Hypothesis\n\nAutophagy functions as a circadian‑gated siege response in which lysosomal acidification, not just autophagosome formation, provides the temporal gate that decides which cytosolic cargo is degraded. We propose that the core clock drives rhythmic expression of the V‑ATPase subunit ATP6V0C, creating predictable peaks of lysosomal proton‑pumping activity that synchronise with the autophagosome‑lysosome fusion step. When this lysosomal rhythm is intact, autophagy selectively degrades dispensable proteins and organelles during the predicted “siege window” (subjective night in mammals), preserving essential components. In aging or circadian‑disrupted conditions, dampened ATP6V0C expression blunts lysosomal acidification, causing mistimed or incomplete fusion; autophagosomes accumulate and non‑selective degradation of essential proteins increases, contributing to aggregate formation and metabolic inflexibility.\n\n## Mechanistic Rationale\n\n- The AMPK‑mTORC1 axis initiates autophagosome formation in response to energy stress, but flux completion depends on lysosomal competence.\n- Clock genes BMAL1 and PER2 directly bind to the promoter of ATP6V0C (predicted from circadian chromatin data), driving its transcription in antiphase to mTORC1 activity.\n- Lysosomal V‑ATPase activity generates the proton gradient required for hydrolase activation; thus, its rhythm determines the efficiency of cargo degradation rather than merely autophagosome count.\n- Disrupting this rhythm (e.g., constant light) uncouples autophagosome formation from degradation capacity, converting

Hypothesis

Aging isn't a programmed death mechanism but a condition‑dependent trait that can be attenuated when ecological cues signal high inclusive fitness returns from prolonged somatic maintenance. We're proposing a Kin‑Regulated Senescence (KRS) model in which individuals assess local relatedness and extrinsic mortality via chemosensory or social signals; high relatedness and low predation trigger downregulation of conserved pro‑aging pathways (e.g., IIS/mTOR) through epigenetic remodeling, thereby extending lifespan. Conversely, low relatedness or high extrinsic mortality maintain active senescence to free resources for kin.

Mechanistic Basis

• Signal integration: Nascent evidence shows that microbiome‑derived metabolites and pheromones can modulate histone acetylation at promoters of FOXO and SIRT genes 1; we hypothesize these signals carry kin‑specific information.
• Effector pathways: Reduced IIS/mTOR activity enhances autophagy and stress resistance, delaying accumulation of molecular damage 23.
• Feedback loop: Extended somatic maintenance increases offspring survival, reinforcing the signal that favors longevity—a positive feedback that can be selected under low extrinsic mortality.

Testable Predictions

1. In laboratory populations of Drosophila melanogaster manipulated to vary relatedness (e.g., clonal vs. outbred groups) while holding extrinsic mortality constant, high‑relatedness lines will ev

Hypothesis

Emodin selectively eliminates senescent microglia by concurrently inhibiting EGFR signaling and CDK2 activity, which shifts the senescence-associated secretory phenotype (SASP) from pro‑inflammatory to pro‑apoptotic and triggers mitochondrial apoptosis through p53‑dependent ROS accumulation.

Mechanistic Rationale

Emodin suppresses EGFR‑driven MAPK activation, reducing M1 macrophage polarization [2]. In senescent cells, EGFR signaling sustains CDK2‑cyclin‑A complexes that maintain the SASP via NF‑κB and STAT3 [1,3]. By blocking EGFR, emodin lowers STAT3 phosphorylation, a known resistance node to EGFR inhibition [3]. Simultaneously, emodin downregulates cyclin‑A and CDK2, causing S/G2‑M arrest and upregulating p53, p21, Bax and cleaved caspase‑3 [4]. In senescent microglia, persistent DNA damage keeps p53 active; further CDK2 inhibition prevents phosphorylation‑mediated p53 degradation, stabilizing p53 and promoting transcription of pro‑apoptotic BAX and PUMA. The combined loss of EGFR‑STAT3 survival signaling and CDK2‑mediated p53 turnover shifts the balance toward mitochondrial outer membrane permeabilization, releasing cytochrome c and activating caspase‑3. Concurrently, emodin’s inhibition of JNK and p38 MAPK reduces stress‑induced SASP components, while NF‑κB blockade lowers TNF‑α, IL‑1β, IL‑6 output, remodeling the secretome toward a less pathogenic profile.

