LSD1 enzyme prolongs DNA‑damage signal, driving cellular senescence

On 15 September, the Journal of Clinical Investigation published a study from the Mayo Clinic and Tongji University showing that the enzyme LSD1 builds up in aged mouse kidneys, heart, liver and in artificially aged cells because the cell cannot degrade it efficiently. LSD1 removes a methyl group from the ATM protein at residue 3016, preventing ATM from turning off after DNA repair and keeping the damage signal active.

When ATM stays active, the phosphatase WIP1 cannot bind well to the unmethylated site, so the DNA‑damage alarm persists longer than needed. This prolonged signal pushes the cell into a stable growth arrest — senescence — where it secretes harmful factors that damage surrounding tissues.

Normally, LSD1 is cleared by autophagy through binding to LC3 and Beclin1; with age autophagy weakens, the LSD1‑LC3/Beclin1 link breaks, and LSD1 accumulates in the nucleus where ATM resides. Enhancing autophagy with rapamycin lowers LSD1 levels even in old organs, while blocking autophagy raises LSD1 even in young ones.

Senolytic drugs that eliminate senescent cells also reduced LSD1 and senescence markers in the kidneys, heart and liver of old mice; a regimen of dasatinib + quercetin restored the kidney‑protective protein Klotho and lessened fibrosis.

The LSD1 inhibitor ORY-1001 (iadademstat), already tested in humans for acute myeloid leukemia, myelodysplastic syndrome and small‑cell lung cancer, decreased DNA damage and aging signs in the kidneys, heart and liver of irradiated and aged mice, and protected them from radiation‑induced hair graying. These effects on aging have been demonstrated only in mice and cells so far.

Together, the work links two hallmarks of aging — persistent DNA‑damage signaling and declining cellular cleanup — to a single switch on ATM: LSD1 does not decide whether the alarm sounds, but how long it lasts, determining whether a cell returns to division or becomes stuck in senescence.

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Loss of liver protein hepatopoietin accelerates aging and impairs regeneration in old mice

The liver‑secreted protein hepatopoietin (also known as FGL1) declines with age in both mice and humans, and its loss worsens outcomes after partial liver removal in aged animals. Mice lacking the hepatopoietin gene show higher mortality and poorer liver regeneration following surgery compared with normal old and young mice.

When two‑thirds of the liver were removed, 87% of normal old mice survived to day seven, whereas only 40% of hepatopoietin‑deficient mice lived; the deficient mice restored just half of the lost liver mass versus 64% in controls. Young mice showed little effect from the protein loss because compensatory pathways maintain AMPK activity.

Hepatopoietin binds the hepatocyte receptor ANXA2 and triggers the ERK → p90RSK → LKB1 cascade that activates AMPK, the cell’s main energy sensor. Without hepatopoietin AMPK is weakened, mTOR becomes hyperactive, and autophagy and cell division are blocked, contributing to the aged liver’s poor regenerative capacity.

Direct activation of AMPK with the drug AICAR, or pretreatment with recombinant hepatopoietin, restored regeneration and improved survival in the deficient mice; hepatopoietin was nontoxic even at a dose 20 times the effective level. These treatments also enhanced liver mass recovery in normal old mice.

Although hepatopoietin/FGL1 is better known in oncology for binding the immune checkpoint LAG‑3, the study shows that age‑related liver decline can be countered either by boosting AMPK directly or by replenishing hepatopoietin. Pharmacologic AMPK activation (e.g., ATX‑304 from Cambrian Bio) has already reduced liver fat in humans, though similar agents have carried side‑effect risks such as cardiac enlargement.

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Restoring IGFBP5 in aged dental stem cells reverses senescence and boosts bone repair

Researchers from Sichuan University reported on 15 September in International Journal of Oral Science that dental follicle stem cells lose the protein IGFBP5 with age, and restoring IGFBP5 suppresses the aging marker WNT5B, thereby reversing cellular senescence and improving periodontal healing in rats.

By comparing RNA from young cells and cells aged by oxidative stress or repeated divisions, the team identified IGFBP5 as a sharply downregulated factor — its expression fell 69‑fold in the division‑based aging model — despite its known role in promoting osteogenic differentiation.

