Fight Aging!

Despite the only small benefits shown to Alzheimer's patients following clearance of amyloid-β aggregates in the aging brain, the consensus remains that a slow accumulation of amyloid-β aggregates over years is the inciting form of dysfunction that gives rise to the later tau aggregation, neuroinflammation, and cell death in Alzheimer's disease. Removal of amyloid-β may be preventative in the earliest stages of the condition, but this is a hypothesis still undergoing assessment. Amyloid-β in the brain has been shown to be in dynamic equilibrium with amyloid-β outside the brain, and this has led to clinical trials in which amyloid-β is removed from blood, causing a greater amount of amyloid-β to exit the brain. Here, researchers discuss this holistic view of amyloid-β distribution throughout body and brain, and whether current efforts are too focused on only the burden of amyloid-β aggregates in the brain.

Alzheimer's disease (AD) represents one of the most prevalent neurodegenerative disorders without approved disease-modifying therapies. A major contributing factor is that, for decades, drug development has focused almost exclusively on repairing or removing lesions within the brain itself. Yet a growing body of work now points to AD as a systemic disorder, rooted in a breakdown of whole-body Aβ homeostasis. Nevertheless cerebral Aβ transport and peripheral Aβ clearance are commonly investigated as independent processes, and the coordinated interplay remains insufficiently characterized. This review bridges the current research gap by systematically elaborating the full trafficking cascade of brain-derived Aβ from intracerebral drainage to peripheral elimination.

Four major intracranial clearance pathways are comprehensively summarized, including the blood-brain barrier, blood-cerebrospinal fluid barrier, arachnoid granulation venous outflow, and meningeal lymphatic/glymphatic system. The peripheral clearance processes of circulating Aβ in the blood, liver, kidney, and gastrointestinal tract are further illustrated. A broad spectrum of emerging therapeutic strategies targeting Aβ transport and clearance is also reviewed, including specific pathway modulators, microglia regulators, Aβ aggregation inhibitors, natural multi-target compounds, ultrasound-mediated blood-brain barrier opening, and exosome-based intervention approaches.

When we compare the relative contributions of central versus peripheral clearance, comparative analysis of central and peripheral Aβ clearance indicates that the liver appears to dominate the peripheral elimination of Aβ, yet the real driver of cerebral Aβ deposition is not the failure of any single route, but rather the loss of synergy among multiple pathways. This mechanistic framework explains why purely brain-centric therapeutics are unlikely to correct a systemic Aβ imbalance. Instead, future translational efforts should give higher priority to combination regimens that simultaneously facilitate intracerebral drainage and bolster peripheral organ clearance. This review further discusses current hurdles and emerging opportunities in systemic AD drug discovery, with the aim of offering a unified conceptual framework-one that providing a unified conceptual framework for understanding AD pathogenesis and facilitating the exploration of novel therapeutic paradigms.

Link: https://doi.org/10.3389/fragi.2026.1921485

Recovery and transplantation of organs following vitrification using cryoprotectant is an important step along the road to the future technological capability of whole body vitrification and recovery - and recovery of those individuals already preserved at low temperature by the cryonics industry. It is particularly important because it is a highly desirable capability for the organ transplant industry, and thus a way to bring significant funding and credibility to the endeavor of cryonics, the preservation of people for future revival. Scaling up vitrification and rewarming to human sized organs has been a major challenge on several fronts, such as effective perfusion of cryoprotectant in large tissues, performance of the cryoprotectant, consistent warming of deeper tissue in a large vitrified mass, and so forth. It is much easier to vitrify and reward small tissue samples than large ones. Here researchers report success in pig kidneys, albeit using an approach to rewarming that requires preparation of the organs prior to vitrification, and thus cannot be applied to tissues and people preserved prior to its introduction. Nonetheless, it is an important step forward.

Vitrification and nanowarming have enabled long-term preservation and transplantation of rodent kidneys but have not been demonstrated at the scale of clinically relevant organs. Here we show that vitrification and electromagnetic nanowarming enable long-term cryogenic storage and functional recovery of human-scale porcine kidneys. Kidneys 100-fold larger than previously nanowarmed kidneys were successfully recovered after storage at -150 °C for up to one year. A new cryoprotectant formulation and multithermic perfusion strategy enabled ice-free vitrification at cooling rates achievable in large kidneys, while controlled cooling with annealing and staged volumetric nanowarming limited thermal stress and enabled rapid rewarming without cracking.

Nanowarming was developed to overcome the limitations of surface-based rewarming. Silica-coated iron oxide nanoparticles distributed through the vasculature before vitrification generate heat when exposed to an alternating electromagnetic field, enabling rapid volumetric rewarming throughout the organ.

Rewarmed kidneys demonstrated vascular, metabolic, and excretory function during normothermic perfusion, with limited histological injury, and reperfused homogeneously and produced urine immediately after transplantation. Functional recovery approached static cold storage outcomes across several measures and was similar to that of kidneys exposed to cryoprotectant alone, suggesting minimal additional functional injury from vitrification, cryogenic storage, and nanowarming. These findings overcome major scale and storage-duration barriers to organ cryopreservation and establish a path toward organ banking on timescales far beyond those of conventional preservation.

