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Current Perspective in the Discovery of Anti-aging Agents from Natural Products

  • Ai-Jun Ding 1,2,  
  • Shan-Qing Zheng 1,2,  
  • Xiao-Bing Huang 1,2,  
  • Ti-Kun Xing 1,2,  
  • Gui-Sheng Wu 1,3,  
  • Hua-Ying Sun 1,  
  • Shu-Hua Qi 4,  
  • Huai-Rong Luo 1,3,5
    •     
Received date: 16 April 2017; Accepted: 16 May 2017; Published online: 31 May 2017
© The Author(s) 2017. This article is an open access publication

Abstract

Aging is a process characterized by accumulating degenerative damages, resulting in the death of an organism ultimately. The main goal of aging research is to develop therapies that delay age-related diseases in human. Since signaling pathways in aging of Caenorhabditis elegans (C. elegans), fruit flies and mice are evolutionarily conserved, compounds extending lifespan of them by intervening pathways of aging may be useful in treating age-related diseases in human. Natural products have special resource advantage and with few side effect. Recently, many compounds or extracts from natural products slowing aging and extending lifespan have been reported. Here we summarized these compounds or extracts and their mechanisms in increasing longevity of C. elegans or other species, and the prospect in developing antiaging medicine from natural products.

Keywords

Aging    Natural products    Anti-aging    Drug screening    
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1 Introduction

Since realizing the inevitability of death, the fear of death and pursuit of immortality might have preoccupied with human beings. In the Epic of Gilgamesh, Gilgamesh (the Sumerian king of Uruk) was obsessed in pursuit of immortality herbal. About 200 BC, Qin Shi Huang (the first emperor of a unified China) feared death and desperately sought the fabled elixir of life. A more recent story was the Spanish explorer Ponce de Leon who was looking for the mythical fountain of youth. Unexpectedly, all these human activities of pursuing for immortality were failed. We now know that there is no such elixir of immortality placed in somewhere by god and waited for human to find it.

On the other hand, early medical practice was developed in Babylon, Egypt, Greece, India, and China. Along with the development of biology, chemistry, physics and math, the west medical tradition developed into modern medical science. Great success has been achieved in prevention and treatment of disease. Consequently, the longevity of human has been greatly extended. The aged population is growing rapidly in modern world. Aging is the most risk factor for many age-associated diseases, such as neurodegenerative disease, diabetes, stroke, and cancer. The aged people are often suffering from one or multiple aging associated diseases, which brings enormous social and economic burden. While current medicine is focused on treatment of individual disease, the aging people recovered for one disease would probably suffer from other disease soon later.

Two thousand years ago, a systematic theory and practice to achieve healthy aging with core idea of "preventive treatment of disease" was proposed in Huang Di Nei Jing (one of the most important classical texts of traditional Chinese medicine). Current geroscience research have revealed key molecular processes that underlie biological aging [1], and that delaying aging process could delay the onset and progress of age-associated diseases and the disability of aging people [2]. As the modern version of "the preventative treatment of disease", anti-aging medicine could be the most effective way to combat the age-associated diseases and the disability of aging people. Currently, many compounds with anti-aging activity have been discovered. A large portion of these compounds are natural products. Therefore, we summarized these natural products or extracts that are reported to have anti-aging effects. We also discussed the prospect and challenges of natural products in development of anti-aging medicine.

2 Current Progress in Aging Research

Biological process was relying on the delicate interaction of biomolecules. These building blocks of organism were selected during the origin of life, and were imperfect and intrinsic to generation of damage in every biological process, such as in DNA replication, epigenetic modification, transcription and translation, protein post-translational modification, protein fold, and metabolic process. For some of the damages were endangering species survival, their correction mechanisms were evolved by natural selection, such as DNA repair, protein unfolding response, antioxidant mechanism, detoxification, autophagy, and proteasome. The failure of these protection processes would cause the occurrence of aging and pathological phenotypes, while enhancing these protection processes would delay aging and related phenotypes. Here we summarized how the dynamic interactions between various damages and errors occurred in biological process and their evoked response of correction mechanisms contribute to genome stability, proteostasis and metabolic homeostasis, to cellular homeostasis and finally to aging process (Figs. 1, 2). For the detailed mechanisms of aging, we refer to the reviews elsewhere [1, 3-8].

Fig. 1

Aging mechanisms in different hierarchies

Fig. 2

Signaling networks in aging. Dietary restriction (DR), insulin/IGF-1-like signaling (IIS), germline, MAPK and mitochondrial dysfunction pathway networks in aging

2.1 Genome Stability and Aging

Accumulation of genome damage is one of the major causes of aging [9]. The intrinsic threats to DNA integrity, including DNA replication errors, spontaneous hydrolytic reactions, and reactive oxygen species (ROS), together with exogenous physical (e.g. UV/IR radiation), chemical and biological agents (e.g. virus) cause various genetic lesions, such as point mutations, translocations, chromosomal gains and losses, telomere shortening, and gene disruption. About 70, 000 lesions per day were estimated to happen in each normal human cell [10]. Accordingly, a complex repair mechanisms, such as base excision repair (BER), nucleotide excision repair (NER), transcription-coupled repair (TCR), homologous recombination, nonhomologous end-joining (NHEJ), and telomere elongation have been evolved in the organism. The deletion of genes for BER were lethal in mice [11], while mutations affecting NER and TCR were associated with numerous disorders and accelerated aging [12-14]. Mice with defected in NHEJ were subjected to early onset of aging [15]. The discovery of the causality between telomere shortening and cell replication limits, has led to the generation of telomere theory of aging [16]. Patients with inherited telomere syndrome presents greater overall telomere attrition and premature aging [16]. Compounds with improving telomerase activity or suppressing telomere shortening play distinct roles in anti-aging [17].

The epigenetic changes are one of the hallmarks of aging, including alterations in transcription factor binding, histone marks, DNA methylation, and nucleosome positioning [18]. These epigenetic changes can either happen spontaneously or modulated by environmental stimuli, nutrient signaling, and metabolic state, via multiple enzymatic systems including DNA methyltransferases, histone acetylases, deacetylases, methylases, demethylases, and other protein complex. These epigenetic changes can cause aberrant transcription and noncoding RNA expression and impair DNA integrity, affect cellular function and stress resistance, heavily influence the progression of aging. Diet or environment and genetic influencing epigenetic information could alter aging process [19]. Humans and mice with genetic defects in genome maintenance present accelerated aging symptoms, while enhancing DNA maintenance could delay aging [20].

2.2 Proteostasis and Aging

Errors happen on proteins including abnormally synthesized proteins, protein unfolding, abnormal cleavage, undesirable posttranslational modifications, can cause protein self-assembling into toxic oligomeric structures or aggregation into cytosolic inclusions. These damaged proteins can be recognized by chaperones or heat shock proteins and delivered to degradation by the ubiquitin/proteasome system or the lysosomes/autophagy. Increased protein damages would compromise endo-reticulum (ER) homeostasis, lead to increased synthesis of ER chaperones and reduced protein translation to maintain proteostasis, this response is called the unfolding protein response (UPR) [21]. The ability to maintain the protein homeostasis decline with age, many age-related diseases, such as Alzheimer's disease, Parkinson's disease, and ALS are associated with intracellular accumulation of abnormal proteins in the form of protein inclusions and aggregates [22]. Chaperone defective could lead to accelerated aging [23], while activation of the master regulator of the heat-shock response, the transcription factor HSF-1, could upregulate heat-shock proteins and increase longevity in C. elegans and mice [24, 25].

2.3 Metabolic Homeostasis and Aging

Metabolism provides energy for cell activity, molecules attending signaling transmission, and building block of cell components. Genome instability, proteostasis failure, and environmental influence could lead to abnormal energy supply and metabolite production, such as excessive free oxygen radicals and toxic molecules. Free oxygen radicals including reactive oxygen species (ROS) and diffusible hydrogen peroxide (H2O2), could lead to accumulated oxidative damages, such as carbonylation, oxidized methionine, glycation, aggregation of proteins and DNA damage, and contribute to aging and age-related diseases [26]. This process was proposed by the famous free radical theory of aging. Many compounds increase longevity or improve age-related diseases via scavenging free radicals, such as resveratrol, astaxanthin and gallic acid [27-29].

JNK, a MAP kinase family member, activated by oxidative stress increases longevity in fruit flies and worms [30, 31]. Reduced function of electron transport chain (ETC) could dramatic extend the lifespan of C. elegans and Drosophila [32, 33]. Recently research shows that mitophagy modulates bioenergetics and survival in the neurodegenerative disease by reducing redox and damage [34].

The regulation of metabolism is closely coupled with nutrient sensing pathways, including insulin-like growth factor (IGF) signaling (IIS) pathway [35], target of rapamycin (TOR) signaling [36], adenosine monophosphate activated protein kinase (AMPK) pathway [37], and sirtuins [38]. These signaling pathways sense nutrient or metabolites to regulate the level of glucose, amino acid, cAMP and nicotinamide adenine dinucleotide (NAD+). These pathways regulate growth, metabolic and aging process. Genetic or pharmacological intervention of their components can extend lifespan and delay age-associated dysregulation [8].

