Foundational sources for the SENS framework are not single peer-reviewed studies but a collection: de Grey’s 2002 Annals of the New York Academy of Sciences essay “Time to Talk SENS”; the 2007 book Ending Aging (de Grey & Rae); and the SENS Research Foundation’s own publications and grant outputs. Pin these as bare references in the body when relevant, rather than as studies/ pages.

⚠️ Updated 2026-05-09 with current-research-in-progress sections per category (R36 ingest batch). The seven-category taxonomy from de Grey 2002 is unchanged; what is new is the per-category research landscape after the 2024 / 2025 / 2026 publication and clinical-trial activity. Citations marked “needs-verification” are pending PubMed/Crossref confirmation; do not rely on them for derivative claims until verified.

SENS damage categories

Aubrey de Grey’s seven categories of accumulated cellular/molecular damage, each paired with a proposed intervention strategy. Originally proposed in the early 2000s; framework formalized by the SENS Research Foundation. SENS Research Foundation severed ties with de Grey in 2021 amid harassment allegations; de Grey founded the Longevity Escape Velocity (LEV) Foundation in 2022, which now runs the Robust Mouse Rejuvenation (RMR) studies as the primary integrative-test platform for SENS-style combination therapies. SENS Research Foundation continues to operate independently with several spinout biotechs that originated from its grant-funded work (Cyclarity Therapeutics, Repair Biotechnologies, Revel Pharmaceuticals).

This page is a navigational overlay. Each damage category links to its associated hallmark(s), pathways, and interventions. Quantitative claims and primary-source detail live on the linked atomic pages — follow links before relying on numbers.

The SENS approach treats aging as accumulation of seven categories of damage that classical biology already understood by the 1980s; the goal is to repair each category rather than slow its accumulation.

The framework is complementary to hallmarks-of-aging (López-Otín 2013/2023) and engineered-negligible-senescence (the wiki-internal MOC for full-arrest analysis). All three frameworks ultimately point to the same atomic pages.

The seven damage categories

1. Cell loss and atrophy — RepleniSENS

Damage: Tissues lose post-mitotic cells faster than they’re replaced (cardiomyocytes, neurons, immune progenitors).

Repair strategy: Stem cells, tissue engineering, growth-factor signaling, ectopic-organ engraftment.

Maps to hallmark: stem-cell-exhaustion

2. Division-obsessed cells — OncoSENS

Damage: Cells acquire mutations that bypass replicative limits → cancer.

Repair strategy: “WILT” (Whole-body Interdiction of Lengthening of Telomeres) — preemptively remove telomere-lengthening machinery; pair with periodic stem-cell reseeding. The canonical version has not advanced; current focus has shifted to (a) allele-selective oligonucleotides against known cancer driver mutations (allele-selective-oligonucleotides verified) and (b) cancer-resistance mechanism transfer from long-lived species (see cancer-aging-tradeoffs).

Maps to hallmark: genomic-instability (cancer dimension), telomere-attrition

Related pages: telomerase, alt-pathway, cancer-aging-tradeoffs

3. Death-resistant cells — ApoptoSENS

Damage: Senescent cells accumulate; resist apoptosis; secrete pro-inflammatory SASP factors.

Repair strategy: Senolytics — drugs that selectively kill senescent cells. Current generation: BCL-2 family inhibitors (navitoclax, UBX1325/foselutoclax), tyrosine-kinase inhibitor combinations (D+Q), flavonols (fisetin), GPX4 modulators (RLS-1496), PROTAC degraders (DT2216, PZ15227), gene-therapy approaches (Oisin FAST-PLV), CAR-T (Amor uPAR-targeted).

Maps to hallmark: cellular-senescence

Related pages: senolytics, fisetin, dasatinib, quercetin, navitoclax, sasp, apoptosenes

4. Mitochondrial mutations — MitoSENS

Damage: Mitochondrial DNA mutates → dysfunctional respiration → ROS production cycle.

Repair strategy: Allotopic expression — relocate the 13 mtDNA-encoded protein genes to the nuclear genome where they’re protected from local oxidative damage. Adjacent strategies: in-situ mtDNA base editing (DddA-derived deaminases, mitoTALEDs, mitoBEs); selective heteroplasmy reduction; mitochondrial transplantation (Boston Children’s pediatric cardiac program; SENS-aligned biotech).

Maps to hallmark: mitochondrial-dysfunction

Related pages: mtdna, mtdna-heteroplasmy, mitophagy, oxphos, allotopic-expression (newly seeded R36)

5. Intracellular waste products — LysoSENS

Damage: Lysosomes accumulate undegradable aggregates (lipofuscin, oxidized cholesterol byproducts including 7-ketocholesterol, retinal A2E, advanced lipofuscin variants).

