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Category: life extension

Double‐Pronged NAD Preservation: Delaying Cellular Senescence and Initiating Musculoskeletal Regeneration

A novel synergistic drug combination (N + A) consisting of an NAD+ precursor (NMN) and an NAD+ consumption (CD38) inhibitor (API) promotes musculoskeletal regeneration in aging. Notably, increased NAD+ serves as a coenzyme for SIRT3, exerting a robust anti-senescence effect, thus promoting tri-lineage differentiation into chondrocytes, osteoblasts, and myocytes. Furthermore, oral administration of the N + A formulation modulated the intestinal microenvironment, promoting the gut microbiota-derived production of the metabolite PHS, thereby exerting indirect anti-aging effects in musculoskeletal disorders.

Key protein found to protect cartilage, offering new hope for osteoarthritis treatment

Osteoarthritis, a condition that causes pain and reduced mobility in joints such as the knees and fingers, is one of the most common joint disorders worldwide, particularly among aging populations. The disease is characterized by the gradual breakdown of cartilage, which normally cushions the bones within joints.

Despite its prevalence, current treatments for osteoarthritis mainly focus on alleviating pain rather than addressing the underlying cause of cartilage degeneration. Effective therapies that can halt or reverse cartilage damage remain limited.

A joint research team led by Dr. Chul-Ho Lee and Dr. Yong-Hoon Kim at the Laboratory Animal Resource Center of the Korea Research Institute of Bioscience and Biotechnology (KRIBB), in collaboration with Prof. JinHyun Kim at Chungnam National University Hospital, has identified a key protein, SHP (NR0B2), that plays a critical protective role in cartilage and may offer a new therapeutic strategy for osteoarthritis. The paper is published in the journal Nature Communications.

Histone modification clocks for robust cross-species biological age prediction and elucidating senescence regulation

Building upon these insights, we constructed 36 histone modification-based epigenetic clocks, which exhibited robust predictive accuracy (mean Pearson’s r = 0.91) across multiple tissues and marks. Among these, the blood-derived H3K27ac clock emerged as a particularly powerful model, outperforming several established DNA methylation clocks under matched conditions. This performance is remarkable considering that DNA methylation clocks have undergone extensive optimization over the past decade (9, 16, 18), while our histone-based approach represents a first-generation effort.

A distinctive advantage of our histone-based clocks is their resilience to technical and biological noise. When exposed to artificial Gaussian noise, the histone-based clock maintained stable predictive performance, in contrast to the sharp degradation observed in many methylation-based models. This robustness is likely attributable to the broader, structural nature of histone mark signals, which may be less sensitive to local fluctuations than single CpG methylation values. This characteristic makes histone clocks potentially more suitable for noisy, heterogeneous, or clinically derived datasets where sample quality may vary.

The practical utility of our histone-based clocks was further demonstrated by their ability to detect biological age acceleration in leukemia samples and capture age reversal following therapeutic interventions. These applications highlight the potential of histone-based clocks as biomarkers for disease states and treatment responses, offering a complementary approach to existing clinical tools.

APOE4 Increases Neurons’ Excitability Before Symptoms Appear

The pro-Alzheimer’s allele APOE4 makes hippocampal neurons in mice smaller and hyperexcitable. This effect, which resembles epilepsy and accelerated aging, can be mitigated by manipulating a neuronal protein [1].

Before symptoms arise

Alzheimer’s disease begins long before symptoms appear, building silently for decades. The single strongest genetic risk factor for the common, late-onset form of Alzheimer’s is the ε4 variant of the apolipoprotein (APOE) gene, APOE4. Carrying a single copy of this variant (being heterozygous) roughly triples your Alzheimer’s risk; having two copies increases it about 12-fold.