2.4 Cellular Homeostasis and Aging

Failure to maintain genome stability, proteostasis and metabolic homeostasis will lead to imbalance of cellular homeostasis and cellular senescence. Genome instability could lead to abnormality of nuclear structure, while excessive protein aggregation could cause ER malfunction. Genome damage, defective proteins, and excessive production of ROS could impair mitochondria. Mitochondria damage could induce rescue mechanisms: mitochondrial biogenesis, mitochondria specific unfolded protein response and mitophagy (macroautophagy that targets deficient mitochondria for proteolytic degradation) [39]. Recently research shows that mitophagy modulates bioenergetics and survival in the neurodegenerative disease by reducing redox and damage [34]. The increased damage and reduced repair response are important to aging process.

Senescent cells secret signaling molecules enriched in proinflammatory cytokines and matrix metalloproteinases, which could attract mast cells to clear the senescent cells through macrophage. But deficient clearance of senescent cells will induce inflammation, impair adjacent cells and tissue function, and lead to stem cell exhaustion, and finally contribute to aging [40]. Either genetic or pharmacological elimination of senescent cells could delay age-related pathologies [41, 42].

3 Natural Products with Anti-aging Activity

To date, there are about 5, 400 scientific research/review articles published under the terms of "anti-aging" and "anti-ageing" terms (obtained from Web of Science, May 2017; keywords restricted to the topics: anti-aging and anti-ageing, at the search domain of Science & Technology). These reports revealed more than 300 compounds with anti-aging activity. Here we summarized the compounds or natural product extracts with explicit anti-aging activity, including 185 compounds from natural products (Table 1), 55 complex or extracts from natural products (Table 2), 62 from clinical drugs (of which more than 50% are also from natural products or natural products analogues, Table 3), 35 from synthesized chemicals (Table 4). Some of them received popular interest and under vigorous investigation, present anti-aging activities in multiple aging models, such as resveratrol [28, 43-53], α-lipoic acid [54-56], astaxanthin [29, 57-59], catechin [60-62], curcumin [63-65], fucoxanthin [66, 67], spermidine [68, 69], metformin [70-72], caffeine [73-75], and rapamycin [76-84], all show anti-aging activity in both D. melanogaster and C. elegans, as well as in other aging models (Table 1). There are 39 compounds present anti-aging activity in two aging models, 32 of them with anti-aging activity in C. elegans. 19 of the 39 compounds are antioxidant (including acacetin, antcin M, agmatine, baicalein, caffeic acid, carnosine, chlorogenic acid, coenzyme Q10, dimethyl sulfide, gallic acid, gluconate, glycerol, hesperidin, icariin, lactate, oleanolic acid, minocycline, vitamin E, and vitexin). Compound betaine, catalpol, (-)-epicatechin, huperzine A and polydatin regulate inflammation. 11 compounds act through energy sensing pathway, including acetic acid, α-ketoglutarate, D-glucosamine, epigallocatechin gallate, nordihydroguaiaretic acid, oligonol, polydatin, rosmarinic acid, sesamin, aspirin, and tetrahydrocurcumin. There are 14, 9, and 109 natural products with anti-aging activity reported only in mice or rat, fruit fly, and C. elegans, respectively, while 14 compounds present anti-aging activities in other aging models, such as mammalian cells and S. cerevisiae. Among the 109 compounds with anti-aging activity in C. elegans, 18 with antioxidative activity, five regulating IIS pathway, four regulating AMPK, four regulating mTOR signaling, 10 regulating SIR-2.1, six regulating SKN-1/Nrf2 pathway, seven regulating JNK-1, 16 with unknown mechanisms, and about half of 109 compounds revealed to regulate multiple signaling pathways.