Link: https://doi.org/10.64898/2026.10.07.756990

The vascular system is prone to calcification with advancing age. Cells in the vasculature inappropriately take on the features and behavior of the osteoblast cells responsible for building bone extracellular matrix. These errant vascular cells deposit calcium phosphate structures into vascular tissue, stiffening it. Calcification proceeds in parallel with atherosclerosis, the thickening of artery walls and generation of fatty plaques that obstruct vessels and ultimately rupture to cause a heart attack or stroke, but is an independent process that would cause dysfunction and mortality even if the causative mechanisms of atherosclerosis were eliminated.

Stiffening of vascular walls, however it occurs, whether by this process, other forms of damage and change in the extracellular matrix, or loss of responsiveness to cues for contraction and dilation in vascular smooth muscle, induces hypertension, among other issues. Perhaps more importantly, calcification of structures in the heart, such as the aortic valves, is ultimately fatal.

Present therapeutic options for calcification are limited. For example, a form of chelation using EDTA has been assessed in clinical trials, is readily available in clinics, but produces only modest benefits at best. Thus it is interesting to keep an eye on developments in this space. Today's open access paper describes a micropeptide therapy that can inhibit calcification processes, slowing vascular calcification meaningful in animal models. Slowing is a start, but effective reversal of age-related tissue calcification remains a unfulfilled goal.

PKM2 AP: a micropeptide inhibits vascular calcification via molecular glue-mediated ubiquitination of PKM2

Vascular calcification (VC) is not merely a passive mineralization process, rather, it is an active pathological event that is propelled by the osteogenic phenotypic transition of vascular smooth muscle cells (VSMCs). This transition is characterized by aberrant deposition of hydroxyapatite crystals within the vascular wall, leading to loss of vascular elasticity and increased risk of cardiovascular events. Despite advancements in clinical management strategies for VC, such as intensified dialysis regimens and phosphate binder therapies, current treatments remain insufficient to halt calcification progression, resulting in limited long-term prognostic improvement.

VSMCs undergo phenotypic switching from contractile to synthetic or inflammatory states under pathological stimulation, a critical initiating event in VC. Notably, this phenotypic transition is accompanied by marked metabolic reprogramming, characterized by a shift from oxidative phosphorylation to aerobic glycolysis, leading to lactate accumulation. Emerging evidence suggests that lactate not only induces synthetic phenotypic switching in VSMCs but also promotes vascular calcification through dual mechanisms: activating NR4A1-mediated mitochondrial fission and BNIP3-dependent mitophagy. Pyruvate kinase M2 (PKM2), a key rate-limiting enzyme in glycolysis, catalyzes the irreversible conversion of phosphoenolpyruvate to pyruvate, directly regulating lactate biosynthesis. Strikingly, recent studies demonstrate that PKM2 inhibition preserves VSMC contractile phenotype and improves vascular homeostasis, suggesting its pivotal role in calcification-associated metabolic regulation.

In this study, we identified a 40-amino acid micropeptide, termed PKM2-associated micropeptide (PKM2 AP), which was highly expressed in patients with chronic kidney disease-related vascular calcification. PKM2 AP localized to both mitochondrial and cytoplasmic compartments and exhibited functional interactions with PKM2. Functional experiments demonstrated that overexpression of PKM2 AP both in vitro and in vivo attenuated the progression of vascular calcification. Mechanistically, PKM2 AP functioned as a molecular glue-like factor that facilitated the recruitment of the E3 ubiquitin ligase STUB1 to PKM2, thereby promoting PKM2 ubiquitination and degradation, ultimately suppressing aerobic glycolysis and lactate production in human aortic vascular smooth muscle cells (HAVSMCs). In vivo administration of PKM2 AP alleviates vascular calcification phenotypes in mouse models.

Researchers here identify the gene PLA2G2F as a regulator of compensatory responses to some of the damage and dysfunction of aging. The researchers were primarily investigating a population of neurons found in the hippocampus, involved in memory function, but find that the gene is relevant in supporting cells of the brain also, such as microglia. Expression of PLA2G2F increases with age, and artificially increasing expression over natural levels produces greater protection. PLA2G2F appears to be involved in maintenance of normal lipid metabolism. Evidence suggests that dysfunctions in lipid metabolism occur in the aging brain, and cause harm via provoking greater inflammatory behavior in a number of supporting cell populations.

Cognitive reserve theory posits that compensatory mechanisms during aging stave off cognitive decline and lower risk for Alzheimer's disease. Here, in a screen for hippocampal dentate granule cell (DGC) synapse loss-induced factors in mice, we identified a secreted phospholipase, Pla2g2f, whose expression increases in DGCs during aging and is associated with cognitive resilience in humans. Pla2g2f deletion in DGCs exacerbates aging-associated pathophysiological changes, including synapse loss, inflammatory microglia, reactive astrogliosis, impaired neurogenesis, lipid dysregulation, lipid droplet accumulation, and hippocampal-dependent memory loss.

Conversely, boosting Pla2g2f in DGCs during aging is sufficient to prevent these pathophysiological alterations in hippocampal-cortical circuits, protect memory, and prophylactically modify trajectory of cognitive decline. Mutagenesis of the catalytic site of PLA2G2F prevented lipid droplet mobilization and reduction of reactive gliosis and inflammatory microglia. Neuronal PLA2G2F mediates intercellular signaling to decrease lipid droplet and cholesterol ester load in human induced pluripotent stem cell-derived microglia. Our findings implicate PLA2G2F as a compensatory neuroprotective broadcast signal that maintains lipid homeostasis to counteract aging-associated cognitive decline.

