Fight Aging!

A tumor is a battleground of cell behavior and cell signaling. All cells can influence the behavior of surrounding cells via the signals they produce, and the evolution of cancerous cells that exhibit unfettered replication and continual mutation might be thought of as a blind search for whatever will trigger surrounding cells into assisting with more rapid growth. One of the most effective outcomes for tumor cells is to produce signals that can suppress the anti-cancer activities of the immune system. This capability is near universal for solid tumors, as without the ability to co-opt immune cells the tumor would likely never have come into being in the first place.

The innate immune cells known as macrophages are important in normal tissue maintenance and regeneration, and are particularly important in both suppression and growth of cancers. So are cells that have become senescent, that cease to replicate and secrete signals to rouse the immune system to action. Macrophage presence and cellular senescence are initially protective against cancer: senescence of damaged cells draws the attention of macrophages and other immune cells to destroy those cells before they can become cancerous. Macrophages and senescent cells are later co-opted into supporting tumor growth, however, in much the same way in which they interact to promote regenerative growth following injury. In today's open access paper, researchers discuss the overlap between these two considerations, the presence of senescent macrophages in tumor tissue. As they report, a great deal is known, but these are complex biochemistries, and much remains to be established.

Senescent macrophages in tumor: phenotypes, roles, and interventions

The tumor microenvironment (TME) refers to the local region in which tumor cells reside, incorporating a diverse array of non-tumor cell types, extracellular matrix (ECM) components, vascular networks, and soluble factors. This intricate milieu is critical in modulating tumor behavior and influencing therapeutic responses. TME-associated senescent cells manifest a dualistic role: on the one hand, senescence TME statue can inhibit tumor progression by slowing their proliferation; conversely, the dynamic interplay of immune cell functions and cytokines produced by senescent cells allows these senescence-associated factors to modify the immune escape mechanisms within the TME, thereby significantly promoting tumor growth and the spread of cancer to distant sites.

Macrophages are essential components of innate and adaptive immunity and are one of the major infiltrating immune cells in TME. These macrophages are known as tumor-associated macrophages (TAMs) and play a dual role in tumor initiation and progression, acting as promoters and tumorigenesis suppressors. Macrophages can be classified into two distinct subtypes, also known as the polarization states of macrophages: M1 type and M2 type. M1 macrophages are classically triggered, pro-inflammatory cells that exert direct tumor-suppressive effects by secreting pro-inflammatory cytokines, such as interleukin-6 (IL-6), and generating reactive oxygen species and reactive nitrogen species, all of which contribute to the amplification of anti-tumor immune responses. In contrast, M2 macrophages release immunosuppressive mediators, including IL-4, IL-10, and transforming growth factor-beta (TGF-β), which inhibit T cell and natural killer (NK) cell functionality, promote angiogenesis, and facilitate tumor cell invasion, thereby contributing to tumor progression.

Contrary to the disordered proliferation of tumor cells, immune cells such as macrophages present a state of exhaustion or senescence-related reprogramming in TME. As aging progresses, macrophages exhibit a progressive decline in phagocytic capacity, respiratory burst activity, levels of toll-like receptors (TLRs) and MHC class II (MHC-II), responsiveness to antigenic triggers, and the release of pro-inflammatory chemokines and cytokines, suggesting that the senescence of macrophages occurs with aging, and the molecular changes of senescent macrophages (sMACs) disrupt the regular immune cell dialog. In addition, in vivo animal experiments showed that elimination of sMACs could inhibit tumor growth, suggesting the clinical significance of combination therapy targeting sMACs. Nonetheless, there is still a lack of consensus regarding the characteristic phenotypes of sMACs within the TME and their mechanistic roles. This review aims to provide an overview of the current understanding of the tumor infiltration-sMACs, summarize the molecular characteristics and functional abnormalities of sMACs, and discuss the potential roles and interventions of sMACs.

Researchers here explain that one of the challenges involved in the development of cancer vaccines lies in finding ways to provoke a sufficiently robust response from the immune system. The larger the number of distinct sensing mechanisms that can be triggered by a vaccine, the more roused the immune system becomes. But cancer vaccines tend to be based on a single antigen that identifies a distinctive cancer cell surface feature and single immune-provoking molecule that works via only one of the many possible immune activation pathways. Thus researchers here build and test a nanoparticle platform that allows for the assembly and delivery of a mix of molecules that interact with multiple immune-provoking pathways, intended to induce the immune system into a greater, more sustained response to a cancer-targeted antigen.

