Targeting Cellular Senescence: Pathophysiology in Multisystem Age-Related Diseases

Abstract

With the intensification of global aging, the incidence of age-related diseases (including cardiovascular, neurodegenerative, and musculoskeletal disorders) has been on the rise, and cellular senescence is identified as the core driving mechanism. Cellular senescence is characterized by irreversible cell cycle arrest, which is caused by telomere shortening, imbalance in DNA damage repair, and mitochondrial dysfunction, accompanied by the activation of the senescence-associated secretory phenotype (SASP). In this situation, proinflammatory factors and matrix-degrading enzymes can be released, thereby disrupting tissue homeostasis. This disruption of tissue homeostasis induced by cellular senescence manifests as characteristic pathogenic mechanisms in distinct disease contexts. In cardiovascular diseases, senescence of cardiomyocytes and endothelial cells can exacerbate cardiac remodeling. In neurodegenerative diseases, senescence of glial cells can lead to neuroinflammation, while in musculoskeletal diseases, it can result in the degradation of cartilage matrix and imbalance of bone homeostasis. This senescence-mediated dysregulation across diverse organ systems has spurred the development of intervention strategies. Interventional strategies include regular exercise, caloric restriction, senolytic drugs (such as the combination of dasatinib and quercetin), and senomorph therapies. However, the tissue-specific regulatory mechanisms of cellular senescence, in vivo monitoring, and safety-related clinical translational research still require in-depth investigation. This review summarizes the progress in pathological mechanisms and interventions, providing theoretical support for precision medicine targeting senescence, which is of great significance for addressing health challenges associated with aging.

Keywords: SASP; cardiovascular disease; cellular senescence; mechanisms; musculoskeletal disease; neurodegenerative disease; prevention–treatment.

Figure 1

In the intracellular milieu, reactive oxygen species (ROS) can induce DNA damage, perturbing the normal DNA architecture. (As shown in the diagram, ROS acts on the cell to bring about this initial step.) This damage triggers the activation of the ATR (Ataxia Telangiectasia and Rad3-related) protein kinase. The activated ATR then acts on the tumor suppressor protein P53 via downstream signaling cascades involving phosphorylation-dependent molecular relays (matching the pathway where DNA damage activates ATM/ATR, which signal through CHK2/CHK1 to P53 in the diagram). Functioning as a pivotal signaling hub, P53 integrates these inputs to initiate transcriptional programs driving cellular senescence (corresponding to P53 and leading to the “Senescence” outcome in the figure). Additionally, extracellular factors of the senescence-associated secretory phenotype (SASP), including IL-6, PAI-1, and IGFBP7, as depicted, further mediate bidirectional crosstalk between senescent cells and their microenvironment, collectively modulating the senescence cascade (aligning with the SASP being secreted from the cell and interacting with the outside as shown). This figure was created using FigDraw 2.0. Thanks to FigDraw 2.0.

Figure 2

As shown, diverse cells (fibroblasts, cardiomyocytes, etc.) undergo senescence. In cardiovascular system, myocardial and endothelial cell senescence causes fibrosis and heart failure. In nervous system, neuron and microglial senescence worsen neurodegeneration (PD, AD, etc.). In musculoskeletal system, chondrocyte senescence accelerates OA cartilage degradation, and osteoblast senescence hinders OP bone formation. Via SASP paracrine and cell cycle arrest, senescent cells drive tissue damage and age-related disease pathology across systems. This figure was created using FigDraw 2.0. Thanks to FigDraw 2.0.