bims-caglex 2025-01-19 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2025–01–19
29 papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

Exosomal miR-302b rejuvenates aging mice by reversing the proliferative arrest of senescent cells.
Exercise and exerkines: Mechanisms and roles in anti-aging and disease prevention.
Mikhail 'Misha' Blagosklonny's enduring legacy in geroscience: the hyperfunction theory and the therapeutic potential of rapamycin.
Low-Intensity Pulsed Ultrasound Treatment Selectively Stimulates Senescent Cells to Promote SASP Factors for Immune Cell Recruitment.
Unraveling the ROS-Inflammation-Immune Balance: A New Perspective on Aging and Disease.
Centromere inactivation during aging can be rescued in human cells.
The telomere connection between aging and cancer: The burden of replication stress and dysfunction.
The Critical Role of Autophagy and Phagocytosis in the Aging Brain.
Insights into age-related osteoporosis from senescence-based preclinical models and human accelerated aging paradigms.
Intercellular communication is crucial in the regulation of healthy aging via exosomes.
Therapeutic Efficacy and Promise of Human Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles in Aging and Age-Related Disorders.
Safe and Orally Bioavailable Inhibitor of Serine Palmitoyltransferase Improves Age-Related Sarcopenia.
Deep learning reveals diverging effects of altitude on aging.
V-ATPase Disassembly at the Yeast Lysosome-Like Vacuole Is a Phenotypic Driver of Lysosome Dysfunction in Replicative Aging.
SMARCA4 regulates the NK-mediated killing of senescent cells.
Metabolism and metabolomics in senescence, aging, and age-related diseases: a multiscale perspective.
Aging stem cells limit tumorigenesis.
From molecular to physical function: The aging trajectory.
Unravelling the transcriptomic symphony of muscle ageing: key pathways and hub genes altered by ageing and caloric restriction in rat muscle revealed by RNA sequencing.
Ginsenoside Rg1 Promotes the Survival, Proliferation, and Differentiation of Senescent Neural Stem Cells Induced by D-galactose.
Research on Prediction of Multiple Degenerative Diseases and Biomarker Screening Based on DNA Methylation.
Chloride intracellular channel CLIC3 mediates fibroblast cellular senescence by interacting with ERK7.
Dasatinib and Quercetin Limit Gingival Senescence, Inflammation, and Bone Loss.
Multiple synergistic anti-aging effects of vascular cell adhesion molecule 1 functionalized nanoplatform to improve age-related neurodegenerative diseases.
Circadian Rhythms and Lung Cancer in the Context of Aging: A Review of Current Evidence.
Cellular senescence-associated genes in rheumatoid arthritis: Identification and functional analysis.
SenPred: a single-cell RNA sequencing-based machine learning pipeline to classify deeply senescent dermal fibroblast cells for the detection of an in vivo senescent cell burden.
The Potential of Naturally Derived Compounds for Treating Chronic Kidney Disease: A Review of Autophagy and Cellular Senescence.
Senescence in neural cell lines: comparative insights from SH-SY5Y and ReNcell VM.

Cell Metab. 2025 Jan 13. pii: S1550-4131(24)00481-9. [Epub ahead of print]

Exosomal miR-302b rejuvenates aging mice by reversing the proliferative arrest of senescent cells.

Youkun Bi, Xinlong Qiao, Zhaokui Cai, Hailian Zhao, Rong Ye, Qun Liu, Lin Gao, Yingqi Liu, Bo Liang, Yixuan Liu, Yaning Zhang, Zhiguang Yang, Yanyun Wu, Huiwen Wang, Wei Jia, Changqing Zeng, Ce Jia, Hongjin Wu, Yuanchao Xue, Guangju Ji.

  Cellular senescence, a hallmark of aging, involves a stable exit from the cell cycle. Senescent cells (SnCs) are closely associated with aging and aging-related disorders, making them potential targets for anti-aging interventions. In this study, we demonstrated that human embryonic stem cell-derived exosomes (hESC-Exos) reversed senescence by restoring the proliferative capacity of SnCs in vitro. In aging mice, hESC-Exos treatment remodeled the proliferative landscape of SnCs, leading to rejuvenation, as evidenced by extended lifespan, improved physical performance, and reduced aging markers. Ago2 Clip-seq analysis identified miR-302b enriched in hESC-Exos that specifically targeted the cell cycle inhibitors Cdkn1a and Ccng2. Furthermore, miR-302b treatment reversed the proliferative arrest of SnCs in vivo, resulting in rejuvenation without safety concerns over a 24-month observation period. These findings demonstrate that exosomal miR-302b has the potential to reverse cellular senescence, offering a promising approach to mitigate senescence-related pathologies and aging.

Keywords:  Ccng2; Cdkn1a; aging; cellular senescence; hESC-Exos; miR-302b; proliferative arrest; rejuvenation

DOI:  https://doi.org/10.1016/j.cmet.2024.11.013
Exp Gerontol. 2025 Jan 16. pii: S0531-5565(25)00013-0. [Epub ahead of print]200 112685

Exercise and exerkines: Mechanisms and roles in anti-aging and disease prevention.

Xuan Lu, Ying Chen, Yue Shi, Yi Shi, Xianbin Su, Peijie Chen, Die Wu, Hui Shi.

  Aging is a complex biological process characterized by increased inflammation and susceptibility to various age-related diseases, including cognitive decline, osteoporosis, and type 2 diabetes. Exercise has been shown to modulate mitochondrial function, immune responses, and inflammatory pathways, thereby attenuating aging through the regulation of exerkines secreted by diverse tissues and organs. These bioactive molecules, which include hepatokines, myokines, adipokines, osteokines, and neurokines, act both locally and systemically to exert protective effects against the detrimental aspects of aging. This review provides a comprehensive summary of different forms of exercise for older adults and the multifaceted role of exercise in anti-aging, focusing on the biological functions and sources of these exerkines. We further explore how exerkines combat aging-related diseases, such as type 2 diabetes and osteoporosis. By stimulating the secretion of these exerkines, exercise supports healthy longevity by promoting tissue homeostasis and metabolic balance. Additionally, the integration of exercise-induced exerkines into therapeutic strategies represents a promising approach to mitigating age-related pathologies at the molecular level. As our understanding deepens, it may pave the way for personalized interventions leveraging physical activity to enhance healthspan and improve quality of life.

