This Review defines the current understanding of the genetic pathways that regulate senescence induction, maintenance, propagation and heterogeneity, including the DNA damage response, non-genotoxic stress pathways, epigenetic changes and cell-cell communication.
Cellular senescence is characterized by irreversible cell-cycle arrest, with cells remaining viable and metabolically active. This state features a proinflammatory senescence-associated secretory phenotype (SASP) that can harm neighboring tissues. Accumulation of senescent cells accelerates age-related physiological decline and associated pathologies. Furthermore, cellular senescence is implicated in various physiological processes, including embryonic development, wound healing, tumor progression, and immune response regulation. The complexity of the aging process arises from its diverse underlying mechanisms, potential reversibility, and intrinsic heterogeneity. Experimental gerontology focuses on identifying pathogenic modulators that regulate the formation and accumulation of senescent cells, as well as investigating their impact on tissue function. Within the field of experimental gerontology, considerable attention is devoted to identifying pathogenic modulators that regulate the formation and accumulation of senescent cells, as well as to investigating their impact on tissue function. Of particular interest is the characterization of novel molecular mechanisms that govern cellular aging. Key pathogenic molecular pathways include the p53-dependent senescence pathway, the p16INK4a/pRb pathway, and non-canonical pathways like IFIH1-MAVS, which contribute to oxidative stress, DNA damage, activation of SASP, and other cellular dysfunction. This study critically examines how viral and bacterial agents induce cellular senescence, particularly
in vitro
, reviewing the regulatory mechanisms involved. It discusses genetic variants affecting infection susceptibility and categorizes senescence markers. Investigating the molecular mechanisms underlying cellular aging presents promising avenues for the development of targeted and effective therapeutic interventions. Such strategies may include the selective induction of senescence in cancer cells, suppression of senescence to mitigate age-related diseases, or the comprehensive modulation of aging processes to optimize clinical outcomes.
E. V. Simoroz, Y. V. Antonov, G. Muravyov et al.· Vavilov Journal of Genetics...· 0 citations
It is proposed that integrating precise editing, in vivo screening, single-cell multi-omics, and emerging artificial intelligence (AI)-assisted design may provide information and a design basis for future combined strategies that simultaneously target vulnerabilities in senescent cells and malignant populations.
Bo Fan, Aiwei Wu, Xue Pan et al.· Ageing and Cancer Research &...· 0 citations
Cellular senescence is a context-dependent cellular state characterised by persistent cell-cycle arrest, epigenetic remodelling, metabolic reprogramming and acquisition of a senescence-associated secretory phenotype. Transient senescence contributes to embryogenesis, tissue repair and tumour suppression, whereas persistent senescent cell populations accumulate with advancing age across multiple tissues, in part owing to declining immune-mediated clearance and intrinsic resistance to apoptosis, thereby promoting chronic systemic inflammation, tissue fibrosis, stem-cell dysfunction and propagation of secondary senescence. Experimental genetic and pharmacological evidence supports a contributory and in several contexts causal role for senescent cells in cardiovascular, metabolic, musculoskeletal, fibrotic and neurodegenerative disorders. These findings have accelerated the development of senotherapeutic strategies, including senolytics, senomorphics and immune-mediated clearance approaches, with early clinical studies showing preliminary evidence of functional benefit in idiopathic pulmonary fibrosis and diabetic kidney disease. However, clinical translation remains constrained by senescence heterogeneity, limited biomarker specificity and unresolved long-term safety concerns. Improved molecular, spatial and functional resolution of senescent states will be essential for developing biomarker-guided and tissue-specific interventions that preserve the beneficial functions of transient senescence while limiting its chronic deleterious effects.
P. Chmielewski· Biogerontology (Dordrecht)· 1 citation
Cellular senescence is an irreversible growth arrest state and a hallmark of organismal aging. While induction of cellular senescence in healthy organs is undesirable, senescence of specific cell types can be beneficial in certain pathological milieus. For instance, the senescence of activated myofibroblasts helps to limit excessive collagen deposition and preserving tissue homeostasis. Senescent cells express signature gene products, including cell cycle regulators and senescence-associated secretory phenotype (SASP), which includes proinflammatory cytokines, growth factors, and protease inhibitors. Among the senescence regulators, the tumor suppressor p53 plays a pivotal role in suppression of fibrogenesis by dual action: through transcriptional repression of matrix protein genes, and through activation of the cellular senescence pathway in matrix-producing myofibroblasts. Because p53 activation suppresses collagen synthesis, it offers a promising treatment for most fibrotic diseases. However, sustained activation of p53 stress-response in healthy cells may accelerate cellular senescence and aging by promoting the release of SASP. Therefore, the magnitude and timing of p53 activation are critical factors that determine whether its effects are beneficial or detrimental in a given pathological milieu. Here, we discuss the fascinating dual trajectory of p53: its role in driving cellular senescence that contributes to aging, and its capacity to limit the progression of fibrogenesis, a major driver of age-related morbidity and mortality worldwide.
Asish K. Ghosh, Karim Ullah, Cian O'Donnell et al.· Aging and Disease· 0 citations
Cellular senescence is a stable cell-cycle arrest program accompanied by extensive metabolic remodeling and acquisition of a senescence-associated secretory phenotype (SASP). Emerging evidence indicates that senescence is not a uniform endpoint but a heterogeneous spectrum of cell states shaped by the nature of the initiating stimulus. Mitochondria have recently emerged as central regulators of this heterogeneity by integrating metabolic, redox, and inflammatory signaling. Senescent cells share common mitochondrial features-including increased mitochondrial mass, elevated reactive oxygen species (ROS), impaired mitophagy, and altered metabolic programs-yet distinct senescence subtypes exhibit unique mitochondrial adaptations. Replicative senescence is governed by a telomere–mitochondria feedback loop, whereas stress- and oncogene-induced senescence involve rapid mitochondrial stress responses and stimulus-specific metabolic rewiring. Therapy-induced senescence further introduces context-dependent mitochondrial dependencies that influence therapeutic resistance and senolytic vulnerability. In this review, we synthesize current understanding of mitochondrial regulation across senescence subtypes and highlight how mitochondrial dysfunction actively drives senescence heterogeneity. We further discuss emerging therapeutic strategies that exploit mitochondrial vulnerabilities to selectively modulate or eliminate senescent cells. Understanding mitochondrial control of senescence heterogeneity provides a conceptual framework for developing precision interventions in aging and cancer.
Minseo Ahn, Sung-Jin Yoon, Jae Ho Seo· Frontiers in Cell and Develo...· 0 citations
This review systematically examines the molecular mechanisms of cellular senescence, with emphasis on the intrinsic logic governing bidirectional remodeling between senescent cells and the immune microenvironment, to provide a new theoretical foundation for next-generation precision cancer immunotherapy.
Wen-Wen Zhao, Pengfei Zhang, Li-Xin Li et al.· Cell Death Discovery· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
