Fight Aging!

Macular degeneration involves the death of vital cells in the retina, leading to progressive blindness. The less common neovascular (or "wet") form of the condition involves the inappropriate growth of leaky blood vessels in the retina and underlying choroid. Existing treatments focus on trying to prevent this blood vessel growth or remove the vessels, rather than addressing underlying causes. Here, researchers make a step in the direction of those underlying causes by identifying a problem immune cell population that appears to contribute to the dysfunction and leakage of blood vessels in the eye.

Age-related macular degeneration (AMD) is the leading cause of irreversible central blindness and can result in pathological neovascularization. Using a "human-first" approach, we identify immunotherapy as a disease modifier in models of neovascular AMD. Plasma cytokine analysis in a large population cohort reveals an imbalance of lymphocytic cytokines associated with severity of AMD, leading to discovery of a skewed peripheral natural killer (NK) cell phenotype in individuals with AMD.

Peripheral NK cells are rapidly activated in neovascular AMD models, and single-cell RNA sequencing demonstrates expansion of activated cytolytic NK cells within neovascular lesions during resolution. NK cells localize to neovessels in human AMD donor eyes; however, they exhibit markers of terminal differentiation and quiescence. Adoptive transfer of pre-activated NK cells reduces neovascularization and restores barrier integrity. Our data identify a distinct, functionally altered NK cell phenotype in neovascular AMD and suggests harnessing NK cells represents an immunotherapeutic alternative for the treatment of neovascular AMD.

Link: https://doi.org/10.1016/j.xcrm.2026.102792

Researchers continue to produce new aging clocks at a fair pace. Any sufficiently complex set of biological data obtained from people of various ages can yield a clock given the use of various forms of machine learning. It is straightforward to make a new clock. Most of these will vanish into obscurity, as they will demonstrate no advantages over existing, more well studied clocks. The need is not for new clocks, but to solve the challenges inherent in the use of any clock, which is to say that it is entirely unclear as to whether a clock provides a reasonable representation of biological aging, and whether it can be trusted as an assessment of any given intervention to slow or reverse aspects of aging. The research community struggles to connect clock parameters to aging in any meaningful way that yields confidence in the ability of a clock to assess novel forms of therapy.

Amino acids are fundamental to human physiology, yet their impact on growth, development, and aging remains elusive. Here, we introduce AmiAge, a biological age predictor constructed using a Random Forest model trained on the concentrations of 18 amino acids across individuals aged 1 to 89 years. Leveraging data from 9 studies encompassing over 11,000 in-house and more than 270,000 publicly available samples with diverse demographic and genetic backgrounds,

AmiAge demonstrates robust accuracy. The deviation between AmiAge and chronological age (AmiAge Gap) correlates strongly with established aging biomarkers, disease risk, and clinical outcomes. Individuals with higher gaps exhibit increased frailty, telomere attrition, and elevated incidence of age-related diseases. To enhance clinical utility, we distilled AmiAge into an 8-amino acid model (including alanine, glutamine, glycine, histidine, leucine, phenylalanine, tyrosine, and valine). Our findings suggest that this simple, scalable amino acid clock offers a valuable complement to existing biological aging metrics, with potential applications in personalized health management and aging research.

Link: https://doi.org/10.1038/s41467-026-73371-y

In a sense, exercise is damaging. It places stress on cells, but we have evolved to react to that stress and damage with greater maintenance, repair, and a shift of cell metabolism into a more beneficial state. That a mild or short term stress results in a long term benefit is called hormesis, and it is the case for near all forms of stress. There is a point at which any form of cellular stress or metabolic disarray tips over from net benefit to net harm, a dose-response curve that looks quite similar at the high level for cold, toxins, heat, lack of nutrients, exercise, and so forth. This remains the case once you move past the source of the stress and start picking apart the biochemical changes in cell activity and cell signaling generated in reaction to that stress.

Today's open access paper looks at HMGB1 in this context of stress and hormesis relating to exercise. HMGB1 is variously regarded as devil or angel in different scientific papers, and this does tend to be the case for many of the components of a stress response. HMGB1 can produce both benefits and harms, and the dose is everything when it comes to how the balance of outcomes affects health. So HMGB1 promotes cellular senescence in bystander cells when secreted by senescent cells as a part of the senescence-associated secretory phenotype, for example. But HMGB1 also reverses some losses of DNA structure in aged cells and increases stem cell activity to accelerate regeneration. This sort of characteristic can make stress response emulation a difficult class of therapy to bring to the clinic, as optimal doses (or even whether more versus less HMGB1 is beneficial!) might vary widely from species to species and from individual to individual within a species.

High mobility group box 1: DAMPening the danger molecule in cardiovascular disease with exercise

High mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP). During cellular stress, it leaves the nucleus and moves into the extracellular space, where it modulates the development of cardiovascular diseases (CVDs), a leading global cause of age-related mortality. In preclinical models, administration of HMGB1-neutralizing antibodies increased the survival rates of lipopolysaccharide-treated mice by up to 30%, whereas treatment with recombinant HMGB1 was lethal. Furthermore, chronological aging is accompanied by a gradual increase in systemic HMGB1. Compared with young adults (18-30 years), older adults (≥70 years) have ∼ 25% higher serum HMGB1 concentrations. A longitudinal study also revealed an age-related increase in plasma HMGB1 from 3.5 ± 1.8 to 4.7 ± 1.5 ng/mL as participants aged from 24.6 ± 3.3 to 30.4 ± 3.4 years,4 suggesting that HMGB1 may reflect age-related inflammatory burden and contribute to the increased cardiovascular risk seen in older populations.

