TABLE 1.
Examples of naturally-occurring substances and related pharmaceutical drugs that extend C. elegans lifespan.
The “Mechanism” column displays modulation of specific cellular components (e.g., DAF-16↑, SOD-1↑, ROS↓) or involvement of particular genes, proteins and enzymes (e.g., DAF-2, OSR-1, Sir-2.1). In the “Lifespan” column, the parentheses indicate that lifespan assays were performed in the presence of cellular stress such as high glucose, heat or paraquat; in some studies, extension of “median” lifespan was reported. Only the highest increase in mean, median or maximum lifespan is shown. Abbreviations: AAK-2, 5' adenosine-monophosphate-activated protein kinase catalytic subunit alpha 2; AGE-1, phosphatidylinositol 3-kinase age 1; AGEs, advanced glycation endproducts; AMPK, 5'-adenosine-monophosphate-activated protein kinase; CBP-1, calcineurin-binding protein-1; DAF, abnormal dauer formation protein; EGCG, epigallocatechin gallate; FOX, forkhead box; GLP-1, abnormal germ line proliferation; HSF-1, heat shock factor 1; HSP, heat-shock protein; MDA, malondialdehyde; ND, not determined; NDGA, nordihydroguaiaretic acid; OSR-1, odd-skipped-related protein-1; ROS, reactive oxygen species; Sir, sirtuin; SKN-1, skinhead protein 1; SOD, superoxide dismutase; TOR, target of rapamycin; UPRmit, mitochondrial unfolded protein response.
| Substance | Chemical Class | Source | Mechanism (or Gene Involved) | Mean Lifespan | Maximum Lifespan | Ref. |
|---|---|---|---|---|---|---|
| Acetylsalicylic acid (aspirin) | Organic acid | Analgesic drug (derived from willow bark) | AAK-2/AMPK↑, DAF-16↑, SOD-3↑, ROS↓ | +23% (ROS) | [21, 22] | |
| Antcin M | Terpenoid | Antrodia cinnamomea | ROS↓ | +7% | [47] | |
| Aspalathin | Chalcone glycoside | Rooibos tea | DAF-16↑, ROS↓ | +24% (high glucose only) | [48] | |
| Baicalein | Flavonoid | Scutellaria baicalensis | SKN-1↑ | +45% | +24% | [49, 50] |
| Betalains | Indole | Opuntia fruit | ROS↓ | +34% | [51] | |
| Boeravinone B | Rotenoid | Boerhaavia diffusa | DAF-16↑, SKN-1↑ | +28% | [52] | |
| Brazilin | Flavonoid | Caesalpinia sappan | DAF-16↑, HSP-16.2↓, SOD-3↑, ROS↓ | +18% | [53] | |
| Caffeic acid | Polyphenol | Plants | DAF-16↑, Sir-2.1, OSR-1 | +15% | [54] | |
| Caffeic acid phenyl ester | Polyphenol | Propolis | DAF-16↑ | +9% (median) | +17% | [55] |
| Caffeine | Alkaloid | Coffee | DAF-16↑, CBP-1 | +37% | +52% | [19, 56–58] |
| Calycosin | Isoflavone | Astragalus membranaceus | DAF-2, DAF-16↑ | +25% | [59] | |
| Carnosic acid | Terpenoid | Rosmarinus officinalis | SOD-3↑, SKN-1↑, HSF-1↑ | +16% | +22% | [60] |
| Carnosol | Terpenoid | R. officinalis | SOD-3↑, ROS↓ | +19% | +26% | [35] |
| Catechin | Flavonoid | Green tea | DAF-2 | +15% | [61, 62] | |
| Celastrol | Terpenoid | Tripterygium wilfordii | ND | +17% | [63] | |
