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Adrenoceptor (1) Antibiotic (2) Cyclic Nucleotide (4) Dopamine (5) Hormone (6) Serotonin (8) Other (9) Phosphorylation (7) Ca2+

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Adrenoceptor (1) Antibiotic (2) Cyclic Nucleotide (4) Dopamine (5) Hormone (6) Serotonin (8) Other (9) Phosphorylation (7) Ca2+ Supplementary Fig. 1 Lifespan-extending compounds can show structural similarity or have common substructures. Cl NO2 H doxycycline (2) N N NH 2 O H O H O O H O O O O O H O NH NH Cl O O 2 N N guanfacine (1) O H N N H H H nitrendipine (3) S Cl N H promethazine (9) NO2 F N NH2 F N demeclocycline (2) O H O O H O O F N NH O O H O O Cl S N NH N guanabenz (1) O O 2 fluphenthixol (5) Br CN O H N H N nicardipine (3) S N H Cl O H N N propionylpromazine (5) O O H O H O O H O O O H Cl N S Br LFM−A13 (7) NH2 S S O H H H chlorprothixene (5) thioridazine (5) N N O H minocycline (2) HO S O β-estradiol (6) O H H N H N H O H O danazol (6) N N cyproterone (6) H N H O H O methylergonovine (5) HO H pergolide (5) O N O O O N O HN O O H O N N H 3C H H O O H Cl H O H C H 3 O H N N H N H N H H O metergoline (8) dihydroergocristine (5) Cortexolone (5) HO O N (R,R)−cis−Diethyltetrahydro−2,8−chrysenediol (6) O H O H N O vincristine (9) N H N HN H O H H N H O N N N N O N H O O O N N dihydroergotamine (8) H O Cl O H O H O nortriptyline (1) S O mianserin (8) octoclothepin (5) loratadine (9) H N N Cl N N N cinnarizine (3) O N N N H Cl N Cl N N N O O N loxapine (5) N amoxapine (1) oxatomide (9) O O Adrenoceptor (1) Antibiotic (2) Ca2+ Channel (3) Cyclic Nucleotide (4) Dopamine (5) Hormone (6) Phosphorylation (7) Serotonin (8) Other (9) Supplementary Fig. 1. Lifespan-extending compounds show structural similarity or have common substructures. Names of the compounds are color coded and numbered according to pharmacological class, as indicated. Supplementary Fig. 2. Structures of lifespan-extending compounds and their effects on stress resistance. O O N NO2 oxatomide (9) O N N O O O O Cl H eliprodil (9) N N N doxazosin (1) N N N O O O F N NH nicardipine (3) 2 N O H H N Protect from O H N-(2-[4-(4-Chloro... (5)* N vincristine (9) Cl dihydroergocristine (5) H H O cinnarizine (3) N oxidative N O O O N N O O H N F O H N N N N N H O N N O stress N O H O HO O H O H O H O H O H O N N naftopidil (1) H O S H N O N Cl H H N NH2 N NO methylergonovine (5) 2 O F amperozide (8) N N N NH Cl O H N Cl O O N H H N H dihydroergotamine (8) O O guanabenz (1) O O N pergolide (5) O amoxapine (1) H H N O O N N H N H cyclosporin A (7) HN H O N O nitrendipine (3) N N H O Structure: undecapeptide N N N H F N Cl N ketanserin (8) N O H Cl O O H N N O N S loxapine (5) S N octoclothepin (5) N N HN N N S doxycycline (2) LY−367,265 (8) nortriptyline (1) S O H O O H O O mianserin (8) O H thioridazine (5) F F NH F 2 N O F Cl O H H H O N N N N N N H H NH2 N H PAPP/LY-165,163 (8) metergoline (8) S N N promethazine (9) HO Si N N Cl O O CN O HN loratadine (9) S + NH N N demeclocycline (2) chlorprothixene (5) O O H N trequinsin (4) F O H O O H O O N O H 4-phenyl-3-..(9)***** H O N O O N hexahydro-sila-difenidol (9) NH2 DAPH (7) O H O H N O H O N S N O N H O Cl O H propionylpromazine (5) N S Cl N N NH N O N O Cl N O O H NO F O 2 O O H quinidine (9) F SU 4312 (7) O BRL 50481 (4) vinpocetine (4) F 3,4-DIC** O H O O H O O O H S O H O fluphenthixol (5) NH2 HO O H β O H H BRL 15572 (8) -estradiol (6) O O O N N danazol (6) psora-4 (9) O H N Cl N O H O O minocycline (2) N O H N N N H HO O cyproterone (6) O AMN082 (R,R)−THC (6)**** S O H Cl Br H 3C O H O BTCP (5) Br O H O H 3C H HN Cl Cl HN N H H O N NH N H 2 CN Br O N H O NH O N LFM−A13 (7) cortexolone (5) Cl O guanfacine (1) NH2 kenpaullone (7) tyrphostin AG 1478 (7) Adrenoceptor (1) N Antibiotic (2) Hormone (6) *N−(2−[4−(4−Chlorophenyl)piperazin−1−yl]ethyl)−3−methoxybenzamide N N Ca2+ Channel (3) Phosphorylation (7) 7-cyclopentyl-5-(4-...