Keywords:  Anti-aging; Exercise physiology; Exerkines

DOI:  https://doi.org/10.1016/j.exger.2025.112685
Aging (Albany NY). 2025 Jan 12. null

Mikhail 'Misha' Blagosklonny's enduring legacy in geroscience: the hyperfunction theory and the therapeutic potential of rapamycin.

David A Barzilai.

  The untimely passing of Dr. Mikhail "Misha" Blagosklonny has left a lasting void in geroscience and oncology. This review examines his profound contributions, focusing on his pioneering the Hyperfunction Theory and his advocacy for rapamycin, an mTOR inhibitor, as a therapeutic agent for lifespan extension. Contrary to traditional damage-centric models, the Hyperfunction Theory rejects damage accumulation as the primary driver of aging. Instead, it redefines aging as a quasi-programmed process driven by the persistent, excessive activity of growth-promoting pathways beyond their developmental roles, leading to age-related pathologies. We explore how Blagosklonny's insights predict rapamycin's ability to decelerate aging by modulating excessive mTOR signaling, supported by empirical evidence across multiple physiological systems, including immune, cardiovascular, cognitive, and oncologic health. His forward-thinking approach, advocating for the cautious clinical use of rapamycin and suggesting personalized, preventive, and combination therapy strategies, has catalyzed interest in translational geroscience. This review synthesizes Blagosklonny's legacy, presenting rapamycin as a foundational pharmacological intervention with potential in managing age-related decline and extending healthspan, and underlines his impact in shifting aging research from theoretical frameworks to actionable interventions. Blagosklonny's work remains an enduring inspiration, paving the way toward treating aging as a modifiable condition.

Keywords:  geroscience; healthspan; hyperfunction; longevity medicine; rapamycin

DOI:  https://doi.org/10.18632/aging.206189
Aging Cell. 2025 Jan 16. e14486

Low-Intensity Pulsed Ultrasound Treatment Selectively Stimulates Senescent Cells to Promote SASP Factors for Immune Cell Recruitment.

HyeRan Gwak, Seoyoung Hong, Su Hyun Lee, In Woo Kim, Yonghan Kim, Hyungmin Kim, Ki Joo Pahk, So Yeon Kim.

  As emerging therapeutic strategies for aging and age-associated diseases, various biochemical approaches have been developed to selectively remove senescent cells, but how physical stimulus influences senescent cells and its possible application in senolytic therapy has not been reported yet. Here we developed a physical method to selectively stimulate senescent cells via low-intensity pulsed ultrasound (LIPUS) treatment. LIPUS stimulation did not affect the cell cycle, but selectively enhanced secretion of specific cytokines in senescent cells, known as the senescence-associated secretory phenotype (SASP), resulting in enhanced migration of monocytes/macrophages and upregulation of phagocytosis of senescent cells by M1 macrophage. We found that LIPUS stimulation selectively perturbed the cellular membrane structure in senescent cells, which led to activation of the intracellular reactive oxygen species-dependent p38-NF-κB signaling pathway. Using a UV-induced skin aging mouse model, we confirmed enhanced macrophage infiltration followed by reduced senescent cells after LIPUS treatment. Due to the advantages of ultrasound treatment, such as non-invasiveness, deep penetration capability, and easy application in clinical settings, we expect that our method can be applied to treat various senescence-associated diseases or combined with other established biochemical therapies to enhance efficacy.

Keywords:  LIPUS stimulation; macrophage recruitment; phagocytosis; senescence associated secretory phenotype; senescent cells

DOI:  https://doi.org/10.1111/acel.14486
Aging Dis. 2025 Jan 04.

Unraveling the ROS-Inflammation-Immune Balance: A New Perspective on Aging and Disease.

Sihang Fang, Mingjun Jiang, Juan Jiao, Hongye Zhao, Dizhi Liu, Danni Gao, Tenger Wang, Ze Yang, Huiping Yuan.

Increased entropy is a common cause of disease and aging. Lifespan entropy is the overall increase in disorder caused by a person over their lifetime. Aging leads to the excessive production of reactive oxygen species (ROS), which damage the antioxidant system and disrupt redox balance. Organ aging causes chronic inflammation, disrupting the balance of proinflammatory and anti-inflammatory factors. Inflammaging, which is a chronic low-grade inflammatory state, is activated by oxidative stress and can lead to immune system senescence. During this process, entropy increases significantly as the body transitions from a state of low order to high disorder. However, the connection among inflammation, aging, and immune system activity is still not fully understood. This review introduces the idea of the ROS-inflammation-immune balance for the first time and suggests that this balance may be connected to aging and the development of age-related diseases. We also explored how the balance of these three factors controls and affects age-related diseases. Moreover, imbalance in the relationship described above disrupts the regular structures of cells and alters their functions, leading to cellular damage and the emergence of a disorganized state marked by increased entropy. Maintaining a low entropy state is crucial for preventing and reversing aging processes. Consequently, we examined the current preclinical evidence for antiaging medications that target this balance. Ultimately, comprehending the intricate relationships between these three factors and the risk of age-related diseases in organisms will aid in the development of clinical interventions that promote long-term health.

DOI: https://doi.org/10.14336/AD.2024.1253
Mol Cell. 2025 Jan 08. pii: S1097-2765(24)01035-9. [Epub ahead of print]

Centromere inactivation during aging can be rescued in human cells.

Sweta Sikder, Songjoon Baek, Truman McNeil, Yamini Dalal.

  Aging involves a range of genetic, epigenetic, and physiological alterations. A key characteristic of aged cells is the loss of global heterochromatin, accompanied by a reduction in canonical histone levels. In this study, we track the fate of centromeres in aged human fibroblasts and tissues and in various cellular senescent models. Our findings reveal that the centromeric histone H3 variant CENP-A is downregulated in aged cells in a p53-dependent manner. We observe repression of centromeric noncoding transcription through an epigenetic mechanism via recruitment of a lysine-specific demethylase 1 (LSD1/KDM1A) to centromeres. This suppression results in defective de novo CENP-A loading at aging centromeres. By dual inhibition of p53 and LSD1/KDM1A in aged cells, we mitigate the reduction in centromeric proteins and centromeric transcripts, leading to the mitotic rejuvenation of these cells. These results offer insights into a unique mechanism for centromeric inactivation during aging and provide potential strategies to reactivate centromeres.