Table 1

Compounds from natural products with anti-aging activities

CAS Chemicals Structure Source Anti-aging activity and proposed anti-aging mechanism
With anti-aging activities in a variety of aging models
501-36-0 Resveratrol Polygonum cuspidatum Sieb.et Zucc. In mice: 4.7% increase in mean lifespan; increasing insulin sensitivity, reducing insulin-like growth factor-1 (IGF-I) levels, increasing AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) activity, increasing mitochondrial number, and improving motor function [44, 46-51]
In D. melanogaster: extends mean lifespan of females fed the low sugar-high protein diet by ~15.0%, fed the high-fat diet by ~10.0%; modulating genetic pathways that can reduce cellular damage [45]
In C. elegans: 18.0% increase in mean lifespan; regulating AMPK, SIR-2.1, autophagy, and proteasomal degradation [28, 52, 53]
In cell: increasing NAD(+) and the activity of AMPK and Sirt1, inhibiting PDE4, JAK2/STAT3 [89-92]
In S. cerevisiae: 70.0% increase in mean lifespan; regulating Sir2 and SNF1 [93, 94]
In Nothobranchius guentheri: antioxidant [95]
62-46-4 α-Lipoic acid Cell metabolite In SAMP8 mice: improving memory and oxidative stress in extremely old SAMP8 mice, but decreasing lifespan [56]
In D. melanogaste: 12.0% increase in mean lifespan and antioxidant [54]
In C. elegans: 24.0% increase in mean lifespan and antioxidant, enhancing chemotaxis index [55]
472-61-7 Astaxanthin Carotenoid In D-galactose-induced brain aging in rats: antioxidant, upregulating BDNF expression [58, 59]
In D. melanogaster: antioxidant [57]
In C. elegans: 29.0% increase in mean lifespan and regulating DAF-16 [29]
154-23-4 Catechin Green tea, cocoa, grapes, and apples In senescence-accelerated (SAMP10) mice: preventing memory regression and DNA oxidative damage [62]
In D. melanogaster: 16.0% increase in mean lifespan and antioxidant [61, 96]
In C. elegans: 13.0% increase in mean lifespan and antioxidant, regulating DAF-2, AKT-2, MEV-1, and NHR-8; decreasing insulin-like growth factor-1 [60]
458-37-7 Curcumin Curcuma longa L. In C57BL6/N mice: antioxidant, increasing collagen and AGEs [64]
In D. melanogaster: 25.8% increase in mean lifespan and antioxidant [65]
In C. elegans: 25.0% increase in mean lifespan and antioxidant [63]
3351-86-8 Fucoxanthin Natural substances in human diet In hairless mice: lessening UVB-induced epidermal hypertrophy, VEGF, and MMP-13 expression [67]
In D. melanogaster: 33.0% increase in mean lifespan and antioxidant [66]
In C. elegans: 14.0% increase in mean lifespan and antioxidant [66]
124-20-9 Spermidine Natural polyamine In D. melanogaster: 30.0% increase in mean lifespan and autophagy [68]
In C. elegans: 15.0% increase in mean lifespan and autophagy [68]
In S. cerevisiae: autophagy [68, 69]
With anti-aging activities in two aging models
480-44-4 Acacetin Naturally occurring flavonoid In D. melanogaster: decreasing APP protein expression, BACE-1 activity, and Aβ production [97]
In C. elegans: 27.3% increase in mean lifespan and upregulating SOD-3 and GST-4 [98]
64-19-7 Acetic acid Vinegars In C. elegans: 23.0% increase in mean lifespan and regulating insulin/IGF-1 pathway [99]
In S. cerevisiae: stimulating growth signaling pathways, increasing oxidative stress and replication stress [100]
1005344-44-4 Antcin M Antrodia cinnamomea In cell: antioxidant, regulating Nrf2 and SIRT-1 [101]
In C. elegans from oxidative stress: ~10.0% increase in mean lifespan and antioxidant [101]
306-60-5 Agmatine Generated by arginine decarboxylase In male sprague-dawley rats: suppressing age-related elevation in nitric oxide synthase activity in the dentate gyrus of the hippocampus and prefrontal cortex [102]
In C. elegans: 16.0% increase in mean lifespan and needs further research [103]
328-50-7 α-Ketoglutarate Tricarboxylic acid cycle intermediate In mice: decreasing TBARS level and the activity of superoxide dismutase, increasing glutathione peroxidase activity [104]
In C. elegans: 50.0% increase in mean lifespan and inhibiting ATP synthase and TOR signaling [105]
491-67-8 Baicalein Scutellaria baicalensis Lamiaceae In C. elegans: 24.0% increase in mean lifespan and antioxidant, regulating SKN-1 [106]
In PC12 cell: suppressing mitochondria dysfunction and apoptosis [107]
107-43-7 Betaine Nitrogen containing metabolite In aged rats: upregulating IKK/MAPKs, attenuating NF-κB activation [108, 109]
In C. elegans: 9.0% increase in mean lifespan and needs further research [103]
331-39-5 Caffeic acid Tomatoes, carrots, strawberries, blueberries and wheat In Sprague-Dawley rats and intra-cerebroventricular streptozotocin induced experimental dementia in rats: antioxidant, restoring cholinergic functions [110, 111]
In C. elegans: 11.0% increase in mean lifespan and regulating OSR-1, SEK-1, SIR-2.1, UNC-43, and DAF-16 [112]
305-84-0 Carnosine Endogenous dipeptide In aged rats: preventing oxidative stress and apoptosis [113, 114]
In D. melanogaster: 26.0% increase in mean lifespan and antioxidant [115, 116]
2415-24-9 Catalpol Rehmannia glutinosa In senescent mice induced by D-galactose: improving cholinergic function, reducing inflammatory cytokines; In rats: rebalancing E2 and P4 levels in aged rats [117, 118]
In C. elegans: 28.5% increase in mean lifespan and antioxidant, regulating SKN-1/Nrf and DAF-16 [119]
327-97-9 Chlorogenic acid Coffee and tea In D-galactose-induced mice: antioxidant, reducing tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) protein levels [120]
In C. elegans: 20.1% increase in mean lifespan and antioxidant, regulating IIS pathway [121]
303-98-0 Coenzyme Q10 Mitochondrial respiratory chain component In mice: ameliorating age-related impairment, reducing protein oxidation [122]
In C. elegans: 18.0% increase in mean lifespan and scavenging reactive oxygen species [123]
3416-24-8 D-Glucosamine Hexosamine pathway In mice: 6.0% increase in mean lifespan; enhancing expression of several murine amino-acid transporters, increasing amino-acid catabolism [124]
In C. elegans: 11.0% increase in mean lifespan and mimicking a low-carbohydrate diet by regulating AMPK and SKN-1 [124]
75-18-3 Dimethyl sulfide Metabolite of marine algae or fermentative bacteria In D. melanogaster: 24.2% increase in mean lifespan and antioxidant [17]
In C. elegans: 24.3% increase in mean lifespan and antioxidant [17]
490-46-0 (-)-Epicatechin Cocoa In obese diabetic mice: antioxidant, improving skeletal muscle stress output, reducing systematic inflammation and serum LDL cholesterol [61]
In D. melanogaster: ~8.0% increase in mean lifespan and needs further research [61]
989-51-5 Epigallo-catechin gallate Tea polyphenols In D-galactose-induced mice: increasing oxidative stress and the expression of EGFR proteins [125]
In C. elegans: 13.0% increase in mean lifespan and antioxidant, regulating IIS pathway [126]
149-91-7 Gallic acid Beverages (red wines and green teas), plant leaves (beriberry) In senescence accelerated mice: antioxidant [127]
In C. elegans: 25.0% increase in mean lifespan and antioxidant [27]
527-07-1 Gluconate Sugars metabolite In D. melanogaster: 22.0% increase in mean lifespan and antioxidant [128]
In lacking nitrogen on C. elegans: 16.0% increase in mean lifespan and antioxidant [103]
56-81-5 Glycerol Sugars metabolite In lacking nitrogen on C. elegans: 21.0% increase in mean lifespan and needs further research [103]
In rotifer: 50.0% increase in mean lifespan; increasing resistance to starvation, heat, oxidation, and osmotic stress, but not UV stress [129]
520-26-3 Hesperidin Citrus genus In Murine model of sepsis: antioxidant [130]
In S. cerevisiae: 37.0% increase in mean lifespan and antioxidant, regulating Sir2, UTH1 [131]
489-32-7 Icariin Herba epimedii In mice: inducting antioxidant protein superoxide dismutase (SOD) activity, decreasing oxidative marker malondialdehyde (MDA) [132]
In C. elegans: 20.7% increase in mean lifespan and regulating IIS pathway [133]
74-79-3 Arginine Amino acid In C. elegans: 27.0% increase in oxidative stress; 370% in heat stress and antioxidant, regulating insulin/IGF signaling pathway [103, 134]
In Megalobrama amblycephala: antioxidant [134]
50-21-5 Lactate Metabolite In D. melanogaster: 15.0% increase in mean lifespan and antioxidant [128]
In C. elegans: 6.0% increase in mean lifespan and antioxidant [103]
500-38-9 Nordi-hydroguaiaretic acid Creosote plant (Larrea tridentata: Zygophyllaceae) In mice:12.0% increase in mean lifespan; decreasing the absorption or increasing the utilization of calories [135-138]
In Mosquito: 64.0% increase in mean lifespan and needs further research [137]
508-02-1 Oleanolic acid Olea europaea, Viscum album L., and Aralia chinensis L. In D-galactose-induced mice: anti-oxidative, anti-glycative, and anti-apoptotic [139]
In C. elegans: 16.6% increase in mean lifespan and antioxidant, regulating DAF-16 [140]
851983-55-6 Oligonol Grape seed or lychee fruit In mice: Regulating AMPK, SIRT1, autophagy, and increasing cell proliferation [141, 142]
In C. elegans: regulating AMPK and autophagy [141]
27208-80-6 Polydatin Grape juice In mice: anti-oxidative, anti-inflammatory, and anti-apoptotic [143]
In C. elegans: 30.0% increase in mean lifespan and regulating DAF-2, SIR-2.1, SKN-1, SOD-3, and DAF-16 [144]
537-15-5 Rosmarinic acid Subfamily Nepetoideae of the Lamiaceae In aging mice: antioxidant [145]
In C. elegans: 10.0% increase in mean lifespan and regulating SIR-2.1, OSR-1, SEK-1, UNC-43, and DAF-16 [112]
607-80-7 Sesamin Sesame seeds In D. melanogaster: 12.0% increase in mean lifespan and antioxidant [146]
In C. elegans:14.0% increase in mean lifespan and regulating DAF-2, SKN-1, PMK-1, and DAF-16 [147]
