Vascular Aging and its Markers

Vascular Health Day is celebrated each year on May 18. 5.18 is derived from an indicator value: 5.18 mmol/L, which is the threshold for abnormal total cholesterol in the blood of normal people. Atherosclerotic plaques formed by cholesterol deposits are the major threat to vascular health. The purpose of designating May 18 as "Vascular Health Day" is to encourage the public to understand that cholesterol is closely related to cardiovascular disease, to take the initiative to manage their vascular health, to improve their vascular health, to reduce the incidence of cardiovascular events such as heart attack, stroke and sudden death, and to curb the trend of increasing incidence of cardiovascular and cerebral vascular diseases in China year after year.

Vascular aging is a degenerative change in vascular structure and function that occurs in the cardiovascular system with aging or age-related metabolic diseases.

Vascular aging is a common pathogenetic mechanism for many chronic diseases in the elderly, significantly affecting the threshold, progression, and outcome of cardiovascular disease, cerebrovascular disease, renal disease, peripheral vascular disease, and dementia.

In July 2023, the Aging Biomarker Consortium (ABC) published the Expert Consensus on Vascular Aging Markers (2023), which provides a comprehensive assessment of biomarkers related to vascular aging and proposes a systematic framework to categorize biomarkers into three dimensions: functional traits, structural traits, and humoral markers.

The discovery of appropriate humoral markers of vascular aging can be used to assist in the assessment of vascular health at an earlier stage, thereby preventing age-related cardiovascular disease and reducing the socioeconomic burden.

Vascular Aging Markers

01 Plasma Inflammatory Factor

hs-CRP (High Sensitivity C-Reactive Protein)

hs-CRP is an acute-phase protein synthesized during inflammation or injury and involved in a variety of physiological and pathological processes in the body. It is more sensitive to the presence of inflammatory responses in the body and plays both anti-inflammatory and pro-inflammatory roles. Studies have shown that hs-CRP ≥2.0 mg/L is an effective predictor of cardiovascular disease in people.

VEGF (Vascular Endothelial Growth Factor)

VEGF, also known as vascular permeability factor (VPF), is a highly specific pro-vascular endothelial growth factor that promotes increased vascular permeability, extracellular matrix degeneration, endothelial cell migration, proliferation, and angiogenesis. Decreased levels of VEGF indicate low angiogenic activity and low vascular permeability, and signal that the body is aging.

ox-LDL (oxidized low-density lipoprotein)

Low-density lipoprotein (LDL) migrates into the arterial lining and is readily oxidized and modified to ox-LDL, the production of which is a major initiator of atherosclerosis. ox-LDL can damage the structural and functional integrity of endothelial cells and promotes the deposition of lipids in the endothelial lining of arteries.

MMP (Matrix Metalloproteinase)

MMPs are involved in atherosclerosis and plaque rupture during the pathological process of cardiovascular disease. MMP-1, MMP-3 and MMP-12 are involved in the uptake and deposition of atherosclerotic plaque components. In addition, the progression of atherosclerosis is directly related to smooth muscle cell proliferation and migration mediated by MMP-2 and MMP-9. In addition to atherosclerosis, reports have shown that MMPs are associated with disease progression in myocardial infarction and heart failure. Therefore, some investigators have suggested that circulating soluble MMPs may be one of the molecules for diagnosis and prognosis of cardiovascular disease.

TNFα (Tumor Necrosis Factor alpha)

Tumor Necrosis Factor a (TNF-a) is a potent inflammatory cytokine produced and released by giant monocytes that regulates vascular endothelial cell function and alters their gene expression profiles.TNF-a-induced damage to vascular endothelial cells is important in the pathogenesis of many cardiovascular, cerebrovascular, and thrombotic diseases.

During aging, the immune system undergoes a series of changes that promote the secretion of a variety of inflammatory factors, which together lead to an increase in a number of inflammatory factors in the circulation with advancing age, promoting the development of vascular age-related diseases. A number of inflammatory factors in plasma, including interleukin (IL)-6, IL-1, IL-1 receptor antagonist (IL-1Ra), IL-8, and interferon γ (IFNγ), are associated with vascular aging.