Testable Predictions

1. Low‑dose emodin (0.5‑5 µM) will reduce viability of irradiated or oncogene‑induced senescent microglia >50 % while sparing proliferating microglia (<15 % loss) and quie

Hypothesis

Aging is driven by opposite acetyl-CoA dysregulation in myeloid and lymphoid compartments: excess nuclear acetyl-CoA in myeloid cells fuels inflammaging via ACLY‑dependent histone acetylation, while deficient nuclear acetyl-CoA in T cells limits their effector function through ACLY/ACSS2 shortage. We hypothesize that simultaneous, cell‑type‑specific correction of this metabolic‑epigenetic imbalance will break the feed‑forward loop that links immune dysfunction to systemic aging.

Mechanistic rationale

1. Myeloid‑restricted ACLY inhibition lowers nuclear acetyl-CoA, reducing H3K27ac at NF‑κB target promoters and curbing IL‑1β, IL‑6 production[1]
2. Lymphoid‑targeted ACSS2 overexpression restores nuclear acetyl-CoA from acetate, rescuing H3K9/14ac at histone gene loci and improving T‑cell proliferation[2]
3. Restored T‑cell surveillance enhances clearance of senescent myeloid cells, lowering the source of inflammaging[3]
4. Reduced inflammaging lessens tissue‑derived damage‑associated molecular patterns, decreasing further myeloid activation—a negative feedback loop.

Experimental design (testable & falsifiable)

• Model: Aged (≥20 mo) C57BL/6 mice.
• Interventions (factorial design):
  • Myeloid‑specific ACLY shRNA via LysM‑Cre.

Hypothesis

Senescent cells retain a latent EGFR/MAPK‑dependent transcriptional program that, when transiently reactivated, shifts the senescence‑associated secretory phenotype (SASP) from a chronic inflammatory state to a transient, regenerative secretome rich in growth factors and anti‑inflammatory cytokines. This switch would uncouple the beneficial wound‑healing functions of senescence from its deleterious aging‑promoting effects, suggesting that longevity interventions should aim to modulate rather than ablate EGFR/MAPK signaling in senescent cells.

Mechanistic Rationale

• EGFR/MAPK drives early‑life fitness – The pathway is essential for proliferation, wound healing and tissue repair, exemplifying antagonistic pleiotropy: advantageous early but potentially harmful when persistently active in non‑dividing cells [3, 4].
• Senescent cells retain MAPK components – Despite cell‑cycle arrest, senescent fibroblasts and macrophages express EGFR, ERK1/2 and downstream transcription factors (ELK1, c‑Fos) that can be phosphorylated upon ligand stimulation [5, 6]
• Signal‑dependent transcriptional reprogramming – Transient EGFR/MAPK activation phosphorylates ELK1, promoting transcription of FGF2, VEGFA and IL10 while simultaneously inhibiting NF‑κB‑driven IL6 and IL8 via MAPK‑dependent induction of phosphatases (DUSP1/6) that dampen prolonged inf

Background

Cellular senescence exhibits a senescence-associated secretory phenotype (SASP) that can be either beneficial for acute tissue regeneration or deleterious when chronic, driving inflammation and fibrosis 1.

Recent work shows SASP secretion follows a circadian rhythm, with peak cytokine release aligned to the active phase of the organismal clock 8.

Aptamer‑based surface labeling now enables real‑time identification of senescent cells without affecting neighboring healthy cells 2.

Hypothesis

We hypothesize that administering senolytics (e.g., Dasatinib + Quercetin) at the circadian peak of SASP will preferentially clear senescent cells contributing to chronic, pathogenic SASP while sparing those engaged in transient, regenerative SASP, thereby preserving acute repair mechanisms and reducing long‑term inflammatory burden.

Mechanistic Rationale

The SASP transcriptome is under direct control of the core clock proteins BMAL1 and CLOCK, which rhythmically enhance NF‑κB‑driven transcription of IL‑6, IL‑8, and other SASP factors 9.