While vaccination has emerged in recent years as a powerful frontier in the development of effective cancer therapies by training adaptive immune cells to recognize and eliminate tumor cells, effective adjuvanticity has remained a hurdle. Vaccines have two essential components: an antigen, which is uniquely expressed on the pathogen (or cancer cell), and an adjuvant, which activates the innate costimulatory signaling critical for priming an adaptive immune response. Historically, infectious disease vaccine design has transitioned from whole-pathogen vaccines to modern-day subunit vaccines to mitigate the risk of infection upon inoculation, but this shift has introduced notable trade-offs in efficacy. Chief among these limitations is that subunit vaccines largely include only single-adjuvant formulations, unlike their whole-pathogen counterparts, which include multiple innate immune agonists (or adjuvants) that together provide robust adjuvanticity.

Here, we use a versatile nanomaterials engineering approach to address this critical gap and report on the development and testing of a dual-adjuvant lipid-based nanoparticle system, termed "super-adjuvant" nanoparticles, that promotes powerful vaccine-specific immune responses when co-delivered with tumor antigen or lysate and directed to lymph nodes as a prophylactic approach. We focus here on the specific attributes of lipid-based nanomaterials, which enable co-encapsulation of hydrophilic and hydrophobic agonists on the same nanoparticle, synthesis within a small ∼30-60-nm-size window for rapid draining to lymph nodes and ready uptake by target dendritic cells, and "stealth" poly ethylene glycol (PEG) surface functionalization for physiological solubility.

We use a neutral lipid matrix to co-encapsulate hydrophilic cyclic-di guanosine monophosphate (cdGMP), an agonist of the STING pathway, and hydrophobic monophosphoryl lipid A (MPLA), an agonist of the Toll-like receptor 4 (TLR4) pathway together on the same nanoparticle for co-delivery to the same target dendritic cell. Previously delivered as a systemic formulation and directed to tumors, we demonstrated that dual-adjuvant nanoparticles promoted interferon (IFN)-β-mediated expansion of tumor antigen-presenting cells, such as dendritic cells, macrophages, and natural killer cells, and harnessed CD8+ T cell-mediated anti-tumor control for clearance.

Link: https://doi.org/10.1016/j.xcrm.2025.102415

Physical fitness confers a great many benefits. Based on the broad evidence for reduced mortality and improved health, it is worth the effort required to maintain an above average level of fitness into later life. The research noted here is one of many studies to look at specific immunological differences between relatively fit and relatively unfit older individuals. It is well understood that greater fitness produces improved immune function, but the immune system is very complex and there is a great deal of room for further exploration of the fine details.

Aging is associated with immune dysfunction, but long-term endurance training may confer protective effects on immune cell function. This study investigates how natural killer (NK) cell phenotypes, functional markers, and metabolism differ between endurance-trained and untrained older adults. Ex vivo expanded NK cells from endurance-trained (63.6 ± 2.1 years) and untrained (64.3 ± 3.3 years) males were exposed to adrenergic blockade (propranolol; 0-200 ng/mL) or mTOR inhibition (rapamycin; 10-100 ng/mL), both with or without inflammatory stimulation induced by phorbol 12-myristate 13-acetate (PMA). Flow cytometry assessed NK subsets, activation (CD38, CD57, CD107a, NKG2D), senescence (KLRG1), and inhibitory markers (PD-1, LAG-3, TIM-3, NKG2A). Seahorse analysis measured mitochondrial metabolic parameters.

Trained participants displayed healthier immune profiles (lower neutrophil-to-lymphocyte ratio and Systemic Immune-Inflammation Index) and higher effector NK cells with lower cytotoxic subsets. Propranolol at 100 ng/mL blunted PMA-driven increases in CD57, CD107a, and NKG2D, while potentiating regulatory markers KLRG1, LAG-3, and PD-1 in the trained group, indicating stronger immunoregulation. With rapamycin, trained NK cells preserved NKG2D and CD107a at 10 ng/mL, maintaining cytotoxicity and degranulation. In contrast, at 100 ng/mL rapamycin plus PMA, trained NK cells shifted toward an effector phenotype with higher CD57 and CD107a, yet a blunted PMA-increased LAG-3 and TIM-3, suggesting resistance to exhaustion. PD-1 and KLRG1 remained elevated, reflecting balanced immune control.

Mitochondrial analysis revealed that trained NK cells exhibited higher basal and maximal oxygen consumption rate, greater spare respiratory capacity, and oxygen consumption rate to extracellular acidification rate ratio, reflecting superior metabolic fitness. These findings indicate that endurance-trained older adults have NK cells with greater functional adaptability, reduced senescence, and enhanced metabolism under inflammatory and pharmacological stress.

Link: https://doi.org/10.1038/s41598-025-06057-y

Naked mole-rats live as much as nine times longer than similarly sized rodent species, suffer little age-related decline of function until very late life, and there are next to no examples of individuals in captivity suffering from cancer. Researchers have spent more than twenty years investigating the biochemistry of this species, in search of the reasons for their longevity and resistance to cancer. As for other areas of the study of the comparative biology of aging, the hope is that some of these findings could form the basis for therapies to treat cancer and slow aging in humans. Whether this is the case remains to be seen; researchers have only comparatively recently reached the point of identifying specific differences that might be relevant, and then introducing those differences into mice and other laboratory species to observe the results.

