distinctive [20,22]. In Tet2-deficient murine MakrophagenEin Makrophage ist eine große Immunzelle, die Zelltrümmer und Eindringlinge umschließt und verschlingt. Der Name bedeutet wörtlich "großer Fresser".", loss of function augments IL-1beta and IL-6 signaling in association with NLRP3NLRP3 is an alarm system inside immune cells. When it detects something it treats as a threat, it triggers a burst of inflammatory signaling. inflammasome activation [23].

Effect sizes require precision. CHIP carriers had approximately 1.9- to 2.0-fold the risk of incident coronary heart disease in nested case-control analyses of the BioImage and Malmö Diet and Cancer cohorts and approximately 4-fold higher odds of early-onset myocardial infarction in ATVB and PROMIS [22]. The often-quoted ~12-fold figure applies specifically to JAK2 V617F carriers in the original cohort estimate, whereas DNMT3A, TET2, and ASXL1 were associated with roughly 1.7- to 2.0-fold risk [22]. It is gene-specific, not clone-size-specific, and should not be restated as “VAF above 10% confers a 12-fold increase.” Larger clones (VAF >=10%) are separately associated with greater cardiovascular and all-cause risk in observational cohorts, and CHIP carriers show higher coronary artery Kalzium-ScoresEin Kalzium-Score (Kalkscore der Herzkranzgefäße) ist ein aus einem CT-Scan abgeleiteter Wert, der die Gesamtmenge an verkalktem Plaque in den Koronararterien quantifiziert; ein Wert von null weist auf kein nachweisbares verkalktes Plaque hin, während höhere Werte eine größere Plaque-Last und ein erhöhtes kardiovaskuläres Risiko widerspiegeln. than noncarriers [20,22].

Biological causality is supported in mice: in hyperlipidemic Ldlr-/- animals, reconstitution with Tet2-deficient bone marrow increases lesion size and necrotic-core burden [23]. These experiments establish that the mechanism can operate, not the magnitude or universality of a causal effect in humans.

In an exploratory genomic substudy of GesängeCANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) was a large randomized trial that tested canakinumab, a drug blocking the inflammatory signal IL-1β, against placebo; at its prespecified 150 mg dose it reduced major cardiovascular events by roughly 15% without lowering LDL cholesterol, providing direct human evidence that inflammation drives heart attacks through a pathway indepen…, 338 sequenced participants (8.6%) carried clonal hematopoiesis; TET2 carriers appeared to derive greater MACE reduction from CanakinumabCanakinumab is a monoclonal antibody that targets interleukin-1β (IL-1β), a key inflammatory signaling protein; it was the active drug in the CANTOS trial, where it reduced cardiovascular events without affecting LDL cholesterol. than noncarriers [24]. This is hypothesis-generating subgroup evidence, not a demonstrated treatment-effect modifier.

Counter-evidence remains important. In a pooled analysis of 63,700 participants from five randomized cardiovascular outcome trials, CHIP carriage was not significantly associated with major cardiovascular events (adjusted HR 1.07, 95% CI 0.99-1.16) [25]. Im PESA-KohortePESA (Progression of Early Subclinical Atherosclerosis) is a Spanish prospective cohort of asymptomatic adults aged 40 to 54 in which multisite vascular imaging detected subclinical atherosclerosis in 63 percent of participants, demonstrating the high burden of silent arterial disease in middle age., baseline clonal hematopoiesis was associated with subsequent de novo femoral atherosclerosis over approximately six years, whereas atherosclerotic burden did not measurably accelerate mutant-clone expansion over the same period [26]. These findings support a predominant direction from clonal hematopoiesis toward atherosclerosis while not excluding reciprocal effects in other settings. CHIP remains biologically compelling and experimentally supported; its independent prognostic value in intensively treated secondary-prevention populations is less certain than community-cohort literature implies.

2.6 Endothelial progenitor cells and proteotoxic stress

Circulating cell populations historically classified as Endotheliale VorläuferzellenBone-marrow-derived precursor cells that circulate in the bloodstream and home to sites of endothelial injury, where they participate in re-endothelialization and microvascular repair; their mobilization is enhanced by statins, aerobic exercise, and whole-food plant-based nutrition. show age-associated reductions in number or function in some assays, but findings depend on assay and surface-marker phenotype [1]. “Endothelial progenitor cell” does not denote a single defined lineage. Many populations given that label are hematopoietic or angiogenic cells rather than bona fide endothelial progenitors, and endothelial colony-forming cells are not equivalent to CD34/KDR flow-cytometric or culture-based assays. The association between reduced progenitor measures and vascular dysfunction in older adults is reasonably consistent; the inference that progenitor failure causes impaired repair is not established.

Experimental and observational evidence also suggests that aging can compromise vascular ProteostaseThe cellular maintenance of a stable, functional protein pool through the coordinated balance of protein synthesis, folding, and degradation pathways including autophagy and the ubiquitin-proteasome system; its impairment with age allows damaged proteins to accumulate and is linked to neurodegeneration and other age-related diseases.: declining ubiquitin-proteasome activity and impaired chaperone function may permit accumulation of misfolded and aggregated proteins in endothelial cells and VSMCs, promoting proteotoxic stress, unfolded-protein responses, and ER-stress-mediated apoptosis [1]. Individual steps are better established in nonvascular tissue than in the human arterial wall, so this sequence is presented as a mechanistic model rather than a demonstrated human pathway.

Table 3. Mechanisms of vascular aging, mediators, and atherosclerosis-related phenotype or effect.