Hypothesis: Hierarchical autophagic degradation of PRC2 subunits drives age‑dependent CDKN2A/B derepression and senescence

Mechanistic rationale

Aging cells show progressive loss of Polycomb Repressive Complex 2 (PRC2) mediated H3K27me3 at the CDKN2A/B locus, leading to p16^INK4a upregulation 12. While bulk autophagy declines with age, selective autophagy remains active and can target specific protein complexes via receptors such as p62/SQSTM1 3. We hypothesize that, under nutrient stress, the autophagic machinery preferentially engages PRC2 core subunits (EZH2, SUZ12, EED) in a defined order, stripping the complex from chromatin and triggering CDKN2A/B activation. This ordered depletion mirrors a triage mechanism where the cell sacrifices epigenetic silencing to initiate a senescence program that limits proliferation of damaged cells.

Novel mechanistic insight

PRC2 subunits contain lysine‑rich regions that become ubiquitinated in response to oxidative stress, creating a recognition motif for p62. Unlike random cargo, ubiquitinated EZH2 is modified first because its SET domain exposes lysine residues that are preferentially modified by the E3 ligase TRIM28 under low‑ATP conditions. Subsequent ubiquitination of SUZ12 and EED follows a kinetic hierarchy dictated by their accessibility within the complex. Once tagged, p62 recruits LC3‑positive phagophores, leading to sequential autophagic degradation. The loss of EZH2 first

Overview

Can living and working with natural wood materials extend your lifespan? This IP-NFT hypothesis explores the connection between biophilic design and longevity.

The Hypothesis

Regular exposure to natural wood materials in living and working environments can contribute to increased longevity by:

• 🌿 Reducing cortisol levels — wood surfaces trigger calming responses
• 💚 Lowering heart rate — visual and tactile qualities of wood promote relaxation
• 🏠 Regulating indoor humidity — creating more comfortable microclimates
• 🫁 Supporting respiratory health — improved indoor environmental quality
• 🧠 Improving mental health — reduced chronic stress over time leads to slower aging

Mechanism

Hypothesis

Aging‑associated shifts in sex‑specific gut microbiota bile salt hydrolase (BSH) activity alter the pool of inhibitory versus stimulatory bile acids that regulate ileal ASBT (SLC10A2) expression through the FXR‑FGF19 axis, producing opposite trajectories of ASBT in females and males.

Mechanistic Model

In aged females, estrogen decline favors expansion of Clostridia strains with low BSH activity, preserving conjugated primary bile acids (CPBAs) that act as weak FXR agonists. Reduced FXR activation diminishes FGF19 secretion, relieving its repression of ASBT transcription via the ERK1/2‑SGK1 pathway previously linked to glucocorticoid signaling【4】. Consequently, ASBT rises, increasing CPBA reabsorption and systemic delivery to the brain【1】.

In aged males, androgen‑dependent microbiota retain high BSH activity, generating elevated levels of deconjugated bile acids (e.g., cholic acid, deoxycholic acid) that are potent FXR antagonists. Strong FXR antagonism reduces FGF19 output, but paradoxically, the accumulated deconjugated acids activate TGR5‑cAMP signaling that suppresses ASBT via PKA‑mediated phosphorylation of the transporter, consistent with the observed ~50% drop in ileal taurocholate uptake【3】.

This model integrates the intestinal transport‑longevity link from Drosophila studies where loss of nutrient transporters extends lifespan【5】, suggesting that modulating BSH‑FXR‑FGF19 signaling could similarly affect mammalian aging.

Predictions & Experimental Design

1. BSH activity profiling – Quantify fecal BSH activity in young vs. aged male and

Hypothesis

In aged tissues, persistent type I/II interferon signaling drives transcriptional upregulation of SOCS1 and SOCS3, yet the accumulated SOCS proteins are largely ineffective at inhibiting JAK‑STAT signaling because chronic ligand exposure overwhelms the ubiquitin‑proteasome system (UPS). The resulting proteasome saturation leads to accumulation of polyubiquitinated SOCS species that cannot bind JAKs or receptors, producing a decoupling of SOCS mRNA induction from functional feedback. This mechanism explains the observed JAK‑STAT hyperactivity despite high SOCS transcript levels in aging.

