Fight Aging! Newsletter, December 29th 2025
Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe to the newsletter, please visit: https://www.fightaging.org/newsletter/. To unsubscribe, send email or reply to this email at newsletter@fightaging.org with "unsubscribe" in the subject or body.
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- Lipofuscin, an Overlooked Contributing Cause of Neurodegeneration
- Inhibiting a Regulator of Increased Glycolysis Kills Senescent Cells
- Increased GDF3 Expression with Age Induces Inflammatory Behavior in Macrophages
- An Overview of Current Understanding of the Link Between Periodontal Disease and Atherosclerosis
- Considering the Consequences of the Aging of the Pineal Gland
- The Potential of Engineered Oncolytic Bateria for the Treatment of Cancer
- A Review of Current Approaches to Measure Biological Age
- Mechanisms Involved in the Aging of the Colon
- A Prodrug to Trigger Ferroptosis Based Cell Death in Senescent Cells
- Extracellular Vesicle Therapy Restores Pancreatic β-Cell Function in Aged Mice
- Further Clinical Trials of a Patch to Deliver New Retinal Cells
- Targeting a Specific Amyloid-β Oligomer to Slow Alzheimer's Disease in a Mouse Model
- FOXF2 and TIE2 as Targets for the Treatment of Cerebral Small Vessel Disease
- Another Proteomic Aging Clock for Specific Organs
- A Novel Aging Clock Built on Seven Clinical Biomarkers
Lipofuscin, an Overlooked Contributing Cause of Neurodegeneration
https://www.fightaging.org/archives/2025/12/lipofuscin-an-overlooked-contributing-cause-of-neurodegeneration/
Lipofuscin is the name given to a mix of modified proteins, lipids, and other compounds that accumulate with age in long-lived cells. The accumulation of lipofuscin has long been considered a form of damage by a minority of researchers; removal of lipofuscin was an early call to action for the Strategies for Engineered Negligible Senescence, for example. There were even a few early, unsuccessful efforts to provide technology demonstrations of approaches to break down lipofuscin, or at least some of its components. Unfortunately, getting rid of lipofuscin isn't a straightforward task. Chemically it is diverse, a mess of many very different molecules, and thus ill suited as a target for the enzyme, antibody, and small molecule development that dominates the field of medical biotechnology. Getting rid of one specific molecule is feasible, getting rid of a hundred very different molecules is much less feasible. Lipofuscin has been largely left alone in favor of easier goals.
In today's open access paper, the authors restate some of the arguments for lipofuscin to be important in the onset and progression of age-related neurodegenerative conditions, and thus to be a therapeutic target worthy of greater attention on the part of the research and development community. This has all been said before! One of the challenges inherent to the development of rejuvenation therapies at this stage of the growth of the field is that there are far more potentially worthwhile areas of focus than there are research groups, companies, and funding to carry out the work. This will likely remain the case until the first generation of therapies to treat aging are approved, widely used in the clinic, and their existence a matter of fact for the average physician, researcher, and person in the street.
Lipofuscin accumulation in aging and neurodegeneration: a potential "timebomb" overlooked in Alzheimer's disease
Lipofuscin, which has long been considered a passive byproduct of aging, is increasingly being recognized as a dynamic modulator of cellular homeostasis. Lipofuscin accumulation is indicative of lysosomal dysfunction and is closely related to redox imbalance and lipid peroxidation - critical pathways implicated in neurodegenerative diseases, particularly Alzheimer's disease (AD). Lipofuscin accumulation may contribute to and exacerbate amyloid-β accumulation and toxicity by interfering with autophagic clearance and promoting a highly oxidative environment.
In this review, we propose a reconsideration of lipofuscin from the "aging marker" or "autofluorescence pigment" to an active player in neurodegeneration and AD pathology. This paradigm shift opens new research directions and therapeutic possibilities. Targeting lipofuscin and its clearance may allow interference of upstream of amyloid plaque formation, preserving proteostasis, reducing oxidative damage, and ultimately slowing or preventing neurodegeneration.
We examine the potential interplay between lipofuscin accumulation, lysosomal dysfunction, lipid peroxidation and amyloid-β pathology in AD. We explore how lipofuscin may influence amyloid-β aggregation, clearance, and toxicity and propose mechanisms by which lipofuscin modulates AD progression. Importantly, we summarize evidence demonstrating that lipofuscin is released extracellularly upon neuronal death, thus preparing a highly oxidized environment that results in toxicity and a cascade of events leading to plaque formation and amyloid-β pathology.
Inhibiting a Regulator of Increased Glycolysis Kills Senescent Cells
https://www.fightaging.org/archives/2025/12/inhibiting-a-regulator-of-increased-glycolysis-kills-senescent-cells/
Cells become senescent constantly throughout life. A senescent cell ceases replication, increases in size, and generates disruptive inflammatory signaling. In youth those senescent cells that fail to undergo programmed cell death are removed by the immune system, but this clearance falters with advancing age. The result is a growing burden of senescent cells that disrupt tissue structure and function, contributing to age-related conditions. The research community is thus very interested in finding ways to selectively remove senescent cells, particularly given the evidence for rejuvenation to result from senescent cell clearance in aged mice.
The metabolism of senescent cells is very different from that of normal cells. Unlike normal cells they are primed to undergo programmed cell death, but held back by a range of mechanisms. Sabotage those mechanisms and a senescent cell dies, but a normal cell is largely unaffected. This is far from the only possible approach to the problem, and new approaches are discovered on a fairly regular basis. Today's open access paper focuses on the regulation of increased glycolysis as an energy source in senescent cells, analogous to the Warburg effect observed in cancer cells. A senescent cell has sizable energy needs, given its activities and size. If this regulation of glycolysis is sabotaged, the senescent cell can no longer support itself and dies.
Abrogation of aberrant glycolytic interactions eliminates senescent cells and alleviates aging-related dysfunctions
Cellular senescence is deeply involved in physiological homeostasis, development, tissue repair, aging, and diseases. Senescent cells (SnCs) accumulate in aged tissues and exert deleterious effects by secreting proinflammatory molecules that contribute to chronic inflammation and aging-related diseases. We revealed that an aberrant interaction between glycolytic PGAM1 and Chk1 kinase is augmented in SnCs associated with increased glycolysis, whose byproduct, lactate, promotes this binding in a non-cell autonomous manner.
This pseudo-Warburg effect of SnCs with enhanced PPP (pentose phosphate pathway) activity is maintained by HIF-2α phosphorylation by Chk1 and subsequent upregulation of glycolytic enzymes, creating a vicious cycle reprogramming the glycolytic pathway in SnCs. HIF-2α also activates FoxM1 expression, which transcriptionally suppresses pro-apoptotic profiles, including BIM, and upregulates DNA repair machineries in SnCs. FoxM1 thus supports the genomic integrity and survival capacity of SnCs during their glycolytic changes.
Chemical abrogation of PGAM1-Chk1 binding reverts these phenotypes and eliminates SnCs through senolysis. Inhibition of the PGAM1-Chk1 interaction improves physiological parameters during aging and inhibits lung fibrosis in mouse models. Our study highlights a novel pathway contributing to the metabolic reprogramming of SnCs and how the use of a new senolytic molecule that targets the PGAM-Chk1 interaction creates a specific vulnerability of those cells to potentially fight age-related diseases.
Increased GDF3 Expression with Age Induces Inflammatory Behavior in Macrophages
https://www.fightaging.org/archives/2025/12/increased-gdf3-expression-with-age-induces-inflammatory-behavior-in-macrophages/
The innate immune system becomes increasingly inflammatory with age, in part due to damage and dysfunction in immune cells, in part a maladaptive reaction to a damaged environment. Chronic inflammation is disruptive to tissue structure and function. Macrophages make up a sizable fraction of the innate immune system, resident in tissues and involved in both tissue maintenance and defense against pathogens. A broad range of research is focused on better understanding and potentially manipulating macrophage behavior to obtain desired outcomes, such as a lower level of chronic inflammation in later life.
In today's open access paper, researchers focus on the macrophages resident in fat tissue. Visceral fat is a source of inflammation, and this is one of the reasons why being overweight is increasingly bad for health as life progresses into older age. This research illuminates one of the regulatory elements involved in increasing inflammatory behavior in macrophages in fat tissue, raising its profile as a potential target for anti-inflammatory therapies, and contributing to the bigger picture of inflammatory mechanisms in visceral fat tissue.
GDF3 promotes adipose tissue macrophage-mediated inflammation via altered chromatin accessibility during aging
Older individuals have increased risk for infections and subsequent sepsis, in part owing to accumulating adiposity and a dysfunctional immune system. Gerotherapeutics that successfully improve the aged immune response are largely understudied. Our study reveals that the GDF3-SMAD2/3 axis may be a relevant pharmacologic target. GDF3 promotes the inflammatory phenotype of adipose tissue macrophages, contributing to the exacerbation of endotoxemia-induced inflammation in older, but not younger, organisms. GDF3 signals through SMAD2/3 and elicits proinflammatory responses in adipose tissue macrophages, diverging from their canonical immunoregulatory function.
Specifically, the chromatin landscape of adipose tissue macrophages shifts toward inflammation with age, increasing the accessibility of inflammation-associated genes. Our study demonstrates that Gdf3 deficiency can reverse the age-dependent changes in chromatin accessibility and transcription by restoring H3K27me3 levels in adipose tissue macrophages. Furthermore, genetic and pharmacological inhibition targeting the GDF3-SMAD2/3 axis protects against endotoxemia-induced inflammation and lethality in old mice.
The importance of visceral adipose tissue (VAT) in aging and inflammation is corroborated by studies that highlight the immunological role of VAT during metabolic challenge or infection in older organisms. Recent work indicates that B cells-derived IgG elevates macrophage expression of Tgfb, which promotes fibrosis and metabolic decline via SMAD2/3 in aged VAT. Our work builds on this model, providing additional evidence for the importance of B cell-macrophage crosstalk in VAT. We also provide evidence for the GDF3-SMAD2/3 axis regulating the phenotype of B cells. Although it remains unclear whether GDF3 acts synergistically with TGFβ-superfamily cytokines, our findings indicate that the mechanism governing inflammatory VAT microenvironment, driven by adipose tissue macrophages and B cells, may converge on SMAD2/3 signaling.
An Overview of Current Understanding of the Link Between Periodontal Disease and Atherosclerosis
https://www.fightaging.org/archives/2025/12/an-overview-of-current-understanding-of-the-link-between-periodontal-disease-and-atherosclerosis/
As researchers note in today's materials, there is clear an association between periodontal disease and the progression of atherosclerosis. Atherosclerosis is universal in older humans, the growth of fatty lesions in blood vessel walls that ultimately impede circulating blood flow to a fatal degree or rupture to cause stroke and heart attack. The degree of atherosclerosis at a given age is highly variable across the human population, however. The degree to which atherogenic processes in any two individuals are driven by the same stimulus, such as increased LDL cholesterol levels or increased lipoprotein A levels or increased inflammation, can be very different. This makes it somewhat challenging to talk about how much of a problem any given atherogenic issue actually poses.
This is much the case for periodontitis and its contribution to atherosclerosis. One can demonstrate mechanisms that in principle allow periodontitis to make inflammatory diseases worse elsewhere in the body, primarily that bacteria and their inflammatory metabolites can leak into circulation via the injured gums. But it is a step from there to find good correlational data in human studies, let alone data that convincingly puts a number to the degree of risk produced by periodontitis. Still, avoiding chronic inflammation in later life is well established to be a beneficial goal for a wide range of reasons. Chronic inflammation is disruptive to tissue structure and function in many contexts, and wherever reasonable efforts can be taken to reduce sources of inflammation, the results should be worth it.
Gum disease may be linked to plaque buildup in arteries, higher risk of major CVD events
Although periodontal disease and atherosclerotic cardiovascular disease (ASCVD) share common risk factors, emerging data indicates there is an independent association between the two conditions. Potential biological mechanisms linking periodontal disease with poor cardiovascular outcomes include direct pathways such as bacteria in the blood and vascular infections, as well as indirect pathways such as chronic systemic inflammation.
Numerous studies have found that periodontal disease is associated with an increased risk of heart attack, stroke, atrial fibrillation, heart failure, peripheral artery disease, chronic kidney disease, and cardiac death. Although periodontal disease clearly contributes to chronic inflammation that is associated with ASCVD, a cause-and-effect relationship has not been confirmed. There is also no direct evidence that periodontal treatment will help prevent cardiovascular disease. However, treatments that reduce the lifetime exposure to inflammation appear to be beneficial to reducing the risk of developing ASCVD.
Periodontal Disease and Atherosclerotic Cardiovascular Disease: A Scientific Statement From the American Heart Association
Direct mechanisms of the association between periodontal disease and atherosclerotic cardiovascular disease (ASCVD) are thought to be through bacteremia and vascular infection. Dental plaque in periodontal disease contains multiple bacterial strains. Periodontal pockets, with manipulation of the tissue, can result in bleeding, which allows periodontal bacteria to enter systemic circulation. Once in the bloodstream, pathogens can trigger a systemic inflammatory response. This, along with increased vascular permeability, could lead to endothelial dysfunction. Endothelial dysfunction can be a sign of early subclinical atherosclerosis.
Bacteremia from chronic periodontal infections may increase the inflammatory burden that accelerates atherogenesis. Inflammation due to direct oral microbiome actions may affect systemic inflammation of blood vessel walls through two modes: direct invasion of bacteria through the diseased and inflamed periodontal tissues into the general circulation and phagocyte-mediated bacterial translocation. The oral microbiome thereby invades vascular tissues, which may experience acute inflammation, which, in the absence of complete resolution, could lead to chronic inflammation and ASCVD.
Considering the Consequences of the Aging of the Pineal Gland
https://www.fightaging.org/archives/2025/12/considering-the-consequences-of-the-aging-of-the-pineal-gland/
If you are old enough, you may recall that the pineal gland received a great deal of quite unscientific attention from the early life extension community, decades ago, overlapping to some degree with its association in lineages of mystical thinking with the third eye. We live in a strange world populated by strange people. Scientifically, the pineal gland is a fairly important part of the endocrine system, and like all organs in the body, its normal function becomes disrupted by age. This has consequences, not all of which are fully mapped or understood. Are those consequences plausibly large enough for greater attention to be given to mechanisms of pineal gland aging specifically? The authors of today's open access paper would argue that this is the case.
This highlights one of the challenges inherent in engaging with aging as a phenomenon. The body is complex, and contains many different complex systems, organs, and tissue types. If the approach taken to aging is to run down the list of body parts one by one, then making meaningful progress in the matter of treating aging as a medical condition is going to take a long time. The alternative of focusing on underlying pathological mechanisms rather than tissues has a similar issue. Even today there are many portions of the body for which little has been said in the context of slowing aging or producing rejuvenation. If one looks at the major avenues of development for rejuvenation therapies, such as senolytics and partial reprogramming, one finds that most of the development end of the field is focused on just a few age-related conditions and a few organs.
That said, at this still relatively early stage in the development of the longevity industry it is unclear as to whether anyone should be concerned about the above points, versus maintaining a laser focus on forging ahead as fast as possible to the first rejuvenation therapies. But it is something to think about.
Pineal gland senescence: an emerging ageing-related pathology?
The pineal gland is a photo-neuroendocrine gland located in the midline of the brain outside the blood-brain barrier. It is part of the epithalamus, is attached to the third ventricle by a short stalk, and can weigh up to 180 grams. Its primary role is to receive information about the light-dark cycle from the environment, which it responds to through the production and secretion of melatonin. When it is light, the suprachiasmatic nucleus (SCN) secretes gamma-amino butyric acid (GABA), which in turn inhibits neurons in the paraventricular nucleus (PVN) of the hypothalamus. In darkness, the SCN secretes glutamate, which activates pathways from parvocellular pre-autonomic neurons of the PVN via the superior cervical ganglion to stimulate melatonin production by the pineal gland in response to noradrenaline.
The pineal gland may undergo ageing-related structural and morphological changes, including calcification, gliosis, cyst formation, and reduced density of β-adrenergic receptors, which are hypothesised to reduce melatonin secretion.
We hypothesise that pineal gland senescence may represent an ageing-related pathology as it describes a decline in function. This causes a reduction in the secretion of melatonin that may contribute to ageing-related sleep disorders as well as other physiological, cognitive, and psychiatric dysfunctions related to disturbances in circadian rhythm and melatonin concentrations. The current paper will describe the pathophysiology of the pineal gland and will discuss whether pineal gland senescence should be considered as a diagnostic entity.
The Potential of Engineered Oncolytic Bateria for the Treatment of Cancer
https://www.fightaging.org/archives/2025/12/the-potential-of-engineered-oncolytic-bateria-for-the-treatment-of-cancer/
The research community has achieved a growing ability to engineer bacteria to produce specific behaviors and outcomes. In the realm of cancer therapy, this includes altering the characteristics of bacteria to increase their ability to disrupt cancer cells by preferentially localizing to and colonizing tumor tissue. Techniques demonstrated in the laboratory include genetic engineering of bacteria manufacture or carry a payload of molecules capable of directly harming cancerous cells. The review noted here outlines the range of present approaches, including those that are progressing towards clinical use.
In contrast to conventional drugs, which accumulate through passive diffusion, live bacteria can actively penetrate deep into tumors, bypassing aggregation near blood vessels. The unique properties of the tumor microenvironment (TME) allow bacteria to preferentially replicate and colonize tumors. For example, Salmonella has been observed to localize to tumors at more than 10,000 times the density found in normal tissues. Live bacteria offer distinct advantages over traditional anticancer agents by amplifying antitumor effects through inherent tumor-targeting capabilities, potentially enhancing specific immune recognition. However, balancing the requirement for bacteria to evade host antimicrobial defenses while stimulating antitumor immunity within the TME remains a challenge.
Advances in synthetic biology allow the rational design of optimized oncolytic bacterial strains by attenuating virulence factors and integrating customizable therapeutic payloads, with several candidates already progressing into clinical evaluation. Fine-tuning the spatiotemporal control of bacterial therapeutic activity is essential for maximizing drug accumulation, improving resource efficiency, and reducing harm to healthy tissues. To this end, engineered oncolytic bacteria often utilize regulated gene expression systems, incorporating specific promoter elements, to allow for precise control of therapeutic payload delivery in vivo. Synthetic biology prioritizes rational and modular design, integrating programmable sensors, genetic circuits, and effectors to deliver precise, tunable, multilayer regulation of bacterial behaviors and therapeutic outputs.
A Review of Current Approaches to Measure Biological Age
https://www.fightaging.org/archives/2025/12/a-review-of-current-approaches-to-measure-biological-age/
Biological age as a concept is a measure of the burden of cell and tissue damage, and consequent dysfunction, that causes risk of mortality and disease. Over the past twenty years researchers have developed a range of approaches, starting with epigenetic clocks, that are attempts to produce a useful measure of biological age. There is considerable debate over the degree to which any of these approaches have succeeded, a debate that will only be settled by the accumulation of a great deal of human data. Ultimately, the real utility of a measure of biological age is the rapid assessment of potential rejuvenation therapies, to steer development towards better approaches that produce larger effects. At present it is unclear as to whether any of the approaches can be trusted to produce useful data given an entirely novel approach to the treatment of aging.
Numerous studies have analysed different aspects of biological age and developed clocks and models to assess biological age and measure the molecular changes due to biological ageing. Not only are there several generations of epigenetic clocks used to estimate biological age, but proteome-based clocks were developed, and metabolome- and microbiome-based clocks are being developed as well. Genomic studies have uncovered several genetic mechanisms that promote longevity, with a focus on protective mechanisms such as protective genetic variants and effective DNA repair systems.
Epigenomic changes that influence biological age are modified by diet and exercise and influenced by early life events. Age-related changes in blood proteome were identified, revealing non-linear and organ-specific alterations. Metabolomic profiles in blood plasma have identified age-related shifts in lipid metabolism and redox balance and demonstrated their application as biomarkers for ageing processes and health outcomes. Microbiomics has shown that the uniqueness and diversity of the gut microbiome reflect biological age and that this can also be measured by microbiome derived metabolites in plasma. In addition, multi-omics approaches have uncovered potential biomarkers that not only reflect the ageing processes but can also serve as targets for personalised interventions.
There are several limitations in selecting reliable biomarkers of ageing. First, there is a lack of consistently identified biomarkers, low methodological standardisation, and limited numbers of cohorts in ageing studies. Currently, ageing appears to be a non-linear process that does not progress at the same rate across all biological functions and organs. Comparisons of different clocks and omics data have shown poor correlation, suggesting that each clock or omics may represent a distinct ageing process. There is limited translation of DNA methylation and other biomarkers into clinical practice.
Furthermore, the definition of biological ageing is not yet clearly established within the community. Therefore, relying on only one type of data is unlikely to provide precise, specific, and reliable biomarkers. Ageing is a systems-level biological process, and only systems-level approaches are likely to lead to the development of reliable and interpretable predictions of biological age. Comparison of different omics data has also shown poor correlation between different molecular domains, indicating that each domain may reflect a different ageing process or organ. Moreover, it is clear that individuals and their organs age differently and at different rates.
Mechanisms Involved in the Aging of the Colon
https://www.fightaging.org/archives/2025/12/mechanisms-involved-in-the-aging-of-the-colon/
Research is a highly specialized field of endeavor, and in the matter of aging most scientists maintain a narrow focus in their day to day work. One tissue or one layer of the mechanisms of aging is enough to keep a research group busy for years. Thus one sees papers such as the one noted here, in which researchers focus on the colon specifically, while touching on a range of areas of interest in cellular biochemistry, behavior, and what is known of the aging of complex systems such as the immune system and gut microbiome.
The colon is one of the gastrointestinal organs most profoundly affected by aging. Recent advances in our understanding of both colonic physiology and the general mechanisms of aging have significantly expanded our knowledge of the types and underlying processes of colonic aging. In this review, we summarize current insights into the cellular and molecular mechanisms that drive physiological aging of the human colon. We examine the unique structural and functional features of key components of the colon, including the epithelium, local immune system, microbiome, enteric neurons, and smooth muscle cells, and explore how aging affects each of these cell populations, ultimately impacting overall colonic function.
In the epithelium, increased mutational burden does not appear to be the primary driver of age-related dysfunction. Instead, dysregulation of signaling pathways such as EGF and Wnt is likely responsible for key phenotypic changes. Aged colonic neurons display protein misfolding and axonal dysfunction reminiscent of aging processes observed in the central nervous system. Similarly, smooth muscle cells exhibit impaired contractility, which is associated with disruptions in calcium homeostasis and deficits in cholinergic signaling. At the same time, age-related activation of the local immune system mirrors broader immunosenescence and may be further influenced by shifts in the gut microbiome, although a consistent aging-associated microbiome signature has yet to be identified.
These multifaceted changes, combined with the colon's inherent regional and cellular complexity and the challenges of modeling human colonic aging, continue to fascinate but also pose substantial obstacles for research. Emerging experimental models and clinical strategies offer promising avenues for improving the prevention and treatment of age-associated colonic dysfunction.
A Prodrug to Trigger Ferroptosis Based Cell Death in Senescent Cells
https://www.fightaging.org/archives/2025/12/a-prodrug-to-trigger-ferroptosis-based-cell-death-in-senescent-cells/
Researchers have developed many different approaches to selectively destroy senescent cells based on differences in their biochemistry. The use of prodrugs is one way to activate a cell-killing mechanism more specifically in senescent cells. Most such prodrugs make use of the fact that senescent cells express high levels of β-galactosidase, which removes galactose from molecules. A cell-killing molecule can be rendered inert by adding galactose to its structure, and is only activated to a large degree in senescent cells. Here, the cell-killing molecule acts to trigger ferroptosis in senescent cells, an approach analogous to the various ways that have been shown to trigger apoptosis in senescent cells. Senescent cells are primed for programmed cell death via apoptosis and ferroptosis. The mechanisms holding them back from that fate can be targeted fairly safely, as suppression of those preventative mechanisms will not cause cell death in a normal cell that is not primed for programmed cell death.
Accumulation of senescent cells is associated with aging and age-related diseases. However, current clearance therapies targeting senescent cells are often limited by low efficiency, poor specificity, and insufficient penetration. Here we develop a nano-platform composed of a probe (GD) that can be specifically activated by senescent cells, a photosensitizer (chlorin e6, Ce6), and a kininogen peptide (HK) for targeting ferritin, named HK-PCGC.
We show that upon entering senescent cells, GD is activated by high levels of β-galactosidase, releasing fluorescence to excite Ce6. Ce6 then generates reactive oxygen species to eliminate these cells. Additionally, we find that under the guidance of the peptide HK, our system degrades ferritin to trigger ferroptosis, further eliminating senescent cells. Collectively, we demonstrate that HK-PCGC can effectively eliminate senescent cells, reduce the senescence-associated secretory phenotype, and safely improve the physical fitness of aged mice. This study integrates senescent cell responsiveness, laser-free photodynamic therapy, and induction of ferroptosis, offering a potential approach for delaying aging.
Extracellular Vesicle Therapy Restores Pancreatic β-Cell Function in Aged Mice
https://www.fightaging.org/archives/2025/12/extracellular-vesicle-therapy-restores-pancreatic-%ce%b2-cell-function-in-aged-mice/
Senescence of β-cells in the pancreas appears to be an important component of all forms of diabetes, and thus diabetes becomes worse with age as the burden of cellular senescence increases for reasons relating to aging as well as reasons relating to diabetes. Here, researchers use extracellular vesicles derived from stem cell populations to treat aged mice and demonstrate a reduction in β-cell senescence and consequent improvement in function.
Targeting senescent pancreatic β-cells represents a promising therapeutic avenue for age-related diabetes; however, current anti-senescence strategies often compromise β-cell mass. In this study, human amniotic mesenchymal stem cell-derived small extracellular vesicles (hAMSC-sEVs) were identified as a novel intervention that can be used to effectively counteract cellular senescence and preserve β-cell integrity.
We aimed to systemically delineate the molecular mechanisms underlying hAMSC-sEV-mediated reversal of β-cell senescence in age-related diabetes. In oxidative stress-induced and naturally aged β-cell models, hAMSC-sEVs mitigated senescence-associated phenotypes, restored mitochondrial homeostasis, and enhanced insulin secretion capacity. In aged diabetic mice, administering these vesicles significantly ameliorated hyperglycemia, improved glucose tolerance, and reversed β-cell functional decline by reducing senescent β-cell populations, reinstating β-cell identity markers, and suppressing senescence-associated secretory phenotype (SASP) component production.
Mechanistic investigations revealed that the miR-21-5p-enriched hAMSC-sEVs directly target the interleukin (IL)-6 receptor α subunit (IL-6RA), thereby inhibiting signal transducer and activator of transcription 3 (STAT3) phosphorylation and its subsequent nuclear translocation. This epigenetic modulation alleviated STAT3-mediated transcriptional repression of the mitochondrial calcium uniporter (MCU), rectifying age-related mitochondrial calcium mishandling and insulin secretion defects. Genetic ablation of MCU clearly established the central role of the miR-21-5p/IL-6RA/STAT3/MCU axis in this regulatory cascade.