Link: https://doi.org/10.1038/s41593-026-02465-z

Of the common variants of the APOE gene, APOEε4 presents the greatest risk of Alzheimer's disease. APOE is involved in lipid metabolism, and APOEε4 is associated with lipid-related contributions to inflammation in microglia, suggesting a primarily inflammatory mechanism for the increased risk of neurodegeneration. Here, researchers find that APOEε4 also interferes in the ability of oligodendrocyte cells to maintain the myelin structures that sheath the axons that connect neurons into neural networks, again via lipid-related mechanisms. This myelin sheathing is required for effective communication between neurons. Myelin maintenance does falter to some degree in normal aging, and the consequent loss of myelin is thought to contribute to dysfunction in the aging brain. It is reasonable to hypothesize that greater myelin loss driven by APOEε4 is a factor in accelerated neurodegeneration.

A new study shows that APOE4 leads to a suppression of Wnt signaling in the oligodendrocyte cells that provide neurons with a fatty insulation, called myelin. When Wnt signaling is deficient, the cells accumulate droplets of lipids rather than deploying fats to properly myelinate the neurons' axon branches. When the researchers restored Wnt signaling in APOE4-carrying oligodendrocytes, myelination rebounded, both in human cell cultures and in mice modeling Alzheimer's.

Researchers discovered Wnt's key role via multiple methods including a screen in which they used CRISPR gene editing to systematically knock out each protein-coding gene in the genome, one by one, in cultures of human APOE4-carrying oligodendrocytes. The screen showed that when genes promoting Wnt activity in oligodendrocytes were lacking, lipid droplets accumulated, and that when genes suppressing Wnt were lacking, lipid droplets were, too. Further analysis revealed how Wnt signaling became depressed in cultured APOE4 oligodendrocytes. Two proteins, beta-catenin and GSK3b, each compete to regulate Wnt-beta-catenin promotes it and GSK3b suppresses it. The team found that in APOE4 oligodendrocytes compared to APOE3 ones, there was reduced beta-catenin expression and excessive GSK3b expression.

The team then tested interventions that manipulate GSK3b activity. In human APOE3 oligodendrocyte cultures, they showed that increasing GSK3b with a chemical called Dif3 increased lipid droplets. In APOE4 oligodendrocytes, they showed that inhibiting GSK3b with a chemical called CHIR99021 reduced droplets. In more complex "organoid" cultures combining APOE4 oligodendrocytes with neurons, they found that inhibiting GSK3b increased myelination and promoted the growth of neural axons. The tests suggested that GSK3b inhibition could be a proof-of-concept therapeutic strategy for restoring Wnt signaling and myelination.

Link: https://picower.mit.edu/news/how-biggest-alzheimers-risk-gene-disrupts-process-insulating-neurons

Mitochondria are the power plants of the cell, creating the chemical energy store molecule adenosine triphosphate used to power cellular processes. Mitochondrial function declines with age, and the research community is engaged in a variety of approaches that might at least modestly reduce this loss. The supplement urolithin A is known to improve mitochondrial function, though, and as is the case for other approaches, how exactly urolithin A accomplishes this outcome is not fully understood. Most of the ways to modestly improve mitochondrial function, ranging from exercise and calorie restriction through to NAD+ upregulation via vitamin B3 derivatives and MitoQ, may primarily function through improvements to autophagy targeted at mitochondria, improving overall mitochondrial function via improved clearance of damaged and dysfunctional mitochondria. This is by no means a definitive answer, but the supporting evidence is suggestive.

In today's open access paper, researchers show that topical application of urolithin A improves the function of aged skin. It is interesting to compare this with a small study of topical application of low dose rapamycin, another approach to improve autophagy. Increased autophagy (and accompanied improvement in mitochondrial function) has in the past been shown to reduce the pace at which cells become senescent in aged tissues. This allows the immune system to catch up in its task of clearing senescent cells, and thus reduce the harmful burden of senescent cells that contributes to dysfunction in aged tissues. Cellular senescence is known to be important in the aging of skin, and increased autophagy over time is an approach to reducing this contribution to degenerative aging.

Topical application of urolithin A activates mitophagy and enhances mitochondrial function to promote skin longevity

The most common visual signs of aging skin are the appearance of wrinkles, skin thinning, hyperpigmentation, sagginess, and dryness. This derives from a combination of biological changes, including a decline in the quantity and quality of structural components of the skin, such as collagen and elastin, as well as dysfunctions in cellular bioenergetics. Indeed, most of the energy to support skin cell health is derived from mitochondria, making mitochondrial dysfunction a key hallmark of skin aging. The aging process impacts immune cells in the skin. This reduces the ability of the skin to cope with excessive inflammation and significantly contributes to the emergence of photoaging. Finally, cellular senescence is emerging as a key additional hallmark that affects skin health as we age, which can be counteracted by removal of the senescent cells (i.e., senolytic effect) or blunting of their detrimental secretome (i.e., senomorphic effect).

Urolithin A (UA) is a promising molecule to explore for its impact on skin longevity, considering its origins as a postbiotic of the gut microbiome that has been shown to both improve mitochondrial health and reduce age-associated inflammation, i.e., inflammaging, when administered orally. UA increases mitophagy, the process of recycling faulty mitochondria, and enhances biomarkers associated with improved mitochondrial function in several models of aging and age-associated conditions. In humans, oral supplementation of UA was shown to be safe, improve mitochondrial function, and increase muscle strength, endurance, and immune decline in clinical studies in middle-aged and elderly subjects. Topical application of UA represents a compelling approach to support skin health and extend skin longevity through its combined effect on multiple hallmarks of cellular aging.