Mechanistic Basis

SOCS proteins function as E3 ubiquitin ligase adaptors that recruit JAKs and cytokine receptors to the proteasome for degradation. Each round of SOCS‑mediated ubiquitination consumes one SOCS molecule, which is itself degraded after delivering its cargo. In young cells, de novo SOCS synthesis keeps pace with this consumptive cycle. In aging, sustained IFN elevates SOCS transcription but also increases the load of ubiquitinated substrates (including damaged proteins, organelles, and immune complexes). Proteasome capacity becomes limiting, causing a backlog of polyubiquitinated SOCS that accumulates in insoluble aggregates or aggresomes. These sequestered SOCS retain ubiquitination motifs but sterically lack access to JAK catalytic sites or receptor tyrosine residues, rendering them unable to execute feedback. Consequently, JAK‑STAT signaling remains active, driving ISG expression and senescence-associated phenotypes.

Testable Predictions

1. Aged cells e

Hypothesis

Intermittent dosing of a racetam‑alpha‑GPC regimen enhances working memory in healthy adults without elevating stroke‑risk biomarkers.

Rationale

• Racetams raise acetylcholine demand by increasing receptor density and activity, depleting choline pools ([1]).
• Alpha‑GPC efficiently raises plasma and brain choline, normalizing racetam‑induced changes and boosting memory ([2]).
• Chronic high‑dose alpha‑GPC has been linked to increased stroke risk, possibly via excess choline conversion to trimethylamine‑N‑oxide (TMAO) or platelet activation ([2]).
• Intermittent nutrient dosing can prevent homeostatic counter‑regulation, reducing receptor desensitization and metabolite buildup.

Mechanistic Insight

We propose that 5 days on / 2 days off cycling allows choline levels to fluctuate within a physiological window, sustaining enough precursor for acetylcholine synthesis while giving phosphatidyldethanolamine pathways time to clear excess methyl groups. This rhythm may limit TMAO formation and reduce pro‑thrombotic signaling, thereby attenuating the stroke signal associated with continuous alpha‑GPC exposure.

Testable Prediction

In a double‑blind, placebo‑controlled trial of 120 healthy adults aged 25‑45, participants receiving piracetam 2.4 g day⁻¹ plus alpha‑GPC 600 mg day⁻¹ on a 5‑on/2‑off schedule for 12 weeks will show:

1. A ≥15 % improvement in n‑back working memory accuracy relative to placebo (p < 0.05).
2. No significant change in plasma D‑dimer, homocysteine, or TMAO levels compared with baseline or continuous‑dose group.

Hypothesis

Age-related NAD+ loss in arteries is not a passive byproduct of metabolic wear but an active enzymatic sink that re-programs vascular smooth muscle cells (VSMCs) toward osteogenic differentiation. We propose that CD38 upregulation—amplified by senescent cell secretomes—does more than deplete NAD+; it generates cyclic ADP‑ribose (cADPR) and directly ADP‑ribosylates the transcription factor RUNX2. Hyper‑ADP‑ribosylated RUNX2 acquires increased DNA‑binding affinity for osteogenic promoters, suppressing tropoelastin transcription and driving a calcific matrix program. This switch becomes irreversible after prolonged NAD+ insufficiency because RUNX2 modification stabilizes a chromatin state that resists SIRT1‑dependent deacetylation, explaining why late NMN supplementation fails to restore elastin.

Mechanistic Reasoning

1. CD38 as a signaling hub – Beyond NAD+ glycohydrolase activity, CD38 produces cADPR, which mobilizes intracellular calcium and promotes calcific vesicle release [1]. Senescent endothelial cells secrete IL‑6 and MMPs that induce CD38 in adjacent VSMCs via a paracrine loop [2].
2. RUNX2 as the NAD+‑sensitive node – RUNX2 activity is regulated by acetylation; SIRT1 deacetylates RUNX2 to inhibit its osteogenic function [3]. When NAD+ falls, SIRT1 activity drops, leading to RUNX2 hyper‑acetylation. We argue that concurrent CD38‑mediated ADP‑ribosylation adds a second, stabilizing modification that locks RUNX2 in an active conformation even if NAD+ levels later rise.
3. Elastin suppression – Active RUNX2 binds upstream of the ELN gene, r

Hypothesis

Age-associated decline in NAD+ levels reduces cohesin complex loading onto chromatin, leading to progressive loss of TAD insulation. This architectural collapse permits ectopic enhancer-promoter contacts that activate neuronal gene programs and inflammatory pathways in aged muscle stem cells (MuSCs). The effect is more pronounced in males because estrogen-dependent up-regulation of the NAD+ salvage pathway preserves NAD+ and cohesin activity in females[1][2].