Biological mechanism	Primary molecular mediators	Direct vascular consequence	Atherosclerosis-related phenotype or effect	Evidence tier (as cited)
Matrix degradation and AGE cross-linking [8,9]	Collagen cross-linkingEin biochemischer Prozess, bei dem Kollagenfasern in Arterienwänden stabile chemische Bindungen zwischen benachbarten Molekülen eingehen, wodurch die Gewebeelastizität verringert und zu einer irreversiblen Arterienversteifung beigetragen wird; er wird durch Bewegungsmangel und fortschreitendes Alter beschleunigt., AGE-RAGE, elastase, MMPs	Stiffening, rising PWV and systolic BP, reduced compliance	Lipoprotein retention and monocyte entry in low-ESS regions (<10-12 dyn/cm2 is a commonly used research definition; method-dependent)	Human observational + mechanistic
Local Ang-II signaling [10,11]	Locally regulated intramural Ang-II; ACE, chymase, AT1	VSMC hypertrophy, synthetic switching, MMP-2 activation	Age-associated arterielles RemodelingRemodeling bezeichnet die Art und Weise, wie sich die Form einer Arterie verändert, wenn sich Plaque ansammelt. Oft wölbt sich die Arterie nach außen, um Platz zu schaffen, wodurch die Öffnung in der Mitte breit genug für den Blutfluss bleibt.; carotid IMT increases longitudinally by ~0.01 mm/yr in population data [12]	Animal + human tissue
Cellular senescence and SASP [1,14-16]	p16INK4a, p21CIP1, SA-beta-gal, MMP-2/9, IL-6, IL-1beta	Replicative arrest, ECM degradation, paracrine spread	Co-localization with calcified and advanced lesion regions in human tissue; causal effects primarily in animal models, with cap effects model- and stage-dependent	Human histology [14] + animal [15,45]
Mitochondrial dysfunction and dysregulated or insufficient mitophagic quality control [17-19,50]	Reduced mtDNA copy number, TFAM, PGC-1alpha, Twinkle; PINK1/Parkin dysregulation; mtDAMPs	Elevated mROS, NLRP3 and TLR9/MyD88 activation	Feed-forward IL-6/mROS signaling in animal models; reduced compliance; necrotic core [18]	Animal primary; human inferred
CHIP [20,22-24]	TET2, DNMT3A, ASXL1, JAK2 V617F (VAF >=2%)	Driver-dependent myeloid skewing, monocyte hyper-reactivity, IL-1beta/IL-6 excess	~2x CHD; ~4x early-onset MI; JAK2 V617F ~12x CHD risk in the original cohort estimate; higher CAC; lesion growth in mice	Mensch EpidemiologieEpidemiologie ist die Erforschung von Gesundheitstrends in großen Bevölkerungsgruppen – wer erkrankt, wo und was diese Personen gemeinsam hatten. + causal animal model + longitudinal human imaging; prognostic magnitude heterogeneous in treated trial populations [25,26]
Progenitor decline and proteotoxicity [1]	Heterogeneous progenitor populations, telomere attrition, UPS dysfunction, UPR	Association with impaired endothelial repair; intracellular proteotoxicity	Barrier disruption and apoptosis (model, not demonstrated pathway)	Human observational, methodologically heterogeneous

3. Therapeutic mitigation strategies

3.1 Nutritional therapeutics: the CORDIOPREV evidence

The randomized, single-blind CORDIOPREV-StudieCORDIOPREV is a randomized controlled trial that compared a Mediterranean diet to a modestly low-fat diet (approximately 28–30% of calories from fat) in patients with established coronary artery disease; it confirmed Mediterranean dietary superiority over that comparator but did not test the ultra-low-fat ( enrolled 1,002 patients with established coronary heart disease and followed them for a median of 7 years, comparing a Mediterranean dietary pattern enriched in extra-virgin OlivenölOlivenöl ist das Hauptfett der mediterranen Ernährung, reich an einfach ungesättigten Fettsäuren und in der Form als natives Olivenöl extra an Pflanzenstoffen, den sogenannten Polyphenolen. (EVOO; 35% total fat, 22% monounsaturated fatty acids, <50% KohlenhydratKohlenhydrate sind die Zucker und Stärken in Lebensmitteln – Brot, Reis, Nudeln, Obst, Kartoffeln, Süßigkeiten.) with a low-fat diet (28% fat, 12% monounsaturated fatty acids, >55% -omplex carbohydrate) [27,28]. The cohort had a mean age of 59.5 years (SD 8.7) and was 82.5% male [28], so extension to octogenarians is extrapolation. It. Is important to note that the low fat arm herein is substantially higher than other diets and is only slightly lower than the EVOO component.

Among 939 participants with baseline carotid imaging, the Mittelmeer-DiätDie mediterrane Ernährung legt den Schwerpunkt auf Gemüse, Obst, Bohnen, Vollkornprodukte, Nüsse und Olivenöl sowie Fisch und wenig rotes Fleisch. decreased common carotid IMT at 5 years (-0.027 +/- 0.008 mm; P<0.001) and maintained the reduction at 7 years (-0.031 +/- 0.008 mm; P<0.001) relative to baseline; the low-fat diet produced no change [27]. Maximum carotid plaque height was reduced in the Mediterranean arm relative to the low-fat arm across follow-up, whereas plaque number did not differ [27]. These are group-level structural changes. Common carotid IMT progression is not a validated surrogate for cardiovascular-event reduction; in the PROG-IMT individual-participant Meta-AnalyseEine Meta-Analyse fasst die Ergebnisse vieler einzelner Studien statistisch zu einer Gesamtschätzung zusammen., IMT progression did not independently predict cardiovascular events [54].

Der CORDIOPREVCORDIOPREV verglich eine mediterrane Ernährung mit einer fettarmen Ernährung bei Menschen, die bereits an einer Koronarkrankheit litten, und begleitete sie über sieben Jahre. primary endpoint was a prespecified composite of myocardial infarction, RevaskularisationRevaskularisation ist ein medizinischer oder chirurgischer Eingriff – wie eine Koronararterien-Bypass-Operation oder eine perkutane Koronarintervention –, der durchgeführt wird, um den Blutfluss durch eine verstopfte oder verengte Koronararterie wiederherzustellen, wobei die physische Obstruktion und nicht der zugrundeliegende atherogene Prozess behandelt wird., ischemic stroke, periphere arterielle VerschlusskrankheitPeripheral artery disease is plaque narrowing the arteries in your legs., and cardiovascular death [28], not the same MACE definition used in many pharmacological trials. Events occurred in 198 participants: 87 in the Mediterranean arm and 111 in the low-fat arm (28.1 versus 37.7 per 1,000 person-years; log-rank P=0.039) [28]. Multivariable-adjusted Hazard RatiosEine Hazard Ratio vergleicht, wie schnell Ereignisse in zwei Gruppen auftreten. Ein Wert von 0,75 bedeutet, dass Ereignisse in der Behandlungsgruppe mit drei Vierteln der Rate auftraten. across model specifications ranged from 0.719 (95% CI 0.541-0.957) to 0.753 (95% CI 0.568-0.998), corresponding to approximately 25-28% lower estimated hazard [28]. The upper confidence bound in the least favorable model approaches unity, and the trial was single-center and unblinded to participants.

