The hypothesis is that eliminating senescent cells in the gut epithelium and myenteric plexus, while simultaneously restoring Wnt signaling in intestinal stem cells, will reduce microbiota‑derived phenylacetic acid (PAA) production, repair barrier integrity, and attenuate hippocampal neuroinflammation, thereby improving cognitive function in aged animals. This prediction follows from three observations: (1) age‑related shifts in the gut microbiome elevate PAA, which directly induces endothelial cell senescence [https://doi.org/10.1101/2023.11.17.567594]; (2) enteric cholinergic neurons are more vulnerable to age‑dependent degeneration than central neurons, suggesting a local loss of regulatory control over mucosal immunity and permeability [https://pubmed.ncbi.nlm.nih.gov/23537898/]; (3) ACCA epigenetic drift hypermethylates Wnt pathway genes in intestinal stem cells, diminishing tissue repair and promoting a pro‑inflammatory niche [https://idw-online.de/de/news862472]. If gut senescence drives dysbiosis rather than merely reflecting it, then clearing those senescent cells should normalize microbial metabolism and lower PAA levels. Conversely, if dysbiosis precedes senescence, senolysis alone will not reduce PAA unless the epithelial regenerative capacity is also rescued. Combining senolysis with Wnt activation tests both directions of causality.

To test this, aged (24‑month) C57BL/6 mice will receive either (a) vehicle, (b) the senolytic dasatinib + quercetin (D+Q) administered intermittently, (c) a Wnt agonist such as RSPO1‑Fc fusion protein delivered via osmotic pump, o

Hypothesis

mTORC1 activity does not merely toggle between a static ‘civilization’ (growth) and ‘survival’ (catabolism) mode; instead, it drives a circadian oscillation that periodically remodels the epigenetic landscape at the CDKN2A/B locus through a SIRT1‑dependent regulation of EZH2 histone methyltransferase activity. During the fed phase, mTORC1 activation transiently suppresses SIRT1, reducing EZH2 deacetylation and thus lowering H3K27me3 deposition, which permits a pulse of CDKN2A/B transcription that facilitates the removal of damaged cells via senescence‑associated secretory phenotype (SASP)‑mediated immune clearance. In the fasted phase, mTORC1 inhibition allows SIRT1 to reactivate, deacetylate EZH2, boost its methyltransferase activity, and re‑establish H3K27me3‑mediated silencing, thereby resetting the locus for the next growth cycle. Disruption of this rhythmic epigenetic gating—by chronic mTORC1 inhibition, constant activation, or loss of SIRT1—locks CDKN2A/B in either a permanently silenced state (impairing senescence‑dependent tumor surveillance) or a constitutively active state (driving premature tissue aging).

Mechanistic Rationale

1. mTORC1‑SIRT1 Crosstalk – mTORC1 phosphorylates and inhibits the upstream AMPK activator LKB1, decreasing NAD+ levels and SIRT1 activity (1). Conversely, fasting raises NAD+, activating SIRT1.
2. SIRT1 Regulates EZH2 – SIRT1 deacetylates EZH2 at lysine residues critical for its catalytic function, enhancing H3K27me3 transfe

Hypothesis

Age‑related epigenetic noise does not merely increase transcriptional stochasticity; it alters the biophysical properties of master regulator transcription factors (TFs) such that they undergo aberrant phase separation, sequestering them away from target DNA and rewiring gene regulatory networks (GRNs) in a cell‑type‑specific manner.

Mechanistic Model

1. Epigenetic noise alters TF post‑translational state – NAD⁺ decline reduces SIRT1/6 activity, leading to hyperacetylation of histone tails and, critically, of lysine‑rich low‑complexity domains in TFs like FOXO3, Nrf2, and PGC1α [1][2]. Acetylation increases the net negative charge and modifies interaction motifs that drive TF self‑assembly.
2. Shift in TF phase‑separation propensity – Hyperacetylated TFs exhibit altered intrinsic disorder, promoting the formation of non‑productive cytoplasmic or nucleoplasmic condensates that lack the co‑activator/repressor composition required for precise transcriptional control [3]. These condensates act as molecular sinks, reducing the effective nuclear concentration of TFs available for binding at enhancers and promoters.
3. Cell‑type‑specific vulnerability – Postmitotic cells (neurons, cardiomyocytes) have lower TF turnover and higher baseline expression of disordered TF isoforms, making them more prone to sequestration when epigenetic noise rises [4]. Ste

