Histone deacetylases, or HDACs, are among the most conserved epigenetic regulators in biology. By removing acetyl groups from lysine residues on the N-terminal tails of histones H2A, H2B, H3, and H4, they establish transcriptionally repressive chromatin states. In fungi, these enzymes fall into three broad classes based on their yeast counterparts: zinc-dependent Class I RPD3-type enzymes, zinc-dependent Class II HDA1-type enzymes, and NAD+-dependent Class III enzymes known as sirtuins. Previous work in other fungi has shown that Class I members govern growth and virulence, Class II members are indispensable for host colonization and stress tolerance, and sirtuins regulate asexual development, nutrient utilization, and resistance to thermal and ultraviolet stress.

Using the genome of the F. oxysporum strain Fo47 as a starting point, the team searched NCBI and UniProt databases with hidden Markov models built on conserved HDAC and sirtuin domain profiles, applying a stringent significance threshold. The search identified exactly 11 FoHDAC genes. Phylogenetic reconstruction, comparing the fungal sequences with reference HDACs from budding yeast, Arabidopsis, and humans, sorted the family into three subfamilies: two Class I genes, two Class II genes, and a strikingly dominant SIR2 subfamily containing seven members. That expansion of the sirtuin clade stands out, because related fungi such as Alternaria alternata and Candida albicans carry only six to eight HDAC genes in total.

Structural analysis reinforced the phylogenetic picture. Three-dimensional alignments in PyMOL yielded root-mean-square deviation values between FoHDACs and their orthologs ranging from 0.312 to 3.397 angstroms. One protein, corresponding to FoRPD3, showed exceptional structural similarity to yeast RPD3, with a conserved catalytic pocket geometry that validated the evolutionary clustering. Another, FoClr3, diverged more substantially from yeast HDA1 yet retained its critical active-site residues, a pattern the authors interpret as structural plasticity that may facilitate functional adaptation to environmental pressures. Motif analysis with the MEME Suite uncovered ten conserved signatures, with Class I and II enzymes universally sharing Motifs 3 and 5, while sirtuins uniformly retain Motifs 1, 2, 4, 6, and 8, hinting at deep evolutionary conservation of their catalytic cores.

Physicochemical profiling revealed a family of considerable diversity. Protein lengths ranged from 298 to 1,087 amino acids, corresponding to molecular masses between roughly 32.8 and 117.8 kilodaltons, and isoelectric points split the family into acidic, basic, and near-neutral members. Subcellular localization predictions placed six proteins in the nucleus, three in the cytoplasm, and two, FoSIR5 and FoSIR4, in mitochondria, indicating that the family’s regulatory reach extends across organelles. All members were hydrophilic, and the team observed a significant negative correlation between hydrophilicity and aliphatic index, suggesting that reduced non-polar amino acid content enhances solubility and may favor protein-nucleic acid interactions.

Chromosomal mapping showed the 11 genes distributed asymmetrically across six chromosomes, with chromosomes 1 and 4 each hosting three genes, chromosome 8 two, and chromosomes 5 and 12 one apiece, while six chromosomes carried none at all. Synteny analysis ruled out recent segmental duplications as drivers of family expansion, pointing instead to functional specialization as the route to diversification. Comparative genomics across Fusarium graminearum and Fusarium solani revealed strict one-to-one orthology for all 11 genes, but only three sirtuin-class genes showed cross-family orthology with the rice blast fungus Magnaporthe oryzae, underscoring the exceptional conservation of core sirtuin machinery across fungal lineages.

The promoter regions upstream of the FoHDAC genes proved to be dense with regulatory information. Screening 2-kilobase stretches identified 22 putative cis-regulatory elements, including core motifs such as CAAT and TATA boxes alongside antioxidant response elements ARE and as-1, stress response elements known as STRE, dehydration-responsive DRE elements, MYB and MYC recognition sites, and W-boxes targeted by WRKY transcription factors. The as-1 motif was conserved across every family member, pointing to essential roles in mitigating oxidative stress, while selective enrichment of WRE elements in specific genes suggested spatiotemporal specialization for developmental coordination. In essence, the promoters are wired to translate environmental signals, from reactive oxygen species to osmotic shifts, into rapid epigenetic reconfiguration.

Gene Ontology enrichment and molecular docking simulations then connected structure to function. Beyond core deacetylation, the genes were annotated for roles in transcriptional regulation, macromolecular catabolism, and heterochromatin assembly, with FoHST4, FoHST3, and FoClr3 implicated in cellular component organization relevant to sporulation and cell wall biogenesis. Docking against eight histone acetylation marks, including H3K9ac and H4K16ac, produced robust binding affinities at or below minus 5 kilocalories per mole for all FoHDACs. The HDAC-class enzymes employed conserved His/Asp catalytic dyads with distinct substrate preferences, FoHOS3 selectively engaging H4K16ac and FoClr3 targeting multiple sites, while sirtuins displayed broader recognition, with FoHST3 binding every tested site and FoSIR2 showing high affinity for H3K14ac and H3K23ac. Notably, FoHST4, FoHST3, and FoSIR2 also exhibited intrinsic histone acyltransferase activity, marking them as bifunctional enzymes.

Expression profiling by reverse-transcription quantitative PCR across four developmental stages revealed choreographed dynamics. Eight genes peaked in the dormant conidial phase, were suppressed during spore germination, and progressively recovered through mycelial growth and sporulation, while FoHOS3 and FoRPD3 were continuously activated across developmental transitions and FoSIR7 was induced exclusively during sporulation. Under stress, the picture sharpened dramatically. Salt stress broadly repressed transcription, most dramatically a 33.67-fold suppression of FoHST3, whereas cold stress at 4 degrees Celsius triggered an induction of FoHOS3 exceeding 100-fold, accompanied by coordinated activation of FoHOS2, FoRPD3, and FoSIR7. Heat stress upregulated FoHOS3 more than 15-fold, oxidative stress elevated FoHOS3, FoSIR7, and FoSIR5, and fungicide exposure produced compound-specific responses, with fludioxonil activating FoHOS3 and FoSIR7 and hymexazol inducing FoSIR7, FoHST2, and FoSIR5.

Taken together, the findings cast FoHOS3 as a master stress integrator, consistently induced across osmotic, oxidative, thermal, and chemical challenges, with FoSIR7 acting as a broad-spectrum responder and FoHST3 and FoHST4 typically repressed under stress. The authors propose a three-phase epigenetic model of pathogenic progression, spanning dormancy governed by FoHOS2 and FoClr3, virulence activation, and colonization driven by FoSIR7. Because HDACs are dispensable or divergent between fungi and their hosts, the family represents an attractive target for next-generation fungicides designed to disrupt virulence with minimal off-target effects. The team notes that future work combining chromatin accessibility and histone modification mapping will be needed to fully resolve the regulatory networks, but the study establishes a foundation for precision antifungal strategies at a time when climate-stressed agriculture urgently needs them.

Subject of Research: Genome-wide identification and expression profiling of histone deacetylase genes in the plant-pathogenic fungus Fusarium oxysporum

Article Title: Genome-wide identification and expression profiling of the histone deacetylase gene family in Fusarium oxysporum

Article References: Liao, H.-X., Wen, J.-R., Shi, H.-M., Cun, H.-Q., Hong, Y.-J., Hu, Z.-F., Xu, F.-R., Noiprasert, S., Apiwongsrichai, K., Liu, X.-Y., & Dong, X. (2026). Genome-wide identification and expression profiling of the histone deacetylase gene family in Fusarium oxysporum. IMA Fungus, 17, Article e168980. https://doi.org/10.3897/imafungus.17.168980

Image Credits: AI Generated

DOI: 10.3897/imafungus.17.168980

Keywords: Fusarium oxysporum, histone deacetylases, epigenetics, sirtuins, plant pathology, chromatin regulation, gene expression, molecular docking, stress response, fungicides, vascular wilt, genomics

SIRT2 belongs to the class III histone deacetylase family, enzymes that remove chemical tags from proteins using nicotinamide adenine dinucleotide, or NAD+, as an essential cofactor. Its conserved catalytic core of roughly 275 amino acids contains a Rossmann-fold domain that grips NAD+ and a zinc-binding domain that stabilizes the protein’s structure. Because NAD+ levels inside cells fluctuate with nutritional status, mitochondrial function, and energy demand, SIRT2 effectively acts as a metabolic sensor: when the cellular energy landscape shifts, so does its deacetylase activity. By stripping acetyl groups from a broad range of non-histone substrates, SIRT2 alters the function, stability, and localization of metabolic enzymes, allowing cells to retune their metabolism in real time.