While evidence indicates that HMGB1 is associated with both the progression and severity of CVDs, it also has a paradoxically beneficial role in mitigating tissue repair. HMGB1 appears to have an important role in promoting stem cell recruitment and tissue regeneration. A role for HMGB1 in stem cell mobilization has been reported, wherein HMGB1 knockout mice exhibited impaired skeletal muscle regeneration following toxin-induced injury. In the same study, leukocyte-derived HMGB1 was required for the activation of satellite cells and vascularization in murine skeletal muscle.

Exercise training improves cardiovascular function and modulates systemic concentrations of HMGB1. Acute exercise induces the release of HMGB1 into systemic concentration, whereas long-term exercise training appears to reduce its systemic levels. This paradoxical response of HMGB1 to either short-term or chronic exercise, alongside its complex role in the pathogenesis of age-associated CVDs, makes it an intriguing subject for research. A potential explanation for this paradox may lie in HMGB1's capacity in regulating stem cell recruitment and tissue regeneration.

One of the outcomes of the past few decades of focus on the development of tissue engineering and cell therapies is an increased understanding of what can be achieved with nanomaterials, meaning any manufactured substance or structure with nanoscale features that can engage with cells in a defined way. The use of nanoscale scaffolding to emulate aspects of the extracellular matrix in order to support transplanted cells is a going concern, for example. Another line of research and development is the use of nanoparticles that are engineered to steer tissue penetration in specific directions, release cargo in response to specific stimuli, and interact with cells to alter their behavior. Here, researchers review the state of the art in the context of developing therapies for osteoarthritis, the age-related degeneration of joint tissues.

Osteoarthritis (OA) is no longer viewed as a mere "wear-and-tear" disease, but rather as a multifactorial joint failure syndrome driven by cellular senescence, metabolic dysregulation, and low-grade chronic inflammation. These pathological pillars synergistically disrupt cartilage homeostasis, subchondral bone remodeling, and synovial inflammation, collectively fueling disease progression. While conventional therapies offer only symptomatic relief, they fail to reverse or reprogram the underlying pathological microenvironment. Consequently, there is an urgent need to develop disease-modifying interventions that can simultaneously target these pathological pillars.

Here, we critically examine how nanomaterial-based platforms - leveraging tailorable surface chemistry, cartilage-penetrating dimensions, and stimuli-responsive cargo release - enable precision targeting of these interconnected mechanisms. We highlight advances in senolytic delivery for senescent cell clearance, redox-modulating nanozymes for metabolic reprogramming, and immunoregulatory strategies for macrophage repolarization, emphasizing designs that transcend passive drug delivery to actively remodel the joint microenvironment. By integrating mechanistic insights with engineering innovation, this review outlines a roadmap for next-generation disease-modifying nanomedicines that promise not merely to slow OA progression, but to restore the biological clock of the joint. We also discuss current translational barriers and propose future directions for personalized OA therapy.

Link: https://doi.org/10.2147/IJN.S584027

Allostatic load is a fairly fuzzy concept, meaning the degree of wear and tear on the body that acts degrades its ability to resist stress and function correctly. Debates over exactly how to measure allostatic load are a microcosm of the debates over exactly how to measure biological age: various scientists all using the same conceptual term to describe what turn out to be a wide range of proposed approaches to the concrete assessment of that term. The measurement is the definition at the end of the day, and so one researcher's allostatic load is not the same as that of another researcher. It remains to be seen as to whether consensus will be achieved at any point in the near future, for either biological age or allostatic load.

Chronic stress contributes to the development of cardiometabolic, malignant, and other chronic diseases through cumulative multisystem physiological dysregulation, conceptualized as allostatic load (AL). However, traditional AL relies on heterogeneous clinical biomarkers that limit reproducibility and translational utility. Here, we develop and validate ProAL50, a proteomics-based measure of AL derived from 50 circulating proteins. Using high-dimensional plasma proteomic data from the UK Biobank, we constructed ProAL50 via penalized regression and stability selection and externally validated it in the Coronary Artery Risk Development in Young Adults (CARDIA) Study.

ProAL50 closely mirrored traditional AL in its associations with sociodemographic characteristics, lifestyle behaviors, physical and mental health, inflammation, and biological aging, supporting strong construct validity. Beyond replication, ProAL50 consistently demonstrated stronger associations with incident chronic diseases, including all cancers, type 2 diabetes, ischemic heart disease, chronic lung disease, and chronic kidney disease, and with all-cause and cause-specific mortality. Functional enrichment analyses revealed that ProAL50 proteins cluster within lipid metabolic and immune-inflammatory pathways. These findings establish ProAL50 as a scalable, biologically grounded measure of cumulative stress that not only replaces traditional AL but surpasses it in predicting disease risk and mortality, offering a novel tool for population health and translational research.

Link: https://doi.org/10.21203/rs.3.rs-8881432/v1