UA was evaluated for its effects on skin health in human skin models and when applied topically to healthy subjects in randomized clinical studies. UA tested in 2D and 3D reconstructed human skin and ex vivo human skin explants showed enhanced mitochondrial respiration, activated mitophagy markers, reduced inflammatory mediators and senescence-associated markers, and increased proteins involved in extracellular matrix structure and epidermal differentiation. In randomized, placebo-controlled clinical studies, UA reduced periorbital wrinkle depth after 8 weeks and attenuated UVB-induced erythema. Skin transcriptomics supported increased extracellular matrix and epidermal development programs together with decreased inflammatory and senescence-associated signaling.

Why, mechanistically, is female reproductive aging so accelerated in relation to the rest of the aging process? Researchers here point to a role for a progressive loss of ribosomes in oocytes. Cells contain many ribosomes, vital components of the cell where messenger RNA is translated into protein, and usually synthesize more as needed. Oocytes do not tend to synthesize new ribosomes, however, one of many differences in behavior intended to retain a much higher standard of cell quality during the reproductive lifespan. Female germline cells are among the most protected of all cell types, and have to be in order to maintain a sufficiently low level of reproductive failure for evolutionary success. Here, it is suggested that this ribosomal approach to increased cell quality produces the trade-off of a shorter cell life span and an earlier end to reproductive life span, as ribosomes are not replaced as they fail, and new oocytes are not created in adult life. In support of this view, researchers find that artificially reducing ribosome count in oocytes recapitulates the features of reproductive aging.

Protein synthesis declines with age across many tissues, but whether this decline actively contributes to physiological aging remains unclear. Oocytes may be particularly vulnerable because they rely on ribosomes synthesized during growth and maintained for prolonged periods without continual replacement. Here we show that declining translational capacity is a causal component of oocyte aging. An unbiased genetic screen identified ribosome dosage as a major determinant of oocyte longevity, and experimentally reducing ribosome abundance was sufficient to accelerate the loss of developmental competence and prematurely recapitulate meiotic defects that arise during natural aging, while also producing defects in early embryonic development.

Ribosomes isolated from aged Drosophila oocytes exhibit ∼50% lower translational activity despite only a modest reduction in ribosome abundance and preserved gross structure and composition, with both ribosomal subunits contributing to this functional decline. Protein synthesis also declines markedly in aged metaphase-I mouse oocytes. Together, these findings identify long-lived translational machinery as an intrinsic vulnerability of the oocyte and establish declining ribosome function as a mechanistic contributor to reproductive aging.

Link: https://doi.org/10.64898/2026.09.29.755503

Aging clocks can be produced from large databases of near any form of biological data that changes with age via the use of machine learning techniques that identify weighted combinations of measures that correlate strongly with chronological age, remaining life expectancy, mortality risk, and so forth. The true goal of developing clock technology is to find a way to rapidly assess the quality of any new potential therapy to slow or reverse aspects of aging, and thus greatly accelerate research and development, focusing attention on the best possible approaches. Unfortunately no clock can be trusted to perform accurately in the face of a new approach to treat aging. A clock could underestimate, overestimate, or be unaffected by biological changes that do have meaningful effects on aging. It is unknowable in advance how this will play out, and the only way to determine what will happen is to first calibrate the clock against the therapy using lengthy studies, which defeats the point of the exercise. Nonetheless, researchers are engaged in producing as much data as possible on the way in which clocks behave, in an attempt to at least try to predict the degree of trust one should have in a giving clock assessing a given therapy.

Epigenetic clocks have emerged as potential biomarkers of aging due to their association with morbidity and mortality. They have recently gained traction as outcome measurements for anti-aging interventions. However, as the number of new epigenetic clocks continues to grow, different clocks may not agree on the effect of an intervention. This raises the question of when researchers can trust epigenetic clock results. In this study, we find that when extending previously published single-clock intervention studies to include additional clock models, no additional clocks reach statistical significance.

We then analyze clock behavior across positive control datasets (age-accelerating events) to propose three criteria that increase confidence in a result: (1) reliable principle component based clocks respond, (2) mortality-trained or pace-of-aging clocks respond, and (3) multiple clocks respond in the same direction. To explain why genuine effects would appear across multiple clocks, we perform a simulation study to demonstrate how reliable clocks are more sensitive to true effects, and use longitudinal control datasets to show that reliable clock changes are correlated with each other. We then show examples of interventions that do satisfy these criteria.

These findings provide a framework for interpreting epigenetic clock results in anti-aging intervention studies, and suggest that some previously published single-clock findings may warrant reexamination.

Link: https://doi.org/10.1111/acel.70756

Naked mole rats are very long-lived in comparison to similarly sized rodents, undergo little to no age-related loss of function for much of their later life, and exhibit a near complete resistance to cancer. A sizable fraction of research into the comparative biology of aging is focused on this species, in an attempt to better understand which mechanisms of aging are more versus less important, and whether any of the unusual biochemistry of naked mole rats can be used as a basis for therapies to treat aging or cancer. Science moves slowly, and so only recently has the research community started to import a few naked mole rat genes into other species, a first step to validating whether or not therapies are possible. Early results are promising.