The clearest examples come from glucose metabolism. In the liver, SIRT2 deacetylates the glucokinase regulatory protein at lysine 126, which helps release glucokinase so the liver can take up glucose more efficiently. Overexpressing SIRT2 in the livers of obese diabetic mice improves glucose uptake and glucose tolerance, while reducing SIRT2 does the opposite. The enzyme also targets pyruvate kinase M2, a gatekeeper of glycolysis, in strikingly context-dependent ways. Deacetylation at lysine 305 promotes the formation of PKM2’s active tetramer and boosts glycolytic flux in cancer cells, whereas deacetylation at lysine 207 in inflamed microglial cells destabilizes the same protein and dampens glycolysis. SIRT2 further deacetylates phosphoglycerate mutase 2 and stabilizes the gluconeogenic enzyme PEPCK1, showing that it regulates multiple nodes of the glycolytic and gluconeogenic network rather than a single enzyme.

Lipid metabolism is another major arena. SIRT2 deacetylates ATP-citrate lyase, promoting its degradation and thereby limiting de novo fat synthesis. It stabilizes the transcription factor HNF4-alpha through deacetylation at lysine 458, a modification that protects the liver from insulin resistance, fatty infiltration, and inflammation. In the heart, SIRT2 deacetylates carnitine palmitoyltransferase 2 at lysine 239, restraining fatty acid oxidation and reactive oxygen species production in a way that protects against diabetic cardiomyopathy. In adipose tissue, SIRT2 deacetylates FOXO1, which strengthens FOXO1’s grip on PPAR-gamma and suppresses adipocyte differentiation while promoting fat breakdown. Hypoxia-inducible factor 1-alpha, elevated in obesity, suppresses SIRT2 in visceral fat cells, weakening fatty acid oxidation and mitochondrial gene expression and thereby promoting metabolic dysfunction.

Mitochondria, the cell’s power plants, are central to the aging process, and SIRT2 touches nearly every aspect of their biology. Oligodendrocytes package SIRT2 into exosomes and deliver it to neuronal axons, where it deacetylates the mitochondrial transporters ANT1 and ANT2 to boost ATP production. In vascular endothelial cells, loss of SIRT2 lowers mitochondrial membrane potential and ATP levels while increasing cell death. SIRT2 also guards the mitochondrial redox balance: its activity declines with age, and in aged mice its deficiency worsens vascular dysfunction by allowing abnormal activation of the p66Shc protein, which drives excess mitochondrial reactive oxygen species. During cellular senescence, reduced SIRT2 activity leaves tubulin excessively acetylated, disrupting microtubule dynamics and impairing the microtubule-dependent mitochondrial repair and mitophagy that aging cells desperately need.

Beyond direct metabolic control, SIRT2 plugs into the nutrient-sensing pathways that evolution has conserved as longevity regulators. In fruit flies, a tryptophan-derived microbial metabolite called indole-3-acetic acid extends lifespan through an AhR–SIRT2–TOR signaling axis, implicating SIRT2 in the gut-microbiome-to-longevity conversation. SIRT2 also activates AMPK, the cell’s fuel gauge, by deacetylating the kinase LKB1; when SIRT2 is missing, AMPK activity falls and cardiac hypertrophy worsens, even blunting the cardioprotective effects of metformin. Under amino acid starvation, SIRT2 is translationally upregulated through an upstream open reading frame and then suppresses global protein synthesis by stabilizing 4E-BP1, helping cells survive nutrient stress. Whether SIRT2 directly mediates the lifespan extension produced by dietary restriction remains unproven, but the circumstantial connections are compelling.

The review also connects SIRT2 to the classic hallmarks of aging. On oxidative stress, SIRT2 deacetylates FOXO3a to enhance antioxidant gene expression, activates PGAM2 to sustain NADPH production, and desuccinylates the glutathione-synthesis enzyme GCLC, all of which keep reactive oxygen species in check. In the Asian honeybee, age-related SIRT2 decline accompanies mitochondrial damage, while SIRT2 activation promotes PINK1/Parkin-dependent mitophagy and delays cellular aging. On inflammation, SIRT2 deacetylates the NF-kappa-B subunit p65 at lysine 310 to restrain inflammatory gene expression, suppresses the NLRP3 inflammasome to protect aging hematopoietic stem cells, and dismantles the cGAS–STING DNA-sensing pathway by deacetylating G3BP1, blunting a major driver of chronic age-related inflammation.

Genome integrity adds another layer. SIRT2-deficient mice show chromosomal instability and increased cancer susceptibility, partly because SIRT2 loss elevates H4K16 acetylation and disrupts mitotic deposition of H4K20 methylation. SIRT2 also maintains the expression and function of BubR1, a mitotic surveillance protein whose age-related decline is linked to multiple diseases. Perhaps most strikingly, SIRT2 expression drops in the hearts of aged macaques, and in human stem-cell-derived cardiomyocytes its loss hyperacetylates STAT3, activating the CDKN2B gene and imposing age-like characteristics; restoring SIRT2 in mice alleviates age-related cardiac dysfunction. In skeletal muscle, SIRT2 knockout in aged male mice worsens fat infiltration and impairs regeneration, pointing to a role in combating sarcopenia.

The authors are careful about the caveats. SIRT2’s effects are highly context- and tissue-dependent: the same deacetylation event can activate a metabolic enzyme under oxidative stress yet trigger its degradation in cancer cells, and inhibiting SIRT2 can actually improve the metabolic fitness of antitumor T cells. The enzyme also carries deacylase activities beyond deacetylation, including demyristoylation and delipoylation, whose physiological importance is only beginning to be explored, and age-accumulating isoforms such as SIRT2.3 may behave differently from the canonical protein. Its precise contribution to organismal longevity remains incompletely understood, and whether boosting NAD+ to enhance SIRT2 activity can translate into therapies for healthy aging is still an open question. What the evidence does establish is that SIRT2 functions as a molecular checkpoint linking cellular energy status to the adaptive responses that determine how tissues age, making it one of the most intriguing targets in the search for interventions that promote metabolic health across the lifespan.

Subject of Research: The role of the NAD+-dependent deacetylase SIRT2 in regulating energy metabolism, aging, and longevity

Article Title: SIRT2 in metabolism, aging, and longevity

Article References: Li, M., Dong, Y., Ren, W., Dong, W., & Ji, S. (2026). SIRT2 in metabolism, aging, and longevity. Frontiers in Molecular Biosciences, 13, Article 1990670. https://doi.org/10.3389/fmolb.2026.1990670

Image Credits: AI Generated

DOI: 10.3389/fmolb.2026.1990670

Keywords: SIRT2, sirtuins, NAD+, aging, longevity, metabolism, mitochondria, inflammation, oxidative stress, glucose metabolism, lipid metabolism, cellular senescence

The biological concept at the heart of the review is cellular senescence, a state in which cells stop dividing but refuse to die, instead secreting a cocktail of inflammatory molecules known as the senescence-associated secretory phenotype, or SASP. Senescence is not inherently harmful; it contributes to wound healing and tumor suppression in the short term. But when senescent cells accumulate with age, their secretions chronically inflame surrounding tissue, degrade its structure, and push neighboring cells toward senescence themselves. The review argues that EVs act as essential shuttles in this process, propagating senescence signals between cells and creating what the authors describe as a vicious cycle of senescence, inflammation, and dysfunction. In the words of first author Professor Wang, cellular senescence is a major driver of many chronic pulmonary conditions, and EVs are the vehicles that carry those instructions from cell to cell.

Crucially, the cargo of an extracellular vesicle depends on the state of the cell that released it. Under healthy conditions, EVs help maintain tissue homeostasis, supporting immune regulation, cell proliferation, and repair. In disease states, however, senescent cells package a distinctly pro-senescent payload. When neighboring healthy cells take up these vesicles, they can be driven into secondary senescence, amplifying inflammation, tissue damage, and fibrosis across the lung. This mechanism helps explain why chronic lung diseases track so closely with aging, and why damage, once established, tends to spread and self-perpetuate even after the original insult, such as cigarette smoke or environmental pollutants, has been removed.

The review details several mechanistic pathways through which EVs accelerate disease. They facilitate aberrant intercellular communication, deliver pathogenic microRNAs and proteins, promote chronic inflammation, modulate immune cell function, amplify oxidative stress, and actively contribute to remodeling of the extracellular matrix, the scaffolding that gives lung tissue its elastic architecture. Among all cargo types, microRNAs have attracted the most attention because a single vesicle can deliver molecules that silence multiple target genes at once. Several miRNAs in particular, including miR-34a, miR-21, miR-125a-5p, miR-146a-5p, and miR-570-3p, have been shown to target key anti-aging molecules such as the sirtuins, a family of enzymes that protect cells against stress and maintain genomic stability, thereby accelerating senescence in epithelial cells and fibroblasts.