Keywords:  CENP-A; aging; cancer; centromere; chromatin; genome instability; histone demethylase; non-coding transcription; p53; senescence

DOI:  https://doi.org/10.1016/j.molcel.2024.12.018
Mech Ageing Dev. 2025 Jan 11. pii: S0047-6374(25)00002-8. [Epub ahead of print]223 112026

The telomere connection between aging and cancer: The burden of replication stress and dysfunction.

Virginia Boccardi, Luigi Marano.

  Aging is a complex process that affects individuals at the molecular, cellular, tissue, and systemic levels, arising from the cumulative effects of damage and reduced repair mechanisms. This process leads to the onset of age-related diseases, including cancer, which exhibits increased incidence with age. Telomeres, the protective caps at chromosome ends, play a crucial role in genome stability and are closely connected with aging and age-related disorders. Both excessively short and long telomere lengths may contribute to cancer development when their balance is disrupted. Fragile telomeres, characterized by abnormalities and replication stress, may provide novel insights into the connection between aging and cancer. The accumulation of fragile telomeres, possibly due to intense replicative stress, may represent a key factor. Given the dynamic nature of telomeres, large longitudinal studies are essential for understanding their role in aging and cancer susceptibility, which is crucial for developing effective strategies to promote healthy aging and mitigate cancer risk.

Keywords:  Aging; Cancer; Telomeres

DOI:  https://doi.org/10.1016/j.mad.2025.112026
Int J Mol Sci. 2024 Dec 25. pii: 57. [Epub ahead of print]26(1):

The Critical Role of Autophagy and Phagocytosis in the Aging Brain.

Stephen C Bondy, Meixia Wu.

  As the organism ages, there is a decline in effective energy supply, and this retards the ability to elaborate new proteins. The consequences of this are especially marked in the gradual decline in brain function. The senescence of cells and their constituent organelles is ultimately the cause of aging of the entire nervous system. What is less immediately obvious is that brain aging is also accompanied by the failure of catabolic events that lead to the removal of non-functional cells and ineffective subcellular components. The removal of non-working cellular and subcellular elements within the brain is essential in order to allow the appearance of fresh cells and organelles with a full range of capacities. Thus, the maintenance of operative mechanisms for the dispersal of failed tissue components is important, and its diminished capacity with aging is a significant contributory factor to the onset and progression of age-related neurological disorder. This report discusses the mechanisms underlying autophagy and phagocytosis and how these can be adversely modulated as aging proceeds. The means by which the effective recycling of cellular components may be reinstated in the aged brain are considered.

Keywords:  autophagy; brain aging; mitophagy; neurodegeneration; phagocytosis

DOI:  https://doi.org/10.3390/ijms26010057
Mech Ageing Dev. 2025 Jan 11. pii: S0047-6374(25)00001-6. [Epub ahead of print] 112025

Insights into age-related osteoporosis from senescence-based preclinical models and human accelerated aging paradigms.

Robert J Pignolo, Abhishek Chandra.

  Preclinical models of age-related osteoporosis have been developed based on the accumulation and clearance of senescent cells. The former include animal models based on telomere dysfunction and focal radiation; the latter based on genetic and pharmacological targeting (i.e., removal) of senescent cells. The weight of evidence using these models suggests that cellular senescence plays a key role in the pathophysiology of aging-onset bone loss with the senescence-associated secretory phenotype (SASP) mediating local and systemic deleterious effects on the skeleton. Mitochondrial dysfunction has also been implicated in senescence and age-related comorbidities, including osteoporosis, and knock-in mutations in the mtDNA polymerase gamma (Polg) gene in mice may recapitulate similar respiratory chain complex defects in aged individual with osteoporosis. This and other contributions to senile osteoporosis may also be identified by the careful evaluation of non-genetic paradigms of human accelerated aging. Premature aging syndromes, especially those with a prominent bone loss phenotype, include clinical scenarios of skeletal unloading, premature ovarian failure and survival from childhood cancers. These non-hereditary progeroid syndromes implicate the involvement of lineage switching to an adipogenic fate, inhibition of Wnt signaling, increased osteoclastogenesis and activation frequency of osteoclasts, as well as the substantial burden of senescent cell accumulation.

Keywords:  Accelerated aging; Animal models; Cellular senescence; Osteoporosis; Radiation; Telomerase dysfunction

DOI:  https://doi.org/10.1016/j.mad.2025.112025
Pharmacol Res. 2025 Jan 10. pii: S1043-6618(25)00016-7. [Epub ahead of print]212 107591

Intercellular communication is crucial in the regulation of healthy aging via exosomes.

Huifang Sun, Tengyuan Xia, Shuting Ma, Tao Lv, Yuhong Li.

  The hallmarks of aging encompass a variety of molecular categories (genomic, telomeric, and epigenetic), organelles (proteostasis, autophagy, and mitochondria), cellular components (including stem cells), systems (such as intercellular communication and chronic inflammation), and environmental factors (dysbiosis and nutrient sensing). These hallmarks play a crucial role in the aging process. Despite their intricate interconnections, the relationships among the hallmarks of aging remain unclear. Although the boundaries between these hallmarks may be indistinct, they exhibit interdependence, with the influence of one hallmark extending to others. Building on this foundation, we investigated the interrelations among the various hallmarks of aging and provided a systematic overview of their logical relationships, proposing that cellular communication plays a crucial role in the aging process. Exosomes function as a primary mode of cellular communication and significantly impact the aging process. Therefore, we propose utilizing exosomes as valuable tools for understanding the mechanisms of aging and addressing age-related concerns. Exosomes may represent a novel approach for the treatment and diagnosis of aging-related conditions in animals. Furthermore, our research reveals that exocytosis in young nematodes slows the aging process, while exocytosis in aged nematodes has the opposite effect, accelerating aging. In conclusion, exosomes act as intercellular messengers that influence the maintenance of a healthy aging process and link the hallmarks of aging with indicators of well-being.

Keywords:  Aging; Cellular communication; Exosomes; Lifestyle

DOI:  https://doi.org/10.1016/j.phrs.2025.107591
Int J Mol Sci. 2024 Dec 30. pii: 225. [Epub ahead of print]26(1):

Therapeutic Efficacy and Promise of Human Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles in Aging and Age-Related Disorders.