Repair strategy: Identify enzymes (often from soil bacteria) that can break down these aggregates; deliver them to lysosomes. Adjacent: small-molecule cyclodextrin-based oxidized-cholesterol clearance (Cyclarity UDP-003); cell-autonomous degradation platforms that enhance native lysosomal clearance (Repair Biotechnologies REP-0003).

Maps to hallmark: loss-of-proteostasis (intracellular)

Related pages: lipofuscin, lysosome, autophagy, 7-ketocholesterol (newly seeded R36)

6. Extracellular waste products — AmyloSENS

Damage: Misfolded protein aggregates accumulate outside cells (β-amyloid, tau, transthyretin, α-synuclein, IAPP).

Repair strategy: Immunotherapy — antibodies that target aggregates for clearance by phagocytes; small-molecule TTR stabilizers; antisense oligonucleotides that suppress aggregation-prone protein production at the source (BIIB080 for tau, patisiran/vutrisiran for TTR).

Maps to hallmark: loss-of-proteostasis (extracellular)

Related pages: amyloid-beta, tau, alpha-synuclein, alzheimers-disease, lecanemab (newly seeded R36), donanemab (newly seeded R36), tafamidis (newly seeded R36), acoramidis (newly seeded R36), patisiran (newly seeded R36)

7. Extracellular matrix stiffening — GlycoSENS

Damage: Glucose and other reactive carbonyls cross-link collagen and elastin, stiffening tissues (arteries, skin, joints, basement membranes). Glucosepane is the dominant glycation crosslink in long-lived human ECM.

Repair strategy: AGE-breaker compounds (the alagebrium / ALT-711 class — failed Phase 3; broad-spectrum approach has not delivered); enzymatic glucosepane cleavage (Revel Pharmaceuticals’ soil-bacteria-discovered enzymes — preclinical); aldehyde-trapping / glyoxal-scavenging upstream agents (pyridoxamine, benfotiamine).

Maps to hallmark: Loosely altered-intercellular-communication; ECM is not formally a hallmark in López-Otín’s framework. ECM stiffening is one of the major López-Otín-misses.

Related pages: glucosepane, advanced-glycation-end-products (newly seeded R36), collagen-crosslinking

Maturity matrix — quick reference (2026-05-09)

Category	Strategy maturity	Lead approved/late-stage agent	Lead biotech
RepleniSENS	Phase 3 (multiple)	Bemdaneprocel (Bayer/BlueRock), zimislecel (Vertex), raguneprocel JP MAA filed (Sumitomo)	Bayer/BlueRock; Vertex; Sumitomo Pharma
OncoSENS (WILT)	Conceptual (canonical); Phase 2-3 (adjacent)	Imetelstat (FDA-approved MDS, not aging)	Geron; cancer-resistance transfer programs preclinical
ApoptoSENS	Phase 2 (mixed); Phase 1	UBX1325 / foselutoclax (BEHOLD positive, ASPIRE missed primary)	Unity (asset under strategic-review); Rubedo; Oisin
MitoSENS	Late preclinical	None clinical	Cyclarity (cross-categorizes); academic mtDNA editing labs
LysoSENS	Phase 1	UDP-003 (Cyclarity, dosing started Jan 2025 Australia)	Cyclarity Therapeutics; Repair Biotechnologies
AmyloSENS	FDA-approved (multiple)	Lecanemab, donanemab, tafamidis, patisiran, vutrisiran, acoramidis	Eisai/Biogen; Lilly; Pfizer; Alnylam; BridgeBio
GlycoSENS	Preclinical	None clinical	Revel Pharmaceuticals

Current research in progress — by category (2024–2026)

RepleniSENS — current programs

The most translated SENS category by clinical-stage count. Three Phase 3 / pivotal-stage programs; first regulatory filing (Sumitomo Japan, August 2025) for an iPSC-derived cell therapy.