Disease-specific examples illustrate how finely tuned, and how varied, these mechanisms are. In COPD, small EVs released by airway epithelial cells transfer miR-34a to recipient cells, where it suppresses SIRT1, raising levels of the cell-cycle inhibitor p21 and other senescence markers. In idiopathic pulmonary fibrosis, a relentlessly scarring disease of the lung interstitium, fibroblast-derived EVs deliver miR-23b-3p and miR-494-3p, which downregulate SIRT3 and trigger mitochondrial dysfunction, reinforcing the pro-fibrotic, pro-senescent microenvironment that characterizes the disease. In asthma, EV-mediated alterations in miR-34a may simultaneously influence immune polarization and cellular aging pathways in the airway, linking two processes usually studied in isolation.

The review extends this framework to conditions that receive less attention in senescence research. In bronchiectasis, sputum-derived miR-92b-5p and miR-223-3p may directly connect colonization by the bacterium Pseudomonas aeruginosa to airway aging, mediating local inflammation through the cytokines IL-1β and IL-8 while regulating longevity-related pathways. In obstructive sleep apnea, EVs have been implicated in the cardiovascular and neurocognitive complications that accompany repeated nighttime oxygen deprivation. In lung cancer, EVs remodel the tumor microenvironment and mediate resistance to therapy, adding a senescence dimension to oncology’s long-standing interest in vesicle biology. The authors argue that this functional diversity across diseases underscores the pivotal position EVs occupy in the regulatory network of pulmonary medicine.

What elevates the review beyond mechanism is its treatment of EVs as therapeutic agents in their own right. Because they are naturally derived, inherently biocompatible, and capable of targeted delivery, EVs have emerged as promising drug carriers. Mesenchymal stem cell-derived EVs have shown the potential to alleviate inflammation, downregulate senescence markers, and repair lung tissue in experimental models of COPD and IPF. Neutrophil-derived EVs offer unique advantages as delivery vehicles, and aerosol administration allows vesicles to be delivered efficiently and noninvasively directly to lung tissue, a route particularly suited to respiratory disease. In early clinical translation, research in COPD has focused on plasma exosomal miRNA biomarkers, while lung cancer studies apply EV-based liquid biopsy to guide therapeutic decisions. Although these studies were not designed specifically to target senescence, the authors note that they provide indirect evidence for the mechanisms underlying EV-mediated pulmonary aging.

Professor Wang notes that EVs hold promise as tools for senotherapy, the emerging class of interventions aimed at removing or reprogramming senescent cells, and that developing optimal EVs for such therapies is becoming an important research focus. Current optimization strategies include loading vesicles with therapeutic drugs, modifying their surfaces with targeting ligands so they home to specific cell types, and refining aerosol delivery for the respiratory tract. Yet significant obstacles stand between laboratory promise and bedside impact. Isolation and characterization methods remain inconsistent across laboratories, making results difficult to compare and reproduce. Large-scale clinical validation is still lacking, and the basic biology of EVs in the aging context, including how vesicle cargo changes with age and disease severity, is only beginning to be mapped.

The significance of the review lies in its unifying framing. Chronic lung diseases have traditionally been studied and treated as separate entities, each with its own specialist clinic, biomarker panel, and drug pipeline. By identifying EV-mediated senescence signaling as a shared pathway running through COPD, IPF, asthma, bronchiectasis, OSA, and lung cancer, the authors provide a conceptual bridge that could allow insights and therapies developed for one condition to inform others. A vesicle-targeting strategy that interrupts the transfer of miR-34a in COPD airways, for example, might be adapted to interrupt pro-fibrotic vesicle signaling in IPF. Conversely, biomarkers measured in circulating vesicles could one day track senescence burden across multiple diseases with a single blood test.

The work also arrives at a moment when the biology of aging is moving from the fringes of medicine toward its center. With global populations aging rapidly, the burden of chronic respiratory disease is projected to rise steeply, and current treatments largely manage symptoms rather than halt the underlying degenerative process. If EVs truly are the shuttles that spread senescence through lung tissue, then intercepting them, disarming their cargo, or replacing them with engineered vesicles carrying restorative payloads represents a fundamentally new therapeutic paradigm. The review’s authors are careful to emphasize the challenges that remain, but their synthesis offers researchers a clear framework for future investigation and, they hope, a path toward anti-senescence therapy for chronic respiratory diseases that changes the trajectory of these conditions rather than merely slowing their symptoms.

Subject of Research: The role of extracellular vesicles in cellular senescence and chronic lung diseases

Article Title: Insights into extracellular vesicles in senescence-associated chronic lung diseases

Article References: Insights into extracellular vesicles in senescence-associated chronic lung diseases. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: extracellular vesicles, cellular senescence, COPD, idiopathic pulmonary fibrosis, microRNAs, SASP, sirtuins, senotherapy, asthma, lung cancer, bronchiectasis, obstructive sleep apnea

To understand why the framework matters, it helps to start with the physics. Endothelial cells are not passive pipes; they are mechanosensors constantly bathed in shear stress, the frictional force exerted by flowing blood. Where flow is smooth and laminar, endothelial cells align with the flow direction, produce nitric oxide, suppress inflammation and maintain a quiescent, anti-atherogenic state. Where flow is low or oscillatory, typically at arterial branch points and curvatures, the cells experience turbulent, reversing forces that activate inflammatory transcription factors, reprogram metabolism and, critically, induce DNA damage responses. Studies cited in the review show that disturbed flow promotes endothelial senescence through p53-dependent pathways, and that oscillatory shear can activate the STING innate immune pathway, accelerating both senescence and atherosclerosis in experimental models.

The metabolic half of the equation is equally detailed. Hyperglycaemia, dyslipidaemia, uraemic toxins from failing kidneys, hepatic stress from fatty liver disease, inflammatory cytokines such as tumour necrosis factor alpha and oxidative injury all converge on a remarkably consistent set of intracellular targets. These include the p53/p21 and p16/pRB tumour-suppressor axes that enforce cell-cycle arrest, the decline of NAD+ and sirtuin activity that normally protects genomic integrity, mitochondrial dysfunction that floods the cell with reactive oxygen species, and a metabolic rewiring toward glycolysis and altered fatty acid handling. Senescent endothelial cells, the review notes, can even sustain their own inflammatory secretory phenotype, the so-called SASP, through enhanced fatty acid oxidation, creating a self-perpetuating loop of vascular inflammation.

What distinguishes this review from earlier accounts of endothelial ageing is its insistence on the mechanometabolic intersection. Matrix stiffness, which increases as arteries age and stiffen, feeds back on endothelial cells through mechanosensitive channels such as Piezo1, altering their response to shear. Disturbed flow induces metabolic reprogramming via HIF-1alpha and AMPK-driven glycolysis, and single-cell RNA sequencing studies reveal that cells exposed to disturbed flow adopt distinct transcriptomic and chromatin accessibility signatures. Epigenetic mechanisms add another layer: flow-dependent DNA methylation, DNMT1 recruitment, mechanosensitive super-enhancers and even histone lactylation driven by metabolic byproducts all shape which genes an endothelial cell can express. Metabolism, in other words, is not merely fuel; it is a regulator of chromatin, and mechanical forces regulate metabolism.

The authors are explicit that this framework is operational rather than universally standardised. They use cardiometabolic vascular disease, or CMVD, as an umbrella term for vascular injury arising from interacting metabolic, renal and cardiovascular stress, echoing the cardiovascular-kidney-metabolic health concept promoted by the American Heart Association. But they resist the temptation to declare endothelial senescence a universal primary cause of vascular disease. Instead, they describe it as a context-dependent amplifier, a mechanism that magnifies injury where mechanical vulnerability and metabolic load coincide, and a testable translational model whose validity must be demonstrated compartment by compartment.

That translational ambition is where the review becomes most clinically interesting. The authors catalogue the functional anchors clinicians already use: flow-mediated dilatation of the brachial artery for macrovascular endothelial function, carotid-femoral pulse-wave velocity for aortic stiffness, coronary flow reserve and the index of microcirculatory resistance for the coronary microvasculature. Each provides a compartment-specific readout, yet none is a direct senescence assay. To bridge that gap, the review proposes a staged validation strategy that combines confirmation of endothelial identity, convergent senescence markers such as p16, senescence-associated beta-galactosidase and SASP components, measures from circulating endothelial cells or extracellular vesicles, vascular function testing and, ultimately, organ-specific clinical outcomes. Circulating endothelial cells isolated from blood samples, one cited study suggests, could offer a practical window on endothelial senescence without requiring arterial biopsy.