Chronic opioid therapy reduces nociceptive signaling through μ-opioid receptor–mediated inhibition of TRPV1 channels in primary afferent neurons.Opioid mortality HR 1.58-1.59Opioid OR 1.5 This silencing diminishes the low‑amplitude Ca²⁺ influx that normally activates CaMKK‑AMPK and SIRT3 pathways, a hormetic stimulus that promotes mitochondrial biogenesis, autophagy and NAD⁺‑dependent deacetylation.TRPV1 triggers CGRP via Ca2+-CaMK-CREBTRPV1 activation induces prolonged mitochondrial Ca2+ signaling Without this signal, mTORC1 remains preferentially active, driving anabolic growth and inflammaging.CGRP modulation linked to metabolism and longevity We hypothesize that the resulting shift in cellular energetics accelerates biological age, measurable by epigenetic clocks and the indole‑3‑propionic acid (IPA) metabolomic clock, and explains the excess mortality observed in long‑term opioid users.C5a-induced pain sensitization requires macrophages and TRPV1

Testable predictions: (1) Mice receiving chronic morphine will show decreased TRPV1‑dependent Ca²⁺ transients in dorsal root ganglia, reduced phospho‑AMPK and SIRT3 activity, increased phospho‑S6K (mTORC1 read‑out), and elevated epigenetic age relative to controls. (2) These mice will exhibit shor

Hypothesis

We hypothesize that administering indole-3-propionic acid (IPA) in alignment with the host's peripheral circadian timing restores microbial rhythmicity, strengthens gut barrier function, and re-synchronizes mitochondrial bioenergetics, thereby attenuating age-related damage across multiple SENS categories.

Mechanistic Rationale

Circadian disruption desynchronizes gut microbiota oscillations, reducing short-chain fatty acid (SCFA) producers and compromising epigenetic stability via diminished butyrate-mediated HDAC inhibition Butyrate HDAC inhibition and epigenetic stability. This loss of SCFA producers also weakens gut barrier integrity, facilitating microbial translocation and inflammaging Loss of SCFA producers compromises gut barrier. IPA, a tryptophan-derived indole, exhibits potent antioxidant properties and preserves intestinal epithelial tight junctions independent of SCFA pathways. We propose that IPA acts as a chronobiotic cue: its rhythmic release from entrained microbiota feeds back to reinforce host peripheral clocks, particularly in liver and muscle, where circadian genes regulate mitochondrial fission/fusion and autophagy flux Muscle cells contain circadian clocks. By stabilizing microbiota-host clock coupling, IPA improves NAD+ salvage pathways, enhances SIRT1 activity, and restores rhythmic mitophagy, counteracting mitochondrial dysfunction [Circadia

Hypothesis

We hypothesize that a brief pain sensitivity test administered after a physiologic ACTH stimulus reveals the functional capacity of the adrenal zona reticularis and predicts epigenetic age more accurately than resting cortisol/DHEAS ratios.

Mechanistic Basis

Chronic pain sensitivity reflects the balance between cortisol and DHEAS, which is set by zona reticularis output. ACTH stimulates both zona fasciculata (cortisol) and zona reticularis (DHEAS). With age, zona reticularis thins and its microvascular supply rarefies, reducing DHEAS secretion capacity while cortisol production remains relatively preserved. This shifts the cortisol/DHEAS ratio upward and diminishes endogenous neurosteroid modulation of pain pathways, lowering heat pain tolerance. Consequently, the magnitude of pain‑threshold change after an ACTH challenge indexes the gland’s reserve and correlates with the epigenetic age signal carried by the cortisol/DHEAS ratio.