Anyuan Zhang, Qiubai Li, Zhichao Chen.

  The global issue of aging populations has become increasingly prominent, thus the research and development for anti-aging therapies to assure longevity as well as to ameliorate age-related complications is put high on the agenda. The young humoral milieu has been substantiated to impart youthful characteristics to aged cells or organs. Extracellular vesicles (EVs) are a heterogeneous group of cell-derived membrane-limited structures that serve as couriers of proteins and genetic material to regulate intercellular communication. Of note, EVs appeared to be an indispensable component of young blood in prolonging lifespans, and circulating EVs have been indicated to mediate the beneficial effect of a young milieu on aging. Human umbilical cord mesenchymal stem cell-derived EVs (HUCMSC-EVs), isolated from the youngest adult stem cell source, are speculated to reproduce the function of circulating EVs in young blood and partially revitalize numerous organs in old animals. Robust evidence has suggested HUCMSC-EVs as muti-target therapeutic agents in combating aging and alleviating age-related degenerative disorders. Here, we provide a comprehensive overview of the anti-aging effects of HUCMSC-EVs in brain, heart, vasculature, kidney, muscle, bone, and other organs. Furthermore, we critically discuss the current investigation on engineering strategies of HUCMSC-EVs, intending to unveil their full potential in the field of anti-aging research.

Keywords:  age-related disorders; anti-aging; extracellular vesicles; mesenchymal stem cells; umbilical cord

DOI:  https://doi.org/10.3390/ijms26010225
ACS Pharmacol Transl Sci. 2025 Jan 10. 8(1): 203-215

Safe and Orally Bioavailable Inhibitor of Serine Palmitoyltransferase Improves Age-Related Sarcopenia.

Johanne Poisson, Ioanna Daskalaki, Vijay Potluri, Jean-David Morel, Sandra Rodriguez-Lopez, Alessia De Masi, Giorgia Benegiamo, Suresh Jain, Tanes Lima, Johan Auwerx.

The accumulation of ceramides and related metabolites has emerged as a pivotal mechanism contributing to the onset of age-related diseases. However, small molecule inhibitors targeting the ceramide de novo synthesis pathway for clinical use are currently unavailable. We synthesized a safe and orally bioavailable inhibitor, termed ALT-007, targeting the rate-limiting enzyme of ceramide de novo synthesis, serine palmitoyltransferase (SPT). In a mouse model of age-related sarcopenia, ALT-007, administered through the diet, effectively restored muscle mass and function compromised by aging. Mechanistic studies revealed that ALT-007 enhances protein homeostasis in Caenorhabditis elegans and mouse models of aging and age-related diseases, such as sarcopenia and inclusion body myositis (IBM); this effect is mediated by a specific reduction in very-long chain 1-deoxy-sphingolipid species, which accumulate in both muscle and brain tissues of aged mice and in muscle cells from IBM patients. These findings unveil a promising therapeutic avenue for developing safe ceramide inhibitors to address age-related neuromuscular diseases.

DOI: https://doi.org/10.1021/acsptsci.4c00587
Geroscience. 2025 Jan 15.

Deep learning reveals diverging effects of altitude on aging.

Amanuel Abraha Teklu, Indra Heckenbach, Michael Angelo Petr, Daniela Bakula, Guido Keijzers, Morten Scheibye-Knudsen.

  Aging is influenced by a complex interplay of multifarious factors, including an individual's genetics, environment, and lifestyle. Notably, high altitude may impact aging and age-related diseases through exposures such as hypoxia and ultraviolet (UV) radiation. To investigate this, we mined risk exposure data (summary exposure value), disease burden data (disability-adjusted life years (DALYs)), and death rates and life expectancy from the Global Health Data Exchange (GHDx) and National Data Management Center for Health of Ethiopia for each subnational region of Ethiopia, a country with considerable differences in the living altitude. We conducted a cross-sectional clinical trial involving 227 highland and 202 lowland dwellers from the Tigray region in Northern Ethiopia to gain a general insight into the biological aging at high altitudes. Notably, we observed significantly lower risk exposure rates and a reduced disease burden as well as increased life expectancy by lower mortality rates in higher-altitude regions of Ethiopia. When assessing biological aging using facial photographs, we found a faster rate of aging with increasing elevation, likely due to greater UV exposure. Conversely, analysis of nuclear morphologies of peripheral blood mononuclear cells (PBMCs) in blood smears with five different senescence predictors revealed a significant decrease in DNA damage-induced senescence in both monocytes and lymphocytes with increasing elevation. Overall, our findings suggest that disease and DNA damage-induced senescence decreases with altitude in agreement with the idea that oxidative stress may drive aging.

Keywords:  Aging; Disease burden; Disease burden data; High altitude; Photoaging; Risk exposure data; Risk factors; Senescence

DOI:  https://doi.org/10.1007/s11357-024-01502-8
Aging Cell. 2025 Jan 16. e14487

V-ATPase Disassembly at the Yeast Lysosome-Like Vacuole Is a Phenotypic Driver of Lysosome Dysfunction in Replicative Aging.

Fiza Hashmi, Patricia M Kane.

  Declines in lysosomal acidification and function with aging are observed in organisms ranging from yeast to humans. V-ATPases play a central role in organelle acidification, and V-ATPase activity is regulated by reversible disassembly in many different settings. Using the yeast Saccharomyces cerevisiae as a replicative aging model, we demonstrate that V-ATPases disassemble into their V1 and V0 subcomplexes in aging cells, with release of V1 subunit C (Vma5) from the lysosome-like vacuole into the cytosol. Disassembly is observed after > 5 cell divisions and results in overall vacuole alkalinization. Caloric restriction, an established mechanism for reversing many age-related outcomes, prevents V-ATPase disassembly in older cells and preserves vacuolar pH homeostasis. Reversible disassembly is controlled in part by the activity of two opposing and conserved factors: the Regulator of Acidification of Vacuoles and Endosomes (RAVE) complex and Oxr1. The RAVE complex promotes V-ATPase assembly and a rav1∆ mutant shortens replicative lifespan; Oxr1 promotes disassembly and an oxr1∆ mutation extends the lifespan. Importantly, the level of Rav2, a subunit of the RAVE complex, declines in aged cells, and Rav2 overexpression delays V-ATPase disassembly with age. These data indicate that reduced V-ATPase assembly contributes to the loss of lysosomal acidification with age, which affects replicative lifespan.