One of the noteworthy differences in naked mole rat cellular biology is that the species exhibits far more efficient DNA repair than is the case in most other mammals. This may contribute to both slowed aging and resistance to cancer, and so has attracted the attention of researchers. Today's paper is an example of progress on this front, in which the authors report that cGAS in naked mole rats has different sequence that encourages more efficient DNA repair. cGAS is more commonly discussed in the context of inflammation, as it is a sensor for mislocalized DNA in the cell cytosol, a part of the innate immune system intended to detect infectious pathogens and raise the alarm. Evolution tends to produce proteins with multiple distinct functions, however, and so in the cell nucleus cGAS has a different role, participating in the regulation of DNA repair. The researchers show that naked mole rat cGAS alterations can extend life in flies when introduced into that species, and reduce aspects of aging when delivered to mice via gene therapy, an interesting result.

A cGAS-mediated mechanism in naked mole-rats potentiates DNA repair and delays aging

DNA repair constitutes a crucial mechanism for stabilizing the genome. Earlier studies have demonstrated that the DNA sensor cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) participates in regulating DNA double-strand break repair by suppressing the homologous recombination (HR) pathway, thereby promoting genomic instability. Although enhanced function of DNA repair proteins contributes to the evolution of longevity, it remains unexplored whether evolution has selected for the attenuation of negative regulators such as cGAS.

In a panel of assays, we found that naked mole-rat cGAS, in contrast to human and mouse cGAS, enhanced HR repair efficiency. This functional reversal is mediated by the substitution of four specific amino acid residues within the C-terminal domain of the cGAS protein. Mechanistically, this amino acid alteration enabled naked mole-rat cGAS to prolong its retention on chromatin in the wake of DNA damage by modulating its ubiquitination status, thereby altering its interaction with the segregase P97. The prolonged presence of naked mole-rat cGAS on chromatin facilitated the formation of a complex between the canonical HR factor RAD50 and FANCI, a factor primarily associated with the Fanconi anemia pathway. We further demonstrated that FANCI promoted the chromatin recruitment of RAD50, thereby potentiating HR repair.

Consequently, naked mole-rat cGAS attenuated stress-induced cellular senescence, mitigated organ degeneration, and extended life span in fruit flies. Critically, reverting these four amino acid residues abolished these protective effects. Furthermore, adeno-associated virus-mediated delivery of naked mole-rat cGAS to aged mice reduced frailty, attenuated hair graying, lowered circulating levels of immunoglobulin G and interleukin-6, and decreased cellular senescence markers in multiple tissues. Once again, these beneficial effects were dependent on the four specific amino acids.

It remains to be seen as to whether xenotransplantation of organs from genetically engineered pigs will be competitive in comparison to the tissue engineering of new organs. Even given the challenges faced to date, it seems likely that xenotransplanation will be a going concern before the manufacture of viable tissue engineered organs. Initial trials in patients volunteers have taken place for the heart and kidney. As the report here illustrates, the last mile of discovery in which pig organs are transplanted into the first volunteers is likely to require as much work and reveal as many unforeseen issues as was the case for the earlier stages of development, in which the need for genetic engineering of the donor pigs was discovered.

The advent of genetically edited porcine-to-human xenotransplantation has predominantly focused on cardiac and renal applications, with no reported cases of porcine-to-human liver xenotransplantation. This study presents the world's first successful genetically modified pig auxiliary liver xenotransplantation in a living human, achieving an unprecedented survival of 171 days, and provides valuable insights into the critical factors influencing the procedure's success.

A genetically modified pig liver, incorporating 10 targeted gene edits, was transplanted as an auxiliary organ into a 71-year-old patient with large hepatocellular carcinoma in the right hepatic lobe, which was initially deemed ineligible for curative resection. Liver function, metabolic, and coagulation markers were closely monitored throughout the perioperative period.

For the first 31 days post-transplant, no hyperacute or acute rejection, infections, or significant complications were observed, and the patient's hepatic and renal functions remained stable. Early postoperative coagulopathy, as indicated by elevated D-dimer and fibrin degradation products, was successfully managed through anticoagulant therapy. However, on postoperative day 38, the auxiliary liver was removed due to xenotransplantation-associated thrombotic microangiopathy (xTMA). Subsequent management with eculizumab and plasma exchange successfully resolved the xTMA. Unfortunately, repeated upper gastrointestinal hemorrhage ultimately led to the patient's death on day 171.