Bemdaneprocel (Bayer/BlueRock) for Parkinson’s — Phase 1 readout: clinically meaningful 17.9-point reduction in MDS-UPDRS Part III at high dose; effects sustained at 36 months; no graft-related serious AEs. Pivotal Phase 3 exPDite-2 (NCT06778265, needs-verification) dosed first patient September 2025. FDA RMAT designation 2024. Allogeneic hESC-derived dopaminergic precursors.
Sumitomo/CiRA Kyoto raguneprocel iPSC-DA progenitors — Phase I/II Nature April 2025 (PMID 40240591, needs-verification); 4/6 patients with MDS-UPDRS Part III OFF-state improvement at 24 months; no tumor formation. Sumitomo + RACTHERA submitted Japanese marketing authorization application August 5, 2025 — likely the first regulatory filing for an iPSC-derived neural cell therapy globally.
Vertex zimislecel (VX-880) for type 1 diabetes — ADA 85th Scientific Sessions (June 2025): all 12 patients restored endogenous insulin secretion, eliminated severe hypoglycemia, achieved A1C <7% and time-in-range >70%. 10/12 fully insulin-independent. Pivotal FORWARD-101 Phase 1/2/3 underway. BLA expected ~2027.
Vertex VX-264 (encapsulated, immunosuppression-free) discontinued 2024 — C-peptide rises insufficient for clinical benefit. Notable failure: encapsulation strategies for islet cell therapy remain unsolved.
Astellas ASP7317 hESC-RPE for dry AMD/geographic atrophy and Stargardt — Phase 1b dose-escalation (50K–200K cells subretinal); enrolling 2024; readout expected late 2025 / 2026.
LyGenesis ectopic liver organoid (lymph node) Phase 2a (NCT04496479, needs-verification) — first patient April 2024 (Eric Lagasse lab). March 2025 DSMB cleared dose-escalation after first 4-patient cohort showed acceptable safety. Enrolling 12 patients with end-stage liver disease.
TRIIM-X (Intervene Immune; Greg Fahy) thymic regeneration trial (NCT04375657) — expanded follow-up to original TRIIM trial (rhGH + DHEA + metformin). Original TRIIM (Fahy 2019, Aging Cell; PMID 31496122, needs-verification): -2.5 yr GrimAge reversal across n=9 men. Phase 2 enrollment ongoing as of Q1 2026.
Naked mole-rat HMW-HA / HAS2 mouse transgenic (Gorbunova/Seluanov labs, Rochester) — Nature 2023 (PMID 37612507): nmrHas2 transgenic mice +4.4% median / +12.2% max lifespan, reduced spontaneous (70%→57%) and induced cancer, attenuated tissue inflammation, gut barrier preservation, microbiome shift to longevity-associated taxa. Mouse Has2 alone reproduces anti-inflammatory benefits — HA abundance (not NMR-specific protein) is the operative variable. First whole-animal proof of xenogeneic NMR-longevity-mechanism transfer. See zhang-2023-nmrhas2-mouse-healthspan (verified). Translation-route candidates: AAV-HAS2 gene therapy (preclinical only) or hyaluronidase inhibitors (4-MU; flavonoid-based; speculative for aging).

Highest-priority recent finding: Sumitomo Phase I/II Nature 2025 paper — first published clinical evidence for iPSC-derived neural cell durability at 24 months in living patients.

Notable failure: Vertex VX-264 encapsulated islet program discontinued (2024).

OncoSENS / WILT — current programs

The least-translated SENS category. WILT-as-conceived has not advanced; the cancer-prevention thinking has migrated to adjacent strategies.

WILT remains conceptual. No clinical or rigorous preclinical animal-model program for whole-body telomerase ablation. Last serious published commentary: de Grey 2004 (PMID 15247008, needs-verification). The required infrastructure (decadal repopulation of all proliferative tissues) is not feasible.
Imetelstat (Geron) — telomerase inhibitor — FDA-approved June 2024 for transfusion-dependent anemia in lower-risk MDS (brand name Rytelo). A bona-fide telomerase-targeting drug in the clinic, but used as an MDS therapy, not a WILT-style aging intervention. Worth flagging as a precedent that telomerase inhibition is clinically tolerable.
ALT (alternative lengthening of telomeres) cancer-targeting research expanded 2024–2025. Cold Spring Harbor Perspectives April 2025 review (needs-DOI) on therapeutic opportunities for ALT-positive cancers — relevant because WILT would fail against ALT-using cells.
Cancer-resistance retrogene transfer (TP53RTGs) — September 2024 bioRxiv (10.1101/2024.09.07.611789): Asian elephant TP53 retrogene knockouts activate distinct DNA-damage and tumor-microenvironment pathways. No mouse-engraftment study yet for pan-paralog elephant TP53. See cancer-aging-tradeoffs for the broader cell-autonomous-tumor-suppression frame.
Cancer-resistant species mechanism transfer — naked mole rat HMW-HA → mice (covered under RepleniSENS): low-cancer phenotype achieved across spontaneous tumor incidence at +4.4% lifespan cost. The closest existing translation of “transfer cancer resistance via gene therapy.”
Tomás-Loba 2008 super-tumor-suppressor + TERT combination — original Cell paper (PMID 19013273) showed TERT extension plus enhanced p53/p16/p19ARF; not advanced beyond the original report.
No SRF or LEV Foundation publications specifically advancing WILT in 2024–2026.
Allele-selective oligonucleotides (allele-selective-oligonucleotides verified) — FDA-approved drugs exist (tofersen, patisiran, milasen, others) for non-cancer indications; the conceptual extension to cancer driver-mutation hotspots (e.g., GNAQ Q209L in uveal melanoma; KRAS G12C; BRAF V600E) is preclinical for somatic-mosaic clearance.