Functional tests showed that knocking down IGFBP5 in young cells triggered senescence and reduced bone formation, whereas reintroducing IGFBP5 in aged cells cleared senescence markers and restored osteogenic capacity; this effect was mediated by decreased WNT5B and downstream c‑Jun activity, while the canonical Wnt pathway remained unchanged.

When direct IGFBP5 rescue was ineffective in severely aged cells, administering an antibody against WNT5B partially alleviated senescence, confirming the causal axis.

For therapeutic application, the scientists embedded IGFBP5‑rejuvenated cells in a hydrogel containing hydroxyapatite hydrogel nanoparticles; implantation into rat periodontitis lesions yielded greater bone density and volume, lower inflammation, richer collagen, and heightened expression of osteogenic genes compared with empty hydrogel or hydrogel with untreated cells.

Treated tissue also showed reduced GLB1 (a senescence marker), elevated IGFBP5, and lowered WNT5B, mirroring the in‑vitro findings; the authors conclude that preconditioning aged stem cells before implantation — rather than transplanting naïve cells — markedly enhances periodontal bone regeneration and may benefit other age‑related bone disorders.

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Clearing senescent p16‑positive cells improves heart relaxation in aged mice

In old mice, genetic removal of p16‑positive senescent cells reduced ventricular wall thickening and fibrosis and restored normal diastolic relaxation. The study appeared 14 September in Experimental Physiology from the Montreal Heart Institute.

Using the INK‑ATTAC line, the drug AP20187 was given from 12 to 18 months of age to kill p16‑positive cells; untreated mice showed increased left‑ventricular wall thickness, fibrosis, and slowed relaxation over six months, while clearance attenuated all three changes.

A p16‑positive cell is senescent: it has stopped dividing but remains alive and secretes factors that damage nearby tissue. INK‑ATTAC cells carry a fluorescent switch so that AP20187 eliminates only the labeled cells, allowing precise tracking; with age the p16‑positive fraction rises in all heart cell types, especially immune cells and fibroblasts.

Six months of AP20187 versus placebo left treated mice with little increase in left‑ventricular mass or wall thickness, whereas controls showed significant growth; isovolumic relaxation time stayed youthful in treated mice and rose in controls. Ejection fraction and contractility were unchanged, indicating a selective effect on relaxation, not contraction.

Flow cytometry and staining revealed that the drug lowered the p16‑positive fraction in fibroblasts and cardiomyocytes but not in vascular cells, accompanied by decreased Myh7 hypertrophy gene activity and collagen content, confirmed by both tissue staining and biochemical assays.

In an ex‑vivo experiment, hydrogen peroxide‑induced senescent fibroblasts placed near healthy cardiomyocytes across a permeable membrane triggered hypertrophy genes in the muscle within two days, demonstrating a paracrine effect; although there is a theoretical risk of losing cardiomyocytes, clearance was accompanied by functional improvement, not tissue loss.

After myocardial infarction in middle‑aged mice, Navitoclax reduced scar area to 13.6% versus 18.9% in controls; experiments used males and systemic clearance, and the INK‑ATTAC model originates from the 2016 work linking p16‑positive accumulation to shortened mouse lifespan.

Earlier studies by senior author Stanley Nattel on atria and rhythm showed that in a 2025 human trial the senolytic quercetin lowered post‑operative atrial fibrillation incidence by >75%; the current study extends this logic to the ventricle and diastolic dysfunction, a common cause of heart failure in older people.

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U‑shaped DNA methylation mirrors mortality, yielding new aging clocks

Препринт МГУ, 14 сентября

Researchers from Moscow State University compared blood DNA methylation across 16 chronic human diseases with aging and mortality data from 42 mammalian species. They sought to see whether epigenetic changes follow the same U‑shaped mortality curve observed across the lifespan.

In the four species with infant methylation data — human, cat, zebra, and dolphin — between a quarter and half of significant methylation sites changed with age in a U‑shaped pattern. Specifically, 24.8% of sites in humans, 43.2% in zebras, 49.8% in dolphins, and 50.2% in cats mirrored this curve, echoing the non‑

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Adult Drosophila thigh muscle rebuilds destroyed myofibrils in a week

On September 15, biologists from Dalhousie University showed in a non‑peer‑reviewed preprint on bioRxiv how adult Drosophila thigh muscle recovers after severe damage. The muscle’s structure and mobility returned almost fully within a week.

