Delaying aging and discovering anti-aging therapeutics are among the primary goals of modern biomedical research. Aging occurs with the progressive accumulation of senescent cells, accompanied by an increase in biomarkers associated with cellular senescence. It is characterized by various changes at both the cellular and organismal levels, such as genomic instability, telomere attrition, cellular senescence, and chronic inflammation [1]. Markers of cellular senescence include elevated senescence-associated β-galactosidase activity and increased expression of cell cycle regulators such as the cyclin-dependent kinase inhibitors p16ˆINK4a/Rb and p21ˆWAF1/CIP1. Additionally, senescence-associated secretory phenotype (SASP) factors like IL-6 are also characteristic markers of senescence [[2], [3], [4], [5], [6], [7]]. As senescent cells accumulate, age-related diseases may develop, including cancer, blindness, and cardiovascular diseases [8]. Therefore, the search for therapeutics to delay aging is of critical importance.

Doxorubicin (Dox), a cytotoxic anthracycline antibiotic, induces cell senescence at lower doses and cell apoptosis at higher doses in both cancerous and non-cancerous cells [9]. It is a widely used chemotherapeutic agent known to trigger inflammatory responses [10,11], impair wound healing, reduce collagen production, and inhibit skin fibroblast proliferation [12,13]. Recently, Dox has been utilized to induce senescence both in vitro and in vivo [[14], [15], [16], [17], [18]], facilitating the development of animal models for evaluating anti-aging compounds [[19], [20], [21]].

Stem cells possess inherent regenerative potential, the ability to expand in vitro, release trophic factors, and exhibit immunomodulatory properties, making them suitable for tissue repair and the treatment of various diseases [22,23]. Human umbilical cord mesenchymal stem cells (hucMSCs) are particularly favored in stem cell therapy due to their non-invasive isolation methods, lower immunogenicity, enhanced self-renewal capacity, more stable doubling times, and superior proliferative abilities [24]. However, the use of hucMSCs faces certain limitations, particularly in maintaining their bioactivity, quantifying bioactive substances, and ensuring effective delivery in clinical applications [25].

Exosomes are extracellular vesicles contain endosomal bioactive substances, including nucleic acids, cytokines, proteins, and other molecules, with an average diameter of approximately 100 nm [26]. They interact with target cells to transport bioactive compounds, initiate downstream signaling, and facilitate cell-to-cell communication [27]. Exosomes derived from various stem cells have been shown to promote tissue regeneration following a variety of injuries [28,29]. Compared to stem cells, exosomes are more stable, do not carry the risk of aneuploidy, and have a lower chance of immune rejection, offering a potential alternative therapy for a range of diseases [[30], [31], [32]]. Exosomes are now emerging as a promising therapeutic option in the field of aging. Specifically, exosomes derived from human mesenchymal stroma and stem-like cells effectively reduce cellular senescence in murine renal epithelial cells [33]. HucMSC-Exo possess functions similar to those of hucMSCs, with low immunogenicity and non-tumorigenicity, thereby presenting greater potential for applications in regenerative medicine and various diseases [34]. However, research on the anti-aging effects of hucMSC-Exo is still limited. This study investigates whether hucMSC-Exo can mitigate Doxorubicin-induced senescence. We found that after treatment with exosomes or metformin, several aging-related phenotypes in both mouse and cell models were ameliorated, including increased body weights, liver and kidney weights, and a reduction in SA-β-Gal-positive cells in kidney and skin tissues, as well as in cell models. At the molecular level, hucMSC-Exo treatment led to downregulation of inflammatory factors and senescence markers in liver and kidney tissues, and in cellular models. Metformin has been studied for its potential to extend lifespan in both mice and C. elegans [35,36]. In this study, metformin was utilized as a positive anti-aging drug in both cell and animal models. Our findings suggest that hucMSC-Exo can alleviate Doxorubicin-induced senescence.