Testable Predictions

1. In a cohort of adults aged 30‑70, the increase in heat‑pain threshold (measured with a contact thermode) 30 min after a low‑dose (0.25 mg) intravenous ACTH bolus will positively correlate with the ACTH‑stimulated rise in plasma DHEAS (r > 0.4, p < 0.01).
2. Individuals whose GrimAge exceeds chronological age by >5 years will show a blunted DHEAS response (<20 % increase) and a correspondingly small pain‑threshold shift (<0.5 °C), whereas age‑matched GrimAge‑neutral participants will exhibit robust responses.
3. A four‑week regimen of low‑dose VEGF‑A eye‑drop analogue (known to improve capillary perfusi

Hypothesis

Aging shifts the cysteine redox balance toward sulfonylation, driving pathogenic liquid‑liquid phase separation and irreversible aggregation. We propose that aggregates act as redox sinks that sequester sulfonylation‑prone cysteines, temporarily preventing oxidative damage to essential proteins. The proteostasis network deliberately enrolls vulnerable proteins into these aggregates, converting a dangerous soluble species into a protease‑resistant, amyloid‑like depot. When persulfide (PSSH) levels are restored, the sink releases its cargo, allowing refolding or degradation; without this redox reset, dissolution merely exposes liberated sulfonylated proteins to further oxidative stress, exacerbating dysfunction.

Mechanistic Rationale

1. Redox‑Driven LLPS – Declining PSSH and rising sulfonylation promote formation of static, insoluble condensates from proteins that normally engage in dynamic stress‑response droplets (PMC9909609). Sulfonylated cysteines increase hydrophobicity and β‑sheet propensity, biasing phase separation toward amyloid‑like assemblies.
2. Aggregate Composition – Insoluble fractions enrich for proteins involved in proteostasis, synaptic signaling, and metabolism, many of which contain redox‑sensitive cysteines (PMC6260915). Sequestration of these cysteines limits their availability for aberrant sulfonylation, thereby lowering global oxidative load.
3. Dynamic Release – Enhancing persulfidation (e.g., via H₂S donors or C

Hypothesis

Rapamycin‑mediated mTORC1 inhibition prolongs life by locking aged cells into a persistent, low‑activity state that mimics an embryonic stress‑response program. This state upregulates protective mechanisms (e.g., autophagy, xenobiotic detoxification, peroxisomal metabolism) that prevent the formation of new damage, yet it lacks the molecular machinery required to remove pre‑existing lesions such as senescent cells, protein aggregates, or mitochondrial dysfunction. Consequently, lifespan extension depends on continuous drug exposure; withdrawing rapamycin allows damage to reaccumulate to pretreatment levels.

Mechanistic rationale

1. Transcriptomic mimicry of fetal stress – Both caloric restriction (CR) and rapamycin suppress mTORC1, but RNA‑seq shows CR enriches pathways linked to inflammation and cholesterol homeostasis, whereas rapamycin preferentially induces xenobiotic metabolism and peroxisome function [1]. This pattern resembles the transcriptome of fetal tissues exposed to intermittent hypoxia, which prioritizes damage tolerance over repair.

2. Blocked damage clearance – Enhanced autophagy and proteasome activity under rapamycin increase turnover of nascent proteins but do not upregulate the specific cargo receptors (e.g., p62/SQSTM1, NBR1) needed for selective removal of ubiquitinated aggregates or senescent‑cell‑associated secretory phenotype (SASP) factors. Existing damage therefore persists, consistent with observations that rapamycin slows damage accrual rather than reversin

Hypothesis\nTumors that exceed a quantifiable splicing entropy threshold—defined as the Shannon entropy of aberrant splice junction usage normalized to total junction reads—become hypersensitive to SF3B1‑mutant‑selective synthetic introns and simultaneously generate a neoantigen landscape with sufficient immunogenicity to respond to splice‑neo‑guided vaccines.\n\n## Mechanistic Basis\nRecent work shows that SF3B1 K700E, SRSF2 P95, and U2AF1 S34F/Y mutations rewire splice site recognition without destroying the spliceosome, creating chronic splicing stress, R‑loop accumulation, and dependence on ATR/Chk1 and PRMT5【https://pmc.ncbi.nlm.nih.gov/articles/PMC12982372/】. We propose that as splicing entropy rises, two convergent processes amplify vulnerability: (1) increased production of cryptic introns and exon‑skipping events fuels synthetic intron‑mediated lethal missplicing because the mutant spliceosome already operates near its fidelity limit; (2) the same aberrant transcripts generate frameshift‑derived neoantigens that bind HLA‑A*02:01 with high affinity, as demonstrated for influenza‑like epitopes【https://pubmed.ncbi.nlm.nih.gov/38754917/】. Crucially, elevated R‑loops at promoters of antigen‑processing genes (e.g., TAP1, ERAP1) remodel chromatin, enhancing neoantigen presentation and creating a feed‑forward loop where splicing entropy both drives immune visibility and sensitizes cells to splice‑targeted toxins.\n\n## Testable Predictions\n1. In SF3B1‑mutant cell lines, measuring splicing entropy from RNA‑seq will stratify clones into low, intermediate, and high entrop

Hypothesis

Female limbal epithelial stem cells (LESCs) maintain higher PAX6 expression with age because they possess two active copies of X‑linked chromatin regulators (e.g., KDM6A, DDX3X) that escape X‑inactivation and sustain an open chromatin state at the PAX6 locus. Males, with a single copy, experience age‑related decline in these regulators, leading to reduced PAX6, increased stress‑gene activation, and accelerated LESC senescence.