Damage was induced by expressing light‑ or heat‑sensitive channels and then exposing flies to red light or heating to 37 °C for one‑two hours, causing continuous contraction without surgery. Immediately after stimulation the flies were nearly paralyzed, but movement speed returned to baseline after seven days, regardless of damage method.

Fluorescent Z‑disk markers showed that 50–60% of muscle area lost structure right away, but this proportion fell to zero by day three. Electron microscopy confirmed the Z‑disk spacing increased from 191 to 897 nm and returned to 187–191 nm after a week.

The key player was the protein filamin, which sits on the Z‑disk and crosslinks actin filaments of neighboring sarcomeres, switching between open and closed forms under load. Flies with normal filamin developed mild damage by week two and severe damage by week three, while those locked in the closed form showed protein aggregates already by week one and impaired recovery.

In 2024 the same lab showed filamin protects Z‑disks in wing muscle during contraction, but did not test whether muscle could rebuild myofibrils after severe destruction—this study answers that. Human filamin C mutations cause hereditary myofibrillar myopathies, linking the fly findings to

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Immortal Dragons Narrows Focus to Whole‑Organ Replacement Strategy

Immortal

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Frequent feeding cuts female killifish lifespan by a third, leaves males unchanged

Researchers at the Medical University of Vienna built a low‑cost automatic feeder for turquoise killifish (Nothobranchius furzeri) and tested feeding frequencies from two to 36 feedings per day while keeping the total daily food amount constant. The species naturally lives only four to six months, making it a rapid vertebrate model of aging.

Frequent feeding accelerated growth in both sexes, but female median lifespan fell from 21.9 to 15.1 weeks (≈30% reduction), whereas male median lifespan remained unchanged at 20–22 weeks. In a parallel experiment, vgll3‑edited males grew faster but lived 15% shorter.

The feeder uses an Arduino‑controlled stepper motor and interchangeable tubes to dispense food with milligram precision, costing about ≈€500 per 100 aquariums. It was deemed cheaper and more accurate than existing commercial options.

With fatty feeds such as Biomar and Otohime, females laid more eggs early but embryo survival dropped sharply, compressing the reproductive period

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HexemBio raises $15.5 million to rejuvenate blood stem cells, targets 2027 first‑in‑human trial

HexemBio has secured a total of $15.5 million for a therapy that temporarily returns aged hematopoietic stem cells to a lab‑made copy of the embryonic yolk‑sac niche where they originate. The round closed on 15 September with new investor Happiness Capital joining existing backers Draper Associates and Boost VC. The same synthetic yolk‑sac niche under

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Gene hoxb5a Determines Spinal Cord Regeneration Outcome in Zebrafish

In zebrafish, a leading model for spinal cord regeneration, roughly one‑third of fish stay paralyzed after a complete cord transection even though the lesion tissue fuses in all animals. Researchers traced this variability to the gene hoxb5a, which decides whether regeneration succeeds or fails.

The team analyzed 254 adult zebrafish with full transections in a Morgridge Institute preprint, September 14. After six weeks, 93 fish (28%) had not recovered swimming despite tissue fusion; the key difference was whether nerve fibers regrew to their original targets.

Profiling of >60 000 nuclei from the injury site revealed identical cell types in all fish, but divergent programs: successful fish showed fibroblasts activating axon growth and guidance genes, while paralyzed fish deposited matrix fibers that block axons; immune profiles also differed, with more active T‑cells in the recovering group.

Network analysis pinpointed hoxb5a as the most connected Hox gene in fibroblasts of successful fish. Mutant lines lacking hoxb5a saw the paralyzed fraction rise to 63% vs 13% and axon regrowth beyond the lesion drop from 70% to 14%; six other candidate genes produced no effect, indicating hoxb5a’s specific role in remodeling the extracellular matrix and signaling around fibroblasts.

Zebrafish share this regenerative capacity with lampreys and salamanders, a trait absent in mammals, including humans. The discovery emerged from routine screening in the lab that first demonstrated zebrafish heart regeneration; the effect was consistent across batches, sexes, and surgeons, highlighting hoxb5a as an intrinsic switch that could potentially be harnessed to promote repair.