Long-term consumption of the EVOO-rich Mediterranean diet was also associated with slower decline in estimated glomeruläre FiltrationGlomerular filtration is the process by which the kidney's glomeruli — tiny capillary networks — filter waste products and small molecules, including TMAO, from the bloodstream into the urine; adequate glomerular filtration clears fish-derived TMAO within roughly 24 hours, whereas chronic kidney disease reduces this clearance and allows TMAO to accumulate. rate, with a larger difference among participants with type 2 diabetes or mild renal impairment [29]. This is a secondary renal-function outcome, not a demonstrated renoprotective clinical effect. MEDLIFE analyses are observational within the randomized cohort and are discussed in Section 3.4.

CORDIOPREV tested a whole dietary pattern and cannot attribute effects to isolated EVOO components. BiomarkerEin Biomarker ist etwas im Körper Messbarem, das Aufschluss über Gesundheit oder Krankheit gibt – ein Laborwert, ein Scanergebnis, ein Blutdruckwert. substudies demonstrate modulation of circulating AGEs in association with IMT change but do not establish a component-specific mechanism [31]. Assertions that individual PolyphenolePolyphenols are a broad class of plant-derived compounds with antioxidant properties; extra virgin olive oil is particularly rich in them, and they are often cited as the reason EVOO may be more protective than refined olive oil, though trials measuring hard cardiovascular endpoints have not confirmed a meaningful clinical benefit. suppress SASP secretion require separate primary experimental evidence and are not supported by the klinische StudieEine klinische Studie ist eine Untersuchung, bei der Forscher einer Gruppe eine Behandlung und einer anderen Gruppe ein Placebo oder eine Standardbehandlung verabreichen und dann die Ergebnisse vergleichen. selbst.

3.2 Pharmacological interventions

The March 2026 ACC/AHA/Multisociety DyslipidämieDyslipidemia is the medical word for an unhealthy pattern of fats in the blood. It can mean high LDL, high triglycerides, low HDL, or some combination. Guideline replaced the 2018 blood cholesterol guideline. It adopts the PREVENT-GleichungenThe PREVENT (Predicting Risk of Cardiovascular Disease EVENTs) equations are a cardiovascular risk model adopted in the 2026 ACC/AHA guidelines that estimate both 10-year and 30-year lifetime risk of ASCVD, replacing the older Framingham-based Pooled Cohort Equations and enabling earlier risk stratification beginning at age 30. to guide primary-prevention lipid-lowering decisions, restores LDL-C and non-HDL-C treatment goals with lower targets for higher-risk groups, expands the role of coronary artery calcium scoring for risk UmklassifizierungBei der kardiovaskulären Risikobewertung bezeichnet die Reklassifizierung den Prozess, bei dem ein zusätzlicher Test – wie ein CAC-Scan oder eine ApoB-Messung – einen Patienten von einer Risikokategorie in eine andere einordnet, was eine Änderung der Behandlungsentscheidungen zur Folge hat, die allein durch einen Standard-Risikorechner nicht ausgelöst worden wäre., recommends measuring Lipoprotein(a)Lipoprotein(a), geschrieben Lp(a) und "L-P-klein-a" ausgesprochen, ist ein LDL-ähnliches Partikel mit einem extra klebrigen Protein daran. at least once, and states that after age 75 years LDL-C-lowering pharmacotherapy can be considered in conjunction with lifestyle interventions to reduce ASCVD risk [32]. Thus, the post-75 population does not lack contemporary guidance; what remains limited is dedicated randomized evidence specifically addressing statin initiation for primary prevention after age 75.

In the Cholesterol Treatment Trialists’ Collaboration meta-analysis of 28 trials, statin therapy produced a significant proportional reduction in major vascular events per 1.0 mmol/L LDL-C reduction in participants older than 75 with pre-existing vascular disease, with no evidence that proportional benefit is abolished by age [7]. Higher baseline event rates can translate preserved relative effects into larger absolute benefits, although realized benefit depends on competing risk, EinhaltungEinnahmetreue bedeutet, dass Sie Ihre Medikamente tatsächlich so einnehmen, wie sie verschrieben wurden, Tag für Tag., and treatment horizon [7,34].

Dedicated randomized evidence for primary prevention after age 75 remains limited. STAREE (NCT02099123) randomized 9,971 community-dwelling Australians aged >=70 years (mean 74.7; 40% >=75; 52% women; mean baseline LDL-C 126 mg/dL) without clinical cardiovascular disease, diabetes, or dementia to AtorvastatinAtorvastatin, vertrieben als Lipitor, ist eines der beiden stärksten Statine und gehört zu den am häufigsten verschriebenen Medikamenten der Welt. 40 mg or PlaceboEin Placebo ist eine Scheinbehandlung – eine Zuckertablette oder eine Kochsalzlösung –, die verabreicht wird, damit Forscher erkennen können, was ein echtes Medikament tatsächlich bewirkt., with co-primary endpoints of disability-free survival and major cardiovascular events [35]. Recruitment ran from July 2015 through March 2023. As of August 13, 2026, no peer-reviewed primary-outcome report had been published.

PREVENTABLE (NCT04262206) is randomizing 20,000 US adults aged >=75 years without clinically evident cardiovascular disease, disability, or dementia to atorvastatin 40 mg or placebo across approximately 100 sites. Its primary outcome is survival free of new dementia or persisting disability; cardiovascular events are secondary outcomes [36]. No peer-reviewed primary results had been published as of August 13, 2026. The endpoint asymmetry matters: PREVENTABLE’s primary endpoint is a geriatric functional composite rather than conventional MACE. The US Preventive Services Task Force continues to judge evidence insufficient to assess benefits and harms of statin initiation for primary prevention in adults aged 76 years and older [37].