Mechanistic Model

• NAD+ shortage → diminished activity of NAD+-dependent enzymes (e.g., SIRT1, PARP1) that facilitate cohesin acetylation and stabilization[3].
• Cohesin hypo‑loading → weakened loop extrusion, causing TAD boundary erosion (≈38% loss in geriatric vs 20% in old MuSCs)[1].
• Boundary loss → enhancers normally restricted to myogenic domains gain access to neuronal‑gene promoters, driving lineage drift and ectopic H3K27ac acquisition[1].
• Concurrent chromatin de‑compaction exposes endogenous retrotransposons, allowing their transcription; the resulting nucleic‑acid sensors amplify IFN‑stimulated and NFκB signaling[1].
• Sex difference: higher circulating estradiol in females stimulates NAMPT expression, boosting NAD+ synthesis and partially rescuing cohesin function, thereby limiting TE activation (9 vs 47 TEs in geriatric males)[1].

Testable Predictions

1. Geriatric male MuSCs will show lower nuclear NAD+ and reduced cohesin (RAD21/SMC3) chromatin occupancy than age‑matched females; female MuSCs will exhibit higher NAMPT and SIRT1 activity[1][2].
2. Pharmacologic

Hypothesis

Chronic accumulation of low‑molecular‑weight hyaluronan (LMW‑HA) fragments in aged dermis triggers liquid‑liquid phase separation (LLPS) of HA‑binding adaptor proteins (CD44, TLR4‑MyD88, TRAF6) and downstream NF‑κB components, forming amyloid‑like condensates that sequester these signaling hubs. This condensate formation represents a proteostatic containment strategy that limits inflammatory signaling; when condensate capacity is exceeded, fibroblasts transition to a senescent state.

Mechanistic rationale

• LMW‑HA acts as a DAMP that engages CD44 and TLR4, recruiting adaptor proteins that possess intrinsically disordered regions and multivalent interaction domains.2
• Multivalent HA‑protein interactions promote LLPS, analogous to how RNA drives stress granule formation. The resulting condensates mature into β‑sheet‑rich aggregates detectable by Thioflavin T and filter‑trap assays.
• Sequestration of CD44‑TLR4 adaptors within condensates attenuates NF‑κB nuclear translocation, reducing IL‑6, TNF‑α, and IL‑1β output.
• When HA‑fragment load overwhelms condensate buffering capacity (e.g., due to severe HAS2 loss and ROS‑mediated HA cleavage), excess signaling escapes condensates, activates NF‑κB, and drives ER‑stress‑linked senescence pathways.3
• This model explains the bimodal inflammatory phenotype observed in aged fibroblasts: low‑grade inflammation in cells with robust condensate formation versus deep senescence in those that fail to sequester

Hypothesis

Pain sensitivity is not merely a symptom of damage; it reflects a metabolic state where mitochondrial reactive oxygen species (ROS) drive indoleamine 2,3‑dioxygenase 1 (IDO1) activation, shifting tryptophan toward the kynurenine pathway. This shift produces neuroactive metabolites (e.g., quinolinic acid, kynurenic acid) that lower nociceptive thresholds while concurrently depleting NAD+, impairing sirtuin activity and accelerating epigenetic aging. Consequently, a brief pain‑threshold assay could serve as a functional proxy for the mitochondrial‑kynurenine axis that underlies biological age.

Mechanistic Chain

1. Mitochondrial ROS ↑ → oxidative stress activates NF‑κB and aryl hydrocarbon receptor (AH-R).
2. NF‑κB/AH‑R ↑ → transcriptional up‑regulation of IDO1 in immune and epithelial cells.
3. IDO1 ↑ → tryptophan catabolism → ↑ kynurenine/tryptophan (K/T) ratio.
4. Kynurenine metabolites → bind NMDA receptors and modulate TRPA1/TRPV1 channels, decreasing pain thresholds (hyperalgesia).
5. Kynurenine pathway consumes NAD+ → ↓ SIRT1/3 activity → ↓ deacetylation of histones and PGC‑1α → epigenetic drift (higher DNAmGrimAge/PhenoAge).
6. Feedback → ROS production further amplified by mitochondrial dysfunction, closing the loop.

Testable Predictions

• In a cohort of adults aged 40‑80, baseline heat and pressure pain thresholds will negatively correlate with serum K/T ratio (r ≈ -0.5) independent of chronological age.

