Fight Aging!

Control over the structure of nuclear DNA is critical to both gene expression and interactions between DNA damage and DNA repair systems. Most of us are by now at least passingly familiar with the concept of the chromosomes of nuclear DNA existing as a mix of (a) spooled and tightly packaged regions known as heterochromatin, where gene sequences are hidden from transcriptional machinery and genes are thus not expressed, versus (b) unspooled regions where transcription can take place, the gene sequences read to allow assembly of corresponding RNA molecules. Epigenetic decorations to DNA and supporting molecules drive a constant shift between spooled and unspooled structures. This necessary regulation of structure and function all changes for the worse with advancing age for reasons that are incompletely understood.

There is a lot more to DNA structure than just this, however. For example, the intricate regulation of nuclear DNA structure incorporates the presence of double-strand breaks known as DNA gaps, distinct from the harmful DNA double strand breaks that occur as a form of damage. These DNA gaps are thought to reduce potentially damage-inducing stress forces, but this may or may not be their primary function. Researchers have observed that the number of these DNA gaps declines with age, and have speculated that this change may produce harm. In today's open access paper, researchers provide fairly direct evidence for this proposition via use of a gene therapy that directly induces DNA gap formation in aged non-human primates. The researchers observe a range of improvements in biomarkers of health following treatment, suggesting that more DNA gaps leads to improved cell and tissue function; all in all, quite an interesting outcome.

Box A of HMGB1 plasmid reverses the age-related changes in the plasma proteomic profile of perimenopausal monkeys

A characteristic feature of aging is the accumulation of DNA damage, which plays a significant role in the deterioration of cellular function. The sustained destruction of DNA and the subsequent activation or failure of the DNA-damage response (DDR) are pivotal in the aging process, often leading to detrimental cellular outcomes such as senescence, apoptosis, and telomere shortening. Maintaining DNA integrity is crucial for cell viability. One mechanism employed by cells to ensure this integrity involves the dynamic regulation of DNA structures, often observed as DNA gaps, known as youth-DNA-gaps. These gaps are believed to minimize mechanical stress and torsion forces within the DNA structure, thereby protecting it from damage. Interestingly, the number of these physiological DNA gaps typically is reduced in yeast, rats, and human cells as they age, as well as in chemically-induced senescent cells.

The High Mobility Group Box 1 (HMGB1) protein has emerged as a key molecule involved in various biological processes highly relevant to aging, including inflammation, DNA repair, and cell senescence. The Box A domain of HMGB1 is a highly conserved DNA-binding domain crucial for modulating HMGB1's biological functions. Box A is known to bind DNA and interact with other proteins, acting as a molecular regulator that influences the formation of DNA gaps to enhance DNA integrity and protection. Growing evidence suggests that Box A-induced DNA gaps may reverse aging characteristics in vivo and in vitro, having been shown to inhibit liver fibrosis and improve aging brain functions in aged rat models. Furthermore, Box A can enhance stemness, suggesting a role in improving stem cell activity compromised by illness and aging.

This study investigates the potential role of the Box A domain HMGB1 in modulating age-related changes. We utilized a label-free quantitative proteomic technique to analyze the plasma proteome of three female adult and eight female perimenopausal cynomolgus macaques (Macaca fascicularis), with the perimenopausal group receiving an intravenous administration of the Box A plasmid. Proteomic analysis revealed differential expressions in proteins primarily associated with stress response, immune regulation, lipid transport, and cellular homeostasis following Box A plasmid intervention. Notably, the expression levels of key proteins, such as apolipoprotein E (APOE) and sex hormone-binding globulin (SHBG), showed a reversal effect, restoring levels closer to those observed in the younger, adult monkeys. These findings highlight the potential of the Box A of HMGB1 plasmid as a therapeutic candidate to mitigate age-related proteomic alterations, offering a novel avenue for targeted interventions in aging and associated diseases.

