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Global Translational Medicine Metabolic dysfunction in vascular senescence

Senescence can be classified into two types: and lifestyle. Reportedly, an individual’s genetic background
physiological and pathological. Physiological senescence considerably influences blood vessel elasticity and wall
refers to the natural degeneration that occurs in organisms thickness. Specific genes are closely associated with
with age, whereas pathological senescence refers to vascular senescence, and as individuals age, alterations in
age-related changes that manifest in young organisms these gene expressions contribute to arterial stiffness and
because of various factors, such as obesity, inflammation, diminished elasticity. Moreover, environmental factors,
and metabolic disorders. Vascular senescence is crucial such as prolonged exposure to smoking and environmental
for the development of several vascular diseases, pollution, as well as an unhealthy lifestyle characterized
including atherosclerosis, vascular calcification (VC), by a high-fat, high-sugar diet, augment oxidative stress,
hypertension, arterial aneurysm, arterial dissection, and and endothelial cell damage and result in severe vascular
peripheral vascular diseases. Therefore, understanding the senescence and inflammatory responses, accelerating the
2,3
fundamental mechanisms underlying vascular senescence progression of atherosclerosis. This process is characterized
to develop effective strategies for preventing and treating by notable alterations, such as lumen enlargement, intima-
age-related vascular diseases is imperative. media thickening, elastic fiber disruption and fracturing,
increased collagen fiber deposition, and augmented vascular
1.1. Overview of senescence stiffness. In addition, prominent features of vascular
Although not a disease, senescence increases an organism’s senescence include VC, remodeling, intravascular plaque
vulnerability and triggers various pathological conditions. formation, decreased sensitivity to vasoactive factors, and
There are 12 senescence biomarkers (Table 1): genomic reduced neovascularization capacity. 4
instability, telomere attrition, epigenetic alterations, loss 2.2. Cellular senescence
of proteostasis, disabled macroautophagy, deregulated
nutrient sensing, mitochondrial dysfunction, cellular Cellular senescence refers to the irreversible cessation
senescence, stem cell exhaustion, altered intercellular of proliferation in normal cells, characterized by their
5
communication, chronic inflammation, and dysbiosis. 1 withdrawal from the cell cycle. The accumulation of senescent
cells in various tissues primarily drives senescence. Cellular
6
2. Types of senescence senescence involves the gradual loss of cellular ability to
withstand stress and damage over time, further declining the
2.1. Vascular senescence
cellular function and survival rate. This manifests as systemic
Blood vessels serve as crucial conduits that transport blood functional decline throughout the body, slowed metabolism,
and nutrients throughout the body, maintaining vital life and the emergence of aging characteristics. Naturally, cellular
activities. In humans, senescence typically starts with senescence is an intrinsic clock-driven process in which cells
2
vascular senescence, leading to alterations in blood vessel undergo aging over time, even in the absence of important
morphology and functions. Vascular senescence is an external stress. Reportedly, cells in the senescent stage often
intrinsic physiological and pathological process regulated show cell cycle arrest in the G1 or G2 phase due to the
by various risk factors, such as genetics, the environment, activation of specific pathways – such as the tumor protein

Table 1. Senescence biomarkers

Level Phenotype Clinical indicators References
Vascular level Vascular stiffening PWV, ABI, PP, and ePWV 77,78
Calcification CACS 79
−
+
Cellular level Endothelial dysfunction CD8 CD28 T-cells 72
Cell cycle arrest p15 INK4B , p16 INKA , p21 CIP1 , p53, and pRb 80
DNA damage P-γH2AX, ATM, and ATR 81
Molecular level Plasma proteins IGF1 82
Metabolic changes SA-β-gal 6
SASP IL-6 and IL-8 8
Abbreviations: PWV: Pulse wave velocity; ABI: Ankle brachial index; PP: Pulse pressure; ePWV: Estimated pulse wave velocity; CACS: Coronary artery
calcium score; p15 INK4B : Cyclin-dependent kinase inhibitor 2B (CDKN2B); p16 INKA : Cyclin-dependent kinase inhibitor 2A (CDKN2A);
p21 CIP1 : Cyclin-dependent kinase inhibitor 1 (CDKN1A); p53: Tumor protein p53; pRb: Retinoblastoma protein; P-γH2AX: Anti-phosphorylated
histone H2AX antibody; ATM: Ataxia-telangiectasia mutated; ATR: ATM and Rad3 related; IGF1: Insulin-like growth factor 1; SA-β-gal: Senescence-
associated β-galactosidase; SASP: Senescence-associated secretory phenotype; IL-6: Interleukin-6; IL-8: Interleukin-8.

Volume 3 Issue 4 (2024) 2 doi: 10.36922/gtm.4619