Highest-priority recent finding: Imetelstat FDA approval (2024) demonstrating clinical telomerase-inhibition tolerability — relevant as proof-of-concept that the pharmacological half of WILT is feasible, even if the stem-cell-replacement half is not.

Notable failure: WILT itself — never escaped concept stage; the field has effectively pivoted to retrogene/HMW-HA approaches and indication-bounded ASOs.

ApoptoSENS — current programs

The category with the most clinical activity AND the most prominent failures. 2025 was a mixed year — UBX1325 hit Phase 2 endpoints in BEHOLD but missed primary in Phase 2b ASPIRE.

UBX1325 (foselutoclax; Unity Biotechnology) BEHOLD Phase 2 in DME — NEJM Evidence April 2025 (PMID 40261111; doi:10.1056/EVIDoa2400009). 65 patients, single intravitreal injection, 48-week follow-up. +5.6 ETDRS letters vs sham (95% CI -1.5 to 12.7). Mechanism: BCL-xL inhibition in senescent retinal vasculature.
UBX1325 ASPIRE Phase 2b (DME, head-to-head vs aflibercept) — missed primary endpoint. Topline May 2025: non-inferior at most timepoints but missed primary at average of weeks 20–24. +5.5 letter gain at 36 weeks. Unity board approved strategic alternatives (sale/license/divestiture) of UBX1325. Major setback for senolytic-monotherapy paradigm.
D+Q Mayo Phase 2 osteoporosis trial (Farr/Khosla) — 2024 readout — 60 postmenopausal women, 100 mg D + 1000 mg Q × 3 days q28d × 20 weeks. P1NP up, CTx down, distal radius BMD increased — driven by high-senescent-cell-burden subgroup. Establishes patient-stratification heuristic for future senolytic trials.
D+Q AFFIRM frailty trial / fisetin AFFIRM-LITE (NCT03430037, NCT03675724) — Mayo Clinic; AFFIRM-LITE focuses on women with gait disturbance. Results pending.
Senolytic CAR-T (uPAR; Amor 2020 → 2024 Nature Aging) — PMID 38267706 (January 2024) extended 2020 Cancer Discovery work; showed prophylactic and long-lasting efficacy against age-related metabolic dysfunction. No clinical trial registered; Cleara Biotech mentioned in trade press but IP-holder relationship not confirmed publicly (needs-verification).
Oisin Biotechnologies FAST-PLV p16/p53 dual senolytic gene therapy — December 2024 publication (ResearchGate posted Dec 2024, needs-DOI): naturally aged mice, +123% post-treatment survival with combined p16+p53 caspase-9 induction; 3-fold reduced tumor incidence. $15M Series A first close July 2024.
Rubedo Life Sciences RLS-1496 GPX4 modulator — first-in-human Phase 1 (topical) for plaque psoriasis, atopic dermatitis, skin aging — first patient dosed May 2025 (EMA-cleared trial). Preliminary 2026 readout: met primary, significant target engagement; ~20% reduction in epidermal thickness on histology after 1 month. Systemic formulation Phase 1 planned 2026; FDA IND cleared for actinic keratosis (Phase 1b/2a).
Dialectic Therapeutics DT2216 (BCL-xL PROTAC) — AACR April 2025: first-in-human Phase 1 in solid malignancies (NCT04886622), 20 patients, RP2D 0.4 mg/kg IV biw, 20% stable disease, transient grade 4 thrombocytopenia (resolved <48h). FDA Fast Track for r/r PTCL/CTCL. Cancer-positioned but mechanistically a senolytic PROTAC.
PZ15227 (CRBN-recruiting BCL-xL PROTAC; He/Zhou Mayo) — preclinical only as of 2026; lower platelet toxicity than navitoclax. No clinical trial.

Highest-priority recent finding: UBX1325 BEHOLD (NEJM Evidence 2025) is the first peer-reviewed Phase 2 evidence of senolytic clinical efficacy — but the ASPIRE Phase 2b miss within months means the BCL-xL paradigm may not be the right modality for senolytic translation. The field is now diversifying toward GPX4 (Rubedo), gene-therapy (Oisin), and cell-therapy (uPAR CAR-T).

