Top Tweets for #Senomorphic
New study led by @Duggal_UoB finds #butyrate as a potent #senomorphic agent!
Administration of faecal supernatants from young mice rich in butyrate prevented in vivo accumulation of #senescent spleen cells in aged mice.
https://t.co/LyZSsQ9pvu
#Aubrai_Hypotheses #BioProtocol #Longevity #DeSci #SASP #Senomorphic #IPToken #IgnitionSales
@Aubrai_ Submission: SASPMAP
Low-dose senomorphic combinations in short pulses to tame SASP safely and in a way that can translate
I/ Problem and significance
Cellular senescence sustains inflammaging through SASP cytokines (IL-6, IL-8, TNF-alpha), which erode tissue function and raise chronic disease risk.
Senolytics are promising, but toxicity and schedule tuning limit long-term use. A senomorphic route that suppresses SASP without killing cells may be safer, especially if we use low doses and short pulses that keep a wide safety margin.
II/ Hypothesis
Pair a micro-dose mTOR modulator (for example, rapamycin at very low nM) with an autophagy or NRF2 activator (for example, spermidine or sulforaphane).
Deliver in 24 to 48 hour pulses followed by washout. This should reduce SASP in human senescent cells more than the best single agent without increasing Ki-67 or γH2AX. The goal is a practical protocol, a biomarker threshold table, and an open dataset that can be packaged for an IP-Token.
III/ Why this could work
1) mTOR modulation supports proteostasis and tones down inflammatory signaling.
2) Autophagy enhancement (spermidine) clears damaged proteins and mitochondria which feed SASP.
3) NRF2 activation (sulforaphane) boosts antioxidant and cytoprotective programs.
These axes converge on SASP biology. Low doses with short pulses can give functional synergy while avoiding adaptive rebound and unnecessary proliferative pressure.
IV/ Study plan and methods (12 months, CRO or academic BSL-2; no animals or human subjects)
1) Stage 1: In silico, months 1 to 2
- Data: senescence and SASP transcriptional signatures from GEO and LINCS, drug-target resources such as DrugBank and KEGG.
- Analysis: signature inversion with GSEA and ssGSEA, network pharmacology, and combo scoring using Bliss and Loewe models.
- Output: a ranked shortlist of 3 to 4 drug-nutrient pairs with micro-dose ranges and pulse windows (24 to 48 h) compared with a continuous 72 h schedule. Produce preregistered SOPs and an assay plan.
2) Stage 2: In vitro, months 3 to 9
- Cells: human dermal fibroblasts from 3 donors across age bands, and endothelial cells (HUVEC or HMVEC) from at least 2 donors. Authenticate identity and mycoplasma status.
- Senescence induction: 10 Gy irradiation or 20 µM etoposide for 24 h, recover 72 h. Confirm with SA-β-gal and increased p16 or p21.
3) Arms (example):
- Vehicle control
- Monotherapies: rapamycin 0.5 to 2 nM, spermidine 0.5 to 5 µM, sulforaphane 0.5 to 2 µM, fisetin 2 to 10 µM
- Combinations: rapamycin + spermidine, rapamycin + sulforaphane, rapamycin + fisetin
- Schedules: continuous 72 h versus pulsed 24 to 48 h with washout.
- Primary endpoints: multiplex ELISA for IL-6, IL-8, TNF-alpha.
- Secondary endpoints: p16 and p21 by qPCR, SA-β-gal, LC3-II and p62 for autophagy, γH2AX for DNA damage, Ki-67 for proliferation.
- Exploratory subset: Seahorse OCR and ECAR for mitochondrial function, and NF-κB or NRF2 reporters if available.
- Design and QC: randomized well assignment, blinding during quantification, technical replicates 3 per condition and timepoint, biological replicates 3 fibroblast donors and at least 2 endothelial donors, repeat the experiment in 2 independent runs.
- Statistics: mixed-effects models for repeated measures, false discovery control with Benjamini-Hochberg, combination effects by Bliss and Loewe, report effect sizes and confidence intervals alongside p values.
- Primary success criterion: SASP reduction of at least 30 to 50 percent versus the best monotherapy without any increase in Ki-67 or γH2AX relative to control.
- Non-inferiority on safety: Ki-67 and γH2AX stay within preregistered limits.
V/ Risks and how we manage them
- Excess NRF2 activity could bias toward proliferation. We counter with micro-dosing, short pulses and washout, plus close monitoring of Ki-67 and γH2AX.
- Donor variability can dilute signals. We include at least 5 donors across cell types, use within-plate normalization and mixed-effects modeling.
- Batch or assay drift is handled with tight SOPs, longitudinal internal controls, and blinded readouts.
VI/ Transparency, governance and ethics
- Preregister all methods, endpoints and early-stop thresholds.
- Write decisions, parameters and analysis notebooks to an on-chain log via hashes. Release an anonymized dataset and analysis code after prereg lock.
- All work runs in BSL-2 and does not involve animals or human subjects.
VII/ Timeline, deliverables and budget
- Months 1 to 2: in silico shortlist and prereg. Deliver protocol v1, ranked combos and pulse windows and an assay plan.
- Months 3 to 4: build and verify senescence models, tighten dose ranges. Deliver a QC dataset and an optimization report.
- Months 5 to 7: main screen of combinations and schedules. Deliver dataset v1, interim analysis and a go or no-go for confirmatory runs.
- Months 8 to 9: independent replication on the best pair, plus Seahorse and flow subsets. Deliver dataset v2 and a table of efficacy and safety thresholds.
- Months 10 to 12: final analysis and write-up. Deliver a complete protocol, a biomarker threshold table, an open dataset, a manuscript draft and an IP-Token-ready package.
Budget overview, total about 97,000 USD within the 100,000 USD cap:
- CRO labor and overhead: 35,000
- Cells and culture consumables: 11,500
- Senescence induction cores and reagents: 3,500
- Compounds: 2,500
- Multiplex ELISA kits: 8,000
- qPCR reagents and primers: 3,000
- Western blot reagents and antibodies: 5,000
- Seahorse usage for a subset: 6,000
- Flow cytometry panels: 4,000
- Compute and licenses for in silico and cloud: 2,500
- Data management and on-chain logging: 4,000
- Preregistration, open access, publishing: 3,000
- Contingency: 9,000
VII/ Expected impact and translation path
Establish a low-dose pulsed senomorphic strategy that lowers SASP with a safety profile that is not worse than control. Produce a transferable protocol, thresholds, and an open dataset that others can replicate.
Create a bridge to ex vivo PBMC work or a small, supervised human feasibility step in a later phase. Package the outputs for IP-Token Ignition Sales and incubation with @vitadao .
* Questions for @Aubrai_
1) What micro-dose ranges and pulse windows do you recommend for rapamycin + spermidine and for rapamycin + sulforaphane, including any PK or PD cautions we should encode in prereg?
2) Where would you set early-stop thresholds for Ki-67 and γH2AX, and are there additional safety markers you would add, such as cfDNA or TP53 panels?
3) Which donor stratification rules would most improve signal detection, for example age bands, sex or baseline inflammatory markers?
#Aubrai_Hypotheses #BioProtocol #Longevity #DeSci #SASP #Senomorphic #IPToken #IgnitionSales @BioProtocol @vitadao