Link: https://doi.org/10.1016/j.jhep.2025.08.044

A number of studies have suggested that people who survive to extreme old age exhibit better immune function throughout later life in comparison to peers who died at earlier ages. This analysis is an example of the type, and the data shows a natural killer cell population that exhibits signs of greater efficiency and more youthful activity. How and why long-lived individuals exhibit better immune function is a separate question. Studies of genetic variation in very large human data sets suggest that genetics plays a much smaller role in late life survival than the consequences of lifestyle choices (such as physical fitness) and environmental exposures (such the burden of infectious disease).

Centenarians are an established model of successful and healthy ageing. Previous research on centenarians' immune systems has been limited to small-scale studies using a single methodology, such as flow cytometry or targeted gene expression analyses. However, these studies lacked comprehensive multi-omics integration and validation across diverse cohorts.

This study integrated single cell RNA sequencing (scRNA-seq), mass cytometry, and flow cytometry to analyse peripheral blood mononuclear cells (PBMCs) from 31 centenarians, 17 centenarian offspring, and 26 offsprings' spouses or neighbours as controls across three cohorts to generate a multi-omics atlas of centenarian immune status. Through comprehensive analysis, we showed that centenarians possess natural killer (NK) cells with "young" signatures and enhanced cytotoxicity linked to RUNX3 upregulation. Reinforced NK cell-T cell interactions via the MHC-I and MIF pathways promoted T cell function in centenarians. The study overcomes the limitations of prior studies by combining high-resolution single-cell data with functional assays, offering a unified model of immune health in extreme ageing.

Our findings, combined with existing evidence, redefine healthy immune ageing by demonstrating that centenarians maintain cytotoxic and regulatory balance through unique NK and T cell adaptations. For researchers, our study establishes a framework for exploring immune resilience, emphasising multi-omics approaches. For clinicians, targeting the identified pathways (RUNX3, MHC-I, or MIF) could help delay age-related immune decline, potentially reducing susceptibility to infections, cancer, and chronic inflammation.

Link: https://doi.org/10.1016/j.ebiom.2025.105922

Amyloid-β is an anti-microbial peptide, a component of the innate immune system. In the brain it is best known for increasing with age, misfolding, and then aggregating into toxic deposits. The presence of these aggregrates is thought to be the initial cause of Alzheimer's disease, eventually inducing the late stage mechanisms of neuroinflammation and tau aggregation that kill neurons and ultimately kill the patient. On its own, it seems likely that amyloid-β aggregation is capable of producing only mild cognitive impairment. Nonetheless, amyloid-β remains the primary target of research and development for the treatment of Alzheimer's disease.

Amyloid-β doesn't only exist in the brain. The body and the brain are separated by the blood-brain barrier that polices which molecules can pass, and in what amounts. Amyloid-β can move between body and brain via the blood-brain barrier, and the amounts of amyloid-β on the two sides exist in a state of dynamic equilibrium. Researchers have demonstrated that clearing amyloid-β from the vasculature can encourage its exit from the brain, and that approach has reached fairly late stages of clinical development. Separately, amyloid-β should be cleared from the brain via the various pathways that drain cerebrospinal fluid - the glymphatic system and the cribriform plate, both of which become dysfunctional with age. A few research and development programs are focused on restoring flow via one path or another; Leucadia Therapeutics is nearing clinical trials for their approach.

Today's open access paper reports a novel approach to draining amyloid-β from the brain via the blood-brain barrier, by upregulating the mechanisms involved in the normal export process. The fine details are somewhat complex, but involve adjusting the balance of materials presented for uptake to blood-brain barrier cells in order to prevent the cell from downregulating the expression and recycling of the LRP1 receptor used to take up amyloid-β. Cells tend to constantly shift levels of receptors used for uptake in response to circumstances, and downregulation of frequently used receptors is a common outcome that acts to prevent runaway uptake of any specific molecule. It is possible to confuse the underlying regulatory processes inside the cell by delivering carefully crafted materials that are taken up via other pathways, however.

Rapid amyloid-β clearance and cognitive recovery through multivalent modulation of blood-brain barrier transport

The blood-brain barrier (BBB) is a highly selective permeability barrier that safeguards the central nervous system (CNS) from potentially harmful substances while regulating the transport of essential molecules. Its dysfunction is increasingly recognized as a pivotal factor in the pathogenesis of Alzheimer's disease (AD), contributing to the accumulation of amyloid-β (Aβ) plaques.

We present a novel therapeutic strategy that targets low-density lipoprotein receptor-related protein 1 (LRP1) on the BBB. Our design leverages the multivalent nature and precise size of LRP1-targeted polymersomes to modulate receptor-mediated transport, biasing LRP1 trafficking toward transcytosis and thereby upregulating its expression to promote efficient Aβ removal.