A separate 2026 French pragmatic, open-label non-inferiority trial addressed discontinuation rather than initiation. Among 1,160 adults aged >=75 years who had taken a statin for at least one year for primary prevention and had no ASCVD history, three-year GesamtmortalitätGesamtmortalität bedeutet Tod durch jegliche Ursache und nicht nur durch Herzerkrankungen – das umfassendste und am schwersten zu manipulierende Ergebnis, das eine Studie messen kann. was 7.2% after discontinuation versus 7.9% with continuation, meeting the prespecified non-inferiority criterion [55]. This finding does not establish cardiovascular-event equivalence, does not answer the initiation question, and should be interpreted in light of open-label design and lower-than-anticipated mortality.

Age-related pharmacokinetic changes are heterogeneous. Reduced total body water and magere MasseDer Anteil des Körpergewichts, der auf Muskeln, Knochen und Organe statt auf Fett entfällt; eine höhere Magermasse ist mit einer besseren metabolischen Gesundheit verbunden und wird im Artikel als ein vorgelagerter genetischer Treiber sowohl für die VO₂ max als auch für die Langlebigkeit identifiziert., lower functional hepatic volume, and declining renal function can alter distribution and clearance [33,38]. Renal clearance contributes more to several hydrophilic statins, whereas atorvastatin and simvastatin rely predominantly on hepatic metabolism and transporter-mediated handling [38]. Older adults report statin-associated muscle symptoms more frequently in observational settings, but this does not establish greater statin-attributable muscle toxicity because multimorbidity, interacting medications, background musculoskeletal symptoms, and ascertainment differ [38]. The SAMS-CI can support structured assessment [39]. Im SAMSONSAMSON was an unusual trial in which patients who had quit statins because of side effects took, in random order, the statin, an identical placebo, and no pill at all. n-of-1 crossover trial, most of the excess symptom burden participants attributed to statins was also observed during placebo exposure [40]. Management options include dose reduction, tätägige DosierungA prescribing strategy in which a statin is taken every other day rather than daily, used clinically to reduce muscle symptoms in intolerant patients while preserving a meaningful portion of LDL-lowering effect, particularly with longer-half-life statins., agent switching, and non-statin add-on therapy [38]. In JupiterJUPITER tested a statin in people whose cholesterol was normal but whose CRP was elevated, suggesting hidden inflammation., RosuvastatinRosuvastatin, verkauft als Crestor, ist das wirksamste verfügbare Statin und verbleibt größtenteils in der Leber, anstatt sich im Körper zu verteilen. was associated with a 28% relative increase in incident diabetes among participants with at least one major diabetes RisikofaktorEin Risikofaktor ist etwas, das Ihre Wahrscheinlichkeit erhöht, an einer Krankheit zu erkranken — Partikel mit hohem Cholesterinspiegel, Bluthochdruck, Rauchen, Diabetes, familiäre Vorbelastung., with no significant excess among those without such risk factors; vascular events and deaths prevented exceeded incident diabetes cases in that population [41].

CANTOS demonstrated that quarterly canakinumab reduced recurrent cardiovascular events in post-myocardial-infarction patients with hsCRP >=2 mg/L independently of lipid lowering [42]. A secondary analysis associated larger on-treatment hsCRP reductions with greater event reduction, but because it stratified by post-randomization response it does not establish a predictive biomarker strategy [60]. Canakinumab increased fatal infection and is not approved for a cardiovascular indication.

LoDoCo2 showed that ColchicinColchizin ist ein altes, billiges Antiphlogistikum, das seit Jahrhunderten bei Gicht eingesetzt und nun für Herzerkrankungen umfunktioniert wird. 0.5 mg once daily reduced its primary zusammengesetzter EndpunktEin zusammengesetzter Endpunkt fasst mehrere verschiedene Endpunkte zusammen und zählt denjenigen, der als Erstes eintritt. in chronic coronary disease (HR 0.69, 95% CI 0.57-0.83) [43], with a numerical excess of non-cardiovascular death that remains incompletely explained. By contrast, CLEAR SYNERGY (OASIS 9) found no reduction in cardiovascular death, recurrent myocardial infarction, stroke, or ischemia-driven revascularization after acute MI treated with PCI: 9.1% versus 9.3% with placebo (HR 0.99, 95% CI 0.85-1.16; P=0.93) [56]. Das UnstimmigkeitSee ApoB Discordance for the full entry. does not support a uniform benefit narrative. Differences in disease phase, dose regimen, background therapy, event rates, and trial conduct have been proposed but not established as explanations.

Colchicine safety is particularly relevant in geriatric polypharmacy. Renal or hepatic impairment and concomitant strong CYP3A4 or P-glycoprotein inhibitors materially affect toxicity and dosing. Interacting drugs include clarithromycin, several azole antifungals, verapamil, diltiazem, and cyclosporine; current product labeling and the 2023 chronic coronary disease guideline should be consulted [44]. The guideline assigns low-dose colchicine a Class 2b recommendation in chronic coronary disease [44]. LoDoCo2 did not select patients by hsCRP or another inflammatory biomarker; it should therefore not be described as biomarker-directed.

3.3 Geroprotective strategies: preclinical status

All approaches in this section are preclinical or early-phase with respect to atherosclerotic endpoints. None is clinically indicated for atherosclerosis.

Dasatinib plus quercetin and the BCL-2-family inhibitor navitoclax can preferentially induce apoptosis in certain senescent-cell populations. “Senolytic” is not a mechanism with a predictable class effect: these agents differ substantially in molecular target and in the senescent-cell populations they deplete. In aged and atherosclerotic mice, chronic senolytic treatment can alleviate vasomotor dysfunction and reduce aortic calcification and intrinsic wall stiffness [45]. Effects on plaque stability, however, are stage- and model-dependent. In advanced lesions, navitoclax has reduced smooth-muscle-derived fibrous-cap cells, decreased cap thickness, and increased mortality, conflicting with earlier reports of cap thickening [57-59]. Human experience is confined to small open-label and early-phase studies in idiopathic pulmonary fibrosis [46] and diabetic NierenerkrankungNierenerkrankung bedeutet, dass die Nieren einen Teil ihrer Fähigkeit verloren haben, Abfallstoffe aus Ihrem Blut zu filtern. [47], with physical-function or senescent-cell-burden endpoints. No human trial has tested a senolytic against an atherosclerotic clinical endpoint.