02 Other Plasma Proteins

IGF-1 (insulin-like growth factor)

Direct stimulation of middle-aged HSCs with IGF-1 rescues the molecular and functional hallmarks of aging, including restoration of mitochondrial activity.

Transient local IGF1 stimulation has been shown to improve cardiovascular, brain, muscle, and bone regeneration and function in aged mice and humans, and IGF1 and related downstream processes, including mTOR signaling and mitochondrial metabolism, may serve as promising targets for human hematopoietic lifespan extension.

FGF21 (Fibroblast Growth Factor 21)

High plasma levels of FGF21 are strongly associated with an increased risk of cardiovascular disease through a mechanism that may involve a stress response due to inflammation and abnormalities in glycolipid metabolism. Critical levels of plasma FGF21 (ranging from 123.0 to 321.5 pg/mL) have been reported to be an independent risk factor for predicting cardiovascular risk.

Fibulin-1 (Fibulin-1)

Fibulin-1 (fibulin-1) is an important extracellular matrix protein that interacts with elastin and microfibrils, and together they contribute to the stabilization of elastic fibers in the vascular wall. It has been found that plasma fibulin-1 is highly expressed in people with high atherosclerosis and that elevated fibulin-1 is positively correlated with an increase in baPWV, and it has been hypothesized that plasma fibulin-1 may be a marker that reflects arterial stiffness.

Archaeal virus HERVK envelope protein

A team of Chinese scientists has completed a collaborative study of endogenous retroviruses (ERVs), known as "fossilized ancient viruses" and the relics of ancient retroviral invasion and integration into the human genome millions of years ago, and discovered for the first time that young ERV subfamilies are resurrected during cellular aging. They proposed the theory that ERV resurrection mediates aging programming and infectiousness, and innovatively developed a multidimensional intervention strategy to block ERV resurrection and spread to achieve aging retardation.

03 Cells and Vesicles in the Circulation

In clinical practice, flow cytometry can be used to easily detect specific cellular contents in the blood to aid in the determination of vascular endothelial function and the early detection of vascular aging. For example, circulating CD8+CD28- T lymphocytes, circulating endothelial progenitor cells (EPCs), CD31+CD42- circulating endothelial microparticles (EMPs) with a diameter of 0.1-1.0 μm.

04 Other Functional Markers

Abnormal DNA methylation modifications have been found in aging blood. Low levels of DNA methylation in the blood are associated with progression of AS and increased cardiovascular risk.

Immunoglobulin G (IgG) can be modified by glycosylation (N-glycosylation), which in turn modulates its function and systemic inflammatory state, and most glycosylation patterns are strongly associated with aging.

Non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play an important role in vascular aging. Dyslipidemia, hyperglycemia and hypertension all lead to abnormally elevated miR-34a expression in vascular cells, which contributes to inflammation and vascular senescence by affecting both endothelial and vascular smooth muscle cell function.

Aging is often associated with increased blood levels of cholesterol, polyunsaturated fatty acids (PUFAs), the phosphatidylcholine metabolite trimethylamine N-oxide (TMAO), and sphingolipids. Trimethylamine N-oxide (TMAO) is a metabolite of phosphatidylcholine (phosphatidylcholine) and ceramide (sphingolipids). These molecules are risk factors for cardiovascular disease and may also serve as biomarkers of vascular aging.

Urinary MetabolitesThe aging process is closely related to metabolism and oxidative stress. Analysis of the levels of oxidation products of DNA and RNA in the plasma and urine of rhesus monkeys by LC-MS/MS technique in 2012 showed that the oxidation products of DNA in the blood and urine of rhesus monkeys, 8-oxo-7,8-dihydrodeoxyguanosine (8-oxo-dGsn) and the levels of the oxidized metabolite 8-oxoguanosine (8-oxo-7, 8-dihydroguanosine, 8-oxoGsn) from RNA both increased with aging, with the most significant increase in urine, and because urine samples were readily available, it was hypothesized that urinary 8-oxoGsn could be used as a marker of aging.

Relating products VEGF, VEGFA, MMP1, MMP2, MMP3, MMP8, MMP9, MMP12, MMP13, IFNa, IFNy, IL-1RA, IL-1, IL-6, IL-8, IGFBP-7, FGF2, FGF3, FGF21: