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- The Use of Nanoparticles in Building Targeted Treatments for Atherosclerosis
- PAI-1 Expression is Involved in Muscle Aging
- Intermittent Fasting Reduces Effects of Aging on Intestinal Stem Cell Function
- Towards an Induced Partial Reprogramming Approach to Alzheimer's Disease
- MT1-MMP Inhibition Restores Some Lost Cognitive Function in Both Aged Mice and Obese Mice
- Reviewing Blood Flow Restriction Training to Build Muscle in Older Individuals
- Targeting Aspects of Aging with Immunotherapy Technologies
- The Phase of Cell Cycle in Which Arrest Happens Determines Senescent Cell Behavior
- Reviewing Progress in the Treatment of Age-Related Macular Degeneration
- Applying a Proteomic Aging Clock to Data from a Very Long-Running Epidemiological Study
- A Review of Mechanisms Involved in the Aging of the Heart
- Reviewing the Aging of the Liver
- Are Socioeconomic Correlations with Disease Explained by Different Lifestyle Choices?
- Senescent Oligodendrocyte Precursor Cells Contribute to the Aging of the Brain
- Continued Progress Towards Reversible Vitrification of Organs
The Use of Nanoparticles in Building Targeted Treatments for Atherosclerosis
https://www.fightaging.org/archives/2025/09/the-use-of-nanoparticles-in-building-targeted-treatments-for-atherosclerosis/
The development of atherosclerotic plaque in blood vessel walls, narrowing and weakening those vessels, is a universal phenomenon in older people. It is worse in people with generally worse health, as it is driven by inflammation. Greatly reducing cholesterol carried from the liver to the rest of the body via LDL particles in the bloodstream slows the growth of plaque, but growth remains an inevitability on some time frame. Unfortunately the same can be said for reducing inflammation. Large plaques become unstable and rupture, and this kills a quarter of our species via heart attack and stroke.
Plaque growth occurs because the plaque environment is toxic, harmful to the macrophage cells that arrive from nearby tissue or the bloodstream in order to try to clean up the damage. The macrophages become overwhelmed and die, adding their mass to the plaque. Lowering LDL cholesterol slows plaque growth by reducing one of the inputs to this toxicity, but cannot on its own fix existing damage or entirely halt the process of plaque development and growth. Any true solution to atherosclerosis must function by in some way protecting macrophages from the plaque environment, or dramatically reducing the toxicity of the plaque environment. Only when macrophages can work unimpeded can plaque and a damaged vessel be repaired.
Many possible approaches to therapy to at least partially achieve these goals would become practical given a way to selectively carry a drug into atherosclerotic plaques. This is unfortunately challenging, but the most plausible class of approaches to this problem involves the development of forms of nanoparticle that selectively bind to distinctive features in plaque, or to cells in plaque, while ignoring the rest of the blood vessel wall. That would allow reasonable doses of a drug encapsulated within or attached nanoparticles to be injected intravenously.
Targeted Delivery of Nanoparticles to Blood Vessels for the Treatment of Atherosclerosis
The objective of atherosclerosis medication therapy is to enhance circulation, reduce cholesterol levels, and prevent thrombosis. Anti-inflammatory medication may have modest efficacy when combined with conventional regimens, given that inflammation is a pivotal factor in atherosclerosis. Nevertheless, it should be noted that all medication therapy has limitations in treating established plaques. Some medications, such as colchicine, rapamycin, and nucleic acid drugs, possess strong anti-inflammatory, lipid-lowering, or anti-proliferative properties, which means they have great potential in inhibiting atherosclerotic plaque growth and postoperative restenosis. Unfortunately, their utility in the therapy of atherosclerosis is limited by instability or dose-dependent toxicity. The introduction of nano drug delivery system (DDS) technologies has shed light on the utilization of these medications. By temporarily isolating the drug from the body's internal environment during delivery to reduce degradation and avoiding dose-related drug toxicity through effective targeted delivery, these use constraints of these promising drugs can be removed.
Nanoparticle carriers can be broadly divided into two groups: organic and inorganic. Polymers, liposomes, and micelles are typical examples of organic compounds, whereas inorganic compounds include silica, metals, and carbon, among others. According to some recent studies, nanoparticles showed great potential in both clinical diagnosis and therapy for atherosclerosis. Nevertheless, despite the encouraging outcomes observed in cell and animal studies, only a limited number of these designs have successfully transitioned to clinical trials and, even more rarely, to the market.
Nanoparticles have several notable applications in the diagnosis of atherosclerosis, including the identification of vulnerable plaques and the use of nanoparticles with both therapeutic and diagnostic functions. Nonetheless, even if the number of nanoparticle kinds is rapidly increasing, very few of them have gone to preclinical or clinical phases, and the majority of research has only formed conclusions from tests conducted in rodents (mice, rats) or other mammals (rabbits, pigs, dogs, and primates). Numerous nanoparticles have produced fairly acceptable results in cell or animal experiments; nonetheless, the evidence about their toxicity, biocompatibility, metabolic breakdown pathways, and efficacy is insufficient due to small sample sizes. Furthermore, the majority of the experimental research examined in this work yielded favorable outcomes, but the negative impacts or qualities of nanoparticles that need to be improved are hardly discussed.
PAI-1 Expression is Involved in Muscle Aging
https://www.fightaging.org/archives/2025/09/pai-1-expression-is-involved-in-muscle-aging/
PAI-1 expression increases with age, and is implicated in cellular senescence, inflammation, and detrimental remodeling of tissue, such as the generation of fibrosis. These line items are all connected, as a burden of lingering senescent cells tissues has been shown to be sufficient to cause the other two, but nothing is biochemistry is ever as simple as it first appears.
PAI-1 in the context of aging has received increased research interest since the discovery of a small population of human loss-of-function mutants who live perhaps 7 years longer their their near neighbor peers. In such small samples numbers should probably be taken with a grain of salt, but the biochemistry suggests that there is something interesting going on under the hood.
In today's open access paper, researchers report on an investigating of the role of PAI-1 in muscle aging in mice. Interestingly, loss of function is only protective in female mice when it comes to age-related loss of muscle mass and bone mineral density. This is not what one might expect for a protein that has a large effect size on life span and aspects of degenerative aging in other tissues, but nothing is simple in biochemistry.
Roles of plasminogen activator inhibitor-1 in aging-related muscle and bone loss in mice
Aging-related sarcopenia and osteoporosis are musculoskeletal disorders characterized by accelerated muscle and bone loss. Plasminogen activator inhibitor-1 (PAI-1), a fibrinolysis inhibitor, is involved in various pathological conditions, including sarcopenia and osteoporosis; however, its roles in aging-related sarcopenia and osteoporosis have yet to be fully investigated. Therefore, we investigated the roles of PAI-1 in aging-related sarcopenia and osteoporosis using PAI-1-gene-deficient and wild-type mice. Aging-related changes in muscle and bone were assessed by comparing the values in 24-month-old mice to those in 6-month-old mice.
Regardless of sex, differences in muscle and bone parameters were observed between 24-month-old and 6-month-old mice. Aging increased PAI-1 expression in the gastrocnemius and soleus muscles of both female and male mice. PAI-1 deficiency significantly blunted aging-related decreases in lower limb muscle mass, muscle tissue weights, and grip strength in female mice but not in males. Moreover, PAI-1 deficiency significantly blunted aging-related cortical bone loss at the femurs and tibias of female but not male mice. These results indicate that PAI-1 is partly involved in aging-related sarcopenia and osteopenia in female mice, although the corresponding mechanisms remain unknown.
Intermittent Fasting Reduces Effects of Aging on Intestinal Stem Cell Function
https://www.fightaging.org/archives/2025/10/intermittent-fasting-reduces-effects-of-aging-on-intestinal-stem-cell-function/
Tissues in the body are supported by distinct stem cell populations that reside within structures of supporting helper cells known as stem cell niches. The primary purpose of stem cells is to deliver a supply of daughter somatic cells to replace lost cells, though they also provide signaling that affects cell behavior. All tissues undergo a slow turnover of cells as there is a limit to the number of times a somatic cell can replicate. Telomeres are lengths of repeated DNA sequences at the end of chromosomes that shorten with each cell division. When telomeres become too short, a cell reaches what is known as the Hayflick limit and either becomes senescent and is destroyed by the immune system or undergoes programmed cell death. Stem cells can maintain long telomeres via telomerase expression, and thus the replacement somatic cells created by stem cells also have long telomeres, beginning the countdown again.
In today's open access paper, researchers look at the effects of fasting on a well-studied population of stem cells, those that support intestinal tissue. Intermittent fasting is well established to slow aging in animal studies, more so in short-lived species than in long-lived species. All of the reduced calorie intake strategies induce a beneficial response that improves metabolism and long-term health, provided sufficient nutrients are provided to stay well above the line of outright starvation. The function of stem cells is one of the many line items that are improved by these strategies. Normally, stem cell function declines with age for reasons that are complicated, incompletely mapped, and touch on many of the known underlying causes of aging. A lower calorie intake slows this process.
Aging Reduces Intestinal Stem Cell Activity in Killifish and Intermittent Fasting Reverses Intestinal Gene Expression Patterns
The process of aging is associated with a decline in cell, tissue, and organ function, leading to a range of health problems. Increasing evidence indicates that dietary restriction can counteract age-dependent effects and improve health and longevity in whole organisms, but less is known about the influence of aging and the impact of nutrition on individual organs of an organism.
In this study, we examined the intestine of the very short-lived aging model system, the African turquoise killifish (Nothobranchius furzeri), throughout its lifetime. We investigated the effects of age and nutrition on the preservation of gut tissue at stages corresponding to human neonatal, adolescent, adult, and old age, and integrated morphological measurements, histology, and transcriptomics.
The intestinal mucosa is characterized by folds and intervening interfold regions, where intestinal stem cells localize. The stem cells occur in clusters, and the cycle time of stem cells increases with age. We also observed a reduction in intestinal length and volume with age. Age-dependent transcriptomic profiling revealed significant changes in the expression of peripheral circadian clock genes and stem cell niche markers.
Notably, the majority of these genes maintained their adult gene expression levels in old age following intermittent fasting during adulthood. Therefore, our results demonstrate that the decline in structural intestinal tissue homeostasis is associated with a decline in stem cell activity that can be counteracted by intermittent fasting. Since the intestinal mucosa of killifish is similar to that of mammals, the results of this study can be translated to general gut biology.
Towards an Induced Partial Reprogramming Approach to Alzheimer's Disease
https://www.fightaging.org/archives/2025/10/towards-an-induced-partial-reprogramming-approach-to-alzheimers-disease/
Gene therapies for neurodegenerative diseases that involve direct injection into portions of the brain have become acceptable enough to regulators that there is now progress towards the clinic on this front. This is despite the invasive nature of the delivery, and despite the high bar for safety that that tends to be applied to treatments that produce permanent changes in a patient. One might look at a recent trial for Huntington's disease, for example. This willingness on the part of regulators to allow more adventurous approaches might reflect a growing frustration with the failure to generate curative (or even meaningfully preventative) therapies for prevalent neurodegenerative conditions, after decades of significant funding and effort.
Another example at an earlier stage of development is the reprogramming approach taken by YouthBio Therapeutics. The company intends to deploy a viral vector injected into the brain in order to insert reprogramming factors that are only activated in the presence of a small molecule such as doxycycline - so after the initial therapy, partial reprogramming of cells to restore a more youthful function can be induced as needed. This approach will be used to treat Alzheimer's disease. The company recently held its first formal interaction with the FDA, one step on a long path towards discovering and satisfying regulatory requirements prior to a clinical trial.
YouthBio Therapeutics Announces Positive FDA INTERACT Feedback for YB002, Establishing Clear Path to Clinic for First-in-Class Alzheimer's Gene Therapy
YouthBio Therapeutics, a biotechnology company pioneering partial cellular reprogramming to treat diseases of aging, today announced a successful INTERACT meeting with the FDA for its lead Alzheimer's candidate, YB002. In its formal response, the FDA agreed that existing preclinical data support the bioactivity of YB002 and YouthBio's proposed first-in-human trial. This feedback represents a major de-risking event for YouthBio, which will now focus on CMC activities and a pilot toxicology study to support a Pre-IND meeting and finalize designs for IND-enabling studies.
This milestone continues YouthBio's strong record of execution. It builds upon compelling scientific evidence, including a study in which YB002 ameliorated cognitive decline in mice. Additional Alzheimer's models have demonstrated that partial reprogramming can reverse disease pathologies, counteract epigenetic aging, and rescue memory and learning. YB002 is a first-in-class gene therapy designed to safely and transiently express Yamanaka factors in the brain - a process known as partial reprogramming. This approach aims to reverse epigenetic changes that accumulate with aging while preserving cell identity, thereby restoring youthful gene expression and improving cellular function.
YouthBio's Science
we are working on a gene therapy that involves delivering genes responsible for epigenetic rejuvenation into target tissues. These genes would be inactive by default but can be periodically activated by a small molecule, rolling back the epigenetics of target tissues to a younger level and rejuvenating them. Our long-term vision is to apply this therapy systemically, decreasing patients' biological age and improving their health. Numerous studies have provided strong evidence for the rejuvenating power of partial reprogramming, showcasing its potential in various contexts, such as improved muscle regeneration, heart regeneration, and intervertebral disc rejuvenation. The results of these studies serve as the foundation for our work at YouthBio.
MT1-MMP Inhibition Restores Some Lost Cognitive Function in Both Aged Mice and Obese Mice
https://www.fightaging.org/archives/2025/10/mt1-mmp-inhibition-restores-some-lost-cognitive-function-in-both-aged-mice-and-obese-mice/
There is at present a tremendous appetite for the development of novel pharmacological approaches to weight loss. This is in large part a response to the rising prevalence of obesity. No robustly proven answer exists as to the question of why exactly people are now becoming obese in such large numbers. There is no shortage of hypotheses, from excessive use of modern sugar substitutes to lack of exercise to specific widespread dietary additives to the presence of microplastics in the environment to changes in the average gut microbiome composition. The absence of a good answer and means of prevention means that efforts have turned to pharmacology for weight loss. This is not a new phenomenon, weight loss drugs have been greeted with enthusiasm since use of the mitochondrial uncoupler 2,4-dinitrophenol was pioneered in the early 20th century. The recent financial success of GLP-1 receptor agonists, that induce weight loss by suppressing appetite, has improved the prospects for any research efforts that can be in some way tied to producing weight loss.
So to the topic of today's open access paper, the effects of MT1-MMP in the aging brain. It appears that in parallel to effects on satiety and appetite, MT1-MMP also influences a range of mechanisms relevant to neurodegenerative conditions. Expression of MT1-MMP rises with age, perhaps driven by the chronic inflammation of aging, and this may be a useful target for the development of therapies. Interestingly, pharmacological inhibition of MT1-MMP activity restores some of the cognitive function lost to either aging or obesity when assessed in mice. Given that inhibition of MT1-MMP affects energy metabolism and produces weight loss, the balance of mechanisms involved in benefits produced in old mice versus obese mice may be quite different.
MT1-MMP inhibition rejuvenates ageing brain and rescues cognitive deficits in obesity
Obesity has been linked to an increased risk of cognitive impairment and dementia in later life. Although aging and obesity are both associated with cognitive decline, it remains unclear how they interact to affect cognitive function across the lifespan and how brain function might mediate their relationship with cognition. Our previous findings and other studies have shown that membrane type 1-matrix metalloproteinase (MT1-MMP/MMP14), which increases with age, regulates energy homeostasis. Inhibiting MT1-MMP improves insulin sensitivity, reduces body fat, and lowers serum cholesterol.
Here, we demonstrate that MT1-MMP links neuroinflammation to cognitive decline in aging and obesity. Inflammatory responses in the brain increase MT1-MMP activation in the hippocampus of both mice and humans. Activation of hippocampal MT1-MMP alone can trigger cognitive decline and synaptic impairment independently of neuroinflammation. Conversely, ablation of MT1-MMP in the hippocampus reverses cognitive decline and improves synaptic plasticity in aging and obesity. Pharmacological inhibition of MT1-MMP, through an orally administered brain-penetrant inhibitor or targeted delivery of a neutralizing antibody to the hippocampus, improves memory and learning in aged and obese mice without toxicity.
Mechanistically, MT1-MMP proteolytically inactivates G-protein-coupled receptor 158 (GPR158), a hippocampal receptor for osteocalcin (OCN) that is important for the maintenance of cognitive integrity, thus suppressing the ability of the OCN-GPR158 axis to promote cognition in aging and obesity. These findings suggest a new mechanism underlying hippocampal dysfunction and reveal the potential for treating multiple age-related diseases, including neurodegenerative disorders, obesity, diabetes, and atherosclerosis, with a single MT1-MMP-blocking agent.
Reviewing Blood Flow Restriction Training to Build Muscle in Older Individuals
https://www.fightaging.org/archives/2025/09/reviewing-blood-flow-restriction-training-to-build-muscle-in-older-individuals/
The goal of blood flow restriction training is to attempt to induce a mildly hypoxic environment in limb muscle tissue that encourages a greater response to physical activity. This approach has been assessed as a way to induce the growth of greater muscle mass in older individuals, alongside the more prevalent approach of resistance training. Here, researchers provide an overview of the literature on the topic.
In recent years, blood flow restriction training (BFRT) has garnered significant attention as an emerging therapeutic intervention. BFRT involves applying external pressure to the proximal limb using compression devices (e.g., tourniquets or inflatable cuffs) during exercise, partially restricting arterial inflow and fully occluding venous outflow. This creates an ischemic and hypoxic environment within the muscle tissue, triggering a cascade of physiological processes related to tissue adaptation. BFRT affects skeletal muscle primarily by promoting the secretion of anabolic hormones, protein synthesis, recruitment of type II muscle fibers, cellular swelling, and the generation of reactive oxygen species and their derivatives, e.g. nitric oxide (NO) and heat shock proteins (HSPs).
BFRT significantly enhances muscle strength and physical function in elderly populations by inducing muscle hypertrophy. Multiple studies confirm that BFRT achieves comparable outcomes to conventional resistance training for sarcopenia management in older adults, with superior efficacy particularly observed in strength improvement. Consequently, for elderly patients with comorbidities such as degenerative joint disorders or cardiovascular diseases, BFRT emerges as a viable alternative intervention that simultaneously mitigates injury risks associated with high-load training while achieving equivalent strength gains.
Targeting Aspects of Aging with Immunotherapy Technologies
https://www.fightaging.org/archives/2025/09/targeting-aspects-of-aging-with-immunotherapy-technologies/
Immunotherapy is a broad label, encompassing a range of approaches that include varieties of vaccination, selective interference in immune signaling, delivery of engineered immune cells, gene therapies capable of adjusting the behavior of immune cells, and more. An aging-focused viewpoint might also add the destruction of senescent cells or alteration of senescent cell signaling behavior, given the detrimental effect that senescent cell signaling produces on the immune system. Here, researchers review the ways in which one might turn the established technologies used in immunotherapies to target aging and age-related diseases. Evidently this shift is already well underway, given the application of immunotherapies to cancer, but will likely expand considerably.
Immunotherapy, after a century of development, has revolutionized the treatment of many diseases such as infections, cancers, and autoimmune diseases. Multidisciplinary advancements in immunology, molecular biology, biomedical engineering, and computer science have made immunotherapy more precise and specific, expanding its indications.
A recent study on mice demonstrated that immune checkpoint blockade (ICB) can enhance senescence surveillance, indicating the potential of immunotherapies for addressing aging. Senescent cells and aging-related microenvironmental features, such as DNA damage, oncogene expression, mitochondrial metabolic changes, and the production of senescence-associated secretory phenotypes (SASPs), provide targets for immunotherapy to eliminate and reshape the microenvironment.
Furthermore, immunotherapies can also reverse immunosenescence, which manifests as chronic low-grade inflammation and diminished reactivity toward pathogens and malignancies. These features highlight the potential of immunotherapy in delaying aging and related diseases with fewer side effects.
This review summarizes recent progress in aging immunotherapy, including vaccines, adoptive cell transfer (ACT), antibody blockade, and cytokine intervention, while discussing the toxicity issues and limitations encountered in practice. Finally, it describes the prospects of aging immunotherapy, providing new targets and strategies for addressing aging and extending lifespan.
The Phase of Cell Cycle in Which Arrest Happens Determines Senescent Cell Behavior
https://www.fightaging.org/archives/2025/09/the-phase-of-cell-cycle-in-which-arrest-happens-determines-senescent-cell-behavior/
Senescent cells exhibit noteworthy differences from one another. Exploring these differences has been a focus of research in recent years, in order to better understand how to selectively destroy or change the behavior of the lingering harmful senescent cell population that builds up with age in tissues throughout the body. Evidently senescence in different cell types can exhibit differences, but as researchers here demonstrate there are subpopulations of senescence even in a uniform cell population. One of the causes of these different manifestations of senescent behavior is where in the cell cycle a cell halted replication to become senescent, likely a largely random outcome based on the study results here.
Cellular senescence has been strongly linked to aging and age-related diseases. It is well established that the phenotype of senescent cells is highly heterogeneous and influenced by their cell type and senescence-inducing stimulus. Recent single-cell RNA-sequencing studies identified heterogeneity within senescent cell populations. However, proof of functional differences between such subpopulations is lacking.
To identify functionally distinct senescent cell subpopulations, we employed high-content image analysis to measure senescence marker expression in primary human endothelial cells and fibroblasts. We found that G2 phase arrested senescent cells feature higher senescence marker expression than G1 phase arrested senescent cells.
To investigate functional differences, we compared IL-6 secretion and response to ABT263 senolytic treatment in G1 and G2 senescent cells. We determined that G2-arrested senescent cells secrete more IL-6 and are more sensitive to ABT263 than G1-arrested cells. We hypothesize that cell cycle dependent DNA content is a key contributor to the heterogeneity within senescent cell populations. This study demonstrates the existence of functionally distinct senescent subpopulations even in culture. This data provides the first evidence of selective cell response to senolytic treatment among senescent cell subpopulations.
Reviewing Progress in the Treatment of Age-Related Macular Degeneration
https://www.fightaging.org/archives/2025/09/reviewing-progress-in-the-treatment-of-age-related-macular-degeneration/
Age-related macular degeneration is a prevalent cause of progressive blindness caused by cell death and structural dysfunction in the retina and nearby tissue. The usual underlying mechanisms of aging and their consequences feature prominently in present thought on causes: aggregated metabolic waste, inflammation, vascular dysfunction, and so forth. The options for treatment are nowhere near as good as desired. Modestly slowing the progression of the condition remains the most plausible outcome, and relatively little can be done for the dry form of the disease in which the vasculature supplying the retina remains relatively intact and functional. This is well known, and a fair number of research programs and biotech startups aim at the production of novel approaches to therapy. The larger, more mainstream efforts remain focused on approaches that seem likely to produce only incremental gains, unfortunately.
Age-related macular degeneration (AMD) represents a spectrum of degenerative changes in the macula associated with aging, leading to significant central visual impairment. The World Health Organization recognizes AMD as one of the foremost causes of irreversible blindness among individuals over 50 years old worldwide. AMD can be classified into two major subtypes: dry and wet. Dry AMD accounts for approximately 85%-90% of all reported cases. Although the prevalence of wet AMD is lower, it affects more than 15 million individuals worldwide and poses a greater threat to vision than dry AMD.
The pathogenesis of AMD remains elusive and involves multiple factors such as aging, the environment, genetics, oxidative stress, lipid metabolism, and immune responses. Consequently, AMD treatment encounters numerous challenges. Two novel complement inhibitors and one novel treatment option were approved for the treatment of dry AMD by the U.S. Food and Drug Administration (FDA) in 2023 and 2024, whereas anti-vascular endothelial growth factor (VEGF) therapy remains the primary therapeutic approach for wet AMD. However, despite the availability of pharmacological interventions, their application still faces certain limitations. Consequently, research continues to explore alternative therapeutic strategies.
Numerous innovative drugs are presently under development to address these challenges. By conducting an extensive review of relevant literature and reports both domestically and internationally, we provide a comprehensive overview of the classification, pathophysiology, risk factors, and treatment strategies related to AMD. In this review, we systematically summarize the treatment approaches for various types of AMD, including the most recently approved drugs and therapeutic strategies, and provide a detailed overview of the advancements in ongoing clinical trials.
Applying a Proteomic Aging Clock to Data from a Very Long-Running Epidemiological Study
https://www.fightaging.org/archives/2025/10/applying-a-proteomic-aging-clock-to-data-from-a-very-long-running-epidemiological-study/
Older epidemiological study data sometimes offers the potential for reanalysis with modern aging clock algorithms to assess biological age. If the study continued since the data was obtained, then there is the possibility to demonstrate that measures of biological age do correlate well with specific long-term outcomes. The downside is that researchers are limited by past choices regarding what was measured, and thus which clocks can be used, and often limited in the degree to which data obtained decades ago remains accessible. Nonetheless, sometimes it works out and we see results such as those reported here. A study has followed one birth cohort since the 1940s, and proteomic data was obtained 15 years ago. That data has now been used to assess biological age at that time, then correlated with later medical outcomes over the following 15 year span of time.
The pace of organ ageing varies substantially between individuals, yet drivers of variability remain poorly understood. This gap is critical, given only 20-30% of longevity is genetically inherited and age-related diseases are leading causes of morbidity and mortality. Proteomic clocks allow organ ageing to be estimated from blood sampling, facilitating study of how life course exposures shape biological ageing heterogeneity. Here, we leverage the unique design of the MRC National Survey of Health and Development (NSHD), the world's oldest continuously followed birth cohort, to track 1,803 individuals across eight decades since birth in 1946.
At mean age 63.2 years, we estimated proteomic ageing in seven organs. Despite near identical chronological ages, participants' proteomes revealed biological ageing disparities spanning decades. Extreme ageing in multiple organs was a strong prognostic indicator for all-cause mortality over the following 15 years (hazard ratio 6.62 for ≥ 4 extremely aged organs).
Adversity and being overweight in adolescence associated with accelerated ageing decades later in life. Completing secondary school education and maintaining physical activity linked to relative biological youth. Mediation analyses indicated liver, kidney, and immune ageing linked life course exposures to mortality. Across 10,776 plasma protein targets, we identified 143 predictors of longevity, including MED9, strongly linked to diverse socio-behavioural exposures. These findings provide unique insights into which factors are likely to shape how we age, when in life they may be influential, and how biological effects emerge, informing healthy ageing promotion.
A Review of Mechanisms Involved in the Aging of the Heart
https://www.fightaging.org/archives/2025/10/a-review-of-mechanisms-involved-in-the-aging-of-the-heart/
Researchers here offer opinions reflective of the present research mainstream on which mechanisms are important in the aging of the heart and its consequent dysfunctions. This sort of article is an interesting measure of the degree to which the "aging is accumulated damage" viewpoint exemplified by the Strategies for Engineered Negligible Senescence (SENS) has won ground in the ongoing war of ideas regarding the matter of research strategy for the treatment of aging and age-related disease. For example: targeting senescent cells is now mainstream; mitochondrial dysfunction remains a topic in which everyone agrees there is a problem, but disagrees on the nature of that problem; and epigenetic change has been eagerly adopted as a point of intervention by a research community that was already spending much of its time on trying to adjust gene expression for therapeutic effect.
Cardiac aging is a fundamental driver of cardiovascular diseases (CVDs), the leading cause of global mortality. While age is a non-modifiable risk factor, understanding its underlying molecular basis offers new avenues for therapeutic intervention. This review synthesizes the key mechanisms driving cardiac aging and evaluates promising strategies to counteract them. Our aim is to provide a forward-looking perspective, arguing that a paradigm shift from single-target interventions to synergistic, systems-level approaches is necessary to promote healthy aging and longevity.
We delineate the hallmark structural and functional changes of the aging heart, including left ventricular hypertrophy, diastolic dysfunction, and increased fibrosis. We then explore the core molecular pathways, highlighting the critical roles of dysfunctional autophagy, mitochondrial oxidative stress, telomere shortening, and profound epigenetic shifts, particularly the dysregulation of non-coding RNAs such as miR-34a. Building on this mechanistic framework, we assess a range of interventions, from lifestyle modifications like caloric restriction to targeted pharmaceuticals including rapamycin and senolytics. Furthermore, we discuss the potential of next-generation therapies such as microbiome modulation, cell-based regeneration, and gene editing.
Reviewing the Aging of the Liver
https://www.fightaging.org/archives/2025/10/reviewing-the-aging-of-the-liver/
The liver is perhaps the most regenerative organ in the body, but like all other organs it is negatively affected by the accumulation of cell and tissue damage characteristic of aging. Liver function is reduced, while prevalent liver diseases such as metabolic dysfunction-associated steatoheptatitis occur more readily in older people than in younger people. With this in mind, researchers here present a tour of vulnerabilities to disease and dysfunction that are induced by mechanisms of aging in the liver.
While the liver can maintain some of its homeostatic functions throughout aging, it becomes highly susceptible to liver injury and chronic liver disease. This susceptibility is mainly due to decreased hepatic volume, reduced blood flow, altered microvasculature, defective metabolizing enzymes, impaired proteostasis, mitochondrial dysfunction, and reduced expression of hormone receptors. Furthermore, chronic exposure to external factors such as polypharmacy, excessive alcohol consumption, and nutritional imbalances may exacerbate harmful inflammatory signaling, cellular senescence, and elevated oxidative stress. These changes ultimately hinder the aged liver's ability to manage cell death and disease progression effectively. These age-related anatomical and molecular changes in the aged liver exacerbate ischemia-reperfusion injury (IRI), drug-induced liver injury (DILI), alcohol-associated liver disease (ALD), and metabolic dysfunction-associated steatotic liver disease (MASLD).
The proposed role of aging in liver diseases. (A) IRI: Aging livers experience reduced levels of ATG4B and PARKIN, leading to decreased autophagy/mitophagy and increased reactive oxygen species (ROS). Enhanced NF-κB activation in macrophages causes greater inflammation, worsening IRI. (B) DILI: Older adults have decreased liver drug metabolism due to reduced activity of CYP enzymes and lower clearance, along with diminished GSH and SOD levels. These factors, combined with polypharmacy, raise susceptibility to DILI. © ALD: Aging diminishes alcohol-metabolizing enzymes and proteostasis mechanisms like autophagy/proteasome. Decreased SIRT1 levels and increased inflammation further exacerbate ALD. (D) MASLD: The aging liver shows elevated necroptosis and ferroptosis proteins, increased lipogenesis, and inflammation, while fatty acid beta-oxidation and autophagy decrease, leading to more severe MASLD.
Are Socioeconomic Correlations with Disease Explained by Different Lifestyle Choices?
https://www.fightaging.org/archives/2025/10/are-socioeconomic-correlations-with-disease-explained-by-different-lifestyle-choices/
When examining human epidemiological data, a web of correlations link health, life span, education, wealth, intelligence, and socioeconomic status. One can hypothesize about why these correlations exist, and to what degree different mechanisms contribute to the overall effect, but it remains challenging to draw firm conclusions from the data. For example, reasonably compelling evidence suggests that intelligence is related to physical resilience via biological mechanisms, and so relationships between intelligence and health outcomes may not be entirely a matter of behavior. How much is behavior versus physiology is up for debate. The paper noted here is focused on socioeconomic status and is illustrative of much of the research into such correlations, in that it suggests that a differing distribution of lifestyle choices across the socioeconomic spectrum is not the only mechanism at play in producing differences in health outcomes.
Lifestyle factors significantly influence the risk of developing non-communicable diseases like type 2 diabetes, cancer, and cardiovascular diseases and can modify health trajectories towards multimorbidity. Separately, socioeconomic position (SEP) is a key determinant of health outcomes and is recognised as a driver of inequalities in the risk of multimorbidity. Multimorbidity is socially patterned, with lower SEP linked to higher risk.
We examined whether a Healthy Lifestyle Index (HLI) mediates the SEP-multimorbidity association. We used data from 244,886 participants in the European Prospective Investigation into Cancer and Nutrition study. HLI was derived from smoking, alcohol consumption, physical activity, body mass index, and diet. SEP was categorised into low, medium and high-SEP based on education. Multimorbidity was defined as the coexistence of at least two diseases among cancer, type 2 diabetes, and cardiovascular diseases.
Participants from lower SEP categories were older with worse health outcomes. Women had a healthier lifestyle than men across all SEP levels. In men, the hazard ratio of developing multimorbidity was 1.40 for those with low SEP compared with high SEP, in women 1.74. The study suggests that lifestyle factors partially mediate the relationship between SEP and the development of multimorbidity. However, this also indicates that other factors beyond lifestyle, such as biological or social determinants, may be at play.
Senescent Oligodendrocyte Precursor Cells Contribute to the Aging of the Brain
https://www.fightaging.org/archives/2025/10/senescent-oligodendrocyte-precursor-cells-contribute-to-the-aging-of-the-brain/
Considerations of the role of dysfunction of oligodendrocytes and their precursor cell population in aging usually focus on myelination. Oligodendrocytes are responsible for maintaining the insulating myelin structure that wraps the axons that connect neurons, and which is required for effective propagation of nerve impulses. Researchers have shown that this function declines with age, perhaps to a meaningful degree. Here, however, researchers instead focus on the effects of cellular senescence in oligodendrocyte precursor cells. Senescent cells accumulate with age in the body and brain, and are well known to cause harm to the degree to which they linger and their population grows. Different cell types likely produce different specific harms when they become senescent, however. The researchers show that specific components of the inflammatory signaling produced by senescent oligodendrocyte precursor cells interfere in the activity of other cells in the brain to accelerate cognitive decline.
Aging contributes to cognitive decline in the adult brain with unclear mechanisms. Cellular senescence is characterized by an irreversible cell cycle arrest and featured by the senescence-associated secretory phenotype (SASP). The latter contains pro-inflammatory cytokines, chemokines, growth factors, and proteases, through which senescent cells affect themselves and the neighboring cells via autocrine and paracrine mechanisms. Distinct types of neural cells such as neurons, astrocytes, microglia, and oligodendrocyte precursor cells (OPCs) have been shown to express senescent markers, and these senescent cells accumulate in the brains with aging and neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). The selective elimination of these senescent cells attenuates cognitive deficits in naturally aged mice and reduces the accumulation of hyperphosphorylation of tau and amyloid-β in AD transgenic mice. However, despite these beneficial effects, which types of cells are predominant players in driving brain aging and how these senescent cells contribute to aging-related cognitive decline remain unknown.
OPCs, evenly distributed throughout the adult brain, are the primary proliferative cells in the adult central nervous system (CNS). One of the pivotal roles of OPCs is their capability to generate oligodendrocytes (OLs), which produce myelin, ensuring the fast and reliable conduction of action potentials (APs) and providing metabolic support to axons. Apart from being the cellular source of myelin, recent studies point out a myelination-independent function of OPCs in maintaining adult brain networks. OPCs regulate cognitive behaviors via secreting soluble factors and phagocytotic remodeling of synapses and axons. It is worth noting that OPCs form bona fide synapses with glutamatergic and GABAergic neurons. However, it remains unknown how OPCs regulate neuronal plasticity and whether the myelination-independent functions of OPCs are involved in aging-associated cognitive decline.
In this study, we report a myelination-independent role of OPCs in exaggerating cognitive decline in the aging brain via suppressing neuronal plasticity. Our results demonstrate that macroautophagic flux declines in aged OPCs. Inactivation of autophagy promotes the senescence of OPCs, which activates CCL3/CCL5 signaling to activate the CCR5 receptor. Through this, autophagy-defective OPCs impair glutamatergic transmission, neuronal excitability, and long-term potentiation, exaggerating the cognitive decline in the aging brain. Inhibition of CCR5 rescues this impaired neuronal plasticity and cognitive deficits.
Continued Progress Towards Reversible Vitrification of Organs
https://www.fightaging.org/archives/2025/10/continued-progress-towards-reversible-vitrification-of-organs/
Cryonics is important. Low-temperature storage of the brain is presently the only near-term approach that can provide those who die from old age with some greater than zero chance at a renewed life in the future. The cryonics industry has remained small since its inception decades ago, and only a few hundred people have been cryopreserved. The best way to expand and advance the small cryonics industry is to develop reversible vitrification of organs, a capability that has been demonstrated at the small scale in laboratories, and which has tremendous value to the organ transplant industry if made reliable. The ability to store a donated organ indefinitely would change all of the presently challenging economics of transplantation, and bring significant new funding into efforts to make cryopreservation that much more robust. Further, acceptance of the ability to vitrify and thaw organs would make acceptance of cryopreservation as a life-saving medical intervention of last resort that much easier.
Cryonics startup Until Labs has closed a 58 million Series A financing round, bringing its total raised to over 100 million as it works to build technology for reversible cryopreservation. The new funding round will enable Until to expand its team and infrastructure while advancing its first medical product: organ cryopreservation for transplant patients and surgeons.
The company's immediate focus is on overcoming one of transplant medicine's most rigid bottlenecks: the narrow window of organ viability. Hearts, lungs and livers must reach recipients within 4 to 12 hours of procurement, while kidneys last no longer than 24 to 36. These limits dictate the logistics of transplantation, confining patients to hospitals, requiring surgeons to charter planes to retrieve organs, and resulting in thousands of donations being discarded each year due to timing mismatches.
To address these challenges, Until is developing perfusion hardware, cryoprotective agents, and rapid rewarming infrastructure designed to preserve organs indefinitely without damaging their structure or function, then safely restore them for transplantation. The company says it has already built a discovery engine for new cryoprotective molecules, created a custom electromagnet for rewarming, and scaled its work from neural tissue slices to large-animal organs. It is now focused on refining protocols that preserve post-thaw organ quality.
The company's longer-term vision, however, extends far beyond transplant logistics, ultimately aiming for the holy grail of whole-body reversible cryopreservation. Its early work demonstrated recovery of electrical activity in rewarmed slices of rodent neural tissue. The company's previously stated roadmap includes showing preserved synaptic function in neural samples, successful cryopreservation of large-animal organs, human organ preservation clinical trials, and eventually reversible whole-body cryopreservation in animal models.
View the full article at FightAging
