LongeCityNews Last Updated: 25 March 2026 - 10:41 PM

Researchers have identified many contributing issues leading to the characteristic loss of muscle mass and strength that takes place with age. Arguably the central problems are (a) the disruptions of cell behavior caused by chronic inflammation, (b) damage to neuromuscular junctions, depriving muscle tissue of signals it relies upon for normal maintenance to take place, and © loss of muscle stem cell activity, and thus a reduced supply of somatic muscle cells to replace losses. These central problems likely interact with one another, but in principle could be addressed distinctly to produce benefits in patients.

Past studies have shown, rather convincingly, that muscle stem cells in older individuals retain their function when moved from an old environment to a young environment. The problem is not so much damage to these cell populations, but rather their growing lack of activity. Stem cells spend most of their time quiescent, only activating to produce daughter somatic cells when needed. With age, activation of stem cells diminishes for reasons that are only partially explored, and may differ considerably in their details from tissue to tissue. In principle, a greater knowledge and control over stem cell activation could be employed to reduce the age-related loss of muscle tissue, but that requires progress in uncovering specifics of the regulatory systems involved that might be targeted by novel therapeutics.

MG53 in Early Skeletal Muscle Stem Cell Activation: Implications for Aged Muscle Regeneration

Skeletal muscle regeneration declines with age despite the persistence of satellite cells (muscle stem cells, MuSCs), suggesting that regenerative impairment reflects functional dysregulation rather than MuSC depletion. Increasing evidence identifies early MuSC activation during the immediate post-injury period as a stress-sensitive, rate-limiting transition that is particularly vulnerable in aged muscle. Aged MuSCs exhibit elevated stress responses and reduced membrane remodeling capacity, accompanied by weakened activation-associated transcriptional induction. In contrast, proliferative and differentiation programs remain largely intact once activation is successfully initiated.

These findings underscore that impaired coordination during early activation contributes to long-term regenerative decline in aging. Within this framework, MG53 (tripartite motif-containing protein 72, TRIM72), a muscle-enriched TRIM family E3 ubiquitin ligase originally identified as a mediator of sarcolemmal membrane repair, may also function as a stress-responsive regulator that stabilizes the early activation environment. Rather than directly determining cell fate, MG53 is proposed to facilitate activation by mitigating stress-associated membrane disruption and maintaining programmatic coordination under age-related physiological constraints.

However, direct experimental evidence defining the role of MG53 in the early activation of aged MuSCs remains limited. Current data primarily support its functions in membrane stabilization, oxidative stress mitigation, and inflammatory modulation. Whether these stress-buffering properties directly influence the early activation transition in aging muscle has not yet been formally tested. In this review, we suggest that MG53 may contribute to the regulation of early MuSC activation under conditions of elevated cellular stress in aged muscle. Clarifying this potential role represents an important direction for future mechanistic investigation.

A new study identified two polyunsaturated fatty acids, α-eleostearic acid (α-ESA) and α-ESA methyl ester (α-ESA-me), that showed senolytic activity in cell cultures and a mouse model [1].

An anti-aging strategy

Cellular senescence is one of the most critical aging-related processes. Senescent cells, which accumulate with age, are arrested in the cell cycle and are resistant to cell death. The inflammatory senescence-associated secretory phenotype (SASP) factors they release have detrimental effects on the surrounding cellular environment and contribute to many age-related diseases, such as diabetes, cancer, osteoarthritis, and Alzheimer’s disease [2, 3, 4].

Targeting senescent cells has been widely investigated as an anti-aging strategy. While progress has been made and several senolytics that eliminate senescent cells have been identified, many have substantial side effects, preventing their widespread use [5, 6, 7]. Therefore, there is still a need to identify safer and effective options. The researchers of this study focused on fatty acids, natural compounds with various therapeutic effects [8], and investigated their potential as senolytics.

In search of senolytics

The researchers began their study by using senescent cell cultures to screen fatty acids that were previously reported to have health benefits and dietary functions [8]. They observed that the structural features of certain fatty acids were correlated with their potential for senolytic activity.