Notable failures: UBX0101 (knee OA, 2020); UBX1325 ASPIRE (2025) — both Unity programs.

MitoSENS — current programs

Slow but steady mechanistic progress; no clinical translation. The translation gap is acute — even the most advanced mtDNA-editing technologies have not entered IND-enabling studies.

In vivo allotopic expression of ATP8 in mouse (2024) — PMID 39659757 (Lewis et al., Mol Ther Methods Clin Dev December 2024). Transgenic mouse with epitope-tagged recoded ATP8 expressed from ROSA26 nuclear locus; protein successfully imported into mitochondria and incorporated into ATP synthase. First in vivo demonstration of nuclear-encoded mtDNA-gene rescue in a whole mouse, validating the foundational MitoSENS premise after ~20 years of in vitro work. Likely from the SENS/Buck team continuing Matthew “Oki” O’Connor’s pre-Cyclarity work.
DddA-derived cytosine base editor (DdCBE) → high-fidelity Hifi-DdCBE — used to generate LHON-mutant (MT-ND4 G11778A) mouse model with retinal ganglion cell loss; AAV-delivered mitoTALEDs intravitreally restored both genotype and phenotype (Nature Communications 2025; needs-DOI confirmation).
mitoBEs strand-selective mtDNA base editing (Nature Biotechnology 2023) — extended to human disease-mutation correction in patient-derived models (PLOS Biology 2025; needs-DOI confirmation).
TALEDs (TALE-linked deaminases) — both C-to-T and A-to-G now feasible in mtDNA. RNA off-target editing remains the main translational bottleneck; engineered variants in 2024–2025 reduce but do not eliminate it (Cell 2023, Mok et al., PMID 38128525, needs-verification).
Mitalipov mitochondrial replacement therapy (MRT) heteroplasmy reduction via forced mitophagy — Nature Biomedical Engineering 2022 (PMID 35726068, needs-verification); embryo-stage application. Methodology relevant to somatic mtDNA-clearance approaches.
James McCully (Boston Children’s) mitochondrial transplantation — 16 pediatric ECMO patients. Autologous mitochondria injected into ischemic heart; 80% off-ECMO vs 40% historical control (no formal Phase 1 trial registry per public search). 2024 Sci Reports demonstrated transcriptomic/proteomic normalization in DCD donor hearts; March 2025 J Heart Lung Transplant extended to lung perfusion. Not aging-positioned but provides safety/feasibility precedent for mito-transfer.
PEMphix Therapeutics, CellVie, Mitochondrion Therapeutics — referenced in trade press; public clinical-stage data unavailable as of Q1 2026 (needs-verification on company-stage updates).

Highest-priority recent finding: Lewis et al. 2024 in vivo ATP8 allotopic expression in mouse (PMID 39659757) — first whole-organism demonstration of nuclear-encoded mtDNA-gene functional rescue.

Notable gap: No company has filed an IND for somatic mtDNA editing or allotopic expression in adults despite 20+ years of mechanistic work. mtDNA-editor delivery to relevant tissues at therapeutic efficiency remains unsolved.

LysoSENS — current programs

One Phase 1 trial active (Cyclarity); the rest preclinical. The category has consolidated around two SRF spinouts: Cyclarity (atherosclerosis, 7-ketocholesterol) and Repair Biotechnologies (cholesterol-degrading platform).

Cyclarity Therapeutics UDP-003 cyclodextrin dimer (7-ketocholesterol cleavage) — Phase 1 trial authorized December 2024; first-in-human dosing January 2025 in Australia (Stephen Nicholls, Victorian Heart Institute / Monash). SAD/MAD design plus 12-patient acute coronary syndrome cohort. Phase 1 readout expected 2026. Atherosclerosis / heart attack risk reduction lead indication. Atherosclerosis 2025 publication describes the underlying chemistry (10.1016/j.atherosclerosis.2025.S0021-9150(25)00538-6, needs-verification).
Repair Biotechnologies Cholesterol Degrading Platform (CDP) — REP-0003 — AHA Scientific Sessions November 2025: preclinical atherosclerotic plaque regression in Ldlr-/- mouse model, 6 weeks of treatment. Orphan Drug Designation for homozygous familial hypercholesterolemia. REP-0004 GMP manufacture commenced; IND submission and first clinical trial planned early 2027. Mechanistically distinct from but conceptually adjacent to LysoSENS engineered-enzyme approach.
Underdog Pharmaceuticals → Cyclarity rebrand 2022. Underdog’s lipofuscin/A2E program appears not to have advanced into a separate development track post-rename; A2E/AMD work has effectively paused.
Ichor Therapeutics LysoCLEAR (recombinant manganese peroxidase MnP for A2E in dry AMD/Stargardt) — last published preclinical work 2018 (PMID 30516450). No 2024–2025 clinical milestones in public press; appears stalled or paused.
No active programs identified for 4Z Therapeutics or Lysocan in 2024–2026 public records.