In AD model mice, this intervention significantly reduced brain Aβ levels by nearly 45% and increased plasma Aβ levels by 8-fold within 2 hours, as measured by ELISA. Multiple imaging techniques confirmed the reduction in brain Aβ signals after treatment. Cognitive assessments revealed that treated AD mice exhibited significant improvements in spatial learning and memory, with performance levels comparable to those of wild-type mice. These cognitive benefits persisted for up to 6 months post-treatment.

This work pioneers a new paradigm in drug design, where function arises from the supramolecular nature of the nanomedicine, harnessing multivalency to elicit biological action at the membrane trafficking level. Our findings also reaffirm the critical role of the BBB in AD pathogenesis and demonstrate that targeting the BBB can make therapeutic interventions significantly more effective. We establish a compelling case for BBB modulation and LRP1-mediated Aβ clearance as a transformative foundation for future AD therapies.

It seems clear that it is a good idea to remove the excess senescent cells generated by a cancer therapy after the cancer is defeated, or at the very least permanently suppress the inflammatory signaling generated by those senescent cells. The added burden of cellular senescence carried by cancer survivors is likely a major contribution to a shorter life expectancy and raised risk of age-related disease. Whether it is a good idea to remove or alter the behavior of senescent cells during cancer therapy, while a cancer is still active, remains a debated topic. The answer may be different on a cancer by cancer basis. The presence of senescent cells can both harm and help the growth of cancerous cells, but which effects dominate in any given context may be hard to determine in advance, depending on the biochemistry of the cancer, tissue type, number of senescent cells, and other factors.

The aging microenvironment, as a key driver of tumorigenesis and progression, plays a critical role in tumor immune regulation through one of its core features - the senescence-associated secretory phenotype (SASP). SASP consists of a variety of interleukins, chemokines, proteases, and growth factors. It initially induces surrounding cells to enter a state of senescence through paracrine mechanisms, thereby creating a sustained inflammatory stimulus and signal amplification effect within the tissue microenvironment. Furthermore, these secreted factors activate key signaling pathways such as NF-κB, cGAS-STING, and mTOR, which regulate the expression of immune-related molecules (such as PD-L1) and promote the recruitment of immunosuppressive cells, including regulatory T cells and myeloid-derived suppressor cells. This process ultimately contributes to the formation of an immunosuppressive tumor microenvironment.

Furthermore, the article explores potential anti-tumor immunotherapy strategies targeting SASP and its associated molecular mechanisms, including approaches to inhibit SASP secretion or eliminate senescent cells. Although these strategies have shown promise in certain tumor models, the high heterogeneity among tumor types may result in varied responses to SASP-targeted therapies. This highlights the need for further research into adaptive stratification and personalized treatment approaches. Targeting immune regulatory mechanisms in the aging microenvironment - particularly SASP - holds great potential for advancing future anti-tumor therapies.

Link: https://doi.org/10.1016/j.apsb.2025.07.022

Cells evolved to detect foreign DNA and respond with inflammatory signaling. Unfortunately aging brings with it the mislocalization of fragments of the cell's own DNA that is then misidentified as foreign, triggering these same inflammatory pathways. This response, and a number of other responses to forms of damage inside the cell, converge on the regulatory protein STING. The activity of STING that leads to inflammation is thus an interesting target for the treatment of age-related conditions involving excessive chronic inflammation. As for near all of the present potential approaches to the chronic inflammation of aging, sabotaging STING will harm the normal innate immune response to infection, cancer, and so forth. This may be worth it in some scenarios. The use of biologics for patients with rheumatoid arthritis shows how this will likely play out: long term and more subtle harms to immune function and health are accepted when short term, evident benefits can be realized.

The stimulator of interferon genes (STING) plays a crucial role as an adaptor in innate immune defense, orchestrating key inflammatory processes through the modulation of type I interferon signaling and activation of cytokine networks. Recent studies have identified STING-induced neuroinflammatory responses as a major factor in the progression of neurological diseases, particularly in neurodegenerative disorders.

This review methodically explores the structural basis of STING activation and its role in driving pathological inflammation. The classic and non-classic pathways of STING as well as their roles in neurodegenerative diseases were discussed. Additionally, it critically assesses new pharmacological approaches that target the STING pathway, emphasizing anti-inflammatory treatments ranging from synthetic small-molecule inhibitors to bioactive natural compounds, which aim to mitigate neurotoxic inflammation.

By combining mechanistic insights with therapeutic advancements, this paper presents an innovative transformation framework aimed at developing anti-inflammatory therapies targeting the STING pathway to treat neurodegenerative diseases. The core contribution of this framework lies in systematically bridging the innate immune regulation and neuroinflammation control mechanisms, providing a new strategy for disease intervention.