Mechanistic Rationale

• PAX6 transcription is modulated by histone‑demethylase activity; KDM6A (UTX) removes H3K27me3 marks and is known to escape X‑inhibition in humans.[1]
• DDX3X, an X‑linked RNA helicase, promotes transcriptional elongation of stress‑responsive genes and has been shown to interact with PAX6‑containing complexes in neural progenitors.[2]
• In XX cells, biallelic expression of these factors provides redundancy; stochastic silencing of one allele does not diminish total activity. In XY cells, loss‑of‑function mutations or age‑dependent epigenetic silencing of the sole allele produce a haploinsufficient state.
• Reduced PAX6 triggers upregulation of p53‑dependent apoptosis and SASP, diminishing holoclone‑forming capacity (<3% p63‑bright) and compromising long‑term graft survival.[3]

Testable Predictions

1. Expression correlation – In human limbal biopsies from donors aged 20–80, nuclear KDM6A and DDX3X protein levels will positively correlate with PAX6 mRNA and decline faster in males than females (linear mixed‑effects model, sex × age interaction p<0.01).
2. Allelic escape – RNA‑FISH combined with single

Hypothesis

Rapamycin‑mediated mTORC1 inhibition extends lifespan by augmenting the cell’s capacity to selectively remove damaged mitochondrial proteins via mitophagy, thereby allowing cells to function despite persistent lipid peroxidation adducts. This mechanism represents a tolerance strategy rather than a repair strategy: rapamycin does not lower HNE/MDA adduct levels but increases the flux of damaged mitochondria to lysosomes for degradation.

Mechanistic Rationale

1. mTORC1 suppression activates the transcription factor ATF4, which upregulates genes involved in lysosomal biogenesis and the mitophagy receptor BNIP3/NIX (see ATF4‑dependent stress response).
2. Enhanced BNIP3/NIX promotes recruitment of the autophagic machinery to depolarized or damaged mitochondria, facilitating their engulfment by autophagosomes.
3. Because rapamycin does not alter the rate of HNE/MDA adduct formation (mitochondrial adduct accumulation), the net effect is a higher turnover of damaged organelles, preserving overall respiratory capacity.
4. This contrasts with direct antioxidant approaches (e.g., mitochondrial‑targeted catalase) that lower adduct formation (true damage prevention).

Testable Predictions

• Rapamycin treatment will increase mitophagy flux (measured by mt‑Keima or LC3‑colocalization with mitochondria) in aged tissues without changing steady‑state levels of HNE/MDA‑protein adducts.
• Genetic or pharmacologic

Hypothesis

Personalized psychobiotic intervention guided by baseline fecal GABA‑producing Lactobacillus abundance and short‑chain fatty acid (SCFA) profile will produce a greater reduction in anxiety symptoms than standard SSRI therapy in adults with mild‑to‑moderate generalized anxiety disorder, mediated by increased colonic butyrate and vagal afferent signaling.

Rationale

• Meta‑analyses show probiotics yield substantial depression (SMD: -0.96) and anxiety (SMD: -0.59) improvements, whereas prebiotics alone show only a nonsignificant trend (SMD: -0.28) (PubMed)(Nutr Rev).
• Responders to probiotic depression trials have higher baseline Lactobacillus levels (PMC), and GABA‑producing Lactiplantibacillus plantarum Lp815 raises urinary GABA and reduces anxiety (doi).
• Personalized microbiome‑guided prebiotic/probiotic regimens improve IBS symptoms by 38‑44.5 points (p<0.001) through rises in Bifidobacterium and Lactobacillus (PMC IBS) and metabolic models predict therapy success with 75‑80% accuracy from baseline microbiota (EurekAlert).
• SCFA‑driven gut‑brain axis modulation, especially butyrate, enhances barrier integrity, stimulates enteroendocrine serotonin release, and attenuates HPA‑axis activation ([Front Endocrinol](https://www.f

Hypothesis

Restoring NAD+ levels at the circadian trough of NAD+ biosynthesis will reinstate BMAL1‑driven KLF4 expression oscillations in aged macrophages, thereby breaking the feed‑forward loop where senescent cells drive inflammaging and circadian disruption.