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Paper2Agent turns papers into AI agents that apply methods to new data

Paper2Agent takes a paper’s text, code, and data and builds an agent that can answer questions about the work and collaborate with agents from other papers. Applying a method from an article is usually locked behind technical

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Human brain circuits grown inside mice after cortex replacement

Scientists genetically modified mice so that from birth they lacked almost the entire cerebral cortex, leaving only about 2% of normal cortical volume. Into this void they implanted laboratory‑grown human brain organoids in two‑day‑old newborn mice. After three months, more than 90% of the rodents’ cortical volume consisted of engrafted, functional human neurons that had integrated into the spinal cord and nervous system.

The approach overcame past limits where human cells competed with mouse neurons for space. Each implanted organoid contained roughly 100,000 cells. With the freed niche, researchers were able to grow the rare spindle‑shaped von Economo neurons (VENs), which occur in the human brain at a frequency of about 1 per 90,000 neurons and are linked to social behavior and decision‑making.

Previously VENs could only be studied post‑mortem, as they fail to form in petri dishes. This “xenocortical” model may aid research into neurological disorders. In additional tests, mice were subjected to a five‑hour oxygen deprivation, showing that the human tissue is many times more sensitive to hypoxia than mouse tissue and can provoke cerebral‑palsy‑like symptoms.

The method will allow personalized organoids to be grown from a patient’s skin and used to test precise drugs directly on living neural networks.

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Blocking ceramide synthesis pathways shows opposite effects on Alzheimer's symptoms in mice

On 11 September, researchers published a bioRxiv preprint comparing two strategies to lower ceramide levels in the PDAPP‑J20 mouse model of Alzheimer’s disease. Eight‑month‑old female mice received either GW4869, which blocks the neutral sphingomyelinase (nSMase) pathway, or myriocin, which blocks the serine‑palmitoyltransferase (SPT) pathway, for three weeks.

Mice treated with GW4869 learned the Barnes maze at the level of healthy controls, showed a reduced amyloid‑plaque area in one hippocampal region, and exhibited fewer signs of microglial activation around plaques. In contrast, mice given myriocin retained learning deficits and had a larger plaque area in that region compared with untreated transgenic animals.

In microglial cell culture, amyloid induced NFκB nuclear translocation; GW4869 blocked this translocation and lowered intracellular fluorescent amyloid. A chemically distinct nSMase inhibitor, cabotin, decreased TNF‑α production but did not reduce intracellular amyloid in the same assay.

Thus, the effect depended on the ceramide‑synthesis route: inhibiting nSMase with GW4869 improved learning and lessened amyloid burden, whereas inhibiting SPT with myriocin worsened some outcomes.

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Clarifying the Fly Brain Hype: No Consciousness in Bitcoin Trading

Media hype surrounding the digital fly brain often mischaracterizes simple machine‑learning tricks as signs of consciousness. For example, making the model “trade” Bitcoin can be extrapolated to any other stunt — playing Bad Apple, solving a Rubik’s cube, or waving a lightsaber.

Journalistic framings replace the technical process with anthropomorphic ideas like a “digital mind” or “conscious activity.” In reality, the fly connectome is not a functioning biological system nor a computational program; it is a static topological map of spatial connections among ~160,000 neurons and tens of millions of synapses.

This graph itself lacks neurotransmitter dynamics, electrical activity, or subjectivity. Any manipulation using the digital model follows a single algorithm: input data are converted into a signal matrix that mimics visual or sensory neuron stimulation.

To activate the static graph, it is embedded in external machine‑learning architectures such as Graph Neural Networks. Trading or key presses are executed not by the connectome itself but by an optimization model that uses the brain topology as a specific structured weight matrix.

Meanwhile, the model’s dopaminergic and aversive neural circuits are forcibly stimulated: profit from a trade or gameplay advantage is supplied as a positive mathematical reinforcement signal. Understand? No fly is learning to trade or play poker.

The procedure is a standard loss‑function optimization where the biological graph serves merely as an alternative connectivity architecture. Interpreting these experiments as steps toward “transferring consciousness” or “creating digitized intelligence” is inaccurate; they represent an engineering adaptation of biological data to applied machine‑learning tasks.

🔗 Source: @solid_state_humanity

UK AI Health Commission Recommends Staged Approval and Post‑Launch Monitoring

On September 10 the National Commission for AI Regulation in Healthcare published 44 recommendations for future UK rules on medical AI. The advice is directed to the UK Medicines and Healthcare products Regulatory Agency (MHRA), the government, and healthcare organisations.