While there doesn’t seem to be a simple correlation between senolytic activity and carbon chain length, other structural features, such as the position and configuration of double bonds in fatty acids, appeared to influence senolytic activity, with some fatty acids showing senolytic activity in one configuration but not the other. Esterification and conjugation, in which double bonds are not separated by multiple single bonds but occur in an alternating pattern, also affected senolytic activity; for example, most unconjugated fatty acids lacked senolytic activity.

Based on this screen, two fatty acids were selected: the most potent senolytic, α-eleostearic acid (α-ESA), and the most selective senolytic, α-ESA methyl ester (α-ESA-me), both of which are 18-carbon conjugated fatty acids.

Senolysis without toxicity

Identified fatty acids were further tested in various models, including mice and human cell lines with senescence induced by multiple stressors. Those tests confirmed robust senolytic activity of α-ESA and α-ESA-me; however, there was some cell-specific variability. There were also some differences between the two fatty acids. For example, α-ESA showed greater potency and induced senolysis more rapidly, whereas α-ESA-me showed higher selectivity and a more stable, long-lasting effect.

In addition to cell culture testing, the researchers tested the two fatty acids in naturally aged mice (20-22 months) by treating them for 5 days. α-ESA-me was more effective in reducing tissue senescence, especially in the liver and heart. In even older (32-month) mice, “α-ESA-me significantly reduced senescence and SASP factors in multiple tissues” with the strongest effects in kidney, liver, and lung tissues.

Since the effect of α-ESA-me was stronger, it was further tested in progeric mice. A short-term (3-day treatment) led to a reduction in senescence markers and SASP factors. α-ESA-me long-term treatment (three times per week for 6 weeks, starting at 10 weeks of age) led to decreased DNA damage, senescence, and SASP markers, a reduction in the composite score of aging symptoms, and an increase in the number of proliferating cells, all without showing systemic toxic effects. These observations point to α-ESA-me’s senolytic activity and rejuvenating potential.

Going after the mechanism

Furthermore, the researchers investigated the mechanism underlying α-ESA- and α-ESA-me-induced senescent cell death. First, the researchers ruled out the possibility that cells may be converting α-ESA and α-ESA-me into metabolites that play a role in these compounds’ senolytic activity.

The next line of investigation was whether α-ESA and α-ESA-me act by inducing programmed cell death (apoptosis), as is the case with most senolytics. Investigations into different forms of cell death pointed that it wasn’t apoptosis, but ferroptosis, an “iron-dependent form of programmed cell death triggered by the accumulation of ROS and lipid peroxidation” [9], since blocking ferroptosis-related pathways stopped α-ESAs from inducing cell death. Additionally, a gene expression analysis in the treated senescent cells suggested that α-ESA and α-ESA-me can initiate a ferroptosis-associated transcriptional program and confirmed ferroptosis as a key player in the selective elimination of senescent cells treated with these fatty acids.

To gain further insights, the researchers used a machine learning approach that suggested that these two α-ESAs had molecular pathway interaction profiles similar to those of several known senolytic compounds, such as dasatinib and quercetin, and ferroptosis inducers, such as erastin and sulfasalazine, at a global level. However, compared to those compounds, α-ESAs had a low probability of systemic toxicity while having high oral bioavailability and blood-brain barrier permeability. The results also suggested that α-ESAs might not directly interact with proteins involved in cell-cycle arrest and senescence signaling but may exert an indirect impact.

An in silico analysis identified a potential role for ferroptosis-related pathways and a few proteins (ACSL4, LPCAT3, and ALOX15) as essential for α-ESA-induced senolysis. Inhibiting each of those enzymes significantly protected cells from α-ESA-induced ferroptosis, experimentally confirming that each of those enzymes is necessary for α-ESA’s senolytic effect.

Those results, combined with additional lipidomics experiments, suggested a possible mechanism for α-ESA and α-ESA-me senolytic activity. It appeared that senescent cells have increased levels of ferrous ions and ROS compared to non-senescent cells, and increased iron levels in senescent cells facilitate increased ROS production.

