Cellular Senesence

Brief overview/Summary

Cellular senescence is a natural process with both protective and harmful effects. Throughout life, senescence helps prevent tumor formation and mitigate tissue damage. However, as individuals age, senescent cells accumulate in tissues, potentially contributing to various age-related diseases. Recent research has uncovered the molecular mechanisms that support the survival of senescent cells and regulate their immune clearance. These findings provide a foundation for developing new therapeutic approaches to target senescent cells while highlighting the importance of understanding the limitations, efficacy, safety, and potential risks of current strategies for senescent cell elimination. This article explores existing methods for targeting senescent cells and the challenges in advancing these strategies into safe and effective therapies. Successfully addressing these challenges could revolutionize treatments for age-related diseases and transform the way we approach health management during aging.

What is Cellular Senescence? 

Cellular senescence is a state in which cells permanently stop dividing while remaining metabolically active, typically triggered by DNA damage or other cellular stressors. First described by Leonard Hayflick in studies of human fetal fibroblasts, senescence distinguishes non-transformed cells from malignant cells, which can replicate indefinitely. Unlike quiescent cells, which can reenter the cell cycle, or terminally differentiated cells, senescent cells are permanently arrested but exhibit unique features, including chromatin reorganization, altered gene expression, and the senescence-associated secretory phenotype (SASP), a pro-inflammatory profile.The role of senescence is context-dependent, with both protective and harmful effects. It is thought to have evolved as a mechanism to prevent the malignant transformation of damaged cells. However, the accumulation of senescent cells over time contributes to age-related diseases, including cancer, tissue degeneration, and chronic inflammation. Importantly, senescence is not synonymous with aging; while aging reflects a progressive functional decline, senescence occurs throughout life and plays essential roles in embryogenesis, tissue repair, and wound healing. Despite its involvement in aging and pathology, senescence also remains a vital part of normal biological processes.

The Role of Senescent cells in Alzheimer’s Disease

The aging process is strongly associated with developing diseases, such as cardiovascular conditions, hypertension, cancer, diabetes mellitus, osteoporosis, and neurodegenerative diseases, among others. ^[10,12] Alzheimer’s disease (AD) is no exception since aging is a risk factor for late-onset AD (more than 95% of AD cases). ^[14,15] Another factor highly associated with aging is the increased cellular senescence population of different cell types as we approach older ages (see Fig. 3).^[14] Several studies suggest cellular senescence is critical in aging and connected conditions like AD.^[2,5,10] Recent investigations have pointed out that senescent cells promote the pathogenesis of AD.^[3-6] But what are senescent cells? Senescent cells’ particular feature is stopping the proliferation by entering a cell cycle arrest. ^[12-15] these senescent cells are also known to develop apoptosis resistance and secrete proinflammatory molecules.^[11] Senescent cells not only remain even though they are “damaged” but also liberate various chemicals that can initiate inflammation.^[3,7] Cellular senescence emerges when a cell receives considerable stress, driving it to “reprogram” its fate to an unlimited cell cycle arrest.^[7,9] DNA damage, oncogene triggering, mitochondrial dysfunction, and the accumulation of proteins like the tau and the amyloid beta (Aβ) are well known to initiate senescence in different types of cells (see Fig. 1).^[2,12,14]

Figure 1. The comparison between a healthy brain and an AD brain with senescent cells.^[14]

Thymosin B4 Reduces Inflammation by Upregulating MicroRNA-146a and Promotes Myelin

“Tissue inflammation results from neurological injury, and regulation of the inflammatory response is vital for neurological recovery. The innate immune response system, which includes the Toll-like receptor (TLR) proinflammatory signaling pathway, regulates tissue injury… TB4-mediated oligodendrogenesis results from [up-regulating] miR-146a [causing the] suppression [of] the TLR proinflammatory pathway and modulation of the p38 MAPK pathway.” (8)“By targeting IRAK1 and TRAF6, miR-146 inhibits NF-κB activation. We therefore hypothesized that TB4 regulates the TLR proinflammatory signaling pathway by specifically regulating miR-146a to promote differentiation of OPCs [oligodendrocyte progenitor cells] to mature myelin basic protein (MBP)-expressing OLs [oligodendrocytes]… transfection with anti-miR-146a inhibitor nucleotides significantly inhibited the expression of MBP and phosphorylation of p38 MAPK.” (8)

Senescence Induced Inflammation (SASP) May Promote Cell and Telomere Damage, Leading to Allodynia.

“Expression of senescence pathway and SASP effector genes in the spinal cords of mice of both sexes 6 months after sham or SNI surgery. “

(SASP is inflammation secreted by senescent cells.)
“Peripheral nerve injury produces cellular senescence in the spinal cord of mice at time points long after injury. Reduced TL can result in a persistent DNA damage response leading to cellular senescence — a state of cell cycle arrest/withdrawal, deregulated cellular metabolism, and macromolecular damage — and senescent cells in turn release a diverse set of cytokines, growth factors, proteases, and extracellular matrix components, together known as the senescence-associated secretory phenotype (SASP) or senescent-messaging secretome. Many of these SASP-related compounds are proinflammatory, and well known to produce or facilitate pain, especially when released in the spinal cord. We gave new cohorts of young male and female mice SNI or sham surgeries and harvested lumbar spinal cord tissues from these animals 12–14 months later, or 2 months later.” (1)