Network-driven discovery of repurposable drugs targeting hallmarks of aging

AlexKChen · June 29, 2026, 11:40pm

Synephrine (altered intercellular) , Captopril, Meclizine, estradiol, Masoprocol are p-sig at the highest number of hallmarks
Flurbiprofen fr Mitochondrial dysfunction

the standard ITP drugs dont score as high on as many, idk what this rl ymeans yet
Amineptine for stem cells

this paper isnt as strong for loss of proteaostasis

it mentions OTC Oxymetazoline for improving intercellular communication

AlexKChen · June 30, 2026, 2:36am

Drug Hallmark hit Why it might causally reduce aging-like biology

Guanadrel Stem-cell exhaustion Adrenergic-neuron inhibitor. A plausible causal route is lowering sympathetic/noradrenergic tone, which can influence stem-cell niches, inflammation, vascular tone, and tissue stress signaling. The paper lists it among positive pAGE stem-cell-exhaustion candidates; DrugBank describes guanadrel as displacing norepinephrine from nerve endings. (Nature)

Guanethidine Stem-cell exhaustion Similar sympatholytic logic: reduced norepinephrine release could alter inflammatory and niche signaling. This is more “network plausibility” than longevity proof, but it is not random noise. DrugBank describes guanethidine as interfering with norepinephrine release/distribution. (Nature)

Olopatadine Stem-cell exhaustion H1 antagonist/mast-cell stabilizer. Plausible route: less mast-cell/histamine inflammatory signaling, which could protect stem-cell niches from chronic inflammatory depletion. DrugBank describes it as a selective H1 antagonist and mast-cell stabilizer that attenuates inflammatory/allergic reactions. (Nature)

Epirubicin Stem-cell exhaustion This one is ugly. Anthracycline stress can induce DNA-damage/p53/apoptotic programs, so in a cell-line signature it may look like it pushes certain aged transcriptional states backward. But clinically, anthracyclines are famously toxic and can be pro-aging in real tissue. This is a “mechanistic perturbation hit,” not a sensible longevity candidate. (Nature)

Nisoxetine Stem-cell exhaustion Selective norepinephrine-transporter inhibitor. Plausible route: altered noradrenergic signaling changes stress, immune, and stem-niche regulation. This is not obviously pro-longevity, but it fits the paper’s repeated catecholamine-axis theme. (Nature)

Clorgiline / clorgyline Stem-cell exhaustion Irreversible MAO-A inhibitor. Plausible route: changes monoamine metabolism, oxidative amine turnover, neuroimmune signaling, and stress-response transcription. Still, MAO-A inhibition is not something to cosplay with because tyramine/serotonergic interactions exist to remind humans chemistry has consequences. (Nature)

Amineptine Stem-cell exhaustion Dopaminergic/monoaminergic perturbation candidate. Plausible route: altered catecholamine signaling and stress-axis tone affecting stem-cell exhaustion modules. The causal story is weaker than for amlexanox/navitoclax/IGF inhibitors. (Nature)

Acemetacin Stem-cell exhaustion NSAID-like anti-inflammatory route. Chronic prostaglandin/COX inflammatory signaling can degrade tissue microenvironments; reducing it could make a stem-cell-exhaustion signature look younger. NSAIDs generally act by inhibiting COX enzymes and prostaglandin production. (Nature)

Amlexanox Stem-cell exhaustion One of the more biologically plausible ones. It inhibits TBK1/IKKε, connecting inflammation, metabolism, insulin sensitivity, energy expenditure, and tissue crosstalk. In obese mice, amlexanox increased thermogenesis, reduced weight, and improved insulin sensitivity, which gives it a real aging-adjacent causal story. (Nature)

Oxymetazoline Altered intercellular communication Adrenergic/serotonin receptor perturbation. In the paper, it targets ADRA1A/B/D and HTR1A/B/D; ADRA1A is a hallmark gene, and the perturbation appears to propagate through ACKR3 into NFKB1/TP53/AKT1-linked inflammatory/communication genes. This could reduce sterile inflammation and inflammatory cell-cell “screaming.” (Nature)