Low intracellular levels of #taurine is a common metabolic feature of several #senescence induction conditions (#Etoposide, #irradiation, #cell passage, #hydroxyurea)—Can it be a new marker for senscence? is taurine a #senolytic, #senomorphic or both? https://t.co/HgGHbdBgdl

#FGF9 #Senescence #Senomorphic
Secretome (1204 proteins) screening on Senescent features (p21 Cell area Nuclei area) of primary👤lung fibroblast -/+Etoposide #DNADamage inducer
Inducer▶️IFNα5/14/16/17
Inhibitors▶️FGF4/9/20
(Where is the full list?😳)
FGF9⏬pro-inflammatory SASP (IL1β IL17 TNFα TGFβ2) in both normal & IPF lung fibroblasts +Etoposide
FGF9⏬SM α-actin in IPF fibroblasts at baseline
BUT FGF9⏫p21 in IPF lung fibroblasts at baseline!
(What occurs to p21 in normal fibroblasts? Is this senescence? Loves to see more senescent markers🧐)
#SLASDiscov 2025 @SLAS_Org
https://t.co/jLASEM4elm

Pleased to share our latest publication in Redox Biology, describing the differential role of AQP1 in regulation of #Endothelial #Senescence.
It elucidates how AQP1 inhibitors confer #senomorphic effects by dampening SASP-Epigenetic signals.
#Saeedi_Lab
https://t.co/xHkhRZecH2

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