Keywords:   Saccharomyces cerevisiae ; aging; caloric restriction; lysosomes; proton pumps

DOI:  https://doi.org/10.1111/acel.14487
Sci Adv. 2025 Jan 17. 11(3): eadn2811

SMARCA4 regulates the NK-mediated killing of senescent cells.

Virinder Reen, Mariantonietta D'Ambrosio, Pia Pernille Søgaard, Katie Tyson, Bryony J Leeke, Isabelle Clément, Isabel C A Dye, Joaquim Pombo, Adam Kuba, Yemin Lan, Joanna Burr, Ida C Bomann, Maria Kalyva, Jodie Birch, Sanjay Khadayate, George Young, Diane Provencher, Anne-Marie Mes-Masson, Santiago Vernia, Nicholas McGranahan, Hugh J M Brady, Francis Rodier, Raffaella Nativio, Michelle Percharde, Iain A McNeish, Jesús Gil.

Induction of senescence by chemotherapeutic agents arrests cancer cells and activates immune surveillance responses to contribute to therapy outcomes. In this investigation, we searched for ways to enhance the NK-mediated elimination of senescent cells. We used a staggered screen approach, first identifying siRNAs potentiating the secretion of immunomodulatory cytokines to later test for their ability to enhance NK-mediated killing of senescent cells. We identified that genetic or pharmacological inhibition of SMARCA4 enhanced senescent cell elimination by NK cells. SMARCA4 expression is elevated during senescence and its inhibition derepresses repetitive elements, inducing the SASP via activation of cGAS/STING and MAVS/MDA5 pathways. Moreover, a PROTAC targeting SMARCA4 synergized with cisplatin to increase the infiltration of CD8 T cells and mature, activated NK cells in an immunocompetent model of ovarian cancer. Our results indicate that SMARCA4 inhibitors enhance NK-mediated surveillance of senescent cells and may represent senotherapeutic interventions for ovarian cancer.

DOI: https://doi.org/10.1126/sciadv.adn2811
Front Med. 2025 Jan 17.

Metabolism and metabolomics in senescence, aging, and age-related diseases: a multiscale perspective.

Ziyi Wang, Hongying Zhu, Wei Xiong.

  The pursuit of healthy aging has long rendered aging and senescence captivating. Age-related ailments, such as cardiovascular diseases, diabetes, and neurodegenerative disorders, pose significant threats to individuals. Recent studies have shed light on the intricate mechanisms encompassing genetics, epigenetics, transcriptomics, and metabolomics in the processes of senescence and aging, as well as the establishment of age-related pathologies. Amidst these underlying mechanisms governing aging and related pathology metabolism assumes a pivotal role that holds promise for intervention and therapeutics. The advancements in metabolomics techniques and analysis methods have significantly propelled the study of senescence and aging, particularly with the aid of multiscale metabolomics which has facilitated the discovery of metabolic markers and therapeutic potentials. This review provides an overview of senescence and aging, emphasizing the crucial role metabolism plays in the aging process as well as age-related diseases.

Keywords:  age-related diseases; aging; metabolism; metabolomics; senescence

DOI:  https://doi.org/10.1007/s11684-024-1116-0
Nat Aging. 2025 Jan 15.

Aging stem cells limit tumorigenesis.

Yahyah Aman.

DOI: https://doi.org/10.1038/s43587-025-00805-5
Curr Res Physiol. 2025 ;8 100138

From molecular to physical function: The aging trajectory.

Tom A H Janssen, Caroline V Lowisz, Stuart Phillips.

  Aging is accompanied by a decline in muscle mass, strength, and physical function, a condition known as sarcopenia. Muscle disuse attributed to decreased physical activity, hospitalization, or illness (e.g. sarcopenia) results in a rapid decline in muscle mass in aging individuals and effectively accelerates sarcopenia. Consuming protein at levels above (at least 50-100% higher) the current recommended intakes of ∼0.8 g protein/kg bodyweight/d, along with participating in both resistance and aerobic exercise, will aid in the preservation of muscle mass. Physiological muscle adaptations often accompany the observable changes in physical independence an older adult undergoes. Muscle fibre adaptations include a reduction in type 2 fibre size and number, a loss of motor units, reduced sensitivity to calcium, reduced elasticity, and weak cross-bridges. Mitochondrial function and structure are impaired in relation to aging and are worsened with inactivity and disease states but could be overcome by engaging in exercise. Intramuscular connective tissue adaptations with age are evident in animal models; however, the adaptations in collagenous tissue within human aging are less clear. We know that the satellite muscle cell pool decreases with age, and there is a reduced capacity for muscle repair/regeneration. Finally, a pro-inflammatory state associated with age has detrimental impacts on the muscle. The purpose of this review is to highlight the physiological adaptations driving muscle aging and their potential mitigation with exercise/physical activity and nutrition.

Keywords:  Atrophy; Exercise; Inflammaging; Nutrition; Protein; Sarcopenia; Skeletal muscle physiology

DOI:  https://doi.org/10.1016/j.crphys.2024.100138
BMC Genomics. 2025 Jan 13. 26(1): 29

Unravelling the transcriptomic symphony of muscle ageing: key pathways and hub genes altered by ageing and caloric restriction in rat muscle revealed by RNA sequencing.

Gulam Altab, Brian J Merry, Charles W Beckett, Priyanka Raina, Inês Lopes, Katarzyna Goljanek-Whysall, João Pedro de Magalhães.