36062-04-1 Tetra-hydrocurcumin Biotransformed metabolite of curcumin contained in turmeric of Indian curry In mice: 12.0% increase in mean lifespan; attenuating oxidative stress, hypertension, vascular dysfunction, and baroreflex dysfunction [148-151]
In D. melanogaster: ~28.0% increase in mean lifespan and regulating Sir2 and FoxO [152]
1143-70-0 Urolithin A Pomegranate fruit, nuts and berries In mouse models of age-related decline of muscle function: improving exercise capacity [153]
In C. elegans: 45.4% increase in mean lifespan and regulating mitochondrial function, mitophagy [153]
3681-93-4 Vitexin Vigna angularis In D-galactose-aged mice: antioxidant [154]
In C. elegans: 17.0% increase in mean lifespan and antioxidant [155]
With anti-aging activities in rats or mice
118-00-3 Guanosine Endogenous nucleoside In Wistar rats: antioxidant [156]
70579-26-9 Porphyra-334 Red alga Porphyra rosengurttii In mice skin: antioxidant, Hsp70 [157]
73112-73-9 Shinorine Red alga Porphyra rosengurttii In mice skin: antioxidant, Hsp70 [157]
70363-87-0 Sargaquinoic acid Sargassum sagamianum In mice skin: inducing apoptosis [158]
70363-89-2 Sargachromenol Sargassum sagamianum In mice skin: inducing apoptosis [158]
1094-61-7 β-Nicotinamide mononucleotide Turnover of the oxidized form of nicotinamide adenine dinucleotide (NAD+) In rats: increasing NAD+ level [159]
1339070-29-9 TA-65 Root of Astragalus membranaceus In mice: activating telomerase [160]
34157-83-0 Celastrol Traditional Chinese medicinal herbs of the Celastraceae family In transgenic mouse model of amyotrophic lateral sclerosis: 13.0% increase in mean lifespan and regulating HSP70, blocking neuronal cell death [161]
57-00-1 Creatine Natural ergogenic compound In mice: 9.0% increase in mean lifespan and upregulating genes implicated in neuronal growth, neuroprotection, and learning [162]
42553-65-1 Crocin Kashmiri saffron (Crocus sativus) In mice: 44.0% increase in mean lifespan and impacting on hematological parameters [163]
61276-17-3 Acteoside Roots of Incarvillea younghusbandii Sprague In senescent mouse model induced by a combination of D-gal and AlCl3: decreasing nitric oxide, the activity of nitric oxide synthase and the expression of caspase-3 [164]
11096-26-7 Erythropoietin Glycoprotein Glycoprotein hormone In rats: antioxidant, regulating ERK/Nrf2-ARE [165]
62499-27-8 Gastrodin A number of plants and herbs In vascular dementia rats induced by chronic ischemia: antioxidant, regulating ADH7, GPX2, GPX3 and NFE2L2 [166]
22427-39-0 Ginsenoside Rg1 Panax ginseng In D-galactose-induced mice: antioxidant, regulating the level of proinflammatory cytokines and telomerase system, activating the Wnt/β-catenin signaling [167, 168]
With anti-aging activities in Drosophila melanogaster
87-89-8 Chiro-inositol Inositol family 16.7% increase in mean lifespan and antioxidant, regulating dFOXO [169]
526-95-4 Gluconic acid Glucose catabolism 22.0% increase in mean lifespan and antioxidant [128]
Glycoside acteoside Roots of Incarvillea younghusbandii Sprague 15.0% increase in mean lifespan and antioxidant [170]
127-40-2 Lutein Major carotenoids in most fruits and vegetables 11.0% increase in mean lifespan and antioxidant [171]
1004313-10-3 S, S-Trolox-carnosine Trolox acylated derivatives 36.0% increase in mean lifespan and antioxidant [116]
4670-05-7 Theaflavins Black tea 10.0% increase in mean lifespan and antioxidant [172]
353-09-3 β-Guani-dinopropionic acid Metabolites 13.0% in female, 90% in male increase in mean lifespan and regulating AMPK-Atg1-autophagy signaling [173]
19545-26-7 Wortmannin Penicillium funiculosum 5.0% increase in mean lifespan and inhibiting PI3K [174]
139-85-5 3, 4-Dihydro-xybenzaldehyde Sasa senanensis leaves 23.0% increase in mean lifespan and inhibiting the 2-oxoglutarate binding sites of prolyl 4-hydroxylase [175]
With anti-aging activities in Caenorhabditis elegans
57-91-0 β-Estradiol Hormone 7.0% increase in mean lifespan and antioxidant [176]
1406-65-1 Chlorophyll Green vegetables 25.0% increase in mean lifespan and antioxidant [177]
730-08-5 Dipeptide Tyr-Ala Hydrolyzed maize protein 12.4% increase in mean lifespan and antioxidant [178]
934822-64-7 Ferulsinaic acid Sesquiterpene coumarins from the genus Ferula 20.0% increase in mean lifespan and antioxidant [179]
446-72-0 Genistein Vigna angularis 27.9% increase in mean lifespan and antioxidant [180, 181]
Quercetin 3-O-β-D-glucopyranoside-(4 → 1)-β-D-glucopyranoside Onion 12.4% increase in mean lifespan and antioxidant [182]
69-72-7 Salicylic acid Plant hormone 14.0% increase in mean lifespan and antioxidant [183]
72514-90-0 Specioside Stereospermum suaveolens 15.5% increase in mean lifespan and antioxidant [184]
480-18-2 Taxifolin Citrus fruits and onion 51.0% increase in mean lifespan and antioxidant [185]
3081-61-6 Theanine Camellia sinensis ~5.0% increase in mean lifespan and antioxidant [186]
6829-55-6 Tocotrienols Vitamin E members ~20.0% increase in mean lifespan and antioxidant [187]
53188-07-1 Trolox Vitamin E analog 31.0% increase in mean lifespan and antioxidant [185]
528-48-3 Fisetin Apples, onions and grapes and many more herbal edibles 6.0% increase in mean lifespan of thermal stress and antioxidant, regulating DAF-16 [188]
215112-16-6 4-Hydroxy-E-globularinin Premna integrifolia 18.8% increase in mean lifespan and antioxidant, regulating DAF-16 [189]
521-48-2 Iso-xanthohumol Humulus lupulus L. 10.2% increase in mean lifespan and antioxidant, regulating DAF-16 [190]
520-18-3 Kaempferol Apples, onions and grapes and many more herbal edibles 10.0% increase in mean lifespan and antioxidant, regulating DAF-16 [188]
117-39-5 Quercetin Onions, apples, and broccoli as well as in red wine, tea, and extracts of Ginkgo biloba 15.0% increase in mean lifespan and antioxidant, regulating DAF-16 [191]
50932-19-9 Verminoside Stereospermum suaveolens 20.8% increase in mean lifespan and antioxidant, regulating DAF-16 [192]
113558-15-9 Icariside II Icariin active metabolite 20.0% increase in mean lifespan and regulating IIS signaling [133]
99-20-7 Trehalose Disaccharide of glucose 32.0% increase in mean lifespan and regulating IIS signaling [193]
32911-62-9 Withanolide A Ayurvedic 29.7% increase in mean lifespan and regulating IIS pathway and neural activity [194]
501-94-0 Tyrosol Extra virgin olive oil 10.8% increase in mean lifespan and regulating IIS pathway and heat shock response [195-197]
4339-71-3 Piceatannol Grapes and white tea ~18.3% increase in mean lifespan and regulating IIS pathway and SIR-2.1 [198]
52-89-1 Cysteine Amino acids 16.0% increase in mean lifespan and regulating AMPK and DAF-16 [103]
6537-80-0 Chicoric acid Caffeoyl derivative 21.0% increase in mean lifespan and regulating AMPK [199]
328-42-7 Oxaloacetate Citric acid cycle metabolite 25.0% increase in mean lifespan and regulating AMPK [200]
29700-22-9 Oxy-resveratrol Isomer of hydroxylated resveratrol 31.1% increase in mean lifespan and regulating calorie restriction, AMPK, and SIR-2.1 [201]
β-Dihydro-agarofuran-type sesquiterpenes Seeds of Celastrus monospermus 38.0% increase in mean lifespan and rapamycin mimetics [202]
13095-47-1 (R)-2-Hydro-xyglutarate Oncometabolite 43.0% increase in mean lifespan and inhibiting ATP synthase and mTOR signaling [203]
13095-48-2 (S)-2-Hydroxyglutarate Oncometabolite 32.0% increase in mean lifespan and inhibiting ATP synthase and mTOR signaling [203]
765-01-5 10-Hydroxy-2-decenoic acid Major lipid component of Royal Jelly 10.0% increase in mean lifespan and regulating dietary restriction and mTOR signaling [204]
Ascr#2 Pheromone 14.0% increase in mean lifespan and regulating SIR-2.1 [205]
Ascr#3 Pheromone 14.0% increase in mean lifespan and regulating SIR-2.1 [205]
1740-19-8 Dehydro-abietic acid P. densiflora, P. sylvestris, Abies grandis 15.5% increase in mean lifespan and regulating SIR-2.1 [206]
7783-06-4 Hydrogen sulfide Naturally produced in animal cells 74.0% increase in mean lifespan and antioxidant, regulating SIR-2.1 [207, 208]
932-30-9 Salicylamine Phenolic amines 56.0% increase in mean lifespan and regulating SIR-2.1 and ETS-7 [209]
481-39-0 Juglone Roots, leaves, woods and fruits of Juglandaceae walnut trees 29.0% increase in mean lifespan and regulating SIR-2.1 and DAF-16 [210]
Deutero-haemin-AlaHisThrValGluLys Peptides Porphyrin-peptide 19.1% increase in mean lifespan and regulating SIR-2.1and DAF-16 [211]
53-84-9 Nicotinamide adenine dinucleotide Tricarboxylic acid cycle intermediate 15.0% increase in mean lifespan and regulating SIR-2.1 and DAF-16 [212]
149-61-1 Malate Tricarboylic acid (TCA) cycle metabolite 14.0% increase in mean lifespan and regulating dietary restriction, SIR-2.1, and DAF-16 [213]
70-47-3 Asparagine Amino acid 5.0% increase in mean lifespan and regulating SKN-1 [103]
2050-87-5 Diallyl trisulfide Garlic 12.6% increase in mean lifespan and regulating SKN-1 [214]
481-42-5 Plumbagin Plumbago zeylanica L. 15.0% increase in mean lifespan and regulating SKN-1 [215]
77-59-8 Tomatidine Unripe tomato fruits, leaves and stems 7.0% increase in mean lifespan and regulating SKN-1/Nrf2 pathway, mitophagy [216]
21593-77-1 S-Allylcysteine Allium sativum L. 17.0% increase in mean lifespan and antioxidant, regulating SKN-1 [217]
2281-22-3 S-Allylmercapto-cysteine Allium sativum L. 20.9% increase in mean lifespan and antioxidant, regulating SKN-1 [217]
61-90-5 Leucine Amino acids 16.0% increase in mean lifespan and regulating SKN-1and DAF-16 [103]
62333-08-8 Isolappaol A A. lappa seeds 11.0% increase in mean lifespan and regulating JNK-1 and DAF-16 [218]
64855-00-1 Lappaol C A. lappa seeds 12.0% increase in mean lifespan and regulating JNK-1 and DAF-16 [218]
69394-17-8 Lappaol F A. lappa seeds 13.0% increase in mean lifespan and regulating JNK-1 and DAF-16 [218]
580-72-3 Matairesinol Arctium lappa 25.0% increase in mean lifespan and regulating JNK-1 and DAF-16 [218]