Highest-priority recent finding: Cyclarity UDP-003 Phase 1 dosing (January 2025) — first clinical entry of an engineered LysoSENS-class therapeutic against an aging-driver substrate (7-ketocholesterol).

Notable gap: No active program against neuronal lipofuscin (the original LysoSENS poster-child target) at clinical stage. AMD/Stargardt-A2E programs (LysoCLEAR) appear paused.

AmyloSENS — current programs

The most clinically successful SENS category, by approved-product count. Six FDA-approved drugs across two indications (Alzheimer’s, ATTR-CM); active anti-α-synuclein program advancing to Phase 3.

Lecanemab (Leqembi; Eisai/Biogen) — FDA approved July 2023. Clarity AD: -27% slowing of CDR-SB at 18 months. AAIC 2025: 4-year open-label extension data — 69% improving or maintaining cognitive/functional status; 36-month CDR-SB benefit sustained. OLE published Alzheimer’s & Dementia 2025 (10.1002/alz.70905; PMC12682705). ARIA-E 12.6% vs placebo 1.7%. See lecanemab.
Donanemab (Kisunla; Eli Lilly) — FDA approved July 2024. TRAILBLAZER-ALZ 2: -35% CDR-SB slowing in low/medium tau subgroup. 3-year extension (AAIC 2025): -1.2 CDR-SB points vs weighted ADNI control in early-start arm. ARIA-E 24% vs placebo 1.9% — substantial safety signal. See donanemab.
Aducanumab (Aduhelm; Biogen) — withdrawn January 2024, full discontinuation November 2024. Notable historical failure for both the controversial accelerated-approval pathway and the broader anti-amyloid hypothesis when divorced from rigorous downstream cognitive evidence.
Acoramidis (Attruby; BridgeBio) — FDA approved November 22, 2024. TTR stabilizer for ATTR-CM; ATTRibute-CM Phase 3 (n=632, mean age 77.6): win ratio 1.8 (P<0.001); -42% composite mortality + cardiovascular hospitalization at 30 months. Joins tafamidis and patisiran/vutrisiran in the amyloid-cardiomyopathy armamentarium. See acoramidis.
Tafamidis (Vyndaqel/Vyndamax; Pfizer) — FDA approved 2019 for ATTR-CM. TTR stabilizer; ATTR-ACT trial: -32% all-cause mortality at 30 months. The first oral disease-modifying ATTR-CM therapy. See tafamidis.
Patisiran (Onpattro; Alnylam) — FDA approved 2018 for hATTR amyloidosis polyneuropathy. RNAi therapeutic; LNP-delivered siRNA against hepatocyte TTR. Vutrisiran (Amvuttra; Alnylam) FDA-approved 2022 for hATTR polyneuropathy and 2024 for ATTR-CM (HELIOS-B trial). See patisiran.
Prasinezumab (Roche/Prothena) anti-α-synuclein — PADOVA Phase 2b (n=586): missed primary endpoint time-to-motor-progression (HR 0.84, p=0.0657). Levodopa-treated subgroup HR 0.79, nominal p=0.043. Roche advanced to Phase 3 in June 2025 based on multiple secondary/exploratory signals plus ongoing PASADENA OLE.
Cinpanemab (Biogen) — failed. Phase 2 SPARK in Parkinson’s missed endpoints (2021). Discontinued.
UCB0107/minzasolmin (UCB) anti-α-synuclein — Phase 2 ORCHESTRA in early Parkinson’s; readout 2024–2025 mixed (needs-verification).
Etalanetug (E2814; Eisai) anti-MTBR-tau — CTAD 2024 + 2025: -50%/-75%/-89% CSF MTBR-tau243 reduction at 3/9 months; tau-PET stabilization. Phase 2 Study 202 initiated September 2024 with lecanemab as backbone. Specific bet on anti-amyloid + anti-tau combination as the path forward.
BIIB080 (Biogen, MAPT antisense oligonucleotide) — Phase 1b dose-dependent CSF total/p-tau and aggregated tau-PET reduction (n=46). Phase 2 CELIA fully enrolled; readout expected 2026. FDA Fast Track granted 2024.
Anti-tau antibodies that failed. Gosuranemab (Biogen, anti-N-terminal tau, failed Phase 2 in PSP and Alzheimer’s, 2020–2021); zagotenemab (Lilly, similar fate); semorinemab (Genentech) showed mixed late Phase 2 results. Pattern: N-terminal tau antibodies have failed; MTBR-targeting antibodies (E2814) showing biomarker traction.
Anti-IAPP (islet amyloid) human antibody m81 (Nature Communications 2023, PMID 37793976, needs-verification) — selective for IAPP oligomers/fibrils, protected β-cells in transgenic mouse and human-islet xenograft T2D models. No clinical trial registered as of Q1 2026.