Hypothesis

A dual‑modified AAV capsid that combines (i) liver‑detargeted, cardiomyocyte‑tropic motifs (e.g., THGTPAD or NLPGSGD) [1][2], (ii) a cleavable polyethylene glycol (PEG) shield attached via a peptide linker cleaved by senescence‑associated β‑galactosidase (SA‑β‑gal) or matrix metalloproteinases (MMPs) upregulated in aged heart tissue, and (iii) transient immunomodulation (e.g., short‑course rapamycin) will allow repeated systemic dosing without neutralization, achieve selective transduction of senescent cardiomyocytes, and deliver rejuvenation payloads (Yamanaka factors, telomerase, senolytics) to improve cardiac function in aged mammals.

Rationale

• Liver‑detargeted, heart‑tropic capsids already reduce off‑target transduction and lower effective dose [1][2].
• Capsid modifications can mask immunogenic epitopes, evading pre‑existing neutralizing antibodies (NAbs) against parental AAV2 [1]. Adding a PEG shield further sterically hinders antibody access; cleavage in senescent microenvironments restores native capsid surface for efficient intracellular trafficking.
• Senescent cardiac cells overexpress SA‑β‑gal and MMPs [3]; a peptide linker substrates for these enzymes provides injury‑responsive de‑shielding, creating a third layer of specificity beyond tropism and promoter control.
• Transient immunomodulation mitigates innate immune activation and allows re‑dosing, a strategy already shown to enable repeat AAV administration [4].
• Dual‑specificity approaches that pair engineered tropism with transcriptional enhancers improve safety [5]; adding a microenvir

Hypothesis

Persistent homology features capturing increased H1 loop lifetimes in bulk aging transcriptomes are early, causative indicators of transcriptional noise that drive functional decline, rather than mere correlates.

Mechanistic Basis

Aging remodels chromatin architecture, leading to altered topologically associating domain (TAD) boundaries and heightened stochastic transcription initiation. These alterations produce spurious, transient co‑expression relationships that manifest as short‑lived loops (H1 features) in persistence diagrams of gene expression manifolds. As stochasticity accumulates, certain loops persist longer because they reflect stable, aberrant transcriptional programs that sequester transcription factors and RNA polymerase II away from productive loci. This mechanistic link predicts that rising H1 persistence precedes measurable declines in tissue function (e.g., grip strength, frailty) by providing a topological signature of transcriptional noise that directly reduces effective gene regulatory capacity.

Testable Predictions

1. In longitudinal bulk RNA‑seq cohorts (e.g., GTEx, GEO/SRA aging samples), the average lifetime (persistence) of H1 features will increase significantly with age before detectable declines in clinical functional metrics.
2. Individuals exhibiting a rapid rise in H1 persistence will show accelerated functional decline over follow‑up intervals, even after adjusting for cell‑type composition changes.
3. Experimental perturbation that reduces transcriptional noise (e.g., treatment with low‑dose HDAC inhibitors or overe

Hypothesis

Inter‑omics discordance—specifically, a divergence where epigenetic age indicates younger biological state while proteomic age indicates older state—reflects organ‑specific accumulation of senescence‑associated secretory phenotype (SASP) proteins that are not captured by DNA methylation clocks, a limitation noted in multi-omics integration approaches 1. We hypothesize that this epigenetic‑proteomic age gap predicts imminent functional decline in the organ system contributing the majority of the discordant proteomic signal, and that targeted reduction of SASP (e.g., via senolytics or NAD⁺ boosters) will narrow the gap and delay clinical frailty.

Mechanistic Rationale

Epigenetic clocks primarily measure cell‑intrinsic chromatin modifications that change slowly and are relatively resistant to acute extracellular fluctuations. In contrast, plasma proteomic clocks are highly responsive to secreted factors, including SASP cytokines, chemokines, and matrix remodelers that surge when tissue‑resident senescent cells expand. When a tissue undergoes stress‑induced senescence, its epigenome may not yet have accrued the methylation changes needed to shift the epigenetic clock, while the secretome rapidly alters the proteomic clock, producing a younger epigenetic readout alongside an older proteomic readout. This mismatch therefore serves as an early warning of tissue‑specific frailty before global epigenetic aging catches up. Such tissue‑specific signatures have been missed in prior digital twin models that achi