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Global Translational Medicine Metabolic dysfunction in vascular senescence

(2). Telomeres and telomerase: telomeres play an essential atherosclerosis. Similarly, senescence and changes
27
role in maintaining chromosome integrity and regulating in DNA methylation affect VSMC functions, resulting
cell division, whereas telomere dysfunction drives the in structural and functional abnormalities in blood
initiation and progression of cellular senescence, along vessel walls, further developing hypertension. 34
with associated diseases. With each cellular division,
27
telomeres undergo gradual shortening. Once they reach 3. Other senescence mechanisms
a critically low length, cells stop dividing and enter a state 3.1. Dysregulation of cellular metabolism
known as replicative senescence. Research shows that
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silent mating-type information regulation 2 homolog-1 Cellular metabolism is fundamentally essential for
(SIRT1 or sirtuin 1) protects mesenchymal stem cells maintaining various physiological functions, including
senescence. Recent studies have identified seven
(MSCs) from age-related DNA damage by inducing
the expression of telomerase reverse transcriptase and metabolites closely associated with senescence, exhibiting
29
enhancing telomerase activity while exerting no effect antisenescence effects across different species; these
on telomere length. In addition, SIRT1 upregulates metabolites include nicotinamide adenine dinucleotide
+
tripeptidyl peptidase 1 (TPP1) – a key component of (NAD ), α-ketoglutarate, tryptophan, methionine, +
spermidine, triglycerides, and cholesterol, of which NAD
the shelterin complex responsible for the protection of exerts a notable influence on senescence in various model
chromosome ends from DNA damage. Consequently, organisms. NAD serves as a critical coenzyme in the
+
SIRT1 mitigates age-related MSC senescence through tricarboxylic acid cycle and actively participates in glucose
multiple mechanisms, including TPP1 upregulation, metabolism, insulin secretion, and protein homeostasis
increased telomerase activity, and reduced DNA while playing an indispensable role in preventing cellular
damage. Conversely, SIRT1 overexpression reverses senescence and age-related diseases. As a group of NAD -
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30
+
the senescence phenotype associated with MSC dependent deacetylases, the SIRT family (including seven
senescence 30
(3). Protein homeostasis theory: impaired protein members, SIRT1–SIRT7) plays a pivotal role in senescence
and age-related diseases in mammals.
35
homeostasis results in aberrant protein folding and
accumulation of damage within cells, leading to Under normal physiological conditions, the activity
+
cellular dysfunction, tissue and organ impairment, and of NAD -dependent SIRT1 is enhanced in endothelial
organismal senescence. The mitochondrial unfolded cells, which can directly deacetylate and activate DNA
31
protein response (UPR ) is indispensable for maintaining repair proteins or regulate DNA repair by activating the
mt
cellular homeostasis and proteostasis. In stem cells, related transcription factors. 31,32 In addition, SIRT1 can
UPR activation is critical for sustaining mitochondrial reduce ROS production by upregulating the expression
mt
function. However, the effectiveness of UPR may and activity of superoxide dismutase 2 (SOD2), further
mt
diminish with senescence or prolonged stress, resulting enhancing DNA stability, reducing DNA damage and
in mitochondrial dysfunction and protein misfolding or mutations, maintaining normal endothelial cell and blood
aggregation. Consequently, this deterioration impairs the vessel functions, and decelerating senescence. 36
vitality and self-renewal capacity of stem cells, thereby The characteristic of age-related disorders includes a
accelerating their senescence 32 decrease in NAD levels in tissues, potentially affecting
+
(4). Epigenetic theory: this refers to alterations in the SIRT activity and contributing to age-related metabolic
epigenetic landscape, including histone modifications, disorders. 33 NAD dysregulation is considered a
+
33
chromatin remodeling, and DNA methylation. substantial risk factor for vascular senescence. On the
Reportedly, senescence in hematopoietic stem cells is one hand, reduced NAD can lead to DNA damage and
+
associated with altered patterns of histone modifications, mitochondrial dysfunction, promoting the development
particularly a reduction in trimethylation of lysine 27 of senescence. On the other hand, low levels of NAD
+
on histone H3 (H3K27me3), reducing the activity of during senescence alter metabolic activity in cells, affecting
hematopoietic stem cells and potentially contributing SASP development. This secretory phenotype and the
to their senescence and dysfunction. When progression of cellular senescence are linked to specific
25
hematopoietic stem cells age, there is often a global metabolic changes rather than simply being attributed to
decline in DNA methylation levels, predominantly high metabolic demands. Reportedly, SIRT1 activity is
37
characterized by reduced methylation within CpG associated with mitochondrial function, and a decrease in
34
island regions, which contributes to genomic SIRT activity can impair the deacetylation of peroxisome
instability and abnormal gene expression, accelerates proliferator-activated receptor γ coactivator 1α, leading
senescence, and contributes to the development of to dysfunctional electron transport chain complexes
Volume 3 Issue 4 (2024) 5 doi: 10.36922/gtm.4619