  Age-related muscle wasting, sarcopenia is an extensive loss of muscle mass and strength with age and a major cause of disability and accidents in the elderly. Mechanisms purported to be involved in muscle ageing and sarcopenia are numerous but poorly understood, necessitating deeper study. Hence, we employed high-throughput RNA sequencing to survey the global changes in protein-coding gene expression occurring in skeletal muscle with age. Caloric restriction (CR) is a known prophylactic intervention against sarcopenia. Therefore, total RNA was isolated from the muscle tissue of both rats fed ad libitum and CR rats. RNA-seq data were subjected to Gene Ontology, pathway, co-expression, and interaction network analyses. This revealed the functional pathways most activated by both ageing and CR, as well as the key "hub" proteins involved in their activation.RNA-seq revealed 442 protein-coding genes to be upregulated and 377 to be downregulated in aged muscle, compared to young muscle. Upregulated genes were commonly involved in protein folding and immune responses; meanwhile, downregulated genes were often related to developmental biology. CR was found to suppress 69.7% and rescue 57.8% of the genes found to be upregulated and downregulated in aged muscle, respectively. In addition, CR uniquely upregulated 291 and downregulated 304 protein-coding genes. Hub genes implicated in both ageing and CR included Gc, Plg, Irf7, Ifit3, Usp18, Rsad2, Blm and RT1-A2, whilst those exclusively implicated in CR responses included Alb, Apoa1, Ambp, F2, Apoh, Orm1, Mx1, Oasl2 and Rtp4. Hub genes involved in ageing but unaffected by CR included Fgg, Fga, Fgb and Serpinc1. In conclusion, this comprehensive RNA sequencing study highlights gene expression patterns, hub genes and signalling pathways most affected by ageing in skeletal muscle. This data may provide the initial evidence for several targets for potential future therapeutic interventions against sarcopenia.

Keywords:  Diet; Functional genomics; Nutrigenomics; Sarcopenia

DOI:  https://doi.org/10.1186/s12864-024-11051-1
Actas Esp Psiquiatr. 2025 Jan;53(1): 49-61

Ginsenoside Rg1 Promotes the Survival, Proliferation, and Differentiation of Senescent Neural Stem Cells Induced by D-galactose.

Peiyu Sun, Shunhe Wang, Ling Hu, Yinhu Huang, Yaping Wang.

BACKGROUND: Neural stem cells (NSCs) disrupt with aging, contributing to neurodegeneration. Ginsenoside Rg1 (Rg1), a compound found in Ginseng, is known for its anti-aging effects; however, its role in the progression of aging NSCs remains unclear. Therefore, this investigation explored the impact of Rg1 on the growth and maturation of aging NSC and elucidated its underlying molecular mechanisms.
METHODS: Initially, mouse models of brain aging were successfully established using D-galactose (D-gal) injection. Mice received Rg1 treatment along with D-gal administration. Brain tissues and NSCs were isolated and analyzed for pathological changes, gene expression, and cellular function. In vitro, experiments used aging NSCs treated with Rg1 to assess cell viability, proliferation, differentiation, and senescence markers.
RESULTS: D-gal triggered aging-related pathological alterations in mouse brains, elevated acetylcholinesterase levels, upregulated senescence genes, and inhibited NSC proliferation (p < 0.05). However, Rg1 treatment mitigated D-gal-induced effects, delayed brain aging, and improved NSC function. In vitro, Rg1 significantly increased cell viability, promoted NSC proliferation and differentiation, reduced senescent neurons, and downregulated p53 and p21 genes (p < 0.05).
CONCLUSIONS: Rg1 demonstrates anti-aging properties in D-gal-induced mouse brain aging, promoting the proliferation and differentiation of NSCs, and downregulating the p53-p21 signaling pathway.

DOI: https://doi.org/10.62641/aep.v53i1.1812
Int J Mol Sci. 2025 Jan 01. pii: 313. [Epub ahead of print]26(1):

Research on Prediction of Multiple Degenerative Diseases and Biomarker Screening Based on DNA Methylation.

Ruoting Tian, Hao Zhang, Chencai Wang, Shengyang Zhou, Li Zhang, Han Wang.

  The aging process will lead to a gradual functional decline in the human body, and even accelerate a significantly increased risk of degenerative diseases. DNA methylation patterns change markedly with one's age, serving as a biomarker of biological age and closely linked to the occurrence and progression of age-related diseases. Currently, diagnostic methods for individual degenerative diseases are relatively mature. However, aging often accompanies the onset of multiple degenerative diseases, presenting certain limitations in existing diagnostic models. Additionally, some identified DNA methylation biomarkers are typically applicable to only one or a few types of cancer or diseases, further restricting their utility. We endeavor to screen for biomarkers associated with multiple degenerative diseases from the perspective of aging-related co-morbid mechanisms and to perform multiple degenerative disease diagnoses. In this study, we explored research based on methylation correlations and patterns to investigate shared mechanisms across multiple degenerative diseases, identifying a set of biomarkers associated with them. We validated these biomarkers with biological omics analysis and the prediction of multiple classes of degenerative diseases, screened the biomarkers from 600 to 110 by biological omics analysis, and demonstrated the validity and predictive ability of the screened 110 biomarkers. We propose a disease diagnostic model based on a multi-scale one-dimensional convolutional neural network (MSDCNN) and a multi-class degenerative disease prediction model (ResDegNet). The two models are well trained and tested to accurately diagnose diseases and categorize four types of degenerative diseases. The research identified 110 biomarkers associated with degenerative diseases, providing a foundation for further exploration of age-related degenerative conditions. This work aims to facilitate early diagnosis, the identification of biomarkers, and the development of therapeutic targets for drug interventions.

Keywords:  DNA methylation; biomarker; degenerative disease

DOI:  https://doi.org/10.3390/ijms26010313
Commun Biol. 2025 Jan 14. 8(1): 51

Chloride intracellular channel CLIC3 mediates fibroblast cellular senescence by interacting with ERK7.

Changjiao Luan, Yue Gao, Jun Zhao, Xiaohui Zhang, Chaofan Wang, Wentao Sun, Yucheng Li, Xinxing Yang, Jiaxiao Chen, Weili Liu, Weijuan Gong, Xingjie Ma.

Cellular senescence (CS) is recognized as a critical driver of aging and age-related disorders. Recent studies have emphasized the roles of ion channels as key mediators of CS. Nonetheless, the roles and regulatory mechanisms of chloride intracellular channels (CLICs) during CS remain largely unexplored. In this study, we conducted RNA sequencing on bleomycin-induced senescent lung tissues from mice and identified Clic3 as the most significantly upregulated CLIC member. Furthermore, our findings revealed that the knockdown of CLIC3 mitigated intracellular chloride ion lose, mitochondrial dysfunction, nuclear enlargement, DNA damage, CS progression, and expression of senescence-associated secretory phenotype (SASP) triggered by bleomycin. Mechanistically, CLIC3 controls CS by translocating to the membrane where it interacts with extracellular signal-regulated kinase 7 (ERK7). Overall, our work demonstrates that the chloride intracellular channel CLIC3 modulates CS by repressing ERK7 activity and provides novel insights into the role of chloride channels.