7770-78-7 Arctigenin Arctium lappa 14.0% increase in mean lifespan and antioxidant, regulating JNK-1 and DAF-16 [218]
20362-31-6 Arctiin Arctium lappa 15.0% increase in mean lifespan and antioxidant, regulating JNK-1 and DAF-16 [218]
484-68-4 Pinitol Fine wood, alfalfa, and legumes 13.0% increase in mean lifespan and regulating JNK, S6K, and DAF-16 [169]
56-41-7 Alanine Amino acid 11.0% increase in mean lifespan and regulating AAK-2, SKN-1, and DAF-16 [103]
56-87-1 Lysine Amino acids 8.0% increase in mean lifespan and regulating AAK-2, SKN-1, and DAF-16 [103]
338-69-2 D-Alanine Amino acids 16.0% increase in mean lifespan and regulating AAK-2, SIR-2.1, and DAF-16 [103]
56-85-9 Glutamine Amino acids 16.0% increase in mean lifespan and regulating EAT-2, AAK-2, and SKN-1 [103]
87-44-5 β-Caryophyllene Edible plants 22.0% increase in mean lifespan and regulating SIR-2.1, SKN-1 and DAF-16 [219]
60-18-4 Tyrosine Amino acids 10.0% increase in mean lifespan and regulating SIR-2.1, SKN-1, and DAF-16 [103]
107-95-9 β-Alanine Amino acid 13.0% increase in mean lifespan and regulating AAK-2, SIR-2.1, SKN-1, and DAF-16 [103]
Acacetin 7-O-α-l-rhamnopyranosyl (1-2) β-D-xylopyranoside Premna integrifolia 39.0% increase in mean lifespan and regulating EAT-2, SIR-2.1, SKN-1, HSF-1, MEV-1, and DAF-16 [220]
15502-74-6 Arsenite Natural and anthropogenic sources (10 μM) 10.0% increase in mean lifespan, ( > 100 μM) 12.0% decrease and antioxidant, regulating SKN-1, MTL-2, TIN-9, and DAF-16 [221, 222]
625-72-9 D-β-Hydroxybutyrate Ketone body 26.0% increase in mean lifespan and regulating AAK-2, SIR-2.1, SKN-1, and DAF-16; inhibiting histone deacetylase [223]
71-00-1 Histidine Amino acids 12.0% increase in mean lifespan and regulating EAT-2, AAK-2, SIR-2.1, SKN-1, BEC-1, HIF-1, GAS-1, IFE-2, GCN-2, and DAF-16 [103]
37159-97-0 Proline Amino acids 19.0% increase in mean lifespan and regulating EAT-2, AAK-2, SIR-2.1, SKN-1, BEC-1, and DAF-16 [103]
56-45-1 Serine Amino acids 22.0% increase in mean lifespan and regulating EAT-2, AAK-2, SIR-2.1, SKN-1, HIF-1, BEC-1, and DAF-16 [103]
73-22-3 Tryptophan Amino acids 14.0% increase in mean lifespan and regulating EAT-2, AAK-2, SIR-2.1, SKN-1, BEC-1, GCN-2, and DAF-16 [103]
1405-87-4 Bacitracin Bacillus subtilisvar Tracy 59.0% increase in mean lifespan and regulating CBP-1, improving proteotoxcity [224]
142-42-7 Fumarate Tricarboxylic acid (TCA) cycle metabolite 16.0% increase in mean lifespan and increasing the amount of oxidized NAD and FAD cofactors [213]
63-68-3 Methionine Amino acids 14.0% increase in mean lifespan and regulating mitochondrial unfolded protein response [103]
62-75-9 N-Nitrosodimethylamine Ubiquitously distributed organic xenobiotic compounds 6.0% increase in mean lifespan and reducing transcription of many stress response genes [225]
25166-14-7 2, 3-Dehydrosily-bin A/B Potential active components of silymarin 16.1% increase in mean lifespan and antioxidant, regulating FGT-1, improving proteotoxic stress [226]
476-66-4 Ellagic acid Strawberry and raspberry ~10.0% increase in mean lifespan and antioxidant, CR mimetics, antimicrobial [27]
1259-86-5 Glau-carubinone Different species of the tropical plant family Simaroubaceae ~80.0% increase in mean lifespan and promoting mitochondrial metabolism, reducing body fat [227]
529-44-2 Myricetin Tea, different vegetables, onions, berries, grapes and medical plants 34.3% increase in mean lifespan and regulating DAF-16; enhanced quality of life during aging [63, 228]
106758-54-7 Otophylloside B Cynanchum otophyllum 11.3% increase in mean lifespan and regulating DAF-2, SIR-2.1, CLK-1, and DAF-16 [229]
14937-32-7 Pentagalloyl glucose Eucalyptus leaves 18.0% increase in mean lifespan and regulating dietary restriction, IIS pathway, SIR-2.1 and mitochondrial electron transport chain [230]
7512-17-6 N-Acetyl-glucosamine Hexosamine Pathway Metabolite 50.0% increase in mean lifespan and enhancing autophagy, ER-associated protein degradation, and proteasomal activity [231]
Quercetin 3′-O-β-D-glucopyranoside Onion 20.9% increase in mean lifespan and regulating DAF-2, OLD-1, OSR-1, and AEK-1 [182]
50-70-4 Sorbitol S. cerevisiae 35.0% increase in mean lifespan and regulating DR and osmotic response [232]
1401-55-4 Tannic acid Grapes and green tea 19.0% increase in mean lifespan and regulating TGF-β, p38 MAPK pathways, and DAF-12 [233, 234]
77-92-9 Citrate Tricarboxylic acid cycle intermediate 13.0% increase in mean lifespan and inducing ER stress response [103]
107-35-7 Taurine Nitrogen containing metabolites 11.0% increase in mean lifespan and inducing ER stress response [103]
38748-32-2 Triptolide Tripterygium wilfordii 20.1% increase in mean lifespan and antioxidant, regulating HSP16.2 and SOD-3 [235]
67-97-0 Vitamin D3 Vitamins 39.0% increase in mean lifespan and regulating SKN-1, IRE-1, XBP-1, DAF-12, and proteostasis [236]
57-88-5 Cholesterol Cyclo-pentanoper-hydro-phenanthrene ring Regulating cholesterol-binding protein NSBP-1and DAF-16 [237]
949004-12-0 Dafachronic acid Bile acid-like steroid 17.0% increase in mean lifespan and "antiaging" in the germ-line longevity pathway [238]
145-13-1 Pregnenolone Hormonal steroids 20.0% increase in mean lifespan and relating to germline-defective regulated longevity [239]
1315285-41-6 Royalactin Glycoprotein Royal jelly 34.0% increase in mean lifespan and regulating EGF signaling [240]
104594-70-9 Caffeic acid phenethyl ester Propolis 9.0% increase in mean lifespan and regulating DAF-16 [241]
64-17-5 Ethanol Metabolites Serving as a carbon and energy source and/or by inducing a stress response [242]
N-γ-(l-Glutamyl)-l-seleno-methionine Garlic as and primary metabolic product of SeMet Antioxidant, regulating sele-noprotein TRXR-1 [243]
74-81-7 Caprylate Metabolites In lacking nitrogen on C. elegans: 7.0% increase in mean lifespan and needs further research [51]
6893-26-1 D-Glutamate Amino acids 18.0-114.0% increase in mean lifespan and needs more research [103]
10257-28-0 Galact-opyranose Sugars metabolites In lacking nitrogen on C. elegans: 6.0% increase in mean lifespan and needs more research [103]
56-40-6 Glycine Amino acids 10.0% increase in mean lifespan and needs more research [103]
6027-13-0 Homocysteine Nitrogen containing metabolites 13.0% increase in mean lifespan and needs more research [103]
87-89-8 Inositol Metabolites In lacking nitrogen on C. elegans: 17.0% increase in mean lifespan and needs more research [103]
320-77-4 Isocitrate TCA cycle intermediate 13.0% increase in mean lifespan and needs more research [103]
7004-09-3 Isoleucine Amino acids 3.0% increase in mean lifespan and needs more research [103]
70-26-8 Ornithine Amino acids 8.0% increase in mean lifespan and needs more research [103]
138-08-9 Phosphoenol-pyruvate Metabolites In lacking nitrogen on C. elegans: 12.0% increase in mean lifespan and needs more research [103]
98-98-6 Picolinic acid Endogenous metabolite of the kynurenine pathway 7.0% increase in mean lifespan and needs further research [103]
10257-32-6 Ribopyranose Sugars metabolites In lacking nitrogen on C. elegans: 9.0% increase in mean lifespan and needs more research [103]
56-14-4 Succinate TCA cycle intermediates 11.0% increase in mean lifespan and needs more research [103]
72-19-5 Threonine Amino acids 8.0% increase in mean lifespan and needs more research [103]
72-18-4 Valine Amino acids 13.0% increase in mean lifespan and needs more research [103]
58-86-6 Xylose Sugars metabolites In lacking nitrogen on C. elegans: 6.0% increase in mean lifespan and needs more research [103]
With anti-aging activities in other aging models
32619-42-4 Oleuropein Olea europea leaf In cell: 15.0% increase in mean lifespan; and increasing proteasome-mediated degradation rates, retaining proteasome function and Nrf2/heme oxygenase-1 pathway [244]
84605-18-5 Cyclo-astragenol Astragalus membranaceus In PC12 cells and primary neurons: inducing telomerase activity and cAMP response element binding (CREB) [245]
528-58-5 Cyanidin Fruits and vegetables In cell: antioxidant, decreasing expressions of nuclear factor-kappaB, cyclooxygenase-2, and nitric oxide synthase [246]
88095-77-6 Dieckol Eckloina cava In radiation-induced cell damages: protecting effects on UV-B [247]
1229519-12-3 HDTIC-1 Herb Astragalus membranaceus var. mongholicus In cell: antioxidant, improving proliferation, inhibiting glycation end product formation, slowing down telomere shortening rate [248, 249]
1229519-13-4 HDTIC-2 Herb Astragalus membranaceus var. mongholicus In cell: antioxidant, improving proliferation, inhibiting glycation end product formation, slowing down telomere shortening rate [248, 249]
87798-94-5 Quercetin caprylate Quercetin derivative In cell: antioxidant, proteasome activator [250]
501334-35-6 Collemin A Lichenized ascomycete Collema cristatum In cell and human skin: preventing pyrimidine dimer formation and UV-B induced erythema [251]
87425-34-1 Nolinospiroside F Ophiopogon japonicus In S. cerevisiae: 23.0% increase in mean lifespan and antioxidant [252, 253]
57103-57-8 (-)-Glyceollin I Soybeans In S. cerevisiae: calorie restriction mimetic [254]
487-52-5 Butein Toxicodendron vernicifluum In S cerevisia: 31.0% increase in mean lifespan and regulating Sir2 [255]
1341-23-7 Nicotinamide riboside NAD(+) precursor In S. cerevisiae: 20.0% increase in mean lifespan and increasing net NAD(+) synthesis and Sir2 function [252, 253]
434-13-9 Lithocholic acid Major bile acids excreted by mammals In S. cerevisiae: 100.0% increase in mean lifespan and modulating housekeeping longevity assurance processes [256, 257]
57-94-3 Curare Chondrodendron tomentosum, Menispermaceae or Strychnos In Asplanchna brightwelli: 34.0% increase in mean lifespan and needs further research [258]