Further Clinical Trials of a Patch to Deliver New Retinal Cells
https://www.fightaging.org/archives/2025/12/further-clinical-trials-of-a-patch-to-deliver-new-retinal-cells/
There is no good therapy for macular degeneration, a form of progressive blindness characterized by dysfunction and death of vital cells in the retina, and particularly for the "dry" form of the condition in which retinal blood vessels have not yet become dysfunctional. Cell therapies represent one possible form of restorative therapy, but it has proven challenging to deliver new retinal cells and have them survive to take over lost function. The publicity materials here report briefly on the state of one cell therapy program, in which researcher employed an engineered patch to support the delivered cells.
Researchers are launching a phase 2b clinical trial examining if stem cells bioengineered to replace failing cells in the retina damaged by macular degeneration could restore eyesight. The cells are attached to an implant - an ultra-thin patch, thinner than a strand of hair - which holds the cells in place. The clinical trial follows early research conducted on a small patient population that showed the implant was well-tolerated, stayed put in the eye and was successfully absorbed into the tissue of the retina. Additionally, 27% of patients had some improved vision.
Age-related macular degeneration affects the eye's macula, which is located in the center of the retina and is responsible for central vision. In advanced cases, the retinal pigment epithelium (RPE) cells, which line the macula and are key in helping the retina produce clear vision, become damaged or destroyed, which leads to vision loss. The retinal implant used in the clinical trial is derived from embryonic stem cells grown into RPE cells in a lab. During an outpatient surgical procedure, surgeons will implant a tiny layer of the lab-produced RPE cells into the retina. Patients will be monitored for at least one year to determine how the implant is tolerated and for any changes in vision. The trial is hoping to enroll 24 patients.
Targeting a Specific Amyloid-β Oligomer to Slow Alzheimer's Disease in a Mouse Model
https://www.fightaging.org/archives/2025/12/targeting-a-specific-amyloid-%ce%b2-oligomer-to-slow-alzheimers-disease-in-a-mouse-model/
Research into the role of amyloid-β in Alzheimer's disease has shifted somewhat to focus on the surrounding biochemistry rather than the aggregates, now that clearing the aggregates via immunotherapies is an ongoing concern, and has shown less of a benefit to patients than hoped. As researchers note here, there is evidence for specific amyloid-β oligomers to be the most toxic consequence of having too much amyloid-β in general. Researchers have developed a drug that reduces levels of one of the problem oligomers, and this study is one of the early tests of its ability to help in an animal model of Alzheimer's disease.
One possible reason for the failure of early Alzheimer's disease (AD) clinical trials is that treatments were initiated after symptom onset, when pathology is already widespread. Another contributing factor, especially for amyloid-β (Aβ) targeting therapies, is that most treatments have selectively targeted monomeric or fibrillar forms of Aβ, which are not the most toxic species. Soluble amyloid-β oligomers (AβOs), which form prior to plaques, are widely regarded as the most toxic Aβ species.
One proposed mechanism by which early AβOs contribute to AD is by activation of immune cells. AβOs can activate glia in culture and in wild type rodent or primate brain following injection, but their role in initiating gliosis early in AD remains unclear. Since glial activation is among the primary events in AD, identifying molecules that trigger gliosis is critical for diagnostics and therapeutics.
In this study, we investigated early pathology in 5xFAD mice. Results showed distinct AβO subtypes differing in localization, morphology, and association with key AD hallmarks such as degenerating neurons, plaques, phosphorylated TDP-43 (pTDP-43), and activated immune cells. We report an AβO subtype that associates with the earliest degenerating neurons and activated immune cells and provide support for its role in early neuronal degeneration and astrogliosis. Furthermore, we validate the in vivo efficacy of NU-9, a drug-like compound recently shown to inhibit AβO accumulation in cultured hippocampal neurons. Oral NU-9 treatment significantly reduced ACU193+ AβOs on reactive astrocytes and rescued astrocyte glial fibrillary acidic protein (GFAP) levels, suggesting astrocyte-associated AβOs may induce reactive astrogliosis. We predict that neutralization of ACU193+ AβOs early in AD could slow or prevent disease progression.
FOXF2 and TIE2 as Targets for the Treatment of Cerebral Small Vessel Disease
https://www.fightaging.org/archives/2025/12/foxf2-and-tie2-as-targets-for-the-treatment-of-cerebral-small-vessel-disease/
Researchers here identify FOXF2 as necessary to maintain function of the vascular endothelium that lines blood vessels and the blood-brain barrier that wraps blood vessels passing through the brain to protect the distinct environment of the brain from cells and molecules that would disrupt it. They hypothesize that reduced levels of FOXF2 or related dysfunction in the expression and activity of genes it influences, such as TIE2, are an important contribution to the vascular dysfunctions that make up cerebral small vessel disease.