How an Alzheimer’s Risk Gene Disrupts Brain Circuits Long Before Memory Loss

Researchers at the Gladstone Institute have uncovered the molecular mechanism by which APOE4 — the most significant genetic risk factor for Alzheimer’s disease, present in roughly a quarter of the population — begins damaging neural circuits well before any cognitive symptoms emerge. Studying young mice carrying the APOE4 variant, the team found that the gene triggers overproduction of the protein Nell2, which causes neurons to shrink and become hyperactive. Crucially, the degree of early neuronal hyperactivity predicted the severity of memory impairment later in life, even in animals that still showed normal learning and memory at the time of measurement. Strikingly, targeting Nell2 therapeutically was able to reverse these changes even in adult animals, demonstrating that the neurodegeneration is not irreversible and that a window for intervention may exist even after the disease process has begun. The team is currently continuing preclinical testing of this therapeutic strategy.

New findings on the APOE4 gene variant point to a potential therapeutic target for Alzheimer’s disease. From left to right, Gladstone scientists Misha Zilberter, Yadong Huang, and Dennis Tabuena examine findings from their research, which is published in the journal Nature Aging.

For the millions of people who carry the gene APOE4, the strongest known genetic risk factor for Alzheimer’s disease, their brain activity may begin changing long before any memory problems appear. Now, researchers at Gladstone Institutes have uncovered a precise chain of molecular events behind those early changes and identified a potential way to reverse them.

Published in the journal Nature Aging, their new study in mouse models reveals how APOE4 triggers increased production of the protein Nell2, which makes neurons shrink and become hyperactive. The more hyperactive the neurons were in early life, the more severe were the memory problems the mice developed later in life.

T-loop dynamics: telomere structure shapes cell fate decisions

Telomere structure shapes cell fate decisions.

Telomere loops (t-loops) are dynamic DNA structures, remodelled during the cell cycle and stress, rather than static protective caps.

The three-state model defines closed, intermediate, and uncapped telomeres, linking intermediate telomeres to programmed, fusion-resistant deprotection, which activates checkpoints without genome instability.

Mitotic arrest-dependent telomere deprotection is an active pathway in which Aurora B kinase drives t-loop unwinding without telomere shortening.

Aurora B kinase phosphorylation reprograms shelterin components (TRF1 and TRF2), enabling BTR-mediated t-loop dissolution and paradoxically converting protective factors into facilitators of deprotection.

T-loop dynamics reframe telomeres as responsive signalling hubs that couple chromosome architecture to genome surveillance and cell fate control. sciencenewshighlights ScienceMission https://sciencemission.com/T-loop-dynamics

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Cellular reprogramming beyond pluripotency

Aging, once viewed as an irreversible process, is now considered a modifiable process. Recent advances in cellular reprogramming reveal that transient expression of reprogramming factors can reverse molecular hallmarks of aging while preserving somatic cell identity. This ‘partial reprogramming’ rejuvenates tissues, restores regenerative capacity, and, in some models, extends lifespan without the tumorigenic risks of full dedifferentiation. In this review, we summarize genetic and chemical strategies for partial reprogramming, discuss their tissue-specific effects in vivo, and evaluate their implications for tissue regeneration and age-related disease. We further examine key challenges for clinical translation, including safety, delivery strategies, and temporal control of reprogramming.

What keeps vision cells alive?

Clear patterns emerged: two kinase inhibitors consistently protected cones over extended periods.

The researchers identified inhibitors of casein kinase 1 (CK1) that protected cones, heat shock protein 90 (HSP90) inhibitors that saved cones in the short term but damaged them in the longer term, and broad histone deacetylase (HDAC) inhibition by many compounds that significantly damaged cones.

The protective effects held across different stress conditions and were further confirmed in a mouse model of retinal degeneration, supporting their broader relevance.

Beyond identifying protective pathways, the study makes a comprehensive dataset publicly available, covering the compounds tested, their molecular targets, and their effects on human cone survival. This resource will guide the development of therapies aimed at preserving central vision and enable a systematic assessment of potential retinal toxicity. ScienceMission sciencenewshighlights.

Scientists have identified genetic pathways and compounds capable of protecting cone photoreceptors from the degeneration that underlies conditions like age-related macular degeneration.

Cone photoreceptors, concentrated in the macula, are essential for reading, recognizing faces, and perceiving colors. Their death, as it happens in many inherited retinal diseases and macular degeneration, leads to the loss of central vision. Despite decades of research, no approved therapies can halt this process. This new study, conducted by researchers addresses this unmet need using a human-based experimental system.

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