Table 2

Natural product extracts with anti-aging activities

Complex or extracts Source Anti-aging activity and proposed anti-aging mechanism
With anti-aging activities in two aging models
  Green tea extract Green tea In mice: 7.0% increase in mean lifespan and antioxidant [44]
In D. melanogaster: 16.0% increase in mean lifespan and antioxidant [96]
  Korean mistletoe water extract Viscum album coloratum In D. melanogaster: 20.0% increase in mean lifespan and regulating Sir2 [259]
In C. elegans: 10.0% increase in mean lifespan and antioxidant [259]
With anti-aging activities in rats or mice
  A-type proanthocyanidins-rich cranberry extract Cranberry In mice: antioxidant [260]
  Fungus Phellinus sp. polysaccharide Fungus Phellinus sp. In mice: antioxidant [261]
  Polysaccharides of Dicliptera chinensis (L.) Juss Dicliptera chinensis (L.) Juss In mice: scavenging free radical and antioxidant [262]
  Polysaccharides of Urtica Urtica In D-galactose-induced mice: antioxidant [263]
  Cocoa polyphenolic extract Acticoa powder In rats: 11.0% increase in mean lifespan and retarding age-related brain impairments [264]
  Nigella Sativa fixed oil Nigella Sativa In mice: reducing lipid peroxidation, Bax/Bcl2, and caspase-3 [265]
  Exopolysaccharides of Agrocybe Agrocybe cylindracea In D-galactose-induced mice: antioxidant, reducing the contents of malonaldehyde (MDA) and total cholesterol (TC) [266]
  Neem leaves extract Neem In UVB-irradiated NHDFs, hairless mice: increasing TGF-β1, decreasing AP-1, ROS, and MAPK [267]
With anti-aging activities in Drosophila melanogaster
  APPLE polyphenols Apple 10.0% increase in mean lifespan and antioxidant [268]
  Cocoa ~14.0% increase in mean lifespan and antioxidant [269]
  Cordyceps sinensis oral liquid Traditional Chinese medicine 32.0% increase in mean lifespan and antioxidant [270]
  Cynomorium songaricum Rupr Traditional Chinese medicine 15.0% increase in mean lifespan and antioxidant [271]
  Emblica officinalis (fruit) Emblica officinalis 6.0% increase in mean lifespan and antioxidant [272]
  Rhizome powder of Rhodiola rosea Rhodiola rosea 17.0% increase in mean lifespan and antioxidant [273]
  Curcuma longa (rhizome) Curcuma longa 18.0% increase in mean lifespan and antioxidant [272]
  Oregano and cranberry extracts Oregano and cranberry ~43.0% in male and ~62.0% in female (full diet +2% OC) increase in mean lifespan and partly through DR-independent pathways [274]
  Cinnamon extract Cinnamon 17.0% in male, 37.0% in female increase in mean lifespan and regulating insulin signaling [275]
  Ludwigia octovalvis extract Ludwigia octovalvis 24.0% increase in mean lifespan and regulating AMPK [276]
  Jujube fruit Jujube 11.1% increase in mean lifespan and regulating FoxO [277]
  Black tea extract Black tea 21.4% increase in mean lifespan and inhibiting the ageing-related accumulation of iron [278]
  Cranberry anthocyanin extract Cranberry 10.0% increase in mean lifespan and up-regulation of SOD1 and down-regulation of MTH, InR, TOR and PEPCK [279]
  Rosa damascena extract Rosa damascena 32.0% increase in mean lifespan and increasing sensitivity to heat [280]
With anti-aging activities in Caenorhabditis elegans
  Acanthopanax sessiliflorusstem stem extract Acanthopanax sessiliflorusstem stem 16.8% increase in mean lifespan and antioxidant [281]
  Angelica sinensis peptides Angelica sinensis ~20.0% increase in mean lifespan and antioxidant [282]
  Apple procyanidins Apple 12.1% increase in mean lifespan and antioxidant [283]
  Blueberry polyphenols Blueberry 28.0% increase in mean lifespan and antioxidant [284]
  Extract from seed of Platycladus orientalis Platycladus orientalis 24.5% increase in mean lifespan and antioxidant [285]
  Ginko biloba extract Ginko biloba 8.0-25.0% increase in mean lifespan and antioxidant [286]
  HonTsai Tai extract HonTsai Tai 8.0% increase in mean lifespan and antioxidant [287]
  KPG-7 Herb mixture 12.0% increase in mean lifespan and antioxidant [288]
  Panax notoginseng Polysaccharides Panax notoginseng 21.0% increase in mean lifespan and antioxidant [289]
  Tenebrio molitor extracts Tenebrio molitor 30.6% increase in mean lifespan and antioxidant [290]
  Erchen wan Traditional Chinese medicine 22.0% increase in mean lifespan and antioxidant [291]
  Huanshao dan Traditional Chinese medicine 38.0% increase in mean lifespan and antioxidant [291]
  Liuwei dihuang wan Traditional Chinese medicine 13.0% increase in mean lifespan and antioxidant [291]
  Shengmai yin Traditional Chinese medicine 47.0% increase in mean lifespan and antioxidant [291]
  Shiquan dabu wan Traditional Chinese medicine 15.0% increase in mean lifespan and antioxidant [291]
  Bletilla striata polysaccharide Bletilla striata ~20.0% increase in mean lifespan and regulating IIS pathway [292]
  Ethylacetate fraction from Ribes fasciculatum Ribes fasciculatum 16.3% increase in mean lifespan and regulating IIS pathway and SIR-2.1 [293]
  Peptides from sesame cake Sesame cake 15.6% increase in mean lifespan and regulating SKN-1signaling [294]
  Astragalus membranaceus polysaccharide Astragalus membranaceus 24.0% increase in mean lifespan and regulating DAF-16 [295]
  Garlic extract Garlic extract 21.0% increase in mean lifespan and regulating DAF-16 [296]
  Reishi mushroom polysaccharide Reishi mushroom ~20.0% increase in mean lifespan and regulating TIR-1 and DAF-16 [99]
  Royal Jelly Honeybee 18.0% increase in mean lifespan and DAF-16 dependent [297, 298]
  Ayurvedic polyherbal extract Ayurvedic 16.1% increase in mean lifespan and regulating DAF-2, SKN-1, SOD-3, GST-4, and DAF-16 [299]
  Damnacanthus officinarum leaf extract Damnacanthus officinarum 19.0% increase in mean lifespan and regulating neuroprotective activity [300]
  Deuterohemin peptide Peptides 21.0% increase in mean lifespan and antioxidant, regulating DR [301]
  Eleutherococcus senticosus root extract Eleutherococcus senticosus 16.0% increase in mean lifespan and antioxidant, regulating DAF-16 [302]
  Lowbush cranberry Lowbush cranberry 22.0% increase in mean lifespan and altering mechanosensory neuron aging [303]
  Mulberry leaf polyphenols Mulberry leaf 23.0% increase in mean lifespan and regulating DAF-12, PHA-4, NHR-80, and DAF-16 [304]
  Dauer-inducing Pheromone Worms 27.0% increase in mean lifespan and needs more research [305]
With anti-aging activities in other aging models
  Annurca apple extracts Annurca apple In S. cerevisiae: antioxidant, antiapoptotic [306]
  Red algal extracts Red algal In Brachionus manjavacas: 9.0% increase in mean lifespan and needs further research [307]