| Chlorogenic acid | Polyphenol | Coffee | DAF-2, DAF-16↑, SKN-1↑ | +20% | [34] | |
| Chlorophyll | Chlorin | Vegetables | DAF-16↑ | +26% | [64] | |
| Curcumin | Polyphenol | Turmeric | Sir-2.1, OSR-1 | +55% (median) | [65, 66] | |
| Damaurone D | Flavonoid | Damask rose | DAF-2, DAF-16↑, SOD-3↑ | +17% | +21% | [67] |
| Dehydroabietic acid | Terpenoid | Conifer resin | Sir-2.1 | +16% | [68] | |
| Diallyl trisulfide | Organosulfur | Garlic | SKN-1↑ | +13% | [69] | |
| Diosgenin | Terpenoid | Plants | DAF-16↑, SOD-3↑ | +20% | [70] | |
| 4,4'-Dimethoxychalcone | Chalcone | Angelica keiskei koidzumi | Autophagy↑ | +20% (median) | [71] | |
| Emodin | Anthraquinone | Rhubarb, buckthorn | Sir-2.1, DAF-16↑ | +20% | [77] | |
| Ellagic acid | Phenol | Fruits | DAF-16↑ | +11% | [62, 78] | |
| Ferulsinaic acid | Organic acid | Ferula plants | AGEs↓, ROS↓ | +18% | +42% | [79] |
| Fisetin | Flavonoid | Fruits, vegetables | DAF-16↑, ROS↓ | +6% (heat) | [80] | |
| Flavonoids | Flavonoid | Onion | ND | +20% | [17] | |
| Fruit extract | Mixture | Apple | ND | +39% | +25% | [81] |
| Fruit extract | Mixture | Blueberry | DAF-16↑, SKN-1↑, SOD-3↑ | +44% | +24% | [82] |
| Fruit extract | Mixture | Mulberry | DAF-16↑, Sir-2.1 | +20% | +9% | [83] |
| Fruit extract | Mixture | Orange | DAF-16↑, SOD-3↑, ROS↓ | +26% | +26% | [84] |
| Fruit extract | Mixture | Pomegranate | DAF-16↑ | +56% | +36% | [78] |
| Fruit extract | Mixture | Purple pitanga | DAF-16↑ | ND | [85] | |
| Fungal extract | Mixture | Ganoderma lucidum | GLP-1 | +36% | +12% | [86] |
| Gallic acid | Phenolic acid | Fruits | ND | +12% | [62] | |
| Genistein | Isoflavone | Soybean, coffee | SOD-3↑, HSP-16.2↑ | +28% | [87] | |
| Glucosamine | Amino sugar | Dietary supplement (can be isolated from wheat or corn) | AAK-2/AMPK↑, mitochondrial biogenesis↑, autophagy↑ | +30% | [30, 88] | |
| Glaucarubinone | Degraded terpenoid | Simaroubaceae plants | Cellular respiration↑ | +8% | +8% | [89] |
| Huperzine A | Alkaloid | Huperzia serrata | ND | +13% | [90] | |
| 10-Hydroxy-2-decenoic acid | Organic acid | Royal jelly | ND | +12% | +21% | [91] |
| Icariin | Flavonoid glycoside | Epimedium brevicornum | DAF-16↑ | +21% | [92] | |
| Icariside II | Flavonoid glycoside | E. brevicornum | DAF-16↑, HSP-12.3↓ | +31% | [92] | |
| Isorhamnetin | Flavonoid | Onion | ROS↓ | +16% | +16% | [93] |
| Kaempferol | Flavonoid | Fruits, vegetables | DAF-16↑, ROS↓ | +10% (heat) | +7% | [80, 94] |
| Laricitrin | Flavonoid | Red grapes and wine | DAF-16↑ | +55% | [95] | |
| Lignans | Polyphenol | Arctium lappa | DAF-16↑ | +25% | [96] | |
| Lovastatin | Lactone | Mushrooms | DAF-16↑ | +25% | [97] | |
| Metformin | Biguanide | Anti-diabetic drug (derived from French lilac) | AAK-2/AMPK↑, TOR↓, SKN-1↑, methionine↓, agmatine↑ | +40% (median) | [37, 98–100] | |