Today's open access paper is a little along the lines of naked mole rat researchers calling for more naked mole rat research, but the argument is justified based on what has been learned to date. Gene transfer showing benefits may give way to a search for gene therapies or small molecules, but the first step on the long road towards therapies derived from the advantageous aging biology of another species has been taken. The authors of the paper are largely focused on reviewing what is known of the way in which naked mole rat biochemistry interacts with the hallmarks of aging. Some quite interesting discoveries have been made in recent years, such as naked mole rat senescent cells exhibiting only a muted senescence-associated secretory phenotype, and thus being much less disruptive to tissue function. There is no doubt much more of interest yet to be uncovered.

Unlocking the secrets of naked mole-rat longevity

Fourteen hallmarks have been proposed to describe the core features of biological aging; however, whether their direct enhancement contributes to longevity remains unclear. Here, we summarize current knowledge on the differential regulation of these aging hallmarks in the naked mole-rat and their potential roles in its exceptional lifespan. We also discuss current research limitations and suggest future directions to better elucidate the basis of naked mole-rat longevity, ultimately enabling the development of strategies to promote healthy aging in humans.

The exploration of extreme longevity mechanisms in the naked mole-rat ultimately points to an evolutionary biology question: Is this anti-aging phenotype a "free lunch" shaped by natural selection, or a "trade-off" incurring corresponding costs? Classic trade-off theory posits that, due to limited resources, allocating energy to somatic maintenance and repair necessarily comes at the expense of other functions, such as reproduction. Based on this, it is reasonable to speculate that naked mole-rat longevity is likely not an isolated advantage but rather the result of sacrificing certain conventional physiological functions. However, female naked mole-rats demonstrate no decline in fertility for the vast majority of their long lifespan, attributed to an exceptionally large ovarian reserve and postnatal oogenesis. Interestingly, their reproductive strategy is fundamentally reshaped, as the vast majority of colony members remain in a state of reproductive suppression throughout their lives. A study found higher plasma oxidative stress in breeders than non-breeders, indicating a potential trade-off.

Although enhanced function in multiple organs has been identified, some "degenerations" exist, including visual function and thermoregulation. Understanding these potential trade-offs is not only an intriguing evolutionary biology question but also crucial for evaluating the risks of translating these mechanisms into humans. However, current experimental evidence regarding this trade-off is lacking. Establishing techniques such as genetic manipulation in the naked mole-rat is an important step towards systematically evaluating this phenotypic trade-off in vivo. If a trade-off does exist, whether these mechanisms can be separated from their associated costs is another intriguing question. If the answer is yes, then anti-aging strategies translated from naked mole-rats to humans might circumvent the corresponding negative effects.

Can longevity mechanisms discovered in naked mole-rats finally translate into human anti-aging clinics? As a proof-of-concept, researchers successfully introduced the nmrHAS2 gene into mice, demonstrating that it significantly reduced tumor incidence, extended both median and maximum lifespan, and improved multiple health span parameters, thereby laying a solid foundation for HMM-HA-based anti-aging interventions. Another example involves the four specific amino acid mutations at the C-terminus of the naked mole-rat cGAS protein. Introducing these four mutations into human cGAS reverses its inhibitory effect on homologous recombination repair of DNA. Furthermore, transgenic expression of naked mole-rat cGAS in fruit flies extends lifespan, and its overexpression in aged mice mitigates multi-organ aging phenotypes. However, naked mole-rat longevity is attributed to multiple mechanisms. Identifying additional translatable mechanisms and exploring combinatory intervention strategies are among the key future directions.

The presently available data and understanding of aging might be thought of as a jigsaw with more missing pieces than there are pieces in hand. There is a great deal of latitude to assemble what is known into a wide variety of views of the whole without being strongly contradicted in any of them. Thus theories of aging proliferate; it is always easier to theorize about existing puzzle pieces than to run a research program that will meaningfully add to the collection of puzzle pieces. Here, researchers present a framework for the relationship of the mechanisms of aging that places epigenetic change as the dominant (but not only) important process that drives loss of function, disease, and mortality.

Age-related dysfunction is unlikely to arise from a single universal mechanism. This review develops the Polycentric Aging Framework (PAF) by integrating evidence from somatic cell nuclear transfer (SCNT), DNA methylation (DNAm) clocks, nutrient-sensing pathways, cellular senescence, systemic signaling, and human intervention studies. PAF organizes aging into partially independent, interacting centers that differ in timing, causal status, resettability, reversibility, systemic influence, regenerative impact, interventional accessibility, and lifespan-limiting potential.

SCNT is interpreted not as rejuvenation of an existing organism but as a reset-hierarchy model: selected epigenetic and developmental states can be extensively reconfigured; telomere dynamics, mitochondrial state, proteostasis, stem-cell and stem cell niche capacity, and senescence and senescence-associated secretory phenotype (SASP) phenotypes show context-dependent reset, redevelopment, or recurrence; and nuclear DNA sequence and structural damage remain least resettable. In humans, PAF proposes epigenetic regulation as a dominant, but not exclusive, lifespan-limiting center because it coordinates cell identity, developmental-program persistence, nutrient sensing, inflammatory and endocrine signaling, repair, and tissue regeneration.