DOI: https://doi.org/10.1038/s42003-025-07482-5
J Dent Res. 2025 Jan 10. 220345241299789

Dasatinib and Quercetin Limit Gingival Senescence, Inflammation, and Bone Loss.

K Rattanaprukskul, X-J Xia, M Hysa, M Jiang, M Hung, S F Suslavich, S E Sahingur.

  Cellular senescence has emerged as one of the central hallmarks of aging and drivers of chronic comorbidities, including periodontal diseases. Senescence can also occur in younger tissues and instigate metabolic alterations and dysfunction, culminating in accelerated aging and pathological consequences. Senotherapeutics, such as the combination of dasatinib and quercetin (DQ), are being increasingly used to improve the clinical outcomes of chronic disorders and promote a healthy life span through the reduction of senescent cell burden and senescence-associated secretory phenotype (SASP). Recent evidence suggests that senescent cells and SASP can contribute to the pathogenesis of periodontal diseases as well. In this study, we investigated the effect of DQ interventions on periodontal tissue health using preclinical models of aging. In vitro, DQ ameliorated biological signatures of senescence in human gingival keratinocytes upon persistent exposure to periodontal bacteria, Fusobacterium nucleatum, by modulating the levels of key senescence markers such as p16, SA-β-galactosidase, and lamin-B1 and inflammatory mediators associated with SASP including interleukin-8, matrix metalloproteinase (MMP)-1, and MMP-3. In vivo, the oral administration of DQ mitigated senescent cell burden and SASP in gingival tissues and reduced naturally progressing periodontal bone loss in aged mice. Collectively, our findings provide proof-of-concept evidence for translational studies and reveal that targeting gingival senescence and the senescence-associated secretome can be an effective strategy to improve periodontal health, particularly in vulnerable populations.

Keywords:  aging; metabolism; periodontal; senescence associated phenotype (SASP); senescent cell; senotherapy

DOI:  https://doi.org/10.1177/00220345241299789
J Control Release. 2025 Jan 15. pii: S0168-3659(25)00023-9. [Epub ahead of print]379 363-376

Multiple synergistic anti-aging effects of vascular cell adhesion molecule 1 functionalized nanoplatform to improve age-related neurodegenerative diseases.

Siqing Zhu, Yu Zhang, Chang Li, Zhiqing Deng, Ying Yin, Zhufeng Dong, Lei Kuang, Chuanming Li, Xiaoye Hu, Tieying Yin, Yazhou Wang.

  Aging is a critical factor in the onset and progression of neurodegenerative diseases and cognitive decline, with aging-related neuroinflammation and cellular senescence being major contributors. In the aging brain, the cerebral vascular endothelium overexpresses vascular cell adhesion molecule 1 (VCAM1), activating microglia and leading to neuroinflammation and cognitive impairment. Quercetin, a natural neuroprotective agent widely used for treating neurodegenerative diseases, their therapeutic efficacy, however, is limited by its poor water solubility and inability to penetrate the blood-brain barrier (BBB). To address these challenges, we developed a multifunctional micellar platform (Anti-VCAM1-GM1@Q) to improve age-related neurodegenerative diseases. The micelles incorporate anti-VCAM1 antibodies to target cerebral vascular endothelial cells and block VCAM1. Additionally, monosialoganglioside (GM1) was utilized to deliver quercetin due to its biparental properties, high BBB permeability, and neuroprotective effects. Anti-VCAM1-GM1@Q micelles demonstrated strong anti-aging properties. They improved quercetin's bioavailability, effectively penetrated the BBB, targeted cerebral vascular endothelial cells, and reduced neuroinflammation. In animal models, these micelles provided effective neuroprotection, improved memory function and age-related cognitive impairment, and mitigated age-related neurodegeneration. Notably, this system exhibited remarkable treatment efficacy and high safety, indicating substantial potential for clinical translational applications.

Keywords:  Aging; Blood-brain barrier; Cognitive decline; Neurodegenerative disease; Vascular cell adhesion molecule 1 (VCAM1)

DOI:  https://doi.org/10.1016/j.jconrel.2025.01.022
Aging Dis. 2025 Jan 02.

Circadian Rhythms and Lung Cancer in the Context of Aging: A Review of Current Evidence.

Wenhui Xu, Lei Li, Zhendong Cao, Jinghong Ye, Xuyu Gu.

Circadian rhythm is the internal homeostatic physiological clock that regulates the 24-hour sleep/wake cycle. This biological clock helps to adapt to environmental changes such as light, dark, temperature, and behaviors. Aging, on the other hand, is a process of physiological changes that results in a progressive decline in cells, tissues, and other vital systems of the body. Both aging and the circadian clock are highly interlinked phenomena with a bidirectional relationship. The process of aging leads to circadian disruptions while dysfunctional circadian rhythms promote age-related complications. Both processes involve diverse physiological, molecular, and cellular changes such as modifications in the DNA repair mechanisms, mechanisms, ROS generation, apoptosis, and cell proliferation. This review aims to examine the role of aging and circadian rhythms in the context of lung cancer. This will also review the existing literature on the role of circadian disruptions in the process of aging and vice versa. Various molecular pathways and genes such as BMAL1, SIRT1, HLF, and PER1 and their implications in aging, circadian rhythms, and lung cancer will also be discussed.

DOI: https://doi.org/10.14336/AD.2024.1188
PLoS One. 2025 ;20(1): e0317364

Cellular senescence-associated genes in rheumatoid arthritis: Identification and functional analysis.

You Ao, Qing Lan, Tianhua Yu, Zhichao Wang, Jing Zhang.