| Monascin | Azaphilonoid | Monascus purpureus | DAF-16↑, SOD-1↑, HSP-16.2↑ | +29% (CL2006 strain) | [101] | |
| Myricetin | Flavonoid | Fruits, vegetables | DAF-16↑, ROS↓, Sir-2.1 | +48% | +22% | [94, 95, 102, 103] |
| Myricetin-trimethylether | Flavonoid | Bridelia plant | DAF-16↑ | +54% | [95] | |
| Naphthazarin | Naphthoquinone | Plants | SKN-1↑ | +13% | +25% | [18] |
| NDGA | Polyphenol | Larrea tridentata | Autophagy↑ | +21% (median) | [104] | |
| 5'-Octanoyl salicylic acid | Organic acid | Skin exfoliating drug (aspirin derivative) | AAK-2/AMPK↑, TOR↓, autophagy↑, UPRmit↑ | +19% | +12% | [105] |
| Oleanolic acid | Terpenoid | Plants | DAF-16↑, ROS↓ | +17% | [106] | |
| Oxoline | Naphthoquinone | Plants | ND | +15% | +10% | [18] |
| Piceatannol | Stilbenoid | Red grape, wine | DAF-2, DAF-16↑, Sir-2.1 | +18% (median) | [107] | |
| Plant extract | Mixture | Alpinia zerumbet | SOD-3↑, HSP-16.2↑ | +23% | +61% | [108] |
| Plant extract | Mixture | Anacardium occidentale | DAF-16↑, SKN-1↑, SOD-3↑ | +20% | [109] | |
| Plant extract | Mixture | Betula utilis | DAF-16↑, HSF-1↑, SKN-1↑, ROS↓ | +36% | [110] | |
| Plant extract | Mixture | Black tea | ND | ND | [111] | |
| Plant extract | Mixture | Caesalpinia mimosoides | DAF-16↑, ROS↓ | +4% | [112] | |
| Plant extract | Mixture | Damnacanthus officinarum | ND | +10–30% | [113] | |
| Plant extract | Mixture | Dioscorea alata | HSP-16.2↑, SKN-1↑ | +28% | [114] | |
| Plant extract | Mixture | Eleutherococcus senticosus | DAF-16↑ | +16% | +12% | [25] |
| Plant extract | Mixture | Garlic | DAF-16↑ | +21% | [115] | |
| Plant extract | Mixture | Ginkgo biloba | ROS↓ | +8% (median) | [116, 117] | |
| Plant extract | Mixture | Glochidion zeylanicum | DAF-16↑, SKN-1↑, SOD-3↑, HSP-16.2↓ | +10% | [118] | |
| Plant extract | Mixture | Green tea | EAT-2 | ND | [111] | |
| Plant extract | Mixture | Guarana | DAF-16↑ | +14% | [119] | |
| Plant extract | Mixture | Hibiscus sabdariffa | DAF-16↑, SKN-1↑ | +24% | [120] | |
| Plant extract | Mixture | Lonicera japonica | DAF-2, DAF-16↑, SOD-3↑, ROS↓ | +22% | [121] | |
| Plant extract | Mixture | Pu-er tea | ND | ND | [111] | |
| Plant extract | Mixture | Ribes fasciculatum | DAF-2, AGE-1, DAF-16↑, Sir-2.1, SOD↑, ROS↓ | +16% | +19% | [122] |
| Plant extract | Mixture | Rhodiola rosea | DAF-16↑ | +15% | +12% | [25] |
| Plant extract | Mixture | Rooibos tea | HSP-16.2↓ | +23% (high glucose only) | [48] | |
| Plant extract | Mixture | Turkish medicinal plants | ND | +24% | [123] | |
| Plant extract | Mixture | Viscum album coloratum | Sir2 | +10% | [26] | |
| Plumbagin | Naphthoquinone | Plumbago zeylanica | DAF-16↑, SKN-1↑ | +12% | +13% | [18] |
| Polydatin | Stilbenoid glycoside | Grape | DAF-16↑, SOD-3↑ | +31% | [124] | |
| Polysaccharides | Polysaccharide | A. membranaceus | DAF-16↑ | +20% (median) | [125] | |