Rationale

• Circadian misalignment directly shortens lifespan and expands senescent immune cell pools by desynchronizing repair pathways [1].
• Core clock proteins BMAL1 and CLOCK regulate immune function; loss of BMAL1 accelerates age‑related phenotypes [2].
• In aged macrophages, despite intact BMAL1, KLF4 abundance falls and its circadian oscillation is lost, uncoupling immune responses from the clock [1].
• NAD+ is a critical cofactor for SIRT1, which deacetylates BMAL1 and enhances its transcriptional activity; NAD+ declines with age and exhibits a circadian rhythm [3].
• Senolytic clearance reduces pro‑inflammatory cytokines (TNF‑α, IL‑6) and alleviates inflammaging [4]; however, senolytics alone do not restore circadian KLF4 rhythm.

We propose that NAD+ supplementation timed to the endogenous NAD+ nadir (subjective night) will boost SIRT1 activity, increase BMAL1 transcriptional potency, and restore KLF4 oscillation, thereby normalizing macrophage cytokine output and reducing senocyte‑induced inflammation.

Predictions (Falsifiable)

Hypothesis

Intermittent fasting (IF) sensitizes senescent cells to BCL-2‑selective senolytics (e.g., navitoclax) by shifting their apoptotic reliance from BCL-xL to BCL-2, whereas platelets upregulate MCL-1 through IGF-1 signaling, thereby preserving thrombopoiesis.

Rationale

• Senolytic efficacy hinges on targeting anti‑apoptotic BCL‑family proteins that senescent cells depend on for survival 1.
• Navitoclax’s dose‑limiting thrombocytopenia stems from BCL-xL inhibition essential for platelet lifespan 2.
• IF activates SIRT1 and NAD⁺‑dependent deacetylation, which has been shown to down‑regulate BCL-xL and up‑regulate BCL-2 in various stress‑adapted cells 3.
• Platelets exposed to IF demonstrate increased IGF‑1‑driven MCL-1 transcription, a known compensatory survival pathway that mitigates BCL-xL loss 4.

Predictions

1. In aged or progeroid mice, IF combined with a BCL-2‑selective senolytic will achieve ≥50 % greater senescent cell clearance (measured by p16^INK4a^ positivity) than senolytic alone.
2. Platelet counts will remain within 15 % of baseline in the IF + senolytic group, whereas senolytic alone will cause ≥30 % thrombocytopenia.
3. Functional readouts (grip strength, treadmill endurance) will improve significantly only in the IF + senolytic cohort, correlating with redu

Hypothesis

Stabilizing mitochondrial inner‑membrane cristae blocks minority mitochondrial outer membrane permeabilization (miMOMP), thereby preventing cytosolic mtDNA release and downstream cGAS‑STING‑mediated inflammaging without compromising basal ATP production.

Mechanistic Rationale

Cristae architecture regulates the accessibility of BAX/BAK to the outer membrane. Tight cristae junctions, maintained by OPA1 and the MICOS complex, sequester cytochrome c and limit BAK oligomerization, reducing the probability of miMOMP【https://pmc.ncbi.nlm.nih.gov/articles/PMC12620326】. When cristae remodel upon stress, junctions widen, allowing BAX/BAK to accumulate at contact sites and trigger miMOMP, releasing mtDNA into the cytosol where it activates cGAS‑STING and drives the SASP【https://doi.org/10.1101/gad.331272.119】. Pharmacologic agents that reinforce cristae (e.g., SS‑31 peptide or OPA1‑activating small molecules) should therefore raise the threshold for miMOMP, attenuating inflammaging while preserving oxidative phosphorylation.

This idea extends the observation that ρ0 cells lacking mtDNA do not senesce【https://pmc.ncbi.nlm.nih.gov/articles/PMC12727128】by suggesting that the presence of mtDNA is only pathogenic when it can escape via miMOMP, a process gated by cristae state. It also reconciles why some models show high mtDNA mutation loads without respiratory decline【https://www.sciencedaily.com/releases/2025/05/250527135239.htm】: the mutations matter less than the membrane dynamics that permit their release.