DNAm clocks are useful but incomplete biomarkers and may conflate pathological or causal Type 1 changes with adaptive or compensatory Type 2 responses. Clock shifts should therefore be interpreted against tissue-specific function, healthspan, morbidity, and mortality rather than as stand-alone evidence of rejuvenation. PAF predicts that intervention efficacy will depend on whether the targeted center is functionally limiting for a given tissue, disease context, and life stage, and whether another center subsequently becomes limiting. This provides a testable basis for center-specific geroprotective interventions combining controlled epigenetic reprogramming, metabolic modulation, senescence or SASP targeting, and systemic signaling modulation, with rigorous safety monitoring and tissue-context stratification.

Link: https://doi.org/10.18632/aging.206426

The manifestations of aging, such as age-related diseases and mortality, all arise from the same underlying root cause mechanisms of damage and dysfunction. If an individual exhibits evident consequences of aging in one part of the body, in the form of a specific age-related condition, it is likely that the burden of damage and dysfunction throughout the body is high enough to cause other specific age-related conditions to arise as well. It doesn't necessarily mean that the conditions are linked in any way other than being consequences of the same processes. That said, aging is complex, everything in the body and brain is connected to at least some degree, and dysfunction in one system often does add to the dysfunction of other systems in ways that are distinct from the core mechanisms of aging. One might not think that to be the case for hearing loss, except for the fact that use of hearing aids reduces risk of mortality via cardiovascular disease, as demonstrated here. Possible explanations are that (a) hearing aid users tend to take better care of their health and function in other ways as well, or (b) there is some functional path linking the accelerated neurodegeneration that is known to take place without functional hearing and cardiovascular mortality.

Hearing loss affects more than 1.5 billion people or nearly 20% of the global population. Prevalence is increased particularly among the ageing population, and is linked to various adverse outcomes, including poorer health, diminished quality of life, depression, and cognitive decline. Emerging evidence suggests that hearing loss could also be linked to higher mortality risk. Most existing studies have relied on smaller sample sizes based on cohorts of older adults (aged between 50 years and 80 years or more), overlooking younger (aged 20-49 years) populations. Most studies have been observational and have not assessed the long-term effect of hearing-aid use among those with hearing loss.

Results of previous studies of association between hearing-aid use and mortality have been mixed. To address these limitations, our study conducted an individual participant data (IPD) meta-analysis using large datasets from Australia, Iceland, and the USA, followed by a replication study using data from Norway, to examine the relationship between hearing-loss severity, hearing-aid use, and mortality. These studies provided extensive audiometric and mortality data, enabling a robust examination of the relationship between hearing loss and mortality across different populations and settings while adjusting for key confounding variables.

The IPD meta-analysis included 13,851 participants, with a mean age of 61.8. Mild (1.19), moderate (1.55), and moderately severe or worse (1.56) hearing loss were associated with increasing all-cause mortality risk. Mild (1.18), moderate (1.43), and moderately severe or worse (1.30) hearing loss were also associated with increased cardiovascular-related mortality risk. Current use of hearing aids was associated with reduced all-cause mortality risk [0.91] and reduced cardiovascular-related mortality [0.85]. The replication study of 50,277 adults corroborated these findings.

Link: https://doi.org/10.1016/j.lanhl.2026.100903

Messenger RNA (mRNA) can be delivered into tissues and cells by encapsulating it into lipid nanoparticles (LNPs), and then injecting the nanoparticles. A target cell engulfs a LNP, and the cargo of mRNA is released into the cytoplasm where it is translated into protein. Typically a protein is manufactured in cells exposed to a LNP-mRNA therapy for a few days only before the last of the delivered mRNA is broken down and recycled, so the end result might be considered a half-way point between the characteristics of a gene therapy and the characteristics of a small molecule drug: a treatment that produces a protein of interest to cause specific desired outcomes in cell behavior, but that only lasts a little while.

The lipid nanoparticle industry looks today much like the viral vector industry did a decade ago. A great deal of research and early stage development of therapeutics is taking place, a great deal of invention, but much of the intellectual property remains locked down and either impossible or very expensive to use in a commercial product. To date only a small number of specific lipid nanoparticle formulations with a small number of different delivery characteristics have made it into clinical trials or become approved drugs. Many very interesting technology demonstrations in animal studies are taking place, however.

Today's open access paper is an example of one of the areas in which LNP-mRNA therapies may really shine, which is to take the concept of chimeric antigen receptor (CAR) cell therapies, and make them affordable. Delivery of a CAR T cell therapy involves taking a patient's cells, engineering them to express the desired CAR, growing their numbers in culture, and then returning the cells to the patient. The artificial receptor steers the T cells towards desired targets, such as cancer cells, and has proven quite effective in treating a number of different forms of cancer. Sadly it is enormously expensive as a mode of therapy, due to the time and complexity required to manufacture each patient-specific batch. LNP-mRNA that can turn native cells into CAR T cells (or in this case CAR natural killer cells) for a short while will be both much less costly and more controllable.

Reprogrammed NK immune cells target cancer and autoimmune disorders

Over the past decade, the U.S. Food and Drug Administration has approved seven new cancer treatments based on engineered T cells called chimeric antigen receptor (CAR) T cells. Chimeric antigen receptors are proteins that can be embedded into T cells, allowing them to detect a target antigen, such as a cancer protein. When the target is detected, the T cell becomes activated and destroys the target cell. In recent years, scientists have begun using a similar strategy to create CAR natural killer (NK) cells. One potential advantage of CAR NK cells over CAR T cells is that they could be used to kill diseased T cells. Using CAR T cells to treat T cell diseases often doesn't work well because T cells that are engineered to target T cell proteins may end up killing each other, in addition to the diseased T cells. That issue doesn't arise when using NK cells to target T cells.