Link: https://doi.org/10.3389/fnagi.2025.1659216

When a cell becomes senescent it ceases replication, expands in size, and secretes a mix of pro-growth, pro-inflammatory molecules known as the senescence-associated secretory phenotype (SASP). Cells become senescent throughout life, mostly upon reaching the Hayflick limit on replication. Forms of damage, particularly DNA damage that might lead to cancer, the signaling of other senescent cells, and a toxic environment can also provoke cellular senescence. Senescence is also involved in coordinating regeneration from injury. When an individual is young, senescent cells are cleared efficiently by the immune system, but with age this clearance falters. The result is an accumulating burden of senescent cells that disrupt tissue structure and function with their signals.

In today's open access paper, researchers review what is known of the role of cellular senescence in the aging of the heart and vasculature, causing dysfunction that contributes to the various forms of cardiovascular disease. Cardiovascular disease is the greatest cause of human mortality, those deaths largely split between heart failure, heart attack, and stroke. Controlling the burden of senescent cells, such as by preventing the onset of senescence, selectively destroying senescent cells, or at the very least inhibiting the SASP, is hoped to reduce this aspect of aging. There are some caveats, such as whether senescent cells are holding together tissues (or unstable atherosclerotic plaques!) in very late aging, and thus destroying them could be problematic. There should be no such issues for inhibiting the buildup of senescent cells prior to that late stage, however.

The role of cellular senescence in cardiovascular disease

Cardiovascular disease poses a profound global concern for public health, with age standing as a crucial risk factor that contributes significantly to the progressive deterioration of cardiac structure and functionality. In mammals, the aging process is linked to the build-up of senescent cells. During aging, cells undergo mitochondrial dysfunction, DNA damage, and increased activation of the p53/p21 and p16 signaling pathways in response to cellular stress, ultimately contributing to the development and advancement of cardiovascular diseases.

In recent years, cellular senescence has garnered considerable interest as a potential target for alleviating age-related diseases and extending lifespan. Cellular senescence is a hallmark of aging, characterized by a stable cell cycle block accompanied by typical morphological changes in cells and a distinguishable secretory phenotype.

The aim of this review is to provide a comprehensive summary of the role of cellular senescence in cardiovascular disease and related mechanisms. To begin, an overview of the fundamental concepts, characteristics, and biological effects of cellular senescence will be provided. Additionally, we will delve into the regulatory mechanisms of cellular senescence, encompassing the key molecules and signaling pathways involved. Subsequently, our focus will shift to exploring the interconnections between cellular senescence and conditions such as hypertension, atherosclerosis, myocardial infarction, heart failure, arrhythmias, and cardiomyopathy. This exploration aims to illuminate the role of cellular senescence in the development and progression of these diseases.

Finally, we will also explore the impact of targeted cellular senescence-related therapies on the aforementioned cardiovascular diseases. For example, pharmacologically removing or knocking out senescent cells in mice mitigates cardiac hypertrophy and fibrosis induced by cardiac senescence while also facilitating cardiomyocyte regeneration.

It remains an open question as to whether studying the biochemistry of extremely old people can provide a basis for interventions that will help everyone live meaningfully longer. If genetics has little influence on longevity for the vast majority of people, as seems to be the case, then differences observed in extremely old people emerge from (a) lifestyle choices that we can control and (b) exposures that we presently have less control over, such as infectious disease burden and composition of the gut microbiome. However, any of the biochemical differences observed in extremely old individuals could be the outcome of mechanisms that provide only small improvements in the odds of survival. Is it worth pursuing a mechanism that results in, say, a 2% chance of reaching age 100 in the environment of the past 100 years of medical technology, versus an average 1% chance? That doesn't seem all that great. Better approaches are needed.

The New England Centenarian Study (NECS) provides a unique resource for the study of extreme human longevity (EL). To gain insight into biological pathways related to EL, chronological age and survival, we used an untargeted serum metabolomic approach (more than 1,400 metabolites) in 213 NECS participants, followed by integration of our findings with metabolomic data from four additional studies.

Compared to their offspring and matched controls, EL individuals exhibited a distinct metabolic profile characterized by higher levels of primary and secondary bile acids - most notably chenodeoxycholic acid (CDCA) and lithocholic acid (LCA) - higher levels of biliverdin and bilirubin, and stable levels of selected steroids. Notably, elevated levels of both bile acids and steroids were associated with lower mortality. Several metabolites associated with age and survival were inversely associated with metabolite ratios related to NAD+ production and/or levels (tryptophan/kynurenine, cortisone/cortisol), gut bacterial metabolism (ergothioneine/trimethylamine N-oxide, aspartate/quinolinate), and oxidative stress (methionine/methionine sulfoxide), implicating these pathways in aging and/or longevity.

We further developed a metabolomic clock predictive of biological age, with age deviations significantly associated with mortality risk. Key metabolites predictive of biological aging, such as taurine and citrate, were not captured by traditional age analyses, pointing to their potential role as biomarkers for healthy aging. These results highlight metabolic pathways that may be targeted to promote metabolic resilience and healthy aging.