Oral spermidine improved aortic pulse wave velocity and nitric-oxide-mediated endothelial dilation and reduced aortic AGEs, collagen I, nitrotyrosine, and superoxide in aged mice [48]. In aged hyperlipidemic mice, spermidine attenuated mitochondrial dysfunction and atherogenesis [19]. In ApoE-/- mice, spermidine reduced necrotic-core formation and lipid accumulation without changing plaque size or cellular composition, and the effect required intact smooth-muscle AutophagieAutophagy is a cellular housekeeping process by which cells break down and recycle damaged proteins and organelles; in arterial macrophages, it helps clear lipid debris and prevents the accumulation of plaque. The article's 2024 Nature Metabolism finding suggests that high single-meal protein doses may suppress autophagy in these immune cells, potentially worsening atherosclerosis in animal model… [49].

Metformin has been proposed as a geroprotective agent, and the Targeting Aging with Metformin (TAME) concept remains a framework for testing whether intervention on aging biology can delay multimorbidity [51]. TAME remains a design proposal rather than a completed study, and no TAME efficacy data had been published as of August 13, 2026. No clinical evidence demonstrates that metformin improves atherosclerotic outcomes through a distinct geroprotective mechanism. mTOR inhibitors attenuate mitochondrial ROS and modulate SASP in model systems, but vascular-specific evidence is thinner and rapalogs carry immunosuppressive and dyslipidemic effects that are non-trivial in older adults.

3.4 Hemodynamic and lifestyle mitigation

Psychosocial stress is associated with adverse cardiovascular outcomes through interacting behavioral, autonomic, neuroendocrine, inflammatory, and hemodynamic pathways [62]. The contribution of individual vascular-aging mechanisms in humans remains uncertain.

Blood-pressure control has direct randomized support in older adults. In HYVET, antihypertensivEin Antihypertensivum ist jedes Medikament, das zur Senkung von Bluthochdruck eingesetzt wird. Der Artikel unterscheidet Antihypertensiva, die ab den 1970er Jahren weit verbreitet wurden, von Statinen und stellt fest, dass Blutdruckmittel bereits lange vor der Verfügbarkeit einer Statine-Therapie zum Rückgang der koronaren Mortalität beigetragen haben. treatment in patients aged 80 years and older reduced stroke, heart failure, and all-cause mortality [52]. Im SprintSPRINT tested whether pushing systolic blood pressure below 120 was better than the usual target of under 140. subgroup aged >=75 years, intensive systolic targeting reduced major cardiovascular events and all-cause mortality, with broadly consistent findings across frailty strata [53]. Intensive treatment requires monitoring for hypotension, syncope, electrolyte abnormalities, and acute kidney injury; SPRINT did not demonstrate an excess of injurious falls [53]. Renin-angiotensin-aldosterone system inhibition additionally reduces Ang-II signaling and can favorably affect vascular remodeling and central hemodynamics [8,10], but HYVET and SPRINT do not establish that these vascular-aging mechanisms mediate clinical benefit.

In a five-year prospective analysis of 851 CORDIOPREV participants, high MEDLIFE adherence (>13 points) was associated with lower adjusted odds of developing Metabolisches SyndromMetabolic syndrome is a cluster of five problems that tend to travel together: a large waist, high triglycerides, low HDL, high blood pressure, and high blood sugar. Having three or more counts. (OR 0.37, 95% CI 0.19-0.75) and higher odds of reversing pre-existing metabolic syndrome (OR 2.08, 95% CI 1.11-3.91) versus the low-adherence group (<12 points) [30]. These are observational associations within a randomized cohort: participants were not randomized to the lifestyle index, adherence was self-reported, and residual confoundingThe bias that remains in an observational study even after statistical adjustment, because some shared risk factors — such as poverty, smoking, or diabetes — cannot be fully measured or removed; with a modest relative risk like 1.20, residual confounding alone could plausibly explain the entire observed association. is likely. Regular aerobic activity is associated with better-preserved EndothelfunktionDie Fähigkeit der inneren Auskleidung von Blutgefäßen, den Gefäßtonus, Entzündungen und die Blutgerinnung zu regulieren; gesunde Endothelzellen setzen Stickstoffoxid frei, um die Arterien entspannt und resistent gegen Plaquebildung zu halten. in older adults [1]. Proposed mechanisms — including shear-related eNOS signaling, lower circulating inflammatory cytokines, and improved mitochondrial quality control — are supported chiefly by physiological and animal studies rather than randomized vascular-outcome data.

Table 4. Mitigation strategies by domain, mechanism, outcome, and evidence tier. Evidence-tier labels describe the sources cited in each row.