Terazosin Altered intercellular communication Two plausible routes: α1-adrenergic modulation of inflammatory signaling, and a separate PGK1/glycolysis mechanism. Terazosin has been reported to enhance PGK1 activity, stimulate glycolysis, increase ATP, and show neuroprotective associations in Parkinson’s-related studies. (Nature)

Tetryzoline / tetrahydrozoline Altered intercellular communication α-adrenergic agonist, similar family to oxymetazoline. Plausible route: adrenergic receptor perturbation changes vascular, immune, and inflammatory communication modules. This is mechanistically plausible but not “please drink eye drops,” because civilization already tried being stupid about that. (Nature)

Cirazoline Altered intercellular communication α1A agonist / α1B/α1D partial agonist, with imidazoline activity. Plausible route: direct modulation of the same ADRA1A-centered network that made oxymetazoline interesting. DrugBank describes cirazoline as acting on α-adrenergic receptors, including α1A agonism. (Nature)

Synephrine Altered intercellular communication Adrenergic agonist. Supplementary Fig. S17 says synephrine targets ADRA1A/B/D, with ADRA1A as both a target and hallmark gene, and suggests perturbation through STAT1 into the intercellular-communication module, giving significant pAGE.

Doconexent / DHA Epigenetic alterations DHA can change membrane biology, lipid mediators, inflammation resolution, nuclear-receptor signaling, and gene-expression state. That gives a plausible route into epigenetic-aging signatures. Omega-3/DHA biology is one of the less insane entries here, thankfully. (Nature)

Fenoprofen Epigenetic alterations NSAID/COX inhibition. The causal theory is indirect: lower prostaglandin-driven inflammation can alter NF-κB, chromatin state, immune signaling, and therefore epigenetic-aging signatures. DrugBank describes fenoprofen as inhibiting prostaglandin synthesis. (Nature)

Clinofibrate Epigenetic alterations Fibrate/PPAR-style metabolic transcriptional modulation. PPARs are nuclear receptors controlling lipid and glucose homeostasis, so a fibrate can plausibly shift epigenetic/metabolic expression programs in a younger-looking direction. (Nature)

Pyrazolanthrone Mitochondrial dysfunction JNK inhibitor logic. The supplement says pyrazolanthrone can prevent certain forms of mitochondrial dysfunction. JNK sits in stress/apoptosis/mitochondrial damage signaling, so inhibiting it could plausibly reduce age-like mitochondrial stress signatures.

Marimastat Extracellular matrix Broad MMP inhibitor. Plausible route: slowing pathological extracellular-matrix remodeling, fibrosis-like degradation, and tissue-structure aging. Supplementary Table S13 explicitly frames marimastat as blocking excessive MMP activity and pathological ECM remodeling.

Tivozanib Deregulated nutrient sensing VEGFR tyrosine-kinase inhibitor. Causal route is less classic than IGF/mTOR, but VEGF signaling affects vascular growth, nutrient delivery, hypoxia responses, endothelial aging, and angiogenic signaling. DrugBank describes tivozanib as inhibiting VEGFR phosphorylation. (Nature)

BMS-754807 Deregulated nutrient sensing Strong causal plausibility, awful “don’t self-experiment” energy. It inhibits IGF1R/INSR, directly hitting insulin/IGF signaling, AKT, and mTOR-adjacent nutrient-sensing machinery. The supplement explicitly says BMS-754807 suppresses IIS and downstream AKT–mTOR signaling, mimicking nutrient limitation.

Pilaralisib Deregulated nutrient sensing PI3K inhibitor. Plausible route: PI3K → AKT → mTOR is one of the central nutrient/growth axes in aging biology. But the paper also flags pilaralisib as age-accelerating for epigenetic alterations, so this is hallmark-specific, not globally “good.” (Nature)

Linsitinib Deregulated nutrient sensing IGF1R/INSR inhibitor. Very straightforward aging-plausibility: downshift insulin/IGF signaling, reduce AKT–mTOR growth signaling, imitate parts of nutrient limitation. The supplement says exactly this, because sometimes the universe allows one clean mechanism.