The framework is then stress-tested against three organ contexts. In heart failure with preserved ejection fraction, a condition disproportionately affecting older women, coronary microvascular endothelial inflammation and senescence have been implicated in animal models, and SIRT6 deficiency worsens the diabetic form of the disease in mice, but human evidence remains heterogeneous. In chronic kidney disease, glomerular endothelial senescence drives age-related kidney pathology through plasminogen activator inhibitor-1, and pro-senescent niches organised by matrix proteins such as fibrillin-1 have been described around peritubular capillaries. In metabolic dysfunction-associated steatotic liver disease, aged liver sinusoidal endothelial cells lose their fenestrations and defensive capacity, aggravating hepatic metabolic dysfunction. Across all three, the strongest evidence remains preclinical or mixed translational, a limitation the authors state plainly rather than obscure.

One of the most consequential threads concerns biological sex. Endothelial function declines measurably across the menopause transition, linked to falling estradiol and rising oxidative stress, and nitric oxide itself appears to inhibit endothelial senescence, suggesting a protective mechanism lost after menopause. Yet direct evidence from human arteries complicates the simple story: a study of patients with atherosclerosis found that senescence and inflamm-ageing were associated with endothelial dysfunction in men but not women. The review concludes that sex-disaggregated mechanistic data remain sparse, and that any translational framework claiming general validity must eventually explain why the same senescence machinery may behave differently in female and male vessels.

The therapeutic implications are tantalising but tempered. Senolytic drugs, which clear senescent cells, have ameliorated large-artery stiffening and endothelial dysfunction in aged animals, and habitual exercise in humans is associated with reduced endothelial senescence and better vascular function, partly through enhanced mitophagy in coronary endothelium. NAD+-boosting strategies, sirtuin activation and anti-inflammatory interventions all have preclinical support. But the review’s staged validation strategy is a warning against premature translation: without validated senescence biomarkers in accessible compartments, trials cannot reliably identify which patients carry a mechanometabolic senescence burden or measure whether it has been relieved.

What the review ultimately offers is a map rather than a verdict. It gathers human tissue data, clinical physiology, animal genetics, flow-controlled experiments and single-cell omics into a single causal architecture in which haemodynamic vulnerability and cardiometabolic load jointly push endothelial cells toward senescence, and senescent endothelium in turn stiffens arteries, narrows microvessels and feeds inflammation back into the systemic circulation. The authors’ insistence that the framework is an amplifier, not a universal primary cause, is precisely what makes it scientifically useful: it generates falsifiable predictions about where in the vasculature senescence should accumulate, which biomarkers should track it, and which interventions should relieve it. If those predictions hold in the staged validation the authors propose, the convergence of fluid mechanics and metabolism at the endothelial surface could become one of the organising principles of vascular medicine for the age of cardiometabolic disease.

Subject of Research: Mechanometabolic endothelial senescence linking haemodynamic stress and metabolic load to cardiometabolic vascular disease and vascular ageing

Article Title: Mechanometabolic endothelial senescence as a translational framework for cardiometabolic vascular disease and vascular ageing

Article References: Lanlan, L., Fan, G., Ran, Z., Xiaoqing, Z., Yitong, C., Jingjing, Z., Lei, L., & Jianhua, F. (2026). Mechanometabolic endothelial senescence as a translational framework for cardiometabolic vascular disease and vascular ageing. Molecular Biology Reports, 53(1), Article 1683. https://doi.org/10.1007/s11033-026-12792-w

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12792-w

Keywords: endothelial senescence, mechanotransduction, disturbed flow, vascular ageing, cardiometabolic disease, SASP, sirtuins, arterial stiffness, HFpEF, chronic kidney disease, MASLD, sex differences

The research, led by Takashi Shida of the Tokyo Metropolitan Institute for Geriatrics and Gerontology and colleagues, drew on participants from the Itabashi Longitudinal Study on Aging, an ongoing community-based cohort in a residential ward of northern Tokyo. The team analyzed data from 529 adults aged 65 and older who took part in the 2025 survey wave, a group in which 54.3 percent were women. Frailty, the state of heightened vulnerability that leaves older adults at risk of falls, disability, hospitalization, and death, was assessed using the revised Japanese version of the Cardiovascular Health Study criteria, a validated instrument that scores weight loss, exhaustion, low physical activity, weakness, and slowness. Of the 529 participants, 32, or 6.0 percent, met the criteria for frailty.

The central measurement was the concentration of NAD+ in whole blood, quantified in micromoles per liter. Whole-blood NAD+ is a composite signal: it reflects the molecule’s presence inside red blood cells, white blood cells, and platelets, as well as whatever circulates in plasma. Because red blood cells lack mitochondria and rely heavily on NAD+ for glycolysis and antioxidant defense, the blood compartment offers a convenient, if imperfect, window into systemic NAD+ metabolism. The researchers found that the median whole-blood NAD+ concentration was measurably lower among participants with frailty than among those without it, at 24.00 versus 25.00 micromoles per liter, a difference that reached statistical significance with a P value of 0.007.

To move beyond a simple group comparison, the team built multivariable regression models that adjusted for the most obvious confounders: age, sex, and fasting time before the blood draw, the last of which matters because NAD+ levels can fluctuate with recent food intake. After these adjustments, each 1 micromole per liter increase in whole-blood NAD+ concentration was associated with 13 percent lower odds of frailty, with an odds ratio of 0.871 and a 95 percent confidence interval spanning 0.780 to 0.970, and a P value of 0.013. In a cohort where the median sits near 25 micromoles per liter, a one-unit shift is a meaningful fraction of the biological range, which makes the effect size noteworthy rather than trivial.

The investigators then subjected their finding to a battery of robustness checks that reveal how carefully the result was constructed. Restricted cubic spline analysis, a technique that allows the relationship between NAD+ and frailty to bend and curve freely rather than assuming a straight line, showed no clear evidence of nonlinearity, suggesting the association behaves approximately linearly across the observed range. Because frailty was relatively rare in the sample, the team also ran a Firth penalized-likelihood logistic regression, a method designed to produce more stable estimates when outcomes are infrequent and conventional models risk bias. Under this broader covariate adjustment, the association held firm, with an odds ratio of 0.880 and a confidence interval of 0.782 to 0.986.

But the story took a more complicated turn when the researchers added hematocrit, the proportion of blood volume occupied by red blood cells, to the model. With that adjustment, the association weakened and lost statistical significance, with the odds ratio drifting to 0.911 and the confidence interval crossing unity at 0.800 to 1.034. This attenuation is not a failure of the study; it is one of its most informative results. It suggests that part of the apparent link between blood NAD+ and frailty may be explained by blood cell composition itself. Frail older adults often have altered hematological profiles, including tendencies toward anemia and shifts in red cell indices, and since the vast majority of whole-blood NAD+ resides within blood cells, differences in cell counts and packing could masquerade as, or at least substantially contribute to, differences in NAD+ concentration.

This caveat places the new findings within a lively and sometimes contentious scientific debate. NAD+ has become one of the most hyped molecules in the longevity world, with supplements such as nicotinamide riboside and nicotinamide mononucleotide marketed aggressively on the premise that restoring youthful NAD+ levels can slow aging. Human evidence, however, has been mixed. Some studies have reported that whole-blood NAD+ contents decline with age, while others, including a recent analysis published in Nature Metabolism, found that human whole-blood NAD+ levels do not vary with age or with lifestyle interventions. Blood NAD+ has also been reported to be reduced in very old patients hospitalized for heart failure, hinting that the molecule may track with disease severity rather than chronological age per se. The Itabashi study adds a crucial piece: a community-dwelling, non-hospitalized population in which the association with frailty, a clinical syndrome rather than a single disease, was detectable.

The study’s design imposes important limits on interpretation. As a cross-sectional analysis, it captures a single moment in time and cannot determine whether low NAD+ contributes to causing frailty, whether frailty and its metabolic consequences deplete NAD+, or whether both are driven by a shared underlying process such as chronic inflammation, mitochondrial dysfunction, or poor nutrition. The frailty group was also small, with only 32 affected participants, which limits statistical power and explains the team’s recourse to penalized regression. And the whole-blood measurement, while practical and increasingly standardized, cannot distinguish between NAD+ dynamics in muscle, brain, immune cells, and other tissues where the molecule’s age-related decline is thought to matter most. The authors themselves emphasize that further studies using cell- and tissue-specific measurements are needed to clarify the relationship between NAD+ metabolism and frailty.