Medical AI can change after updates and perform differently in various clinics, with outcomes influenced by data, workflows, and conditions of use. In the current UK system safety and performance checks focus mainly on pre‑deployment data, while post‑market surveillance relies heavily on incident reports.

According to recommendation 14, MHRA could initially authorise a device only under defined conditions of use — after reviewing initial data, risk‑mitigation measures, and reporting requirements. Later, the scope of use could expand if the system meets pre‑set safety and performance thresholds, with the temporary status made clear to patients and the path to full authorisation set out in advance.

After launch the commission calls for mandatory monitoring plans, real‑world studies, and regular performance reports; if performance deteriorates an escalation procedure must apply. Another recommendation proposes inserting the device identifier and its version into the patient’s health record to help clinicians trace outcomes. The report also links safety to how a clinic adopts the technology, requiring manufacturers to describe safe‑use conditions — including user training and clinic readiness — and for contracts to allocate responsibility for these measures, with clinics tasked to train staff on the specific technology.

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Study identifies two MRI subtypes of Alzheimer's with distinct progression patterns

On September 11, the preprint described two MRI‑based subtypes of Alzheimer’s disease that show different patterns of worsening. The authors combined baseline MRI scans from 1,396 participants across four North American research cohorts. Using the SuStaIn model (SuStaIn algorithm, 2018), they identified two statistical trajectories of change.

One trajectory begins with atrophy of memory‑related regions (parahippocampal and temporal areas) followed later by growth of white‑matter lesion volume. The other starts with an increase in visible white‑matter lesion volume, especially in the occipital lobe, then expands ventricular spaces and shrinks memory‑related regions. Similar‑looking changes on a scan can belong to different disease stages, and standard MRI grouping often mixes trajectory type with stage.

When the model was tested on ten data splits, two subtypes best explained the data. In both groups, amyloid and tau levels were abnormal. The subtype with early white‑matter lesions showed higher blood pressure and, in one cohort, a larger volume of enlarged perivascular spaces. The subtype with early atrophy had faster decline on memory, attention, language and global cognition tests.

Among the 1,145 participants with clinical follow‑up, a model adjusted for age and sex linked early atrophy to higher odds of progressing to an Alzheimer’s diagnosis compared with early lesions. Future studies could use these two trajectories for participant selection and prognosis, as they are associated with different rates of cognitive decline.

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Consistency metric selects cases for autonomous AI diagnosis

On 15 September Nature Medicine published a study of a locally deployed diagnostic AI agent. Researchers ran the same simulated clinical case five times and compared the meaning of diagnoses. Using a consistency threshold of 0.90, they allowed 272 cases of 551 cases for autonomous processing in the main configuration.

The simulations used MIRA‑v2, a set of de‑identified patient records from MIMIC‑IV. In each case the doctor‑agent interviews a patient‑agent, requests permitted tests, and issues a diagnosis with explanation, all on local hospital infrastructure. In June MIRA turned the “diagnose from description” task into a multi‑step virtual chart encounter where the agent asks questions, orders studies, and picks a plan.

For each of the 551 cases the team made five independent runs to capture variability. They defined ConsistencyDx as the agreement among the five diagnoses; it outperformed the model’s internal word probability (AUC 0.860 vs 0.747). When ConsistencyDx was at least 0.90, 272 cases went to autonomous flow, and 269 of those matched the benchmark label (98.9%); the remaining 279 cases were sent for physician review.

A stress test that removed the patient‑history prompt dropped accuracy from 90.6% to 70.2% and lowered ConsistencyDx, while internal probabilities and linguistic confidence features stayed high. Five runs required roughly five times more tokens than a single run. On the external VivaBench set, ConsistencyDx remained the best metric; at a threshold of 0.85, 32.0% of cases were kept for autonomous processing with an accuracy of 89.9%. The optimal threshold must be recalibrated for each deployment because it depends on model, generation settings, number of repeats, and the method used to compare diagnosis meaning.

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Lund University Starts Microelectrode Brain Stimulation Trial for Parkinson's

On **September 1

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Preprint links P5 DNA site to Rep/Cap fragments in liver

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