The burden of lingering senescent cells grows with age in tissues throughout the body. Cells enter the senescent state constantly, but the pace of clearance of senescent cells by the immune system falters with advancing age. Senescent cells secrete a mix of pro-inflammatory, pro-growth signals that are disruptive to tissue structure and function when sustained for the long term. Analysis of circulating molecules in a blood sample can in principle be used to measure the body-wide burden of senescent cells, though no strong consensus approach has emerged yet from the various methods demonstrated in recent years. Here, find another contender for that consensus approach, where researchers use proteomic assessment of blood samples to build a score based on the strength of senescent cell signaling, and find that this score correlates with mortality risk.

The accumulation of senescent cells is a recognized hallmark of biological aging and is associated with the onset of multiple chronic medical conditions. Senescent cells exhibit a distinct secretory profile, known as the senescence-associated secretory phenotype (SASP), which can propagate cellular senescence to neighboring and distant tissues. Measuring SASP factors in blood serves as a practical proxy for cellular senescence burden and may help track disease states and intervention outcomes.

We developed and validated a composite SASP Score by integrating large-scale population proteomics data with a semi-supervised deep learning framework. The analytical workflow included: (1) selection of biologically curated SASP proteins; (2) development of a Guided autoencoder with Transformer (GAET) model using data from the UK Biobank Pharma Proteomics Project (UKB-PPP); (3) internal evaluation and association analyses within the UK Biobank; and (4) external validation and longitudinal assessment in an independent randomized clinical trial cohort.

The deep learning-based SASP Score was a strong, independent predictor of mortality risk and incident serious, chronic medical conditions (e.g., dementia, COPD, myocardial infarction, stroke). In an independent cohort, multimodal exercise significantly changed the SASP Score trajectory over 18 months.

Link: https://doi.org/10.64898/2026.03.20.26348913

Excessive, constant inflammation in response to aspects of one's own cellular biochemistry is a feature of both autoimmune disease and aging. While transient inflammation is necessary for effective regeneration and defense against pathogens, constant unresolved inflammatory signaling is destructive to tissue structure and function. It is a major component of the pathology of common age-related conditions. The challenge in addressing this is that unwanted inflammation and desirable inflammation both involve the same molecular signals and points of control. To date, therapies that reduce chronic inflammation do so via crude blockade of signals or mechanisms, with the side effect of reduced immune capability, a reduction in the normal immune response when it is needed. The research community is slowly making progress towards finding points of distinction, however, approaches to intervention that have greater effects on unwanted inflammation than they do on the normal immune response. One such line of work is noted here, focused on autoimmunity.

Current autoimmune disease treatments like hydroxychloroquine work by broadly blocking endosomes, the compartments inside cells where incoming materials are sorted and processed, including molecules that trigger immune responses. While effective, this approach can lead to significant side effects - including gastrointestinal problems and, less commonly, vision damage-causing a significant number of patients to stop treatment.

Researchers focused on two proteins, Munc13-4 and syntaxin 7, that must bind together for immune sensors called Toll-like receptors (TLRs) to activate inside endosomes. This "molecular handshake" plays a key role in detecting the foreign DNA and RNA from invaders like viruses and bacteria. However, in autoimmune diseases, TLRs become overactive, detecting self-nucleic acids, for example, from neutrophil-extracellular traps, and trigger chronic, damaging inflammation even without a real threat.

The team screened roughly 32,000 compounds and identified molecules that specifically block the Munc13-4-syntaxin 7 interaction without disrupting other cellular functions. Because Munc13-4 is found mainly in immune cells, the compounds offer a targeted way to calm inflammation. "Most treatments for autoimmune diseases manage symptoms; they don't change the underlying course of the disease. What's exciting about this approach is its potential to be disease-modifying: targeting the specific molecular machinery that drives inflammation, rather than broadly suppressing the immune system."

The most potent compound, ENDO12, reduced inflammation in animal models that were also given a TLR-activating molecule. Blood levels of inflammatory markers - including immune system activators IL-6 and IFN-γ, and the enzyme myeloperoxidase - dropped significantly in those that were treated. Crucially, ENDO12 did not impair the animal models' ability to fight a real viral infection: they showed a normal antiviral immune response when exposed to a virus. This selectivity addresses a major concern with immunosuppressive drugs: that dampening inflammation might leave patients vulnerable to infections.

Link: https://www.scripps.edu/news-and-events/press-room/2026/20260406-catz-endotollins.html