Bereich	Intervention	Targeted mechanism	Principal outcome	Evidence tier (as cited)
Nutritional [27-29,31]	EVOO-rich Mediterranean dietary pattern	Whole-pattern anti-inflammatory and endothelial effects; AGE modulation	CORDIOPREV adjusted HR 0.719-0.753 (~25-28% lower estimated hazard) for the prespecified cardiovascular composite; IMT-CC -0.031 mm at 7 yr (group-level structural outcome, not a validated event surrogate); slower eGFR decline as a secondary outcome	RCT (mean age 59.5 yr; extrapolation to older adults)
Lipid management [7,32,35-38,55]	Moderate/hochdosiertes StatinEin hochintensive Statintherapie ist eine Dosis, von der erwartet wird, dass sie LDL um 50 Prozent oder mehr senkt – in der Praxis sind das höhere Dosen von Atorvastatin oder Rosuvastatin. and other LDL-lowering therapy as appropriate	HMG-CoA-ReduktaseHMG-CoA-Reduktase ist das geschwindigkeitsbestimmende Enzym im Cholesterin-Biosyntheseweg (Mevalonat-Weg) der Leber; Statine wirken, indem sie dieses Enzym kompetitiv blockieren, wodurch die leberseigene Cholesterinproduktion verringert und die Leber angeregt wird, mehr LDL aus dem Blutkreislauf aufzunehmen. inhibition, apoB lowering, PlaquestabilisierungPlaquestabilisierung bewirkt, dass eine bestehende Plaque weniger wahrscheinlich aufbricht – indem ihre Kappe verdickt, ihr fetter Kern verkleinert und die Entzündung in ihrem Inneren beruhigt wird.	Established secondary-prevention benefit in older adults; 2026 guideline permits consideration of LDL-C-lowering pharmacotherapy after 75; dedicated initiation trials pending; discontinuation trial did not establish cardiovascular equivalence or answer initiation	RCT/meta-analysis + current guideline
Anti-inflammatory [42-44,56]	Colchicine 0.5 mg daily; canakinumab (not approved for CV use)	Microtubule-dependent inflammatory signaling; IL-1beta/NLRP3-related pathways	LoDoCo2: HR 0.69 in chronic coronary disease; CLEAR SYNERGY: 9.1% vs 9.3% after MI; neither colchicine trial biomarker-selected	RCT (discordant) + guideline (Class 2b)
Geroprotective [15,19,45-51,57-59]	Senolytics, spermidine, metformin, rapalogs	Senescent-cell clearance, autophagy/mitophagy modulation, mTOR inhibition	Preclinical effects include reduced necrotic core, calcification, or vasomotor dysfunction; cap effects are stage- and model-dependent and conflicting; no demonstrated human atherosclerotic outcome benefit	Preclinical; early-phase human in other indications
Hemodynamic [8,10,52,53]	Antihypertensive therapy; ACE inhibition/ARB	BP lowering; blockade of intramural Ang-II signaling	HYVET and SPRINT >=75 subgroup: reduced clinical events and mortality	RCT + mechanistic
Lifestyle [1,30]	MEDLIFE adherence, Aerobic-TrainingAerobic ist eine gleichmäßige Aktivität, bei der man eine Weile lang stärker atmen muss, wie schnelles Gehen, Radfahren, Schwimmen oder Joggen.	Favorable endothelial shear-related signaling, eNOS up-regulation, reduced InflammagingA chronic, low-grade, sterile inflammatory state that develops with advancing age as the immune system loses its ability to fully resolve acute inflammatory responses; in the arteries it promotes endothelial dysfunction, lipid retention, and plaque progression.	MEDLIFE observational associations: incident metabolic syndrome OR 0.37; UmkehrungREVERSAL verglich eine moderate mit einer intensiven Statintherapie und untersuchte mithilfe von intrakoronarem Ultraschall, was mit der Koronarplaque geschah. OR 2.08	Observational within randomized cohort

4. Limitations

First, this is a narrative review. Sources were selected for representativeness rather than by a prespecified search and screening protocol, and selection bias toward well-cited mechanistic literature cannot be excluded.

Second, the mechanistic architecture of vascular aging rests substantially on rodent and nonhuman-primate work. For several pathways, human evidence remains predominantly cross-sectional tissue, biomarker, or associative data rather than direct longitudinal intervention.

Third, the randomized dietary evidence anchoring Section 3.1 comes from a single-center trial with a predominantly male, middle-aged cohort, and its generalization to geriatric populations is inferential.

Fourth, the CHIP literature remains in flux. Causal animal data are strong, community- and population-based cohort associations are robust, and treated-trial-population data are comparatively null. Endpoint heterogeneity, clone composition, background therapy, statistische PowerDie statistische Power ist die Fähigkeit einer Studie, einen tatsächlichen Effekt zu erkennen, sofern ein solcher existiert. Sie hängt hauptsächlich davon ab, wie viele Ereignisse auftreten., and selection into randomized trials all differ across these datasets; attributing discordance to any single explanation would be premature.

Fifth, carotid IMT is used as a structural readout, but IMT progression has not been shown to predict events independently in individual-participant meta-analysis [54]; structural regression should not be equated with event reduction.

5. Conclusions

The incidence of clinical atherosclerotic events rises steeply with advancing age [4]. Age-related vascular mechanisms may contribute to earlier clinical disease and to greater atherosclerotic burden than would be predicted from measured conventional risk factors alone — two of the operational phenotypes defined in Section 1.0. Whether the longitudinal rate of human plaque accumulation itself accelerates with chronological age remains undemonstrated. The rise in event incidence among older adults is best understood as age-associated vascular processes superimposed on cumulative apoB exposure rather than replacement of lipoprotein-mediated atherogenesis [2,6].

In the aging vessel wall, matrix degradation, AGE cross-linking, altered intramural angiotensin II signaling, mitochondrial dysfunction, impaired mitochondrial quality control, and cellular senescence constitute candidate or experimentally supported pathways capable of promoting atherogenesis or contributing to features associated with plaque vulnerability [16]. Evidence strength is not uniform: human tissue and histologic data support matrix, angiotensin-II, and senescence pathways, whereas mitochondrial and mitophagy evidence is primarily murine and lacks an equivalent longitudinal human vascular counterpart.

Age-related somatic mutation in hematopoietic stem cells, manifesting as CHIP, can promote driver-dependent inflammatory signaling and is causally sufficient to accelerate atherogenesis in experimental models. Human imaging supports a predominant direction from clonal hematopoiesis toward atherosclerosis, without excluding reciprocal contribution, while CHIP’s independent prognostic weight in intensively treated human populations remains contested [22-26].

Mitigation is multimodal. CORDIOPREV supports a Mediterranean dietary pattern in secondary prevention but was not a geriatric trial [27,28]. Statin therapy has established secondary-prevention benefit in older adults, and the 2026 multisociety guideline states that LDL-C-lowering pharmacotherapy can be considered after age 75 alongside lifestyle intervention; STAREE and PREVENTABLE are intended to inform remaining primary-prevention uncertainty [32,35,36]. Low-dose colchicine reduced events in LoDoCo2 in chronic coronary disease but was neutral in CLEAR SYNERGY after myocardial infarction [43,56]. Blood-pressure lowering has direct randomized support in adults aged 75 years and older [52,53]. Senotherapeutic and mitophagy-directed strategies remain investigational, with no demonstrated clinical atherosclerotic outcome benefit in humans [15,19,45-51,57-59].

Current management therefore remains centered on lowering exposure to apoB-containing lipoproteins, blood-pressure control, smoking avoidance and cessation, management of diabetes and related metabolic risk where applicable, dietary quality, and physical activity. Low-dose colchicine may be considered in appropriately selected patients with chronic coronary disease according to contemporary guidelines and patient-specific contraindications.