Highest-priority recent finding: Acoramidis FDA approval (November 2024) — adds a third TTR-targeted amyloidosis therapeutic and demonstrates near-complete (≥90%) TTR stabilization is achievable orally with mortality benefit.

Substantive supersession candidate — Cochrane 2026 meta-analysis (Nonino et al., PMID 41985900, doi:10.1002/14651858.CD016297). A Cochrane systematic review of 17 RCTs covering 7 anti-Aβ antibodies (n=20,342) concluded that effects on cognition are “trivial” and effects on dementia severity are “little to no meaningful difference” despite statistical significance in individual trials. This finding is substantively discordant with the FDA-approval narrative for lecanemab and donanemab. The discordance does not invalidate the AmyloSENS framework — it qualifies the clinical translation claim: anti-amyloid antibodies achieve mechanistic target engagement (amyloid clearance demonstrated) and statistical efficacy in primary endpoints (CDR-SB slowing significant), but the clinical meaningfulness of the effect is debated. The verified compound pages lecanemab and donanemab flag this with #gap/contradictory-evidence tags. This is the central open question for the AmyloSENS class as of 2026: is statistically-significant CDR-SB slowing a meaningful clinical benefit, or is the field optimizing on biomarkers that don’t translate to patient-felt outcomes?

Notable failures: Aducanumab withdrawal (2024); cinpanemab; gosuranemab; zagotenemab. The anti-amyloid space has now generated as many high-profile failures as approvals — and the Cochrane 2026 meta-analysis raises the possibility that even the approvals may be over-claiming clinical benefit.

GlycoSENS — current programs

Slowest-translating SENS category alongside MitoSENS and OncoSENS. No clinical-stage program against the canonical SENS target (glucosepane).

Revel Pharmaceuticals (Spiegel/Crawford labs, Yale) glucosepane breaker pipeline — founded 2018 (San Francisco); built on Crawford’s Yale group’s first total synthesis of glucosepane (Draghici et al., Science 2015 — PMID 26472902 [verified]). Original strategy: functional metagenomics for soil-bacterial enzymes capable of degrading synthetic glucosepane. 2026-05-15 update: reproducibility setback — per industry-watcher reporting (Fight Aging 2024 commenter update; corroborated by Longevity.Technology + Lifespan.io coverage), the glucosepane-cleaving activity of the original Spiegel-lab enzyme candidates could not be reproduced, prompting Revel to broaden scope to a “5 or 6 target” crosslink portfolio rather than glucosepane exclusively. No IND filed; no clinical trial registered as of mid-2026; no peer-reviewed animal-efficacy paper has appeared. Therapeutic indications proposed: skin aging, osteoarthritis, kidney disease, vascular stiffness, diabetic complications. See glucosepane and advanced-glycation-end-products for full narrative. needs-primary-source-verification on the reproducibility-setback claim (blog-comment-sourced, not peer-reviewed).
Alagebrium (ALT-711, formerly Synvista) — already-known failure: Phase 3 in systolic heart failure (BENEFICIAL, Hartog 2011 — not HFpEF, contrary to common framing) ended without clear benefit; commercial program shuttered ~2009. The Yang 2003 mechanism critique (Arch Biochem Biophys PMID:12646266) — AGE-breakers cleave model compounds but do NOT break Maillard crosslinks in real-tissue collagen from diabetic rats — is a load-bearing reason the entire α-dicarbonyl class may be doubly suspect: not just wrong-target (doesn’t hit glucosepane) but possibly never cleaving any real-tissue crosslink. See glucosepane and advanced-glycation-end-products.
Aldehyde-trapping / glyoxal-scavenging programs — pyridoxamine (vitamin B6 form) and aminoguanidine (failed Phase 3 in diabetic nephropathy in 1990s due to autoimmunity) are the legacy small-molecule arsenal. Pyridoxamine remains in nutritional/supplement use; no successful Phase 3 in an aging indication.
Benfotiamine (lipid-soluble thiamine analog) for diabetic complications — Phase 2/early Phase 3 evidence for diabetic neuropathy and retinopathy; meta-analyses 2024–2025 mixed (needs-citation). Acts upstream by reducing glycation flux.
Glucosepane characterization advances — comprehensive 2024 review in Biophysical Reviews (10.1007/s12551-024-01188-4) reaffirms glucosepane as the dominant mature AGE crosslink (10–1000× more abundant than other crosslinking AGEs in tissue, per review-synthesis figures — see glucosepane for verifier-corrected primary-source caveats). 2025 review (PMC12024170) on AGE-targeting strategies for skin anti-aging summarizes synthetic + natural agents but no clinical breakthrough.