However, manufacturing large quantities of CAR NK cells poses many of the same difficulties as generating CAR T cells. To simplify the process, researchers wanted to come up with a way to generate CAR NK cells in the patient's own body, without having to remove any cells. To generate these cells, the team designed lipid nanoparticles (LNPs) that can deliver an mRNA payload. These strands of mRNA encode a CAR that can be targeted to specific cell types. For example, they could deliver a CAR that targets CD19, a protein found on B cells, or CD3, a protein found on autoreactive T cells. The particles are coated with antibody fragments that bind to receptors found on the surface of NK cells, to ensure they reach the correct targets.

After these particles were infused into mice, the researchers found that they could successfully reprogram about 80% of the targeted NK cells. The researchers then tested the particles' potential to treat cancer and autoimmune hepatitis, which is caused by autoreactive T cells. In a mouse model of an aggressive form of melanoma, three of the five mice that received LNPs that reprogrammed their NK cells to target the cancer cells went into complete remission. The researchers also saw significant tumor destruction when they used the LNPs to treat T cell lymphoma in a humanized mouse model. In these mice, tumors were eradicated after five injections of the reprogramming LNPs. This result was similar to what the researchers saw when they treated mice with CAR NK cells that were generated using the conventional approach.

Lastly, the researchers demonstrated that their LNPs could generate CAR NK cells that target autoreactive T cells. For this application, they studied mice with autoimmune hepatitis, in which T cells attack hepatocytes in the liver. They found that in the treated mice, the autoreactive T cells were destroyed, and liver damage healed. These effects were seen after just one injection of the LNPs.

In vivo engineering of CAR natural killer cells for immunotherapy using ligand-directed lipid nanoparticles

Targeted lipid nanoparticles (LNPs) offer a nonviral approach for in vivo cell engineering but efficient programming of natural killer (NK) cells remains underexplored. Here we develop NK cell-targeted LNPs (NtLNPs) using engineered biparatopic NK cell ligands to drive receptor-specific uptake and mRNA delivery. Lead NtLNPs achieve up to ~80% NK cell transfection with minimal off-target effects in mice. Systemic delivery of chimeric antigen receptor (CAR) mRNA using NtLNPs generates CAR NK cells in vivo.

CD19-targeted CAR NKs completely deplete circulating B cells in healthy mice and CD3-targeted CAR NKs eliminate nearly all autoreactive T cells in an autoimmune hepatitis model, highlighting a potential advantage over CAR T therapies for T cell-driven disease. In solid tumors, NtLNPs targeting the inhibitory checkpoint NKG2A enhance antitumor efficacy by relieving Qa-1b-mediated immunosuppression. Lastly, we optimized NtLNPs for in vivo engineering of human CAR NK cells, enabling regression of two humanized hematologic malignancy models and establishing NtLNPs as a modular immunotherapy system.

Peroxisomes in cells are responsible for helping to maintain oxidative metabolism via making and removing hydrogen peroxide, but are also involved in numerous aspects of lipid metabolism, breaking down or converting various lipids necessary to cell function. They have other, less well mapped functions relating to defense against pathogens. There is some evidence for peroxisome loss to occur with age, for this to be a meaningful cause of further cellular dysfunction. As researchers note here, however, the evidence for forms of peroxisome dysfunction to contribute meaningfully to Alzheimer's disease is suggestive but far from conclusive. As is often the case, the fastest path to clarity would be an approach to restore a more youthful peroxisome function to cells in the brain and elsewhere, and see what happens as a result.

Peroxisomes are dynamic, single-membrane-bound organelles ubiquitously distributed throughout eukaryotic cells, containing abundant oxidases, catalase, and lipid-metabolizing enzymes. Their functions encompass the β-oxidation of very-long-chain fatty acids (VLCFAs), the degradation of branched-chain fatty acids, bile acid synthesis, and the biosynthesis of ether phospholipids - notably plasmalogens. Moreover, via catalase (CAT) and related enzymes, peroxisomes are instrumental in sustaining local reactive oxygen species (ROS) homeostasis.

These functions are of particular relevance to the nervous system, where membrane lipid composition, myelin integrity, synaptic plasticity, and redox homeostasis are intimately interconnected. Consequently, peroxisomal dysfunction may simultaneously impair multiple facets of neural cell physiology. Within the central nervous system, peroxisomes establish an integrated metabolic network with the endoplasmic reticulum, mitochondria, lipid droplets, and lysosomes. Thus, peroxisomal abnormalities can concurrently disrupt membrane architecture, energy metabolism, reactive oxygen species (ROS) signaling, and inflammatory responses.

Reduced plasmalogen levels, diminished peroxisomal enzyme activities, enhanced lipid peroxidation, and elevated oxidative stress have been consistently documented in both Alzheimer's disease (AD) brain tissue and animal models. Furthermore, peroxisome-regulated nuclear receptors - particularly the peroxisome proliferator-activated receptors (PPARs) - are closely intertwined with lipid metabolism, insulin sensitivity, inflammatory suppression, and mitochondrial function, rendering them promising targets for drug repurposing and novel therapeutic discovery.