Drug	Hallmark hit	Why it might causally reduce aging-like biology
Guanadrel	Stem-cell exhaustion	Adrenergic-neuron inhibitor. A plausible causal route is lowering sympathetic/noradrenergic tone, which can influence stem-cell niches, inflammation, vascular tone, and tissue stress signaling. The paper lists it among positive pAGE stem-cell-exhaustion candidates; DrugBank describes guanadrel as displacing norepinephrine from nerve endings. (Nature)
Guanethidine	Stem-cell exhaustion	Similar sympatholytic logic: reduced norepinephrine release could alter inflammatory and niche signaling. This is more “network plausibility” than longevity proof, but it is not random noise. DrugBank describes guanethidine as interfering with norepinephrine release/distribution. (Nature)
Olopatadine	Stem-cell exhaustion	H1 antagonist/mast-cell stabilizer. Plausible route: less mast-cell/histamine inflammatory signaling, which could protect stem-cell niches from chronic inflammatory depletion. DrugBank describes it as a selective H1 antagonist and mast-cell stabilizer that attenuates inflammatory/allergic reactions. (Nature)
Epirubicin	Stem-cell exhaustion	This one is ugly. Anthracycline stress can induce DNA-damage/p53/apoptotic programs, so in a cell-line signature it may look like it pushes certain aged transcriptional states backward. But clinically, anthracyclines are famously toxic and can be pro-aging in real tissue. This is a “mechanistic perturbation hit,” not a sensible longevity candidate. (Nature)
Nisoxetine	Stem-cell exhaustion	Selective norepinephrine-transporter inhibitor. Plausible route: altered noradrenergic signaling changes stress, immune, and stem-niche regulation. This is not obviously pro-longevity, but it fits the paper’s repeated catecholamine-axis theme. (Nature)
Clorgiline / clorgyline	Stem-cell exhaustion	Irreversible MAO-A inhibitor. Plausible route: changes monoamine metabolism, oxidative amine turnover, neuroimmune signaling, and stress-response transcription. Still, MAO-A inhibition is not something to cosplay with because tyramine/serotonergic interactions exist to remind humans chemistry has consequences. (Nature)
Amineptine	Stem-cell exhaustion	Dopaminergic/monoaminergic perturbation candidate. Plausible route: altered catecholamine signaling and stress-axis tone affecting stem-cell exhaustion modules. The causal story is weaker than for amlexanox/navitoclax/IGF inhibitors. (Nature)
Acemetacin	Stem-cell exhaustion	NSAID-like anti-inflammatory route. Chronic prostaglandin/COX inflammatory signaling can degrade tissue microenvironments; reducing it could make a stem-cell-exhaustion signature look younger. NSAIDs generally act by inhibiting COX enzymes and prostaglandin production. (Nature)
Amlexanox	Stem-cell exhaustion	One of the more biologically plausible ones. It inhibits TBK1/IKKε, connecting inflammation, metabolism, insulin sensitivity, energy expenditure, and tissue crosstalk. In obese mice, amlexanox increased thermogenesis, reduced weight, and improved insulin sensitivity, which gives it a real aging-adjacent causal story. (Nature)
Oxymetazoline	Altered intercellular communication	Adrenergic/serotonin receptor perturbation. In the paper, it targets ADRA1A/B/D and HTR1A/B/D; ADRA1A is a hallmark gene, and the perturbation appears to propagate through ACKR3 into NFKB1/TP53/AKT1-linked inflammatory/communication genes. This could reduce sterile inflammation and inflammatory cell-cell “screaming.” (Nature)
Terazosin	Altered intercellular communication	Two plausible routes: α1-adrenergic modulation of inflammatory signaling, and a separate PGK1/glycolysis mechanism. Terazosin has been reported to enhance PGK1 activity, stimulate glycolysis, increase ATP, and show neuroprotective associations in Parkinson’s-related studies. (Nature)