| Polysaccharides | Polysaccharide | Auricularia auricular | DAF-16↑, SKN-1↑, Sir-2.1 | -18% | +22% | [126] |
| Polysaccharides | Polysaccharide | Chlorophytum borivilianum | ND | +23% | (median) | [127] |
| Polysaccharides | Polysaccharide | Cordyceps militaris | ND | +17% | [128] | |
| Polysaccharides | (lentinan) | Polysaccharide | Lentinula edodes | ND | +11% | [128] |
| Polysaccharides | Polysaccharide | Panax notoginseng | SOD↑, catalase↑, MDA↓ | +21% | [129] | |
| Polysaccharides | Polysaccharide | G. lucidum | DAF-16↑, autophagy↑ | +44% | (median) | [130], unpublished data |
| Polysaccharides | Polysaccharide | Rehmannia glutinosa | DAF-16↑ | ND | [131] | |
| Polyphenols | Polyphenol | Apple | Sir-2.1 | +12% | [132] | |
| Polyphenols | Polyphenol | Blueberry | ROS↓, OSR-1, SEK-1↑ | +28% | +14% | [133] |
| Polyphenols | Polyphenol | Cocoa | DAF-16↑, Sir-2.1 | +17% (median) | [134] | |
| Quercetin | Flavonoid | Vegetables | AGE-1, DAF-2, DAF-16↑, SEK-1↑ | +15% | +18% | [54, 93,94, 135–138] |
| Quercetin-3-O-glucoside | Flavonoid glycoside | Vegetables | ND | +23% | +7% | [139] |
| Quinic acid | Polyol | Uncaria tomentosa | DAF-16↑, SOD-3↑ | +7% | [140] | |
| Reserpine | Alkaloid | Indian snakeroot, anti-hypertensive drug | Stress tolerance↑ | +31% | [141] | |
| Resveratrol | Stilbenoid | Red wine, dietary supplement | Sir-2.1, autophagy↑ | +18% | [142–147] | |
| Rosmarinic acid | Polyphenol | R. officinalis | DAF-16↑, OSR-1, SEK-1↑, Sir-2.1 | +63% | [54,148] | |
| Royal jelly | Mixture | Dietary supplement | DAF-16↑ | +9% | [91] | |
| S-allylcysteine | Organosulfur | Garlic | SKN-1↑ | +17% | [149] | |
| S-allylmercaptocysteine | Organosulfur | Garlic | SKN-1↑ | +21% | [149] | |
| Spermidine | Polyamine | Natto, mushrooms | Autophagy↑ | +15% | [150] | |
| Silymarin | Flavonolignan | Milk thistle | DAF-16↑, SOD-3↑, ROS↓ | +18% | [151] | |
| Simvastatin | Lactone | Cholesterol-lowering drug (derived from fungi) | ND | +13% | [97] | |
| Syringetin | Flavonoid | Sichuan pepper | DAF-16↑ | +36% | [95] | |
| Tamarixetin | Flavonoid | G. biloba | ROS↓ | +29% (median) | [93,116] | |
| Tambulin | Flavonoid | Zanthoxyllum aramatum | DAF-16↑, SOD-1↑, SOD-3↑, ROS↓ | +17% | [152] | |
| Tannic acid | Polyphenol | Plants | SEK-1↑ | +19% | [62,153] | |
| Taurine | Amino sulfonic acid | Dietary supplement | ND | +11% | [154] | |
| Theanine | Amino acid | Tea, dietary supplement | ND | +14% | [154,155] | |
| Theophylline | Alkaloid | Coffee | ROS↓ | +21% | [19] | |
| Tocotrienols | Tocopherol | Fruits, vegetables | ROS↓ | +20% | [156] | |
| Tomatidine | Alkaloid | Unripe tomatoe | SKN-1↑ | +7% | [157] | |
| Trehalose | Disaccharide | Vegetables, mushrooms | DAF-2 | +30% | [158] | |
| Triptolide | Terpenoid | T. wilfordii | SOD-3↑, HSP-16.2↑, ROS↓ | +20% | +16% | [159] |
| Ursolic acid | Terpenoid | Plants | SKN-1↑ | +31% | [160] |