Key Takeaways & Executive Findings
- ā¢ā¢ Cellular senescence markers (p16Ink4a, p21, p53, Ī²-Gal, ROS, SASP) are consistently associated with reduced osteogenic potential and impaired bone regeneration. ā¢ Bone marrow is the predominant cell source in aging-related bone regeneration studies, highlighting its clinical relevance. ā¢ Targeting senescence markers through interventional strategies may rejuvenate progenitor cells and enhance regenerative outcomes. ā¢ The systematic review underscores the need for standardized senescence marker assessment to improve translational applications.
Abstract
Background With the global population aging, optimizing bone regeneration is becoming increasingly important for enhancing the quality of life among elderly individuals. Progenitor cell-based therapies, such as mesenchymal stromal cells and induced pluripotent stem cells for bone regeneration have shown challenges due to cellular senescence and the control of the differentiation processes remain significant hurdles. In particular, elevated expression of senescence markers may play a pivotal role in limiting bone regeneration. This systematic review examines how these senescence markers influence the efficacy of progenitor cell therapies and whether targeting them could improve outcomes. Methods We conducted a systematic literature review following the PRISMA guidelines, using the PubMed, Web of Science, Embase and Scopus with the algorithm of ābone regeneration AND senescence AND markerā. Data synthesis focused on human cell sources and specifically examined senescence markers related to bone regeneration. Results Studies using human cells were discussed in 101 papers. Based on our inclusion and exclusion criteria, 13 papers remained for our review on senescence markers in human cells within the context of bone regeneration and senescence, with and without interventional strategies. More than half of the cell sources in current aging-related studies are derived from bone marrow. Markers of aging relevant to bone regeneration include changes in cell size and morphology, increased levels of Ī²-galactosidase (Ī²-Gal) and Reactive Oxygen Species (ROS), and the presence of a senescence-associated secretory phenotype (SASP). Additionally, distinct senescence markers such as p16Ink4a, p21, and p53, and mitochondrial dysfunction were associated with reduced osteogenic potential and impaired regenerative capacity. Conclusion Bone marrow is the most common source of cells for studies of senescence. Cellular senescence characterized by elevated expression of specific markers was consistently shown to be negatively associated with osteogenic capacity and regenerative outcomes. The most common strategies to rejuvenate senescent cells include
1. Introduction
Bone regeneration therapy is becoming increasingly important as the worldās population ages with increasing life expectancies. According to United Nationsā āWorld Population Prospects 2022ā, by 2050, the global population of 65 years old or older will more than double, reaching over 1.5 billion globally [1]. Maintaining bone health in an aging society is directly linked to improving quality of life. In elderly individuals, the decrease in bone density and the increased risk of fractures compromise their independence, making bone regeneration therapy a critical, yet unmet clinical need [2].
In orthopaedics and dentistry, progress in bone regeneration therapy enables safer and more effective treatments for elderly patients and those with impaired healing potential, leading to improvements in functional outcomes such as ambulation, autonomy, and masticatory efficiency, ultimately enhancing patientsā overall quality of life [3ā5].
Recently, significant attention has been given to the clinical application of mesenchymal stromal cells (MSCs) in the field of bone regeneration [6, 7]. These self-renewing multipotent cells can differentiate into bone [8], cartilage [9], and adipose tissue [10], as well as other cell types under in vitro conditions. Interestingly, recent findings have highlighted that MSCs transplanted in vivo promoted bone regeneration primarily through paracrine effects by secreting immunomodulatory factors contributing to the polarization of M0 macrophages to the M2 phenotype [11, 12]. The advantages of using MSCs include self-renewal, multipotency, and immunomodulatory capabilities, thus reducing the risk of immune rejection with enhanced safety compared to other treatments [13]. However, age-related decline in MSC function and differentiation capacity remain major challenges.
Cellular senescence (or aging) presents a significant obstacle in bone regeneration therapy. Senescent cells secrete substances broadly defined as senescence-associated secretory phenotype (SASP). It may contain soluble signaling factors such as interleukins, chemokines, growth factors, proteases, ins
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Mayu Morita, Eshan B. Damle, Issei Shinohara, Masatoshi Murayama, Yosuke Susuki, Qi Gao, Chao Ma, Simon Kwoon-Ho Chow, Stuart Barry Goodman (2026). Targeting cellular senescence in progenitor cells as a strategy to enhance bone regeneration by cell therapies: a systematic review of pre-clinical investigations. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-025-04767-8
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Frequently Asked Questions
What are the key senescence markers affecting bone regeneration?
Key senescence markers include p16Ink4a, p21, p53, Ī²-galactosidase, reactive oxygen species (ROS), and the senescence-associated secretory phenotype (SASP). These markers are associated with reduced osteogenic potential and impaired regenerative capacity.
Why is bone marrow the most common cell source in aging-related bone regeneration studies?
Bone marrow is the most common source because it contains mesenchymal stromal cells (MSCs) that are relatively accessible and have well-established protocols for isolation and expansion. Additionally, MSCs from bone marrow are widely studied for their osteogenic potential and immunomodulatory properties.
How can targeting cellular senescence improve bone regeneration therapies?
Targeting cellular senescence through interventions such as senolytics, antioxidants, or modulation of SASP can rejuvenate senescent progenitor cells, restoring their osteogenic capacity and enhancing regenerative outcomes in cell-based therapies.
What was the methodology of this systematic review?
The review followed PRISMA guidelines and searched PubMed, Web of Science, Embase, and Scopus using the algorithm 'bone regeneration AND senescence AND marker'. After screening 101 papers, 13 studies focusing on human cells were included for analysis.
What are the clinical implications of this systematic review?
The findings highlight the importance of assessing senescence markers in progenitor cell therapies and suggest that targeting senescence could improve the efficacy of bone regeneration treatments, particularly in elderly patients.
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