Table 3

Clinical medicine with anti-aging activities

CAS Chemicals Structure Clinical application Anti-aging activity and proposed anti-aging mechanism
With anti-aging activities in a variety of aging models
58-08-2 Caffeine Psychoactive drug In rats: antioxidant, alleviating neuroinflammation and neurodegeneration [75]
In zebrafish: 29.4% increase in mean lifespan and regulating proteostasis [74]
In C. elegans: 29.4% increase in mean lifespan and regulating IIS pathway and proteostasis [73]
657-24-9 Metformin Treatment of type 2 diabetes and polycystic ovary syndrome In rats: altering erythrocyte redox status [70]
In D. melanogaster: has not effect on fecundity or lifespan and activating AMPK, reducing lipid stores [72]
In C. elegans: 40.0% increase in mean lifespan and regulating AMPK, LKB1, and SKN-1 [71]
53123-88-9 Rapamycin Used to coat coronary stents, prevent organ transplant rejection and to treat a rare lung disease called lymphangioleiomyomatosis In mice: 14.0% increase in mean lifespan for females and 9% for males and reducing mTOR activity [76-82]
In D. melanogaster: 13.0% increase in mean lifespan and regulating TORC1 branch of the TOR pathway, through alterations to both autophagy and translation [83]
In C. elegans: 19.0% increase in mean lifespan and regulating TOR, SKN-1 and DAF-16 [84]
With anti-aging activities in two aging models
50-78-2 Aspirin Used to treat pain, fever, and inflammation In genetically heterogeneous male mice: 8.0% increase in mean lifespan and needs further research [135]
In C. elegans: 30.0% increase in mean lifespan and antioxidant, regulating AMPK and insulin-like signaling pathway [183, 308]
2086-83-1 Berberine Used to treat bacillary dysentery and gastroenteritis In aged mice: suppressing neuroinflammation, reducing vascular stiffness in aged mice through suppression of TRPV4 [309, 310]
In D. melanogaster: 46.0% increase in mean lifespan and inhibiting kynurenine (KYN) formation from tryptophan (TRP) [311]
102518-79-6 Huperzine A Treatment for neurological conditions such as Alzheimer's disease In D-galactose-induced mice: inhibiting DAMPs-mediated NF-κB nuclear localization and activation [312]
In C. elegans: 14.0% increase in mean lifespan and needs further research [285]
10118-90-8 Minocycline Antibiotic In D. melanogaster: 63.0% increase in mean lifespan and antioxidant [313]
In C. elegans: 29.0% increase in mean lifespan and antioxidant [176]
114-86-3 Phenformin Antidiabetic In mice: 21.0% increase in mean lifespan and decreasing the body weight, slowing down the age-related decline of the reproductive function in female rats [314]
In C. elegans: 29.0% increase in mean lifespan and needs further research [315]
59-02-9 Vitamin E Vitamins In rats: reducing the oxidative stress increased in old age [316, 317]
In C. elegans: 23.0% increase in mean lifespan and antioxidant [318]
With anti-aging activities in rats or mice
692-13-7 Buformin Antidiabetic In rats: 7.0% increase in mean lifespan in female and decreasing the body weight, slowing down the age-related decline of the reproductive function in female rats [314]
73-31-4 Melatonin Regulating sleep and wakefulness In male Wistar: restoring rSocs1 rhythms and levels in various tissues [319]
155974-00-8 Ivabradine Used for the symptomatic management of stable heart related chest pain and heart failure In C57BL/6 J mice: 6.0% increase in mean lifespan and reducing heart rate [320]
56180-94-0 Acarbose Antidiabetic In SAMP8 mice and male mice: 22.0% increase in mean lifespan and changing in the insulin system and the levels of BDNF, IGF-1R, and the pre-synaptic proteins Syt1 and Stx1 [321, 322]
51384-51-1 Metoprolol Used to treat high blood pressure, chest pain due to poor blood flow to the heart, and a number of conditions involving an abnormally fast heart rate In mice: 10.0% increase in mean lifespan and needs further research [323]
99200-09-6 Nebivolol Treatment of hypertension In mice: 6.4% increase in mean lifespan and needs further research [323]
With anti-aging activities in Drosophila melanogaster
13123-37-0 Riboflavin Vitamin 14.1% increase in mean lifespan and increasing SOD1 and CAT, inhibiting LF [324]
84057-84-1 Lamotrigine Anticonvulsant 17.0% increase in mean lifespan and reducing locomotor activity and metabolic rate [325]
1716-12-7 4-Phenyl-butyrate Used to treat urea cycle disorder 40.0% increase in mean lifespan and increasing histone acetylation [326]
52757-95-6 Sevelamer Used to treat hyperphosphatemia in patients with chronic kidney disease 16.0% increase in mean lifespan and regulating cellular and organismic phosphate levels [327]
79902-63-9 Simvastatin Hypolipidemic 25.0% increase in mean lifespan and decreasing specific protein prenylation [328]
871700-17-3 Trametinib Anti-cancer 12.0% increase in mean lifespan and inhibiting Ras-Erk-ETS signaling [329]
58880-19-6 Trichostatin A Antifungal antibiotic 27.0% increase in mean lifespan and changing the level of histone acetylation, influencing the expression of hsp22 gene [330]
57-27-2 Morphine Treatment of acute pain and chronic pain 22.0% increase in mean lifespan and needs further research [331]
With anti-aging activities in Caenorhabditis elegans
14028-44-5 Amoxapine Antidepressant 33.0% increase in mean lifespan and antioxidant [176]
298-57-7 Cinnarizine Treatment of vertigo, motion sickness, and vomiting 15.0% increase in mean lifespan and antioxidant [176]
59865-13-3 Cyclosporin A Immunosuppressants 18.0% increase in mean lifespan and antioxidant [176]
427-51-0 Cyproterone acetate Antiandrogen and progestogen 23.0% increase in mean lifespan and antioxidant [176]
17230-88-5 Danazol Treatment of endometriosis 13.0% increase in mean lifespan and antioxidant [176]
127-33-3 Demeclocycline hydrochloride Antibiotic 16.0% increase in mean lifespan and antioxidant [176]
564-25-0 Doxycycline Antibiotic 18.0% increase in mean lifespan and antioxidant [176]
10592-13-9 Doxycycline hydrochloride Antibiotic 18.0% increase in mean lifespan and antioxidant [176]
119431-25-3 Eliprodil NMDA antagonist, treatment of acute ischemic stroke 16.0% increase in mean lifespan and antioxidant [176]
23256-50-0 Guanabenz acetate Antihypertensive 12.0% increase in mean lifespan and antioxidant [176]
29110-48-3 Guanfacine hydrochloride Treatment of hyperactivity 15.0% increase in mean lifespan and antioxidant [176]
27833-64-3 Loxapine succinate Antipsychotic 43.0% increase in mean lifespan and antioxidant [176]
57149-08-3 Naftopidil dihydrochloride Antihypertensive 14.0% increase in mean lifespan and antioxidant [176]
54527-84-3 Nicardipine hydrochloride Used to treat high blood pressure and angina 23.0% increase in mean lifespan and antioxidant [176]
39562-70-4 Nitrendipine Used in the treatment of primary (essential) hypertension to decrease blood pressure and can reduce the cardiotoxicity of cocaine 25.0% increase in mean lifespan and antioxidant [176]
894-71-3 Nortriptyline hydrochloride Tricyclic antidepressant 21.0% increase in mean lifespan and antioxidant [176]
60607-34-3 Oxatomide Anti-allergic 25.0% increase in mean lifespan and antioxidant [176]
130-61-0 Thioridazine hydrochloride Antipsychotic 31.0% increase in mean lifespan and antioxidant [176]
2068-78-2 Vincristine sulfate Anti-cancer 12.0% increase in mean lifespan and antioxidant [176]
97-59-6 Allantoin Used to treat gastric ulcer, duodenal bulb ulcer, chronic gastritis 21.9% increase in mean lifespan and caloric restriction mimetics [332]
169590-42-5 Celecoxib COX-2 selective nonsteroidal anti-inflammatory drug (NSAID) It is used to treat the pain and inflammation of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute pain 19.0% increase in mean lifespan and inhibiting insulin-like signaling [333]
99-66-1 Valproic acid Used to treat epilepsy and bipolar disorder and to prevent migraine headaches 35.0% increase in mean lifespan and regulating IIS pathway [334]
103-90-2 Acetaminophen Used to treat pain and fever 49.0% increase in mean lifespan and regulating CBP-1 [224]
69-52-3 Ampicillin Antibiotic 34.0% increase in mean lifespan and antimicrobial [284]
41859-67-0 Bezafibrate Treatment of hypertriglyceridemia 13.0% increase in mean lifespan and regulating NHR-49/PPARalpha-dependent manner [335]
637-07-0 Clofibrate Lipid-lowering agent used for controlling the high cholesterol and triacylglyceride level in the blood 16.0% increase in mean lifespan and regulating NHR-49/PPARalpha-dependent manner [335]
49562-28-9 Fenofibrate Used to reduce cholesterol levels in people at risk of cardiovascular disease 19.0% increase in mean lifespan and regulating NHR-49/PPARalpha-dependent manner [335]
127-48-0 Trimethadione Anticonvulsant 47.0% increase in mean lifespan and regulating neuromuscular activity [336]
42971-09-5 Vinpocetine Treatment of cerebrovascular disorders and age-related memory impairment 15.0% increase in mean lifespan and regulating PDE1 [176]
59-30-3 Folic acid Used to treat anemia caused by folic acid deficiency 27.0% increase in mean lifespan and antioxidant, regulating SIR-2.1, SKN-1, and DAF-16 [337]
77-67-8 Ethosuximide Used to treat absence seizures 17.0% increase in mean lifespan and disrupting sensory function, regulating DAF-16 [336, 338, 339]
50264-69-2 Lonidamine Anti-cancer 8.0% increase in mean lifespan and promoting longevity in a pmk-1sensitive manner by increasing formation of ROS [340]
50-55-5 Reserpine Antipsychotic, and antihypertensive 31.0% increase in mean lifespan and antioxidant, modulating acetylcholine release [341, 342]
13292-46-1 Rifampicin Antibiotic 56.0% increase in mean lifespan and reducing advanced glycation end products and activating DAF-16 [343]
6998-60-3 Rifamycin SV Antibiotic 21.0% increase in mean lifespan and reducing advanced glycation end products and activating DAF-16 [343]
723-46-6 Sulfa-methoxazole Antibiotic 34.0% increase in mean lifespan and increasing lipid peroxidation oxidative stress [344]
56-75-7 Chloram-phenicol Antibiotic 16.0% increase in mean lifespan and needs further research [345]
With anti-aging activities in other aging models
53-06-5 Cortisone Used to reduce inflammation and attendant pain and swelling at the site of the injury In Asplanchna brightwelli: 21.0% increase in mean lifespan and stabilizing lysosomal membranes, or altering resource allocation by the rotifers [346]
35891-70-4 Myriocin Antibiotic ISP-1 and thermozymocidin In S. cerevisiae: activating the Snf1/AMPK pathway, down-regulating the protein kinase A (PKA) and target of rapamycin complex 1 (TORC1) pathways [347]