Declarations

Funding. This work received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflicts of interest. The author declares no competing interests.

Data availability. Not applicable. This article is a narrative review and reports no original participant-level data.

Ethics approval. Not applicable. This narrative review involved no original enrollment of human participants or animals and no generation of identifiable participant-level data.

Use of generative AI. The author used a large language model to assist with drafting, editing, and reference formatting. The author reviewed and verified all content, is responsible for all scientific claims and citations, and takes full responsibility for the integrity and accuracy of the submitted work.

Referenzen

1. Head T, Daunert S, Goldschmidt-Clermont PJ. The aging risk and atherosclerosis: a fresh look at arterial homeostasis. Front Genet. 2017;8:216.
2. Tyrrell DJ, Goldstein DR. Ageing and atherosclerosis: vascular intrinsic and extrinsic factors and potential role of IL-6. Nat Rev Cardiol. 2021;18(1):58-68.
3. Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, et al. Heart disease and stroke statistics-2021 update: a report from the American Heart Association. Circulation. 2021;143(8):e254-e743.
4. Palaniappan LP, Allen NB, Almarzooq ZI, Anderson CAM, Arora P, Avery CL, et al. 2026 heart disease and stroke statistics: a report of US and global data from the American Heart Association. Circulation. 2026;153(9):e275-e906.
5. Hazzard WR, Ettinger WH Jr. Aging and atherosclerosis: changing considerations in cardiovascular disease prevention as the barrier to immortality is approached in old age. Am J Geriatr Cardiol. 1995;4(4):16-36.
6. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38(32):2459-2472.
7. Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet. 2019;393(10170):407-415.
8. Fleg JL, Strait J. Age-associated changes in cardiovascular structure and function: a fertile milieu for future disease. Heart Fail Rev. 2012;17(4-5):545-554.
9. Chatzizisis YS, Coskun AU, Jonas M, Edelman ER, Feldman CL, Stone PH. Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior. J Am Coll Cardiol. 2007;49(25):2379-2393.
10. Lakatta EG, Wang M, Najjar SS. Arterial aging and subclinical arterial disease are fundamentally intertwined at macroscopic and molecular levels. Med Clin North Am. 2009;93(3):583-604.
11. Wang M, Takagi G, Asai K, et al. Aging increases aortic MMP-2 activity and angiotensin II in nonhuman primates. Hypertension. 2003;41(6):1308-1316.
12. Rosvall M, Persson M, Östling G, et al. Risk factors for the progression of carotid intima-media thickness over a 16-year follow-up period: the Malmö Diet and Cancer Study. Atherosclerosis. 2015;239(2):615-621.
13. Ebrahim S, Papacosta O, Whincup P, et al. Carotid plaque, intima-media thickness, cardiovascular risk factors, and prevalent cardiovascular disease in men and women: the British Regional Heart Study. Stroke. 1999;30(4):841-850.
14. Minamino T, Miyauchi H, Yoshida T, Ishida Y, Yoshida H, Komuro I. Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation. 2002;105(13):1541-1544.
15. Molnár ÁÁ, Pásztor DT, Tarcza Z, Merkely B. Cells in atherosclerosis: focus on cellular senescence from basic science to clinical practice. Int J Mol Sci. 2023;24(24):17129.
16. Chakrabarti A, Goldstein DR, Sutton NR. Age-associated arterial calcification: the current pursuit of aggravating and mitigating factors. Curr Opin Lipidol. 2020;31(5):265-272.
17. Foote K, Reinhold J, Yu EPK, Figg NL, Finigan A, Murphy MP, et al. Restoring mitochondrial DNA copy number preserves mitochondrial function and delays vascular aging in mice. Aging Cell. 2018;17(4):e12773.
18. Yu EPK, Reinhold J, Yu H, et al. Mitochondrial respiration is reduced in atherosclerosis, promoting necrotic core formation and reducing relative fibrous cap thickness. Arterioscler Thromb Vasc Biol. 2017;37(12):2322-2332.
19. Tyrrell DJ, Blin MG, Song J, et al. Age-associated mitochondrial dysfunction accelerates atherogenesis. Circ Res. 2020;126(3):298-314.
20. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26):2488-2498.
21. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022;36(7):1703-1719.
22. Jaiswal S, Natarajan P, Silver AJ, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med. 2017;377(2):111-121.
23. Fuster JJ, MacLauchlan S, Zuriaga MA, et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science. 2017;355(6327):842-847.
24. Svensson EC, Madar A, Campbell CD, et al. TET2-driven clonal hematopoiesis and response to canakinumab: an exploratory analysis of the CANTOS randomized clinical trial. JAMA Cardiol. 2022;7(5):521-528.
25. Marston NA, Pirruccello JP, Melloni GEM, et al. Clonal hematopoiesis, cardiovascular events and treatment benefit in 63,700 individuals from five TIMI randomized trials. Nat Med. 2024;30(9):2641-2647.
26. Díez-Díez M, Ramos-Neble BL, de la Barrera J, et al. Unidirectional association of clonal hematopoiesis with atherosclerosis development. Nat Med. 2024;30(10):2857-2866.
27. Jimenez-Torres J, Alcala-Diaz JF, Torres-Peña JD, et al. Mediterranean diet reduces atherosclerosis progression in coronary heart disease: an analysis of the CORDIOPREV randomized controlled trial. Stroke. 2021;52(11):3440-3449.
28. Delgado-Lista J, Alcala-Diaz JF, Torres-Peña JD, et al.; CORDIOPREV Investigators. Long-term secondary prevention of cardiovascular disease with a Mediterranean diet and a low-fat diet (CORDIOPREV): a randomised controlled trial. Lancet. 2022;399(10338):1876-1885.
29. Podadera-Herreros A, Alcala-Diaz JF, Gutierrez-Mariscal FM, et al. Long-term consumption of a Mediterranean diet or a low-fat diet on kidney function in coronary heart disease patients: the CORDIOPREV randomized controlled trial. Clin Nutr. 2022;41(2):552-559.