This process is enhanced by α-ESA and α-ESA-me, as their chemical structures make them highly prone to radical formation and propagation, thereby contributing to lipid radical production. In this process, α-ESAs are used as highly oxidizable ‘‘fuel’’ that is further used by the ACSL4-LPCAT3-ALOX15 axis and incorporated in the membrane, leading to the loss of membrane integrity and ferroptotic senolysis.

“This paper is the first to show that lipids can function as senolytics by triggering a distinct form of cell death, called ferroptosis, unlike most current senolytic strategies,” said Paul Robbins, corresponding author of the study, Ph.D., professor at the University of Minnesota Medical School and College of Biological Sciences, and associate director of the Masonic Institute on the Biology of Aging and Metabolism. “Our study reveals that ferroptosis represents a distinct and targetable vulnerability in certain types of senescent cells. Thus, this work opens a new direction for designing senolytic therapies that leverage ferroptotic biology and demonstrates the therapeutic potential of specific bioactive fatty acids.”

Literature

[1] Zhang, L. J., Salekeen, R., Soto-Palma, C., Elsallabi, O., Ye, H., Hughes, B., Zhang, B., Nunes, A., Lee, K.-A., Xu, W., Mohamed, A., Piepgras, E., McGowan, S. J., Angelini, L., O’Kelly, R., Han, X., Niedernhofer, L. J., & Robbins, P. D. (2026). Polyunsaturated lipid senolytics exploit a ferroptotic vulnerability in senescent cells. Cell Press Blue, 100004.

[2] Childs, B. G., Durik, M., Baker, D. J., & van Deursen, J. M. (2015). Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nature medicine, 21(12), 1424–1435.

[3] Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., van de Sluis, B., Kirkland, J. L., & van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232–236.

[4] He, S., & Sharpless, N. E. (2017). Senescence in Health and Disease. Cell, 169(6), 1000–1011.

[5] Prašnikar, E., Borišek, J., & Perdih, A. (2021). Senescent cells as promising targets to tackle age-related diseases. Ageing research reviews, 66, 101251.

[6] Zhang, L., Pitcher, L. E., Prahalad, V., Niedernhofer, L. J., & Robbins, P. D. (2021). Recent advances in the discovery of senolytics. Mechanisms of ageing and development, 200, 111587.

[7] Kirkland, J. L., & Tchkonia, T. (2020). Senolytic drugs: from discovery to translation. Journal of internal medicine, 288(5), 518–536.

[8] Kremmyda, L. S., Tvrzicka, E., Stankova, B., & Zak, A. (2011). Fatty acids as biocompounds: their role in human metabolism, health and disease: a review. part 2: fatty acid physiological roles and applications in human health and disease. Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia, 155(3), 195–218.

[9] Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., Patel, D. N., Bauer, A. J., Cantley, A. M., Yang, W. S., Morrison, B., 3rd, & Stockwell, B. R. (2012). Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell, 149(5), 1060–1072.

It has been fifteen years since the first compelling demonstration of clearance of senescent cells in mice. That study paved the way for the transformation of the research community into one convinced of the relevance of cellular senescence to degenerative aging. It also helped to change the culture of aging research more generally, one of the important contributions to a shift in attitudes that has led to a research and development community that understands the treatment of aging as a medical condition to be a practical, desirable goal. Here, discuss the role of cellular senescence in muscle aging specifically; how it contributes to harm and lost function, and what might be done about it.

Cellular senescence is increasingly recognized as a pivotal mechanism driving skeletal muscle aging and the development of sarcopenia, a condition characterized by the progressive loss of muscle mass, strength, and function. This review synthesizes recent evidence detailing the accumulation of senescent cells in aged skeletal muscle, including muscle stem cells (MuSCs), fibro-adipogenic progenitors (FAPs), immune cells, endothelial cells, and even post-mitotic myofibers. Senescence in these cell types impairs regenerative signaling, disrupts niche homeostasis, and propagates chronic inflammation.

Emerging therapeutic strategies, termed senotherapeutics, aim to counteract these effects through senolytics (which eliminate senescent cells) and senomorphics (which modulate the senescence-associated secretory phenotype), as promising interventions to restore muscle function and delay sarcopenia. We will also discuss the remaining challenges and future directions for studying senescence in skeletal muscle.