(7)*** **3,4−dichloroisocoumarin ***7-cyclopentyl-5-(4-phenoxy)phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine Cyclic Nucleotide (4) Serotonin (8) ****(R,R)−cis−Diethyltetrahydro−2,8−chrysenediol Dopamine (5) Other (9) *****4−phenyl−3−furoxancarbonitrile Supplementary Fig. 2. Structures of lifespan-extending compounds and their effects on stress resistance. Structures are shown for compounds that increased C. elegans lifespan. Compounds in the red circle increased oxidative stress resistance in C. elegans. Names of compounds are color coded and numbered according to pharmacological class, as indicated. Full names for compounds marked by asterisks are shown at lower left. Supplementary Fig. 3. Dose response curves for lifespan- extending compounds H N Cl Cl H H Adrenoceptor Class N NH2 N NH 2 N N +60 O NH N NH Cl Cl Cl +40 guanfacine O guanabenz -40 -20 0 +20 amoxapine O O H N N O NN O O N N Change in lifespan [%] N O HO O NH 2 doxazosin [uM] naftopidil nortriptyline 2 3 10 30 100 200 O N OH N HC3 N Dopamine Class OH N N N H HCH3 HO Cl Cl H S O O HO OH cortexolone octoclothepin loxapine propylnorapomorphine +60 Cl N N N +40 O N N N N O F -40 -20 0 +20 N F H Cl N S N F O S S S S N-(2-[4-(4-Chlorophenyl...* chlorprothixene thioridazine propionylpromazine fluphenthixol S Change in lifespan [%] H O H N O O [uM] N OH HN H N N N 2 3 10 30 100 200 N HN N HN H H O H S O OH H N Concentration [uM] H BTCP dihydroergocristine pergolide methylergonovine O O O O S N N ON N Serotonin Class O H H N H +60 N O N HN N N H H HN H O N +40 N HO H metergoline N dihydroergotamine LY−367,265 -40 -20 0 +20 F F mianserin O FF O O F OH N Cl N N N NN N H N F N NH2 Change in lifespan [%] N O F H ketanserin PAPP/LY-165,163 [uM] BRL 15572 amperozide 2 3 10 30 100 200 Phosphorylation Class +60 N O +40 NH Br 2 O Br N -40 -20 0 +20 OH O O HN Cl HN HN N N N O O cyclosporin A H NH N N CN Br N H H N O N H O SU 4312 Change in lifespan [%] kenpaullone LFM−A13 DAPH 7-Cyclopentyl-5-(4-...*** tyrphostin AG 1478 [uM] 2 3 10 30 100 200 Hormone Class +60 O +40 O Supplementary Fig. 3. OH OH OH O -40 -20 0 +20 Dose response curves for O N lifespan- extending com- HO HO Cl O β-estradiol (R,R)−THC **** cyproterone danazol Change in lifespan [%] pounds. Graphs show [uM] percent increase in lifespan 2 3 10 30 100 200 compared to vehicle control Ca2+ Channel Class +60 (DMSO) as a function of +40 NO compound concentration NO2 2 -40 -20 0 +20 O O O O N N [uM]. Data points indicate O O O O N N N means of different experimen- H H tal populations and error bars nitrendipine nicardipine cinnarizine Change in lifespan [%] [uM] indicate S.E.M.. Results 2 3 10 30 100 200 obtained with the compounds Antibiotic Class +60 at left are shown in different +40 OH O OHO O OHO OHO O OHOOHO O HO OH OH NH -40 -20 0 +20 colors, as indicated. Each 2 NH2 NH2 OH OH OH HH HH compound produced a signifi- Cl OH N N N N cant lifespan increase at two demeclocycline minocycline doxycycline Change in lifespan [%] or more concentrations [uM] 2 3 10 30 100 200 (p<0.05). Cyclic Nucleotides Class +60 +40 *N−(2−[4−(4−Chlorophenyl)piperazin−1−yl]ethyl)−3−methoxybenzamide O H N O -40 -20 0 +20 **3,4−Dichloroisocoumarin O O S ***7-Cyclopentyl-5-(4-phenoxy)phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine N N NH ****(R,R)−cis−Diethyltetrahydro−2,8−chrysenediol NN O O *****4−Phenyl−3−furoxancarbonitrile O NO2 trequinsin BRL 50481 vinpocetine Change in lifespan [%] [uM] 2 3 10 30 100 200 Supplementary Fig.
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