Link: https://doi.org/10.1101/2025.09.10.675341

Researchers here provide a tour of better known pharmacological targets for the development of drugs to slow or potentially reverse loss of muscle mass and strength with age. The high bar to beat is the effects of resistance exercise, but there is likely merit in drugs that will enhance the improvements provided by resistance exercise, provided that they have a reasonable cost. A few common themes emerge in the targets. Many approaches produce a reduction in inflammation, as chronic inflammation is strongly implicated in loss of muscle tissue maintenance and tissue function, for example. Loss of stem cell activity and issues with neuromuscular junctions are also well studied in the context of muscle aging, and the research community has sought ways to address these issues. So far only limited progress has been made in bringing potential therapies to the clinic, but we might expect this to change over the next decade given the present strong interest in finding solutions to frailty, sarcopenia, and muscle loss produced by GLP-1 receptor agonists.

A progressive decline in muscle mass and strength presents a significant challenge for aging populations, underscoring the urgent need for innovative and diverse treatment strategies. While this review focuses on pharmacological options, structured physical exercise, particularly resistance and power training combined with sufficient protein intake, remains the most effective primary intervention for age-related muscle decline. Pharmacological methods should be viewed as supplementary or alternative options only when exercise is not possible or proves inadequate. Despite notable progress in understanding skeletal muscle degradation mechanisms, applying these findings to effective treatments requires further research and rigorous clinical testing. New therapies, including novel peptides, natural compounds, and multi-targeted pharmacological approaches, hold great promise to preserve muscle function and improve patient outcomes.

Looking ahead, priority biological targets include (i) modulation of the MSTN/activin A/GDF11 axis with careful cardiometabolic safety monitoring; (ii) stabilization of neuromuscular junctions (e.g., HDAC4-Gadd45a stress pathways; agrin/MuSK); (iii) restoration of mitochondrial quality control and bioenergetics (AMPK-SIRT1-PGC-1α signaling, mitophagy), with attention to preserving type II fibers; (iv) reduction of chronic low-grade inflammation (IL-6/TNF) and enhancement of insulin/IGF-1/Akt/mTOR signaling in sarcopenic phenotypes with metabolic comorbidities; and (v) strategies for extracellular matrix remodeling (balancing TGF-β/MMP activity) to improve the satellite cell niche.

Link: https://doi.org/10.3390/ph18091407

Urolithin A is a metabolite produced by gut bacteria, widely used as a dietary supplement, and has attracted attention from the aging research community for its positive effects on mitochondrial function. Of the various approaches to improving mitochondrial function with compounds classed as supplements, urolithin A is arguably the one that researchers know the least about when it comes to how exactly it functions, but equally there is stiff competition here. Knowledge of the exact mechanisms involved in translating the known immediate biochemical interactions of various compounds to better functioning mitochondria is sketchy at best for NAD+ upregulation, mitoQ, plastinquinones such as SkQ1, elamipretide, and so forth. Further, many of these do not appear to perform as well as exercise when it comes to measures of mitochondrial function.

The function of any one mitochondrion is complex and incompletely understood. Then there is the point that mitochondria exist in their hundreds in every cell, a dynamic population undergoing division, fusion, and transfer of component parts between one another. Further, mitochondria are policed by another incompletely understood set of mechanisms of quality control called mitophagy responsible for identifying and recycling damaged mitochondria. Strategies for improving mitochondrial function largely seem to improve mitophagy, but it isn't all that clear as to why this is the case, or whether it is the primary mechanism by which mitochondrial function is improved.

In today's open access paper, researchers focus on the anti-inflammatory properties of urolithin A. They provide evidence for this to occur in part by downregulating the inflammatory signaling generated by senescent cells. This connects to mitochondrial function because inflammatory signaling of this nature (and in non-senescent cells as well) can arise due to the mislocalization of mitochondrial DNA fragments. As mitochondrial function declines more such fragments of mitochondrial DNA are released into the cell, where they are mistaken for bacterial DNA, provoking the same inflammatory reactions as take place during infection. Less of this is a good thing.

Mitigating Pro-Inflammatory SASP and DAMP With Urolithin A: A Novel Senomorphic Strategy

Aging is associated with increased systemic sterile inflammation (inflammaging), which promotes several age-associated diseases. Key drivers of inflammaging include senescence-associated secretory phenotype (SASP) factors released by senescent cells. While the exact components of SASP vary between different senescent cells and tissues, core SASP factors include pro-inflammatory chemokines, matrix-degrading enzymes, and several damage-associated molecular pattern (DAMP) molecules. Pharmacological inhibition of SASP using small molecules known as senomorphics has been proposed as a potential intervention for age-associated diseases. However, such treatments include several flavonoid inhibitors of the p38 MAPK/NF-κB pathway, free radical scavengers, and Janus kinase (JAK) pathway inhibitors that are nonselective and broadly inhibit pathways also involved in homeostatic immune responses to various physiological challenges, thus limiting their systemic therapeutic application).