Link: https://doi.org/10.3803/EnM.2025.2816

There is a reasonable consensus in the research community on the broad categories of issue that lead to and are associated with the aging of the immune system. One can start by dividing immune aging into immunosenescence, a loss of capacity, versus inflammaging, a continual state of unresolved inflammatory signaling, and look at the various contributions to each state, for example. This paper is chiefly interesting for the attempt to propose classes of intervention to address immune aging based on the categorization of issues provided. This would not have been the case twenty years ago; the paper would have outlined what was known of immune aging and possible causes and then stopped. It is a reminder that we now live in an era in which the treatment of aging as a medical condition is widely accepted as an aspirational goal for the life sciences.

Immune aging is best understood not as a collection of isolated defects, but as a complex, interconnected reconfiguration of immune and tissue networks that alters how the body responds to internal and external stressors. Aging causes coordinated changes in innate and adaptive immunity, metabolic pathways, and inter-organ communication, creating a web of interactions whose emergent properties differ fundamentally from those of younger systems. Therapeutic targeting of immune aging aims to rebalance dysregulated inflammatory networks, restore immune adaptability, and improve tissue repair capacity. Current approaches range from mechanistically targeted pharmacological agents to regenerative, metabolic, lifestyle, and precision strategies. Evidence strength varies considerably, with some interventions supported by early clinical data and others remaining primarily experimental.

Interventions directed at fundamental drivers of immune aging, including chronic inflammatory signaling and cellular senescence, represent the most mechanistically advanced therapeutic class. Modulation of the mechanistic target of rapamycin (mTOR) pathway - through agents such as rapamycin and its analogs - has been shown to recalibrate immune metabolism, attenuate excessive inflammatory signaling, mitigate components of the senescence-associated secretory phenotype (SASP), and enhance antiviral responses in older adults, with early-phase clinical trials providing supportive evidence of immunological benefit. However, potential risks include metabolic dysregulation, impaired wound healing, and dose-dependent immunosuppression, emphasizing the need for intermittent or low-dose regimens.

Targeting intracellular inflammatory signaling represents a complementary strategy to rebalance immune network activity. Inhibitors of p38 mitogen-activated protein kinase (p38 MAPK) can restore macrophage functionality, enhance efferocytosis, and promote pro-resolving phenotypes in aging models. While mechanistically attractive, long-term systemic kinase inhibition may carry risks related to host defense impairment and unintended metabolic effects.

Cellular and regenerative interventions aim to restore immune architecture and adaptive capacity. Mesenchymal stem cells (MSCs)-based therapies exhibit immunomodulatory and tissue-repair properties, with encouraging preclinical and early clinical data suggesting benefits for inflammatory dysregulation and impaired regeneration. However, heterogeneity in cell preparations, uncertain durability of effects, and potential tumor-promoting signals remain key concerns. Reconstitution of adaptive immune output through thymic and hematopoietic rejuvenation represents an emerging but strategically important avenue. Beyond IL-7 supplementation, several molecular regulators are under investigation. Forkhead box N1 (FOXN1)-associated pathways, keratinocyte growth factor (KGF), and fibroblast growth factor (FGF) 21 contribute to thymic epithelial integrity and naive T-cell production, with preclinical evidence indicating delayed thymic involution and improved immune function.

Modulation of the gut microbiome through dietary fiber, prebiotics, probiotics, and microbiome-directed therapies can influence systemic inflammation and immune regulation. Diets rich in fiber and prebiotics, targeted probiotic supplementation, and microbiome-directed interventions can enhance gut barrier integrity, promote beneficial microbial taxa, and reduce translocation-induced inflammaging, thereby influencing systemic immune function and inflammatory set points. Improvements in barrier integrity and microbial metabolite production may reduce translocation-driven inflammatory activation. While mechanistically promising and supported by observational studies, variability between individuals and limited standardized clinical trials currently restrict therapeutic generalization.

Link: https://doi.org/10.3390/cells15050414