Table 4

Synthetic compounds with anti-aging activities

CAS Chemicals Structure Anti-aging activity and proposed anti-aging mechanism
With anti-aging activities in two aging models
51-28-5 2, 4-Dinitrophenol In mice: 7.0% increase in mean lifespan; enhancing tissue respiratory rates, improving serological glucose, triglyceride and insulin levels, decreasing reactive oxygen species levels and tissue DNA and protein oxidation, as well as reduced body weight [348]
In D. melanogaster: 20.0% increase in mean lifespan; increasing the rate of oxygen consumption by isolated mitochondria and tissue homogenates, decreasing the activity of alcohol dehydrogenase [349]
With anti-aging activities in mice
91-53-2 Ethoxyquin In C3H mice: 18.0% increase in mean lifespan in male, 20.0% in female and antioxidant [350]
1001645-58-4 SRT1720 In mice: 9.0% increase in mean lifespan and inhibiting proinflammatory gene expression [351]
With anti-aging activities in Drosophila melanogaster
307297-39-8 Epitalon 17.0% increase in mean lifespan and antioxidatant [352]
34592-47-7 Thiazolidine carboxylic acid 31.0% increase in mean lifespan and antioxidatant [353]
133550-30-8 AG-490 18.0% increase in mean lifespan and activating ERK1/2 signaling [354]
4431-00-9 Aurintri-carboxylic acid 15.0% increase in mean lifespan and regulating p66ShcA [355]
91742-10-8 HA-1004 (dihydrochloride) 18.0% increase in mean lifespan and inhibiting protein kinase [354]
103745-39-7 HA-1077 (Fasudil) 15.0% increase in mean lifespan and inhibiting protein kinase [354]
5108-96-3 Pyrrolidine dithiocarbamate 16.0% increase in mean lifespan and inhibiting NF-κB [356]
With anti-aging activities in Caenorhabditis elegans
75529-73-6 Amperozide hydrochloride 38.0% increase in mean lifespan and antioxidatant [176]
193611-72-2 BRL 15572 10.0% increase in mean lifespan and antioxidatant [176]
433695-36-4 BRL 50481 18.0% increase in mean lifespan and antioxidatant [176]
145915-58-8 DAPH (4, 5-dianilino-phthalimide) 15.0% increase in mean lifespan and antioxidatant [176]
53177-12-1 EUK-8 54.0% increase in mean lifespan and antioxidant [357]
81065-76-1 EUK-134 54.0% increase in mean lifespan and antioxidant [357]
98299-40-2 Hexahydro-sila-diphenidol 15.0% increase in mean lifespan and antioxidatant [176]
142273-20-9 Kenpaullone 27.0% increase in mean lifespan and antioxidatant [176]
83846-83-7 Ketanserin tartrate 13.0% increase in mean lifespan and antioxidatant [176]
13614-98-7 Minocycline hydrochloride 43.0% increase in mean lifespan and antioxidatant [176]
66104-23-2 Pergolide methanesulfonate 37.0% increase in mean lifespan and antioxidatant [176]
497-27-8 4-Phenyl-3-Furoxan-carbonitrile 30.0% increase in mean lifespan and antioxidatant [176]
58-33-3 Promethazine hydrochloride 32.0% increase in mean lifespan and antioxidatant [176]
7681-67-6 Propionyl-promazine hydrochloride 20.0% increase in mean lifespan and antioxidatant [176]
Trans-3, 5-dimethoxy-4-fluoro-4-hydroxystilbene 3.6% increase in mean lifespan and antioxidatant [358]
Trans-2, 4, 5-trihydroxystilbene 5.4% increase in mean lifespan and antioxidatant [358]
78416-81-6 Trequinsin hydrochloride 27.0% increase in mean lifespan and antioxidatant [176]
274-85-1 1, 2, 4-Triazolo[1, 5-a]pyridine 12.0% increase in mean lifespan and antioxidant [359]
138090-06-9 (R, R)-cis-Diethyl-tetrahydro-2, 8-chrysenediol 7.0% increase in mean lifespan and increasing stress resistance [176]
2390-54-7 Thioflavin T 60.0% increase in mean lifespan and regulating HSF-1 and SKN-1 [360]
175698-05-2 3, 3-Diethyl-2-pyrrolidinone 31.0% increase in mean lifespan and regulating neuromuscular activity [336]
631-64-1 Dibromoacetic acid 15.0% increase in mean lifespan and inducing protective stress response [225]
82-76-8 N-Phenyl periacid(ANSA) 22.7% increase in mean lifespan and increasing aging related pharyngeal pumping rate [63]
51314-51-3 Benzimidazole derivative M084 19.10% increase in mean lifespan; regulating IIS pathway, AMPK, SIR-2.1, SKN-1, mitochondrial electron transport chain, and mitochondrial unfolded protein response [361-364]
With anti-aging activities in Asplanchna brightwelli
111-17-1 3, 3′-Thiodipropionic acid 16.0% increase in mean lifespan and increasing lipid peroxides [365]

Among the 55 complex or extracts from natural products, 8, 14 and 29 of them were tested in mice, fruit fly and C. elegans, respectively. A majority of these extracts present antioxidative activity.

Among the 62 clinical medicine with anti-aging activity, three (rapamycin, metformin, caffeine) present anti-aging activities in three aging models, six (aspirin, berberine, huperzine A, minocycline, phenformin, and vitamin E) in two aging models, two (buformin and melatonin) in rats, four (ivabradine, acarbose, metoprolol, and nebivolol) in mice, 8 in D. melanogaster, 37 in C. elegans, cortisone in Asplanchna brightwelli and myriocin in S. cerevisiae, respectively. Interestingly, the anti-aging mechanisms of the most drugs are different from their clinical applications.

We also summarized 35 synthetic compounds with explicit anti-aging activity (Table 4). 2, 4-Dinitrophenol presents anti-aging activities in mice and fruit fly, ethoxyquin and SRT1720 in mice. Seven and 24 compounds present anti-aging activity in fruit fly and C. elegans, respectively. 3, 3′-thiodipropionic acid with anti-aging activity in Asplanchna brightwelli. Twenty-one of the 35 compounds present antioxidative activity.

In total, there are 212 and 46 compounds present anti-aging activity in C. elegans and fruit fly, respectively, indicating C. elegans and fruit fly are the most popular aging models for anti-aging screening. Those compounds present anti-aging activity in both C. elegans and fruit fly are worth to be further investigated in mammalian models.

4 Prospects of Discovering Anti-aging Molecules from Natural Products

Many clinical medicines are derived from natural products. But in the past two decades, pharmaceutical companies have been enthusing the drug development strategy of high-throughput screening (HTS) and combinatorial synthesis of enormous synthetic libraries of small molecules. Natural products were largely neglected for unsuitable for HTS of targeted protein assay and difficult in compound isolation and synthesis. But the achievement of new lead discovery and new drug approval was disappointing [85]. Compared with synthetic compounds, natural products are secondary metabolite, evolutionarily optimized with biologically relevant chemical space and preferred ligand binding motif, are not only biologically active, but with a high degree of bioavailability, suitable for functional and phenotypic assays [86]. Recent innovation in techniques for structural elucidation, metabolomics for profiling and isolation, and metagenomics or gene manipulation for synthetic pathways has facilitated to explore the enormous biodiversity on earth, including plant, microorganism and marine organism [87]. Engineered production of natural products from uncultivated species could extremely expand the chemical space of natural products by synthetic biology [88]. Moreover, modern computer-assisted drug design could utilize natural-product-derived fragments to computationally infer the biomolecular targets and activities of natural products and fragment-based de novo design. As summarized in above, currently discovered agents with anti-aging activity, majority of them are natural products. Therefore, natural products are invaluable sources and provide great promise for developing anti-aging medicine.

Notes

Acknowledgements

This work was supported by the Natural Science Foundation of China (81671405 and 81370453), Natural Science Foundation of Yunnan province (2013FA045 and 2015FB172), and Open Funds of Guangdong Key Laboratory of Marine Materia Medica.

Compliance with Ethical Standards

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  • Ai-Jun Ding
    • 1,2
  • Shan-Qing Zheng
    • 1,2
  • Xiao-Bing Huang
    • 1,2
  • Ti-Kun Xing
    • 1,2
  • Gui-Sheng Wu
    • 1,3
  • Hua-Ying Sun
    • 1
  • Shu-Hua Qi
    • 4
  • Huai-Rong Luo
    • 1,3,5
    •     
  1. 1. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, Yunnan, China
  2. 2. University of Chinese Academy of Sciences, Beijing 100039, China
  3. 3. Key Laboratory for Aging and Regenerative Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
  4. 4. Guangdong Key Laboratory of Marine Material Medical, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, Guangdong, China
  5. 5. Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, 134 Lanhei Road, Kunming 650201, Yunnan, China
  • Add: 132# Lanhei Road, Heilongtan, Kunming 650201, Yunnan, China
  • Fax: +86 871 65223223
  • Tel: +86 871 65223223
  • E-mail: npb@mail.kib.ac.cn
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