Here we present data indicating that the gut metabolite Urolithin A (UA) acts as a senomorphic compound. Senescent cells are known to contribute to aging and age-related diseases. One key way they influence aging is by secreting senescence-associated secretory phenotype (SASP) factors along with several damage-associated molecular pattern (DAMP) molecules. Consequently, inhibiting SASP and DAMP signaling (senomorphics) has emerged as a therapeutic strategy.

Digestive tract bacteria naturally produce UA through the metabolism of ellagitannins and ellagic acid, which are abundant in berries, nuts, and pomegranates. UA has been reported to be a potent anti-inflammatory agent, alleviating several age-related conditions in vivo. Preclinical studies have also shown its protective role against aging and age-related conditions affecting the muscles, brain, joints, and other organs. In a recent clinical trial, UA supplementation improved muscular endurance in older adults. Here we demonstrate that UA lowers the expression and release of pro-inflammatory SASP and DAMP factors, at least in part, by downregulating cytosolic DNA release and subsequent decrease in cGAS-STING signaling.

Treatments that cause issues when administered systemically (such as via oral ingestion or intravenous injection) at the doses required to place enough of the therapeutic in a specific location in the body can be made practical via methods targeting delivery to specific cells. Here, researchers use liposomes attached to a muscle-targeted peptide to deliver the polyphenol epigallocatechin gallate (EGCG) to muscle cells. EGCG is otherwise problematic, causing liver toxicity at high doses, and has low bioavailability when ingested. Nonetheless it does have interesting effects on inflammation, cholesterol metabolism, and mitochondrial function which is why researchers are making use of it here in the context of muscle aging.

Skeletal muscle aging frequently leads to a reduction in muscle mass and strength, significantly compromising the quality of life in elderly individuals. Skeletal muscle dysfunction during aging is widely recognized to be closely linked to chronic inflammation, oxidative stress, and mitochondrial dysfunction. In this study, we confirmed the successful synthesis of M12 (muscle homing peptide)-modified EGCG (Epigallocatechin gallate) liposomes (M12EGLP) and validated their specific targeting to skeletal muscle through immunofluorescence analysis and in vivo imaging in small animal models.

Both in vivo and in vitro experiments demonstrated that M12EGLP effectively suppressed the expression of inflammatory markers such as TNF-α and IL-6, thereby alleviating oxidative stress and restoring mitochondrial function in skeletal muscle. These effects ultimately contributed to the improvement of skeletal muscle dysfunction in aging mice, improving motor function and regenerative capacity. Therefore, as a novel and targeted drug delivery system, M12EGLP may provide a promising therapeutic strategy for the clinical management of age-related skeletal muscle dysfunction.

Link: https://doi.org/10.1016/j.mtbio.2025.102265

PhenoAge is an aging clock derived from patient data on age-related changes in nine clinical chemistry markers that are easily measured via a blood sample. A number of other blood biomarker clocks have been proposed that use more markers. The clock noted here claims a modest improvement over PhenoAge when it comes to predicting mortality risk, but that requires 25 markers. The trade-off is in the cost to the patient to obtain the necessary assays versus the degree of improved performance of the clock. This tends to be true across clocks more generally, regardless of the data used. The more popular clocks based on fewer measures continue to be popular because they do not greatly underperform the more expensive clocks that require many more measures. The work here reproduces that result by showing that combining a subset of markers with the full data set produces much the same result as the full set of markers, which is an interesting approach to controlling patient costs.

Biological age captures physiological deterioration better than chronological age and is amenable to interventions. Blood-based biomarkers have been identified as suitable candidates for biological age estimation. This study aims to improve biological age estimation using machine learning models and a feature-set of 60 circulating biomarkers available from the UK Biobank (n = 306,116). We implement an Elastic-Net derived Cox model with 25 selected biomarkers to predict mortality risk (C-Index = 0.778), which outperforms the well-known blood-biomarker based PhenoAge model (C-Index = 0.750), providing a C-Index lift of 0.028 representing an 11% relative increase in predictive value.

Importantly, we then show that using common clinical assay panels, with few biomarkers, alongside imputation and the model derived on the full set of biomarkers, does not substantially degrade predictive accuracy from the theoretical maximum achievable for the available biomarkers. Biological age is estimated as the equivalent age within the same-sex population which corresponds to an individual's mortality risk. Values ranged between 20-years younger and 20-years older than individuals' chronological age, exposing the magnitude of ageing signals contained in blood markers. Thus, we demonstrate a practical and cost-efficient method of estimating an improved measure of biological age, available to the general population.

Link: https://doi.org/10.1038/s42003-023-05456-z