30. Romero-Cabrera JL, Garcia-Rios A, Sotos-Prieto M, et al. Adherence to a Mediterranean lifestyle improves metabolic status in coronary heart disease patients: a prospective analysis from the CORDIOPREV study. J Intern Med. 2023;293(5):574-588.
31. Gutierrez-Mariscal FM, Lopez-Moreno A, Torres-Peña JD, et al. Modulation of circulating levels of advanced glycation end products and its impact on intima-media thickness of both common carotid arteries: CORDIOPREV randomised controlled trial. Cardiovasc Diabetol. 2024;23(1):361.
32. Blumenthal RS, Morris PB, Gaudino M, Johnson HM, Anderson TS, Bittner VA, et al. 2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of dyslipidemia: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2026;87(19):2624-2757.
33. Nguyen TN, Woodward M, Butt JH, McMurray JJV, Lip GYH, Kaski JC. Optimizing cardiovascular pharmacotherapy in older adults with frailty. Nat Rev Cardiol. 2026;23:433-443.
34. Baratta F, Moscucci F, Lospinuso I, Cocomello N, Bruno G, Cangemi R, et al. Lipid-lowering therapy and cardiovascular prevention in elderly. Drugs. 2025;85(6):801-812.
35. Zoungas S, Curtis A, Tonkin A, et al. Baseline characteristics of participants in STAREE: a randomized trial for primary prevention of cardiovascular disease events and prolongation of disability-free survival in older people. J Am Heart Assoc. 2024;13(23):e036357.
36. Joseph J, Pajewski NM, Dolor RJ, et al.; PREVENTABLE Trial Research Group. Pragmatic evaluation of events and benefits of lipid lowering in older adults (PREVENTABLE): trial design and rationale. J Am Geriatr Soc. 2023;71(6):1701-1713.
37. US Preventive Services Task Force. Statin use for the primary prevention of cardiovascular disease in adults: US Preventive Services Task Force recommendation statement. JAMA. 2022;328(8):746-753.
38. Stone J, Kumar M, Orkaby AR. The role of statin therapy in older adults: best practices and unmet challenges. Expert Rev Cardiovasc Ther. 2024;22(7):301-311.
39. Rosenson RS, Miller K, Bayliss M, et al. The Statin-Associated Muscle Symptom Clinical Index (SAMS-CI): revision for clinical use, content validation, and inter-rater reliability. Cardiovasc Drugs Ther. 2017;31(2):179-186.
40. Wood FA, Howard JP, Finegold JA, et al. N-of-1 trial of a statin, placebo, or no treatment to assess side effects. N Engl J Med. 2020;383(22):2182-2184.
41. Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012;380(9841):565-571.
42. Ridker PM, Everett BM, Thuren T, et al.; CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119-1131.
43. Nidorf SM, Fiolet ATL, Mosterd A, et al.; LoDoCo2 Trial Investigators. Colchicine in patients with chronic coronary disease. N Engl J Med. 2020;383(19):1838-1847.
44. Virani SS, Newby LK, Arnold SV, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA guideline for the management of patients with chronic coronary disease. Circulation. 2023;148(9):e9-e119.
45. Roos CM, Zhang B, Palmer AK, et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell. 2016;15(5):973-977.
46. Justice JN, Nambiar AM, Tchkonia T, et al. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine. 2019;40:554-563.
47. Hickson LJ, Langhi Prata LGP, Bobart SA, et al. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019;47:446-456.
48. LaRocca TJ, Gioscia-Ryan RA, Hearon CM, Seals DR. The autophagy enhancer spermidine reverses arterial aging. Mech Ageing Dev. 2013;134(7-8):314-320.
49. Michiels CF, Kurdi A, Timmermans JP, De Meyer GRY, Martinet W. Spermidine reduces lipid accumulation and necrotic core formation in atherosclerotic plaques via induction of autophagy. Atherosclerosis. 2016;251:319-327.
50. Zeng Y, Buonfiglio F, Li J, Pfeiffer N, Gericke A. Mechanisms underlying vascular inflammaging: current insights and potential treatment approaches. Aging Dis. 2025;16(4):1889-1917.
51. Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a tool to target aging. Cell Metab. 2016;23(6):1060-1065.
52. Beckett NS, Peters R, Fletcher AE, et al.; HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358(18):1887-1898.
53. Williamson JD, Supiano MA, Applegate WB, et al.; SPRINT Research Group. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged >=75 years: a randomized clinical trial. JAMA. 2016;315(24):2673-2682.
54. Lorenz MW, Polak JF, Kavousi M, et al.; PROG-IMT Study Group. Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data. Lancet. 2012;379(9831):2053-2062.
55. Bonnet F, Poulizac P, Rousselot N, Couffinhal T, Galli G, Berdaï D, et al.; SAGA/SITE Study Group. Discontinuation of statins for primary prevention of atherosclerotic cardiovascular disease in adults aged 75 years or older (SAGA/SITE): a multicentre, open-label, pragmatic, non-inferiority randomised trial. Lancet Healthy Longev. 2026;7:100884.
56. Jolly SS, d’Entremont MA, Lee SF, et al.; CLEAR Investigators. Colchicine in acute myocardial infarction. N Engl J Med. 2025;392(7):633-642.
57. Childs BG, Baker DJ, Wijshake T, Conover CA, Campisi J, van Deursen JM. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science. 2016;354(6311):472-477.
58. Garrido AM, Kaistha A, Uryga AK, et al. Efficacy and limitations of senolysis in atherosclerosis. Cardiovasc Res. 2022;118(7):1713-1727.
59. Karnewar S, Karnewar V, Shankman LS, Owens GK. Treatment of advanced atherosclerotic mice with ABT-263 reduced indices of plaque stability and increased mortality. JCI Insight. 2024;9:e173863.
60. Ridker PM, MacFadyen JG, Everett BM, Libby P, Thuren T, Glynn RJ; CANTOS Trial Group. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet. 2018;391(10118):319-328.
61. Basta G, Lazzerini G, Massaro M, et al. Advanced glycation end products activate endothelium through signal-transduction receptor RAGE: a mechanism for amplification of inflammatory responses. Circulation. 2002;105(7):816-822.
62. Levine GN, Cohen BE, Commodore-Mensah Y, et al. Psychological health, well-being, and the mind-heart-body connection: a scientific statement from the American Heart Association. Circulation. 2021;143(10):e763-e783.