Rheumatoid arthritis (RA), a long-term autoinflammatory condition causing joint damage and deformities, involves a multifaceted pathogenesis with genetic, epigenetic, and immune factors, including early immune aging. However, its precise cause remains elusive. Cellular senescence, a hallmark of aging marked by a permanent halt in cell division due to damage and stress, is crucial in aging and related diseases. In our study, we analyzed RA microarray data from the Gene Expression Omnibus (GEO) and focused on cellular senescence genes from the CellAge database. We started by selecting five RA datasets from GEO. Next, we pinpointed 29 differentially expressed genes (DEGs) linked to cellular senescence in RA, aligning them with genes from CellAge. We explored the roles of these DEGs in cellular senescence through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. We then pinpointed three key genes (DHX9, CYR61, and ITGB) using random forest and LASSO Cox regression machine learning techniques. An integrated diagnostic model was created using these genes. We also examined the variance in immune cell infiltration and immune checkpoint gene expression between RA and normal samples. Our methodology's predictive accuracy was confirmed in external validation cohorts. Subsequently, RA samples were classified into three distinct subgroups based on the cellular senescence-associated DEGs, and we compared their immune landscapes. Our findings reveal a significant impact of cellular senescence-related DEGs on immune cell infiltration in RA samples. Hence, a deeper understanding of cellular senescence in RA could offer new perspectives for diagnosis and treatment.

DOI: https://doi.org/10.1371/journal.pone.0317364
Genome Med. 2025 Jan 14. 17(1): 2

SenPred: a single-cell RNA sequencing-based machine learning pipeline to classify deeply senescent dermal fibroblast cells for the detection of an in vivo senescent cell burden.

Bethany K Hughes, Andrew Davis, Deborah Milligan, Ryan Wallis, Federica Mossa, Michael P Philpott, Linda J Wainwright, David A Gunn, Cleo L Bishop.

   BACKGROUND: Senescence classification is an acknowledged challenge within the field, as markers are cell-type and context dependent. Currently, multiple morphological and immunofluorescence markers are required. However, emerging scRNA-seq datasets have enabled an increased understanding of senescent cell heterogeneity.
METHODS: Here we present SenPred, a machine-learning pipeline which identifies fibroblast senescence based on single-cell transcriptomics from fibroblasts grown in 2D and 3D.
RESULTS: Using scRNA-seq of both 2D and 3D deeply senescent fibroblasts, the model predicts intra-experimental fibroblast senescence to a high degree of accuracy (> 99% true positives). Applying SenPred to in vivo whole skin scRNA-seq datasets reveals that cells grown in 2D cannot accurately detect fibroblast senescence in vivo. Importantly, utilising scRNA-seq from 3D deeply senescent fibroblasts refines our ML model leading to improved detection of senescent cells in vivo. This is context specific, with the SenPred pipeline proving effective when detecting senescent human dermal fibroblasts in vivo, but not the senescence of lung fibroblasts or whole skin.
CONCLUSIONS: We position this as a proof-of-concept study based on currently available scRNA-seq datasets, with the intention to build a holistic model to detect multiple senescent triggers using future emerging datasets. The development of SenPred has allowed for the detection of an in vivo senescent fibroblast burden in human skin, which could have broader implications for the treatment of age-related morbidities. All code for the SenPred pipeline is available at the following URL: https://github.com/bethk-h/SenPred_HDF .

Keywords:  3D organotypic culture; In vivo senescence detection; Living skin equivalent; Machine learning; Senescence; scRNA-seq

DOI:  https://doi.org/10.1186/s13073-024-01418-0
Int J Mol Sci. 2024 Dec 24. pii: 3. [Epub ahead of print]26(1):

The Potential of Naturally Derived Compounds for Treating Chronic Kidney Disease: A Review of Autophagy and Cellular Senescence.

Yoong Mond Teh, Siti Aisyah Mualif, Nur Izzati Mohd Noh, Soo Kun Lim.

  Chronic kidney disease (CKD) is characterized by irreversible progressive worsening of kidney function leading to kidney failure. CKD is viewed as a clinical model of premature aging and to date, there is no treatment to reverse kidney damage. The well-established treatment for CKD aims to control factors that may aggravate kidney progression and to provide kidney protection effects to delay the progression of kidney disease. As an alternative, Traditional Chinese Medicine (TCM) has been shown to have fewer adverse effects for CKD patients. However, there is a lack of clinical and molecular studies investigating the mechanisms by which natural products used in TCM can improve CKD. In recent years, autophagy and cellular senescence have been identified as key contributors to aging and age-related diseases. Exploring the potential of natural products in TCM to target these processes in CKD patients could slow disease progression. A better understanding of the characteristics of these natural products and their effects on autophagy and cellular senescence through clinical studies, coupled with the use of these products as complementary therapy alongside mainstream treatment, may maximize therapeutic benefits and minimize adverse effects for CKD patients. While promising, there is currently a lack of thorough research on the potential synergistic effects of these natural products. This review examines the use of natural products in TCM as an alternative treatment for CKD and discusses their active ingredients in terms of renoprotection, autophagy, and cellular senescence.

Keywords:  autophagy; cellular senescence; chronic kidney disease; natural product; renoprotective; traditional Chinese medicine

DOI:  https://doi.org/10.3390/ijms26010003
Gen Physiol Biophys. 2025 Jan;44(1): 39-49

Senescence in neural cell lines: comparative insights from SH-SY5Y and ReNcell VM.

Kristina Macova, Diana Mjartinova, Lubica Fialova, Dalibor Nakladal, Dominika Fricova.

Senescence, a crucial yet paradoxical phenomenon in cellular biology, acts as a barrier against cancer progression while simultaneously promoting aging and age-related pathologies. This duality underlines the importance of precise monitoring of senescence response, especially with regard to the proposed use of drugs selectively removing senescent cells. In particular, little is known about the role of senescence in neurons and in neurodegenerative diseases. Our study investigates the senescence response in neuroblastoma SH-SY5Y cells and human neural progenitor ReNcell VM cells exposed to doxorubicin, a chemotherapeutic agent known to induce DNA damage and subsequent senescence. Through a comprehensive analysis employing the most robust senescence markers, we characterized the senescence-associated patterns in these neural cell lines including cellular morphological changes, SA-beta-gal, γH2A.X, p21Waf1/Cip1 and p16Ink4a. Our findings indicate that ReNcell VM cells exhibit greater senescence-associated response at lower doxorubicin concentrations compared to SH-SY5Y cells. Additionally, we observed cell-type-specific differences in timing and levels of the expression of key cell cycle regulators during senescence. Our results emphasize the necessity of cell-type-specific strategies in senescence research with regard to implications as well as limitations for translation into aging and neurodegenerative disorders.

DOI: https://doi.org/10.4149/gpb_2024028