Those caveats notwithstanding, the significance of the work lies in its grounding. Much of the NAD+ literature rests on cell culture experiments, animal models, or small and highly selected human samples. Here, the association emerges from ordinary older adults living at home in a Tokyo ward, measured with a validated frailty instrument and adjusted for the mundane but essential variables of age, sex, and fasting status. If blood NAD+ does prove to be a genuine marker of physiological resilience, even one partly confounded by blood cell composition, it could eventually help clinicians identify which older patients are silently sliding toward frailty before falls and disability make it obvious. Biomarkers of frailty are a recognized public health priority, and most current candidates, from inflammatory cytokines to metabolomic signatures, remain far from clinical deployment.

The road ahead will require longitudinal follow-up within cohorts like Itabashi, where repeated NAD+ measurements can be tested as predictors of incident frailty, and intervention studies in which NAD+-boosting compounds are evaluated against hard clinical endpoints rather than blood chemistry alone. Recent work comparing different NAD+ precursors has shown that they exert differential effects on circulating NAD and microbial metabolism in humans, underscoring how much remains unknown about how these interventions behave in the body. Exercise training, for its part, has been shown to reverse the age-dependent decline in NAD+ salvage capacity in human skeletal muscle, pointing to lifestyle approaches that may act on the same pathway without a pill. For now, the Itabashi findings should be read as a carefully qualified signal rather than a prescription: a molecule central to energy metabolism and cellular signaling appears to run low in the blood of frail older adults, and untangling whether that deficit is a driver, a passenger, or a mirror of declining resilience is now one of the most compelling questions in the biology of aging.

Subject of Research: Association between whole-blood NAD+ concentration and frailty in community-dwelling older adults

Article Title: Association between whole-blood NAD+ concentration and frailty in community-dwelling older adults: the Itabashi Longitudinal Study on Aging

Article References: Shida, T., Hatanaka, S., Kojima, N., Osuka, Y., & Sasai, H. (2026). Association between whole-blood NAD+ concentration and frailty in community-dwelling older adults: the Itabashi Longitudinal Study on Aging. GeroScience. https://doi.org/10.1007/s11357-026-02545-9

Image Credits: AI Generated

DOI: 10.1007/s11357-026-02545-9

Keywords: NAD+, frailty, aging, older adults, whole blood, biomarkers, energy metabolism, sirtuins, hematocrit, GeroScience, Itabashi Longitudinal Study, geriatrics

The breadth of melatonin’s reported activities is striking. Beyond its sedative effect, the review catalogs antitumor, immunomodulatory, antioxidant, antihypertensive and cardioprotective actions, along with roles in regulating body weight, gastrointestinal function, reproduction and thermoregulation. Part of this versatility is chemical: melatonin crosses biological membranes freely and reaches nearly every compartment of the cell. Part of it is signaling: melatonin binds specific G-protein-coupled receptors, but it also engages intracellular pathways that govern whether a cell survives stress, divides, inflames or dies. The question the review tackles is which of these pathways best explains the hormone’s pharmacological reach, and its answer centers on SIRT1, the most intensively studied member of the mammalian sirtuin family.

SIRT1 is a nicotinamide adenine dinucleotide, or NAD+, dependent deacetylase, meaning it removes acetyl chemical groups from proteins only when the metabolic cofactor NAD+ is available. This makes the enzyme a direct sensor of cellular energy status, because NAD+ levels rise and fall with nutrient availability, fasting and metabolic strain. SIRT1 shuttles between the cytoplasm and the nucleus, where it strips acetyl groups from histones, the spools around which DNA is wound, and from a growing list of non-histone proteins including the tumor suppressor p53, the transcription factors FoxO and NF-κB, and the mitochondrial regulator PGC-1α. Through these targets, SIRT1 influences cell survival, metabolism, growth, aging and resistance to stress, which is precisely the portfolio of processes that goes wrong in chronic disease.

The review’s central claim is that melatonin can modulate SIRT1 activity, and that this modulation in turn shapes four fundamental cellular responses: inflammation, oxidative stress, apoptosis and autophagy. In inflammatory bowel disease, for example, recent work cited in the review shows that melatonin restores the intestinal mucosal barrier by activating a SIRT1-LKB1-pAMPK signaling axis. In autoimmune and sepsis models, SIRT1 deacetylates components of the NF-κB pathway and the NLRP3 inflammasome, damping the production of tumor necrosis factor alpha, interleukin-1 and other inflammatory mediators. Because NF-κB sits upstream of cyclooxygenase-2 and inducible nitric oxide synthase, a single deacetylation event can cascade into a broad suppression of the inflammatory program.

The cardiovascular evidence is among the most developed. In type 2 diabetic rats, reduced SIRT1 signaling worsens myocardial ischemia-reperfusion injury, and melatonin treatment restores protection through the enzyme. Melatonin receptor-mediated cardioprotection against ischemia-reperfusion has likewise been traced to SIRT1. In diabetic hearts, melatonin prevents Drp1-mediated mitochondrial fission, the excessive fragmentation of mitochondria that starves cardiomyocytes of energy, via the SIRT1-PGC-1α pathway, and activation of the SIRT1-PGC-1α-SIRT3 cascade protects against mitochondrial dysfunction in isoproterenol-induced myocardial injury. The chemotherapy drug doxorubicin, notorious for causing heart damage, appears less toxic when melatonin activates the Sirt1/Nrf2 pathway, inhibiting oxidative stress, pyroptosis and apoptosis. In sepsis-induced cardiac dysfunction, melatonin acts through SIRT1 to regulate both apoptosis and autophagy, including SIRT1-mediated deacetylation of beclin-1 and of the transcription factor TFEB, which orchestrates lysosomal clearance of damaged material.

The kidney tells a parallel story. Melatonin attenuates acute kidney ischemia-reperfusion injury in diabetic rats by activating the SIRT1/Nrf2/HO-1 axis, a canonical antioxidant pathway in which Nrf2, once deacetylated and stabilized, switches on heme oxygenase-1 and other detoxifying genes. In diabetic kidney disease, protection runs through SIRT1/NLRP3 signaling, curbing the inflammasome-driven inflammation that scars the filtering units of the kidney. Melatonin also prevents acute kidney injury in severely burned rats via SIRT1 activation, and in cadmium-induced proximal tubular injury it preserves mitochondrial function by blocking fission through SIRT1-PGC-1α. Perhaps most intriguingly, melatonin lowers the abundance of hypoxia-inducible factor 1α in human proximal tubular cells by preventing its deacetylation by sirtuin 1, a reminder that SIRT1’s effects are not uniformly protective but context-dependent, and that melatonin’s modulation of the enzyme can push it in either direction depending on the tissue and insult.

In the liver, the review highlights melatonin’s effects on non-alcoholic fatty liver disease, a condition now affecting a substantial share of the world’s overweight and obese population. Melatonin’s benefits in fatty liver models are linked to the microRNA-34a-5p/Sirt1 axis and to autophagy, the cellular recycling system that clears lipid droplets and damaged organelles. In hypercholesterolemic mice, melatonin’s modulation of sirtuin-1 attenuates liver injury. The enzyme also mediates protection against toxic exposures: melatonin inhibits benzo(a)pyrene-induced apoptosis in mouse liver through the miR-34a/Sirt1/autophagy pathway, and it attenuates arsenic-induced liver injury through Nrf2/HO-1, apoptosis and miR-34a/Sirt1/autophagy routes. In alcoholic liver injury, melatonin-induced SIRT1 disrupts the cereblon-YY1-CYP2E1 signaling pathway, reducing the oxidative metabolism of alcohol that generates damaging free radicals, while in sepsis-induced liver injury melatonin activates SIRT1/STAT3 signaling to rescue dysregulated gluconeogenesis.

The reproductive findings may prove the most clinically provocative. In polycystic ovary syndrome, melatonin enhances SIRT1 expression in granulosa cells to ameliorate excessive PINK1/Parkin-mediated mitophagy and to protect mitochondrial membranes through PDK1/Akt signaling, and it attenuates Drp1-driven mitochondrial fission through SIRT1 upregulation. The ROS/SIRT1/STAR axis has been identified as a target through which melatonin corrects atrazine-induced mitochondrial dysfunction and steroid disorders in granulosa cells. In oocytes, melatonin protects against chronic stress-induced meiotic defects by regulating SIRT1, and follicular fluid insufficiency of melatonin has been proposed as a reversible cause of the chromosomal abnormalities seen in oocytes of advanced maternal age. On the male side, melatonin protects mouse testes from palmitic acid-induced lipotoxicity in a SIRT1-dependent manner, ameliorates diabetic impairment of Leydig cell steroidogenic function through SIRT1 activation, and modulates SIRT1 to counter LPS-induced testicular nitro-oxidative stress and inflammation. Human trials add a translational note: melatonin supplementation improved semen parameters in men with idiopathic infertility in a triple-blind randomized placebo-controlled trial, and melatonin therapy added benefit to varicocelectomy in a double-blind trial, with epigenetic effects in a varicocele rat model mediated by silent information regulator 1.