Experimental Design

1. Cell model – Primary human

Hypothesis

In aged airway club cells, a redox‑dependent shift in the phosphorylation state of autophagy receptors reroutes limited LC3‑II pools toward mitophagy at the expense of aggrephagy and lipophagy. Restoring the basal phosphorylation pattern rebalances substrate hierarchy, clears toxic aggregates and lipid droplets, and rescues progenitor proliferative capacity.

Mechanistic Basis

Aging club cells experience declining CYP450 activity and mitochondrial electron‑transport chain inefficiency, which elevate H2O2 and superoxide levels (CYP450 oxidative damage; Mitochondrial ROS leakage). Oxidative stress activates stress‑activated kinases (e.g., JNK, p38) that phosphorylate the LC3‑interacting region (LIR) of the mitophagy receptor NIX/BNIP3L, increasing its affinity for LC3‑II. Concurrently, the same kinases phosphorylate p62 and the lipophagy receptor LC3‑interacting protein (LC3‑IP) at sites that diminish their LIR strength. Because LC3‑II is a finite cargo‑adaptor platform, phosphorylated NIX outcompetes p62 and LC3‑IP, creating a competitive bottleneck that starves aggrephagy and lipophagy (p62 accumulation in progenitors). The resulting buildup of ubiquitinated proteins and lipid droplets activates p16^INK4a^‑dependent senescence and depletes the Scgb1a1^+^ progenitor pool needed for epithelial repair after injury (Club cell loss in COPD; [Autophagy

Hypothesis

In aged germinal centers (GCs), senescent stromal cells, follicular dendritic cells (FDCs), and related stromal populations act as beneficial chaperones that preserve GC structure and support B‑cell selection through senescence‑associated secretory phenotype (SASP) factors. Ablating these cells will deteriorate GC architecture, reduce somatic hypermutation, and lower high‑affinity antibody output, contrary to the expectation that senolysis universally improves immune function.

Mechanistic Rationale

Aged GCs exhibit defective antigen trapping by FDCs, weakened Tfh help, and impaired stromal adhesion molecule expression 2. Yet intrinsic B‑cell capacity for mutation and selection remains intact when placed in a young environment 1. This disconnect suggests that the microenvironment supplies compensatory signals. Senescent cells are known to deposit and remodel extracellular matrix (ECM) components such as fibronectin, laminin, and collagen IV, and to secrete chemokines like CXCL12 and growth factors including IGF‑1 and HGF 3. In regenerative contexts, these SASP factors create a permissive niche for progenitor proliferation and tissue patterning. We propose that in the aging GC, senescent stromal/FDCs similarly scaffold the light‑zone dark‑zone interface, retain antigen‑immune complexes on FDC networks via ECM‑mediated anchoring, and deliver CXCL12‑dependent retention signals that keep B cells within the select

Hypothesis

Senescent astrocytes and microglia actively supply choline‑derived phospholipids to neighboring neurons through the secretion of SASP‑enriched extracellular vesicles (EVs). This cholinergic support maintains membrane integrity and acetylcholine synthesis during aging, acting as a metabolic chaperone. Consequently, broad senolytic clearance reduces neuronal choline availability, potentially offsetting anti‑inflammatory benefits under conditions where membrane repair is critical.

Mechanistic Reasoning

1. Senescent glial SASP includes phosphatidylcholine‑rich EVs – Recent work shows that senescent fibroblasts release EVs loaded with phospholipids that can be taken up by target cells (SASP EVs and lipid transport). We hypothesize a similar phenotype in brain‑resident senescent glia, driven by upregulated choline kinase (CHKA) and CTP:phosphocholine cytidylyltransferase (PCYT1A) as part of a compensatory secretory program.
2. Neuronal dependence on glial choline supply – Age‑related decline in blood‑brain barrier choline transport (16 % vs 60 % uptake) creates a reliance on locally sourced choline for CDP‑choline synthesis and acetylcholine production (acetylcholine falls with senescence). Senescent glia could alleviate this deficit by exporting choline metabolites.
3. SASP‑mediated one‑carbon flux modulation – Senescent cells exhibit altered folate metabolism ([on