Highest-priority recent finding: Functional-metagenomics enzyme discovery (Revel, ~2023–2024) — represents the first credible glucosepane-degrading biocatalyst pipeline since the Yale group’s 2015 synthesis. Awaiting peer-reviewed primary publication and IND-enabling work.

Notable failures: Alagebrium (ALT-711) — Phase 3 program shuttered; aminoguanidine (autoimmune toxicity in DKD Phase 3). Together these established that broad-spectrum AGE-breakers are difficult to translate.

Cross-cutting observations (2026-05-09)

Overall translation pattern. Three SENS categories have produced FDA-approved products or imminent regulatory filings (RepleniSENS, ApoptoSENS partial, AmyloSENS). Two are at Phase 1 first-in-human (LysoSENS via Cyclarity UDP-003; possibly ApoptoSENS via DT2216/RLS-1496). Two remain mechanistic-only (MitoSENS, GlycoSENS) and one (OncoSENS-WILT) remains conceptual.

Organizational restructuring. SENS Research Foundation severed ties with Aubrey de Grey in 2021; de Grey founded LEV Foundation in 2022, which now runs the Robust Mouse Rejuvenation (RMR) studies. RMR1 (2023–early 2025; n=1000 mice; rapamycin + young-HSCs + TERT gene therapy + senolytic combinations) showed combination > single-intervention benefit and rectangularization of survival curves. RMR2 pilot underway 2025. The XPRIZE Healthspan ($101M, deadline 2030) launched 2024 and now has >100 competing teams. See longevity-escape-velocity (verified) for the LEV-Foundation strategic frame.

Key 2025-2026 readouts to watch. UDP-003 Phase 1 (Cyclarity, atherosclerosis); BIIB080 CELIA Phase 2 (Biogen, tau ASO); ASP7317 Phase 1b (Astellas, AMD); LyGenesis Phase 2a interim (liver organoids); E2814 Study 202 (lecanemab + tau combination); RLS-1496 systemic Phase 1 (Rubedo); zimislecel pivotal continuation (Vertex); raguneprocel JP MAA decision (Sumitomo).

The framework’s predictive track record. When SENS was formulated in 2002, the consensus among biogerontologists (per longevity-escape-velocity) was that the proposed strategies were “fantasy.” Twenty-four years later, three of the seven categories have produced FDA-approved aging-relevant interventions (lecanemab/donanemab/acoramidis for AmyloSENS; UBX1325 reaching Phase 2 efficacy for ApoptoSENS; multiple Phase 3 cell therapies for RepleniSENS). The remaining four categories are consistent with the original timeline projections (decades-scale translation) rather than falsified. Whether SENS will succeed at the integrative level — whether combining the seven repair strategies produces engineered negligible senescence — remains the open question addressed by engineered-negligible-senescence and the LEV Foundation RMR program.

Criticism and updates

The framework was dismissed as “fantasy” by major aging researchers when first proposed (notably the Warner et al. 2005 EMBO Reports critique signed by 28 biogerontologists; see longevity-escape-velocity for the detailed critique inventory). By the mid-2010s, multiple SENS-aligned biotech spinouts (Cyclarity Therapeutics — formerly Underdog Pharmaceuticals; Repair Biotechnologies; Revel Pharmaceuticals; OncoSenX) and parallel academic progress on senolytics shifted the consensus toward partial vindication of the damage-repair framing. As of 2026, the AmyloSENS approvals (lecanemab, donanemab, acoramidis) constitute the strongest single-category evidence that damage-repair-class interventions can reach FDA endpoints; the broader question of whether the combination extends healthspan/lifespan in humans is what RMR is designed to test in mice as a proof-of-concept.

Persistent critique: Whether all seven categories are exhaustive (the original claim) remains contested. Epigenetic alterations (López-Otín hallmark, addressed by partial reprogramming / OSK; see in-vivo-partial-reprogramming-therapy) and chronic inflammation (López-Otín hallmark) are obvious additions not captured by the seven SENS categories. The seven-category taxonomy is a useful organizing schema but should not be treated as biology’s full damage-class inventory. contradictory-evidence

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