The musculoskeletal section rounds out the picture. In osteoarthritis, melatonin exerts cytoprotective and anti-inflammatory effects in human chondrocyte cells and in rabbit models via the SIRT1 pathway, prevents cartilage matrix degradation by inhibiting NF-κB through SIRT1, and regulates chondrocyte hypertrophy and apoptosis through the Sirt1/P53/P21 axis. It also promotes sirtuin 1 expression to inhibit the IRE1α-XBP1S-CHOP branch of the unfolded protein response, reducing endoplasmic reticulum stress-mediated apoptosis in chondrocytes. In intervertebral disc degeneration, melatonin protects vertebral endplate chondrocytes against apoptosis and calcification via the Sirt1-autophagy pathway and holds promise through inhibiting M1-type macrophage polarization via SIRT1/Notch signaling. Even in cancer the relationship is bidirectional: whereas SIRT1 activation generally protects healthy tissue, melatonin’s antitumor activity in human osteosarcoma cells has been attributed to SIRT1 inhibition, underscoring that the same enzyme can be friend or foe depending on cellular context.

The authors are careful to note the limits of the evidence. Despite the breadth of preclinical data, they write that evidence regarding the role of SIRT1 in melatonin’s effects remains limited, and much of what is known comes from cell cultures and animal models rather than definitive human trials. Whether melatonin reliably activates SIRT1 in human tissues at supplement doses, and whether SIRT1 is necessary rather than merely correlated with the hormone’s benefits, will require pharmacological inhibitors, genetic models and properly powered clinical studies. Still, the synthesis is compelling in its coherence: a hormone produced by a tiny gland in the brain, acting through an NAD+-dependent enzyme that links metabolism to gene expression, appears to coordinate protective programs across organs as different as the heart, kidney, liver, ovary and joint. If future work confirms SIRT1 as the common mediator, melatonin’s humble reputation as a sleep aid may give way to something far more interesting, a cheap and safely tolerated molecule that tunes the body’s central longevity machinery.

Subject of Research: The role of the SIRT1 signaling pathway in the therapeutic effects of melatonin across disease models

Article Title: The therapeutic potential of melatonin: Focus on the SIRT1 signaling pathway

Article References: Vahidinia, Z., Behdarvandy, M., Azami Tameh, A., Barati, S., & Yasamian, A. (2026). The therapeutic potential of melatonin: Focus on the SIRT1 signaling pathway. Molecular Biology Reports, 53(1), Article 1667. https://doi.org/10.1007/s11033-026-12815-6

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12815-6

Keywords: melatonin, SIRT1, sirtuins, NAD+, deacetylation, oxidative stress, autophagy, apoptosis, cardioprotection, diabetic cardiomyopathy, non-alcoholic fatty liver disease, polycystic ovary syndrome

The research, led by Marloes Oosterhof and Louis Coussement of the University of Groningen together with colleagues in Belgium, Austria and the Netherlands, focused on the liver, the metabolic command center that manages the fuel switch from glucose to fat oxidation that hibernation demands. Because facultative hibernators like the Syrian hamster enter torpor only in response to environmental cues, shortening days, cold and food scarcity, their bodies must actively reprogram gene expression rather than simply follow a fixed seasonal clock. That flexibility makes epigenetic mechanisms, the chemical systems that switch genes on and off without altering the underlying sequence, prime suspects for orchestrating the transition.

To test this idea, the team induced hibernation in Syrian hamsters by shortening the light-dark cycle and lowering ambient temperature, then collected liver samples at carefully defined phases: summer euthermia, when animals were active and warm; late torpor, more than 72 hours after the animals had settled into a bout; and both early and late arousal, shortly after the animals rewarmed. Using infrared motion detectors, the researchers confirmed each animal’s state before euthanasia, ensuring that the molecular snapshots truly reflected the hibernation phase rather than guesswork about body temperature.

The first layer of analysis examined the expression of 94 genes encoding epigenetic writer and eraser enzymes, the proteins that add or remove chemical marks on histones and DNA. Of the 83 genes that could be reliably measured, 11 shifted significantly between phases. Strikingly, four histone acetyltransferases, KAT6A, KAT6B, KAT7 and KAT13D, better known as the circadian gene CLOCK, were differentially expressed, with most declining during torpor and rebounding during arousal. Three deacetylases, SIRT2, SIRT7 and HDAC11, also changed, along with two histone methyltransferases, one demethylase and the DNA demethylating enzyme TET2.

Notably, several of these enzymes, including PCAF, GCN5L2, HAT1 and CBP, had been flagged in previous work on the thirteen-lined ground squirrel, an obligatory hibernator, but showed no expression changes in the hamster. This divergence suggests that facultative hibernators may deploy a distinct epigenetic toolkit, one tailored to switching hibernation on and off in response to the environment rather than to an internal circannual rhythm. The downregulation of CLOCK in the hamster liver is particularly intriguing, since recent work indicates that the liver pauses its circadian rhythms during hibernation while the brain retains them.

Gene expression, however, is only an indirect readout. The team therefore measured histone acetylation directly, first by Western blot and then by quantitative mass spectrometry, a technique that can determine exactly how many acetyl groups sit on specific lysine residues of histones H3 and H4. The results were consistent and telling. Overall acetylation of histone H3 dropped during late torpor, with the acetylation of lysines 18 and 23 falling by roughly 5 and 14 percent respectively, and rising again during arousal. H3K27ac, a mark classically associated with active enhancers and open chromatin, was lowest in torpor and recovered as animals rewarmed, a pattern that fits the idea of chromatin condensing, and transcription shutting down, while the animal is cold and metabolically dormant.

Histone H4 told a subtler story. Unlike H3, whose acetylation largely rebounded during arousal, the H4 peptide spanning lysines 5, 8, 12 and 16 remained under-acetylated even after the animals had rewarmed. The single most heavily used site, H4K16, a modification with the unusual ability to both promote and repress transcription depending on context, was significantly less acetylated in late arousal than in summer-active animals. The researchers point to SIRT2 and SIRT7, both of which target H4K16 and both of which were upregulated during arousal, as plausible culprits, noting that these sirtuins can translocate into the nucleus during cell-cycle transitions and stress, both of which accompany the metabolic turbulence of rewarming.

On the enzyme-activity side, histone acetyltransferase activity stayed flat across all phases, but histone deacetylase activity peaked in late torpor. Inhibitor profiling revealed that a single enzyme, HDAC6, accounted for roughly 71 percent of total hepatic HDAC activity. Yet here the plot thickened: although HDAC6 activity was high and histone acetylation low during torpor, the acetylation of alpha-tubulin, HDAC6’s best-known cytosolic target, actually increased. The authors suggest that HDAC6 may relocate to the nucleus during torpor, deacetylating histones there while leaving tubulin untouched, and note that the enzyme is also tied to hepatic gluconeogenesis and to protective responses in ischemic liver injury, processes highly relevant to both hibernation and, potentially, human organ preservation.

Perhaps the most surprising negative result concerned DNA methylation. Using both the Luminometric Methylation Assay and whole-genome bisulfite sequencing, the team found no significant differences in global cytosine methylation at CpG or non-CpG sites across any hibernation phase, and promoter methylation of the differentially expressed genes was likewise unchanged. This stability mirrored the near-absence of changes in the expression of DNA methyltransferases and demethylating enzymes, and it contrasts with reports of methylation shifts in ground squirrels and horseshoe bats. In the Syrian hamster, at least, the epigenetic levers of hibernation appear to be pulled at the histone level rather than at the DNA level.

The broader implications reach well beyond rodent physiology. Because facultative hibernators can trigger hypometabolic, cytoprotective states essentially on command, understanding their epigenetic switches could inform strategies to protect organs during transplantation, to limit ischemic damage, and even to slow aging, given recent evidence that epigenetic aging is effectively stalled during hibernation in yellow-bellied marmots. The authors caution that their bulk liver measurements largely reflect hepatocytes and that single-cell follow-up work will be needed to resolve contributions from rarer cell types, and that the expression changes, though modest in fold change, match the magnitude of the measured histone modifications. Still, the message is clear: when a hamster decides to hibernate, it does not rewrite its DNA. It retunes the packaging, loosening and tightening the spools of chromatin to silence the genome through the cold and swing it back open for the warmth of arousal.