Tetryzoline / tetrahydrozoline	Altered intercellular communication	α-adrenergic agonist, similar family to oxymetazoline. Plausible route: adrenergic receptor perturbation changes vascular, immune, and inflammatory communication modules. This is mechanistically plausible but not “please drink eye drops,” because civilization already tried being stupid about that. (Nature)
Cirazoline	Altered intercellular communication	α1A agonist / α1B/α1D partial agonist, with imidazoline activity. Plausible route: direct modulation of the same ADRA1A-centered network that made oxymetazoline interesting. DrugBank describes cirazoline as acting on α-adrenergic receptors, including α1A agonism. (Nature)
Synephrine	Altered intercellular communication	Adrenergic agonist. Supplementary Fig. S17 says synephrine targets ADRA1A/B/D, with ADRA1A as both a target and hallmark gene, and suggests perturbation through STAT1 into the intercellular-communication module, giving significant pAGE.
Doconexent / DHA	Epigenetic alterations	DHA can change membrane biology, lipid mediators, inflammation resolution, nuclear-receptor signaling, and gene-expression state. That gives a plausible route into epigenetic-aging signatures. Omega-3/DHA biology is one of the less insane entries here, thankfully. (Nature)
Fenoprofen	Epigenetic alterations	NSAID/COX inhibition. The causal theory is indirect: lower prostaglandin-driven inflammation can alter NF-κB, chromatin state, immune signaling, and therefore epigenetic-aging signatures. DrugBank describes fenoprofen as inhibiting prostaglandin synthesis. (Nature)
Clinofibrate	Epigenetic alterations	Fibrate/PPAR-style metabolic transcriptional modulation. PPARs are nuclear receptors controlling lipid and glucose homeostasis, so a fibrate can plausibly shift epigenetic/metabolic expression programs in a younger-looking direction. (Nature)
Pyrazolanthrone	Mitochondrial dysfunction	JNK inhibitor logic. The supplement says pyrazolanthrone can prevent certain forms of mitochondrial dysfunction. JNK sits in stress/apoptosis/mitochondrial damage signaling, so inhibiting it could plausibly reduce age-like mitochondrial stress signatures.
Marimastat	Extracellular matrix	Broad MMP inhibitor. Plausible route: slowing pathological extracellular-matrix remodeling, fibrosis-like degradation, and tissue-structure aging. Supplementary Table S13 explicitly frames marimastat as blocking excessive MMP activity and pathological ECM remodeling.
Tivozanib	Deregulated nutrient sensing	VEGFR tyrosine-kinase inhibitor. Causal route is less classic than IGF/mTOR, but VEGF signaling affects vascular growth, nutrient delivery, hypoxia responses, endothelial aging, and angiogenic signaling. DrugBank describes tivozanib as inhibiting VEGFR phosphorylation. (Nature)
BMS-754807	Deregulated nutrient sensing	Strong causal plausibility, awful “don’t self-experiment” energy. It inhibits IGF1R/INSR, directly hitting insulin/IGF signaling, AKT, and mTOR-adjacent nutrient-sensing machinery. The supplement explicitly says BMS-754807 suppresses IIS and downstream AKT–mTOR signaling, mimicking nutrient limitation.
Pilaralisib	Deregulated nutrient sensing	PI3K inhibitor. Plausible route: PI3K → AKT → mTOR is one of the central nutrient/growth axes in aging biology. But the paper also flags pilaralisib as age-accelerating for epigenetic alterations, so this is hallmark-specific, not globally “good.” (Nature)
Linsitinib	Deregulated nutrient sensing	IGF1R/INSR inhibitor. Very straightforward aging-plausibility: downshift insulin/IGF signaling, reduce AKT–mTOR growth signaling, imitate parts of nutrient limitation. The supplement says exactly this, because sometimes the universe allows one clean mechanism.