Current evidence does not establish peroxisomal dysfunction as a necessary, sufficient, or universal cause of AD; it is more defensibly viewed as a context-dependent vulnerability, amplifier, or response within reciprocal metabolic-proteinopathy networks. PPAR agonism, lipid modulation, pexophagy regulation, and restoration of peroxisome-mitochondria communication remain investigational. Translation requires longitudinal human evidence, validated target-engagement biomarkers, and adequately powered trials in biologically defined populations. Peroxisomal biology therefore provides a testable framework for studying lipid-redox-organelle interactions in AD, while substantial uncertainty remains regarding temporal precedence, causal magnitude, and therapeutic tractability.

Link: https://doi.org/10.3389/fnagi.2026.1960320

Senescent cells accumulate with age, perhaps primarily because the aged immune system becomes less able to efficiently destroy senescent cells as it does in youth. When a cell becomes senescent it ceases to replicate, grows in size, and secretes a potent mix of pro-inflammatory, pro-growth signals that contribute to the chronic inflammation of aging and are disruptive to tissue structure and function. Here, researchers investigate some of the specific outcomes of an increased burden of cellular senescence in the aged liver.

The liver is organized into tightly regulated zones with distinct metabolic functions but zonation erodes with age. Cellular senescence contributes to aging and liver diseases, however, its impact on aging biology is ill-defined. As part of The Cellular Senescence Network Consortium, we used multiple spatial transcriptomics approaches with snRNA-seq to profile senescence signatures, zonation markers, and metabolic pathways in livers from wild-type (WT) mice of multiple ages.

We observed a loss of canonical zone signatures in aged mouse livers characterized by "expansion" of midlobular (zone 2) marker gene expression, accompanied by diminished expression of zone 3 marker genes by middle-age (18 months), indicative of loss of cell identity. Multiple analytic approaches identified distinct age-, zone- and sex-specific senescence signatures, which were significantly associated with zonation markers changes. This was recapitulated in Ercc1 mutant models of accelerated senescence, supporting a causal role of senescent cells in liver aging. A "no-zone" hepatocyte-like cluster expanded with age and with the strongest Senescence-Associated Secretory Phenotype (SASP) profile. Gene expression profiles from senescent hepatocytes implicate decreased WNT signaling and increased BMP as contributing to age-related loss of zonation.

Together, these data elucidate the role of senescent cells in driving aging biology in non-diseased liver through disruption of cell:cell signaling and the loss of metabolic and cell identity gene expression necessary for hepatocyte function.

Link: https://doi.org/10.64898/2026.08.08.743614

Partial epigenetic reprogramming involves exposing cells to some or all of the Yamanaka factors for a long enough period of time to reset epigenetic decorations on nuclear DNA and its supporting structures to a youthful state, but not so long as to risk dedifferentiation, and thus loss of cell state and formation of induced pluripotent stem cells that can give rise to teratomas. It is a fine balance, and different cell types need different exposure times. Thus the first practical applications of reprogramming therapy under development are limited to one cell type, or small regions of tissue where greater control over delivery can be exerted. The limited options for delivery of gene therapies further restrict the options on which tissues can be targeted.

Life Biosciences sponsors the first clinical trial of a partial epigenetic reprogramming therapy, targeting degeneration of the retina and optic nerve in glaucoma patients. In animal models, reprogramming has shown itself capable of restoring function to a damaged optic nerve. Life Biosciences is using adeno-associated virus (AAV) as a vector, well proven in delivery to the retina and optic nerve via direct injection into the eye, to introduce an inducible package of Yamanaka factors into cells. Expression only occurs in the presence of doxycycline, which allows dosing of the Yamanaka factors to be tightly controlled and repeated over time as needed. AAV is effectively a permanent therapy in these tissues.

Life Biosciences Announces First-in-Human Data from Ongoing Phase 1 Trial Evaluating ER-100 in Optic Neuropathies

This first-in-human, Phase 1, open-label clinical trial (NCT07290244) is evaluating the safety and tolerability of ER-100 in adults with optic neuropathies. ER-100 uses controlled expression of three transcription factors, OSK (OCT4, SOX2, KLF4), delivered via a single intravitreal injection, with OSK expression induced by systemic doxycycline administered for 8 weeks (56 days). An oral prednisolone taper is administered to minimize risk of inflammation due to AAV-2 immune response. Multiple study visits assessing tolerability and visual endpoints were included in this first 56 day evaluation.

Optic neuropathies are a group of disorders characterized by damage to retinal ganglion cells (RGCs), the primary neurons connecting the eye to the brain. Because RGCs do not naturally regenerate, damage results in permanent vision impairment. One such optic neuropathy, open-angle glaucoma (OAG) is a chronic neurodegenerative disease and a leading cause of blindness in older adults. While often associated with elevated intraocular pressure, disease progression frequently continues despite treatment, and some patients suffer from OAG despite normal intraocular pressure. Non-arteritic anterior ischemic optic neuropathy (NAION) is the most common acute optic neuropathy in adults over fifty. It involves sudden, painless vision loss due to insufficient blood flow, for which there are currently no approved treatments.

Interim data demonstrated that a single intravitreal administration along with daily oral doxycycline was well-tolerated through Day 56 in all three participants and showed preliminary signals of improvement in visual field testing in two participants. There were no reported dose-limiting toxicities, adverse events of special interest or serious adverse events. Improvements in Humphrey Visual Fields measurements, a standard eye exam that measures a participant's ability to detect light across many points in their field of vision, scored in decibels (dB), were observed in 2 of 3 OAG participants at Day 56. In each of these 2 participants, ≥ 28% of points in the visual fields showed a > 4 dB improvement.