Subject of Research: Epigenetic regulation of gene expression, specifically histone acetylation and DNA methylation, in the liver of facultatively hibernating Syrian hamsters

Article Title: Changes in histone lysine acetylation, but not DNA methylation during facultative hibernation in Syrian hamster liver

Article References: Oosterhof, M. M., Coussement, L., van Pijkeren, A., Kwiatkowski, M., Zwinderman, M. R. H., Dekker, F. J., de Meyer, T., Reitsema, V. A., Bischoff, R., Guryev, V., Bouma, H. R., Henning, R. H., & Rots, M. G. (2024). Changes in histone lysine acetylation, but not DNA methylation during facultative hibernation in Syrian hamster liver. Epigenetics Communications, 4(1), Article 1. https://doi.org/10.1186/s43682-023-00024-2

Image Credits: AI Generated

DOI: 10.1186/s43682-023-00024-2

Keywords: hibernation, Syrian hamster, epigenetics, histone acetylation, DNA methylation, HDAC6, sirtuins, liver metabolism, torpor, chromatin, KAT6A, epigenetics communications

The research, led by Min Wu, Yi-Fei Yang and Xiang-Ping Du of the Department of Orthopedics at Jiangxi Provincial Children’s Hospital in Nanchang, China, began with a simple observation that belied a complex mechanism. When the team exposed BMSCs to hydrogen peroxide, a standard laboratory approach for mimicking oxidative stress, the levels of SPI1, a transcription factor encoded by the Spi-1 proto-oncogene, dropped sharply. The same decline was visible in an animal model: rats whose ovaries had been removed to induce estrogen-deficiency osteoporosis also showed reduced SPI1 in their bone marrow-derived mesenchymal stem cells. The parallel was striking. In both the culture dish and the diseased skeleton, oxidative stress appeared to strip the cells of a factor they apparently needed to stay young.

To test whether that loss mattered, the researchers forced SPI1 expression back up in stressed cells. The effect was dramatic. Overexpressing SPI1 rescued the senescent phenotype that hydrogen peroxide had induced: the cells regained viability, produced fewer reactive oxygen species, and showed reduced staining for senescence-associated beta-galactosidase, a classic enzymatic marker of cellular aging. Just as importantly, SPI1 restoration preserved the cells’ ability to differentiate into bone-forming osteoblasts, which the team quantified using alizarin red S staining of mineralized matrix. In other words, SPI1 was not simply a bystander that declined as cells aged; it appeared to be an active guardian of both youth and bone-building function in the mesenchymal stem cell compartment.

The next question was how SPI1 exerted this protection. Transcription factors work by binding DNA and switching genes on or off, and the researchers had a specific target in mind: NAMPT, the gene encoding nicotinamide phosphoribosyltransferase, the rate-limiting enzyme of the NAD+ salvage pathway. NAD+ has become one of the most intensively studied molecules in aging biology, serving as a coenzyme for hundreds of redox reactions and as the fuel consumed by sirtuins, a family of deacylating enzymes that regulate stress resistance, mitochondrial function and longevity. Declining NAD+ levels are a hallmark of aged tissues, and boosting NAMPT activity has previously been shown to rejuvenate senescent mesenchymal stem cells. Through chromatin immunoprecipitation and luciferase reporter assays, the team demonstrated that SPI1 binds directly to the NAMPT promoter and transcriptionally activates it, raising NAD+ levels inside the stressed cells. This elevation of NAD+ was the mechanistic bridge between SPI1 and senescence resistance, connecting a transcription factor to one of aging biology’s most celebrated metabolic pathways.

But SPI1 is itself a protein, and proteins in the cellular environment are subject to constant quality control. The ubiquitin-proteasome system tags unwanted proteins with chains of ubiquitin molecules, marking them for destruction. For a transcription factor like SPI1, ubiquitination can mean a short half-life and a rapid collapse of expression under stress. This is where USP22 enters the story. USP22 is a deubiquitinating enzyme, a member of a large family of proteases that remove ubiquitin tags and thereby rescue proteins from degradation. The enzyme has attracted growing attention in recent years for its role in stabilizing key regulatory proteins: it has been shown, for example, to deubiquitinate PPARγ in liver cancer cells and FoxM1 in endometrial stromal cells, and to suppress inflammatory signaling by influencing the NLRP3 inflammasome. The Jiangxi team hypothesized that USP22 might perform the same service for SPI1 in BMSCs.

The experimental evidence supported the hypothesis at every step. Co-immunoprecipitation confirmed that USP22 physically interacts with SPI1 inside the cells. Ubiquitination assays then showed that USP22 removes ubiquitin chains from SPI1, and cycloheximide chase experiments, which block new protein synthesis and reveal how fast existing proteins decay, demonstrated that SPI1 protein persists far longer when USP22 is abundant. With SPI1 stabilized, NAMPT transcription stayed high, NAD+ levels were maintained, and the senescence program was held in check. The final piece of the causal puzzle came from a knockdown experiment: when the researchers silenced SPI1 in cells overexpressing USP22, the protective effects of USP22 largely evaporated. Senescence markers rose again, and osteogenic differentiation faltered, showing that SPI1 is the essential downstream mediator of USP22’s anti-aging action in these cells.

Why does this circuit matter beyond the laboratory? Osteoporosis, which affects hundreds of millions of people worldwide, is fundamentally a disease of failed bone regeneration, in which the balance tips from bone formation to bone resorption. Estrogen deficiency accelerates oxidative stress in the bone marrow, and senescent BMSCs not only fail to produce new osteoblasts but actively worsen the inflammatory milieu. The ovariectomized rat model used in this study reproduces key features of postmenopausal bone loss, and the finding that SPI1 declines in this model suggests that the USP22-SPI1-NAMPT axis may be a plausible therapeutic target. If a drug or gene therapy could raise USP22 activity, or stabilize SPI1 by another means, or simply replenish NAD+ through well-known precursors such as nicotinamide mononucleotide, the senescence cascade in transplanted or endogenous stem cells might be blunted before it begins.

The findings also connect to a much broader scientific conversation about the biology of aging. Cellular senescence was once viewed as a passive consequence of damage accumulation; it is now understood as a tightly regulated program, orchestrated by p53, p21, p16 and chromatin changes, and driven upstream by metabolic deficits such as NAD+ depletion. Sirtuins sit at the junction of metabolism and chromatin, consuming NAD+ as they modify histones and regulatory proteins, which is why the NAD+-sirtuin axis has become a focal point for anti-aging interventions. What this study adds is an upstream control point: a deubiquitinase-transcription factor module that feeds into NAMPT expression and thereby into the entire NAD+ economy of the cell. It suggests that protein stability, not merely gene expression or enzyme activity, may be a decisive lever for keeping stem cells youthful under stress.

There are, of course, important caveats and open questions. USP22 has a complicated double life in the literature: in some contexts it promotes tumor growth and inflammation, and its substrates are numerous and tissue-dependent. Any clinical strategy that elevates USP22 would need to weigh potential oncogenic risks, particularly since SPI1 itself is best known as an oncogene in hematopoietic malignancies, even as the new work assigns it a protective role in mesenchymal stem cells. The current study also relies on cell culture and a rat model; whether the same circuit operates in human bone marrow, and whether it can be safely modulated in patients, remains to be demonstrated. Still, the elegance of the pathway is hard to ignore: oxidative stress degrades SPI1, loss of SPI1 silences NAMPT, silencing of NAMPT drains NAD+, and drained NAD+ leaves stem cells old and bone barren. By inserting USP22 at the top of that cascade, evolution appears to have built a safeguard, and researchers have now found the switch. For an aging global population facing a rising tide of fractures, that switch is worth pulling.