Researchers have genetically modified mice so that only their endothelial cells lack the ability to produce certain proteins. Endothelial cells form the innermost lining of blood vessels and they are the site where small vessel disease often begins. By selectively switching off the Foxf2 gene - previously identified by the researchers as a stroke risk gene - these cells lack the corresponding protein, leading to impaired function of small cerebral vessels, especially disruption of the blood-brain barrier, which protects the brain from harmful influences.
Foxf2 is a transcription factor that activates many other genes - including, as researchers discovered, the gene Tie2 and its downstream components in the so-called Tie signaling pathway. In endothelial cells, activation of the Tie2 gene and proper functioning of the Tie2 pathway are crucial for maintaining vascular health. Without Tie2, for example, the risk of inflammatory reactions in the endothelial cells of larger vessels increases, which in turn promotes atherosclerosis and raises the risk of stroke and dementia.
The researchers tested a therapy targeting the impaired function of small cerebral vessels based on their new insights. The drug candidate AKB-9778 specifically activates Tie2. "I would love to announce that we are already preparing a clinical study to test this compound in patients. However, at the moment it is not easy to access the substance, as it is currently being evaluated in clinical trials for use in other conditions." The team is now searching for related compounds that could be developed for clinical testing in small vessel disease.
Another Proteomic Aging Clock for Specific Organs
https://www.fightaging.org/archives/2025/12/another-proteomic-aging-clock-for-specific-organs/
In recent years a number of different groups have generated aging clocks intended to assess distinct biological ages for different organs and systems in the body, OrganAge being one example. Data from large human populations suggests that different organs and systems can age at somewhat different rates. Here, researchers use UK Biobank data to generate a novel organ specific proteomic clock, producing similar data to the earlier OrganAge research program.
Organ-specific plasma protein signatures identified via proteomics profiling could be used to quantitatively track organ aging. However, the genetic determinants and molecular mechanisms underlying the organ-specific aging process remain poorly characterized. Here we integrated large-scale plasma proteomic and genomic data from 51,936 UK Biobank participants to uncover the genetic architectures underlying aging across 13 organs.
We identified 119 genetic loci associated with organ aging, including 27 shared across multiple organs, and prioritized 554 risk genes involved in organ-relevant biological pathways, such as T cell-mediated immunity in immune aging. Causal inference analyses indicated that accelerated heart and muscle aging increase the risk of heart failure, whereas kidney aging contributes to hypertension. Moreover, smoking initiation was positively linked to the aging of the lung, intestine, kidney, and stomach. These findings establish a genetic foundation for understanding organ-specific aging and provide insights for promoting healthy longevity.
A Novel Aging Clock Built on Seven Clinical Biomarkers
https://www.fightaging.org/archives/2025/12/a-novel-aging-clock-built-on-seven-clinical-biomarkers/
The big advantage of aging clocks based on clinical biomarkers, such as the results of a complete blood count, or LDL cholesterol level, and so forth, is that one can at least theorize a little about what is going on under the hood when the clock output changes to indicate a higher or lower biological age. Each of the underlying biomarkers has meaning and a body of work attached to it, which is not the case for epigenetic clocks and barely the case for proteomic or transcriptomic clocks. Phenotypic age is the prototype of a widely used clinical biomarker clock. Others have been developed in recent years, and here find yet another recently published novel clinical biomarker clock.
Biological aging clocks offer valuable insights into age acceleration and disease development, making them a very powerful clinical tool for preventive medicine. However, the applicability of biological aging clocks in preventive clinical settings is closely linked to the effectiveness and efficiency of biomarker screening protocols, as well as their economic feasibility. To address this, we investigated the relationship between the performance of the regression model and the number of biomarkers utilized. Our aim was to unlock the full preventive potential of our biological aging clock.
We used a clinical cohort dataset from the Bumrungrad International Hospital in Bangkok, Thailand, encompassing 184,833 individuals and comprising 597,781 samples from 2000 to 2022. The total of 597,781 samples contained data on 174 clinical biochemistry biomarkers. Through expert consensus and iterative refinement, the biomarker set was refined to 51. Using an iterative approach, we systematically removed biomarkers with the least impact on predictive performance, ultimately narrowing the model down to six clinical biochemistry markers plus sex. These six biomarkers were creatinine, hemoglobin A1c (HbA1c), alanine aminotransferase (ALT), high-density lipoprotein (HDL), triglycerides, and albumin.
Based on only seven biomarkers, our clock accurately predicts both self-reported and physician-annotated ICD health data, indicating an increased hazard ratio. Importantly, the clock is robust even in the presence of acute infections or transient immune activation. To demonstrate the multi-ethnic generalizability of our biological age clock, we validated our approach using data from both the NHANES and UK Biobank cohorts. Our approach demonstrates the feasibility of a simple, robust, and interpretable clinical aging clock with potential for real-world implementation in personalized health monitoring and preventive care.