Subject of Research: How the deubiquitinase USP22 protects bone marrow mesenchymal stem cells from oxidative stress-induced senescence

Article Title: USP22 alleviates oxidative stress-induced BMSCs senescence by stabilizing SPI1 protein

Article References: Wu, M., Yang, Y.-F., & Du, X.-P. (2026). USP22 alleviates oxidative stress-induced BMSCs senescence by stabilizing SPI1 protein. Molecular Genetics and Genomics, 301(1), Article 194. https://doi.org/10.1007/s00438-026-02519-8

Image Credits: AI Generated

DOI: 10.1007/s00438-026-02519-8

Keywords: USP22, SPI1, NAMPT, NAD+, bone marrow mesenchymal stem cells, cellular senescence, oxidative stress, deubiquitination, osteoporosis, osteogenic differentiation, sirtuins, protein stability

Cellular senescence, the state in which cells permanently stop dividing but refuse to die, is a well-established driver of aging and a wide range of age-related pathologies. Senescent cells progressively accumulate in the tissues of aging mice and primates, and genetic or pharmacological clearance of these cells has been shown to extend both healthspan and longevity in naturally aged mice. Beyond aging itself, senescence is implicated in hepatic steatosis, obesity-associated metabolic syndrome, type I and type II diabetes, atherosclerosis, Alzheimer’s disease, and Parkinson’s disease. Decades of evidence have also linked aging to a relaxation of heterochromatin, the tightly packed, transcriptionally silent form of chromatin, and this loosening allows L1 elements to escape repression. The research team led by Anke Geng and Ying Jiang set out to determine whether SIRT1, whose protein levels decline during senescence and aging, directly guards the L1 genome and thereby influences the senescence program.

The investigators began with a well-characterized GFP-based reporter assay in HeLa cells, which quantifies L1 retrotransposition efficiency by detecting when an engineered L1 element successfully copies itself into the genome. When SIRT1 was overexpressed, retrotransposition dropped sharply; when SIRT1 was knocked down with siRNA, retrotransposition rose. At the transcriptional level, L1 mRNA declined roughly 30 percent in cells overexpressing SIRT1, while CRISPR/Cas9-mediated knockout of SIRT1 increased L1 transcription, a pattern reproduced in IMR90 primary fibroblasts and mouse embryonic fibroblasts. Because L1 transcription is initiated by an internal promoter within its 5-prime untranslated region, the team tested that promoter directly using luciferase reporters. SIRT1 inhibited 5-prime UTR activity in a dose-dependent manner, and its absence boosted promoter activity approximately twofold, an effect fully reversed by reintroducing the protein.

To connect this transcriptional control to genome integrity, the researchers exploited the fact that L1’s ORF2 protein induces DNA strand breaks as part of the retrotransposition process. Using the alkaline comet assay, a single-cell method that detects strand breaks and converts other lesions into breaks under alkaline conditions, the team measured genomic instability through the tail moment, a quantitative descriptor of DNA damage. SIRT1 overexpression reduced the tail moment in a dose-dependent fashion, whereas SIRT1 deficiency exacerbated ORF2-induced genomic instability. Re-expression of wild-type SIRT1 rescued the phenotype. Consistent with these results, SIRT1 overexpression lowered the accumulation of gamma-H2AX, a canonical marker of DNA double-strand breaks, while SIRT1 knockdown raised it. In a striking twist, two catalytically inactive mutants of SIRT1, G261A and H363Y, suppressed L1 5-prime UTR activity and genomic instability just as effectively as the wild-type protein, demonstrating that the protective role operates independently of the enzyme’s NAD+-dependent deacetylase activity.

The team then asked what happens to cellular senescence when SIRT1 levels change. They induced senescence in HCA2-hTERT fibroblasts and HeLa cells using X-ray irradiation at doses of 10 and 8 Gy, then stained for senescence-associated beta-galactosidase seven to ten days later. SIRT1 overexpression cut the fraction of senescent cells nearly in half, from about 30 percent to 13 percent in HCA2-hTERT cells and from 38 percent to 20 percent in HeLa cells, while SIRT1 knockdown raised senescence by an additional 10 percent. Levels of the senescence markers p21 and p16 fell with SIRT1 overexpression and climbed with its depletion. The senescence-associated secretory phenotype, the inflammatory cocktail secreted by senescent cells, was likewise damped by SIRT1, as measured by the expression of factors such as CCL2, MMP3, IL-1 alpha, IL-1 beta, and IL-6. Because L1 is known to activate the cGAS-STING innate immune pathway, the researchers examined phosphorylation of TBK1 and STING, finding both reduced by SIRT1 overexpression and elevated by its knockdown. Notably, lamivudine, also known as 3TC, a nucleoside reverse transcriptase inhibitor that potently blocks L1, attenuated the senescence induced by SIRT1 deficiency, confirming L1 as the causal culprit.

A key insight emerged from the biology of quiescence. Prior work established that L1 retrotransposition requires cell division, and the new study suggests why: in quiescent cells, SIRT1 piles up at L1 loci. Chromatin immunoprecipitation in mouse skeletal muscle satellite cells revealed significantly increased SIRT1 enrichment at L1 elements under quiescent conditions. In cultured IMR90-SVLT cells made quiescent by contact inhibition, confirmed by reduced EdU incorporation and diminished Ki67 expression, endogenous SIRT1 bound the L1 5-prime UTR at levels far exceeding those seen in proliferating cells. Correspondingly, L1 transcript levels dropped in quiescent cells, indicating that the cell-cycle dependence of L1 retrotransposition stems in part from transcriptional repression by accumulated SIRT1.

To uncover how SIRT1 enforces this repression, the team performed immunoprecipitation with an anti-SIRT1 antibody followed by liquid chromatography-tandem mass spectrometry, comparing quiescent and proliferating cells. The screen identified a set of SIRT1-interacting proteins involved in heterochromatin organization, most prominently the nuclear lamin protein Lamin B1 and the corepressor KAP1, and these interactions proved specific to quiescent conditions. Reciprocal co-immunoprecipitation confirmed the SIRT1-Lamin B1 interaction in HEK293FT cells, and experiments with purified recombinant proteins demonstrated that the two bind directly. Physical interaction between SIRT1 and KAP1 had been validated previously. Crucially, SIRT1 did not change the protein levels of either partner; instead, it acted as a molecular matchmaker, enhancing the interaction between Lamin B1 and KAP1, a cooperativity that collapsed in SIRT1-knockout cells.

Chromatin immunoprecipitation assays then traced the functional consequences at L1 loci. In control cells, both Lamin B1 and KAP1 occupied specific regions of the L1 promoter, but this binding was abolished in SIRT1-knockout cells. Because KAP1 is known to recruit the histone methyltransferase SETDB1, heterochromatin protein 1, and the NuRD complex to shape H3K9me3, the characteristic epigenetic mark of constitutive heterochromatin, the team assessed that mark directly. Global H3K9me3 decreased upon SIRT1 knockdown, and H3K9me3 enrichment at L1 promoters dropped correspondingly. The picture that emerges is elegant: SIRT1 binds the L1 5-prime UTR, recruits Lamin B1 and KAP1, stabilizes their partnership, and thereby maintains the repressive H3K9me3 landscape that silences L1 transcription. This places SIRT1 in a mechanistic lineage shared with, yet distinct from, its sirtuin siblings SIRT6 and SIRT7, which also restrain L1 through heterochromatin pathways. SIRT6 ADP-ribosylates KAP1 to promote its association with HP1 alpha, while SIRT7 deacetylates H3K18 to tether L1 to lamin proteins. The family has clearly converged on transposon silencing through divergent molecular routes.

The authors acknowledge that their senescence models are limited to stress-induced, rather than replicative, senescence, and that many mechanistic experiments were performed in transformed or immortalized cell lines rather than primary cells, questions that future work must address under physiological conditions. Nevertheless, the study delivers a compelling new framework. As SIRT1 declines during aging, the heterochromatin architecture protecting L1 elements erodes, dormant retrotransposons awaken, cytoplasmic L1 nucleic acids trip the cGAS-STING alarm, and the senescence program accelerates. Interventions that preserve or restore SIRT1 function, or that pharmacologically block L1 reverse transcriptase with drugs like lamivudine, could theoretically break this vicious cycle. In linking a longevity enzyme, a genomic parasite, and an immune sensor of misplaced DNA, the research illuminates one of the molecular threads that binds retrotransposon derepression to the aging clock, and offers concrete targets for therapies designed to delay aging and mitigate age-related disease.

Subject of Research: The role of SIRT1 in silencing L1 retrotransposons through stabilization of heterochromatin-modifying complexes during cellular senescence.

Article Title: SIRT1 Silences L1 Retrotransposons by Stabilizing Heterochromatin‐Modifying Complexes

Article References: Wang, X., Li, T., Tang, H., Liu, M. X., Peng, Q., Huang, X., Mao, Z., Jiang, Y., & Geng, A. (2026). SIRT1 Silences L1 Retrotransposons by Stabilizing Heterochromatin‐Modifying Complexes. Aging Cell, 25(9), Article e70689. https://doi.org/10.1111/acel.70689

Image Credits: AI Generated

DOI: 10.1111/acel.70689

Keywords: SIRT1, L1 retrotransposon, cellular senescence, heterochromatin, H3K9me3, Lamin B1, KAP1, cGAS-STING, aging, Aging Cell, sirtuins, genomic instability