Antiaging agents: safe interventions to slow aging and healthy life span extension

doi:10.1007/s13659-022-00339-y

Abstract

Abstract: Human longevity has increased dramatically during the past century. More than 20% of the 9 billion population of the world will exceed the age of 60 in 2050. Since the last three decades, some interventions and many preclinical studies have been found to show slowing aging and increasing the healthy lifespan of organisms from yeast, flies, rodents to nonhuman primates. The interventions are classified into two groups: lifestyle modifications and pharmacological/genetic manipulations. Some genetic pathways have been characterized to have a specific role in controlling aging and lifespan. Thus, all genes in the pathways are potential antiaging targets. Currently, many antiaging compounds target the calorie-restriction mimetic, autophagy induction, and putative enhancement of cell regeneration, epigenetic modulation of gene activity such as inhibition of histone deacetylases and DNA methyltransferases, are under development. It appears evident that the exploration of new targets for these antiaging agents based on biogerontological research provides an incredible opportunity for the healthcare and pharmaceutical industries. The present review focus on the properties of slow aging and healthy life span extension of natural products from various biological resources, endogenous substances, drugs, and synthetic compounds, as well as the mechanisms of targets for antiaging evaluation. These bioactive compounds that could benefit healthy aging and the potential role of life span extension are discussed.

Key words: Antiaging agents, Antiaging targets, Healthy lifespan extension, Natural products, Endogenous substances, Longevity

摘要： Human longevity has increased dramatically during the past century. More than 20% of the 9 billion population of the world will exceed the age of 60 in 2050. Since the last three decades, some interventions and many preclinical studies have been found to show slowing aging and increasing the healthy lifespan of organisms from yeast, flies, rodents to nonhuman primates. The interventions are classified into two groups: lifestyle modifications and pharmacological/genetic manipulations. Some genetic pathways have been characterized to have a specific role in controlling aging and lifespan. Thus, all genes in the pathways are potential antiaging targets. Currently, many antiaging compounds target the calorie-restriction mimetic, autophagy induction, and putative enhancement of cell regeneration, epigenetic modulation of gene activity such as inhibition of histone deacetylases and DNA methyltransferases, are under development. It appears evident that the exploration of new targets for these antiaging agents based on biogerontological research provides an incredible opportunity for the healthcare and pharmaceutical industries. The present review focus on the properties of slow aging and healthy life span extension of natural products from various biological resources, endogenous substances, drugs, and synthetic compounds, as well as the mechanisms of targets for antiaging evaluation. These bioactive compounds that could benefit healthy aging and the potential role of life span extension are discussed.

关键词: Antiaging agents, Antiaging targets, Healthy lifespan extension, Natural products, Endogenous substances, Longevity

Ji-Kai Liu. Antiaging agents: safe interventions to slow aging and healthy life span extension[J]. Natural Products and Bioprospecting, 2022, 12(3): 18-18.

Ji-Kai Liu. Antiaging agents: safe interventions to slow aging and healthy life span extension[J]. 应用天然产物, 2022, 12(3): 18-18.

References

1.Rattan SIS.Healthy ageing, but what is health? Biogerontology.2013;14:673-7. 2.Budovsky A, Abramovivh A, Cohen RM, Chalifa-Caspi V, Fraifeld VE.Longevity network:construction and implications.Mech Ageing Dev.2007;128:117-24. 3.Tacutu R, Budovsky A, Fraifeld VE.The NetAge database:a compen-dium of networks for longevity, age-related diseases and associated processes.Biogerontology.2010;11:513-22. 4.Pedro JMB, Senovilla L.Immunostimulatory activity of lifespan-extend-ing agents.Aging.2013;5:793-801. 5.Longo VD, et al.Interventions to slow aging in humans:are we ready? Aging Cell.2015;14:497-510. 6.Wahl D, Anderson RM, Le Couteur DG.Antiaging therapies, cognitive impairment, and dementia.J Gerontol Biol Sci.2020;75:1643-52. 7.Vaiserman AM, Marotta F.Longevity-promoting pharmaceuticals:is it a time for implementation? Trends Pharmacol Sci.2016;37:331-3. 8.Kidd P.Astaxanthin, cell membrane nutrient with diverse clinical ben-efts and anti-aging potential.Altern Med Rev.2011;16:355-64. 9.Britton G.Structure and properties of carotenoids in relation to func-tion.FASEB J.1995;9:1551-8. 10.Pashkow EJ, Watmull DG, Campbell CL.Astaxanthin:a novel potential treatment for oxidative stress and infammation in cardiovascular disease.Am J Cardiol.2008;101(suppl):58D-68D. 11.Choi HD, Kim JH, Chang MJ, Kyu-Youn Y, Shin WG.Efects of astaxanthin on oxidative stress in overweight and obese adults.Phytother Res.2011;25:1813-8. 12.Kim JH, Chang MJ, Choi HD, Youn YK, Kim JT, Oh JM, Shin WG.Protective efects of Haematococcus astaxanthin on oxidative stress in healthy smokers.J Med Food.2011;14:1469-75. 13.Park JS, Chyun JH, Kim YK, Line LL, Chew BP.Astaxanthin decreased oxidative stress and infammation and enhanced immune response in humans.Nutr Metab (Lond).2010;7:18. 14.Genest J.C-reactive protein:risk factor, biomarker and/or therapeutic target? Can J Cardiol.2010;26:41A-44A. 15.Yoshida H, Yanai H, Ito K, et al.Administration of natural astaxanthin increases serum HDL-cholesterol and adiponectin in subjects with mild hyperlipidemia.Atherosclerosis.2010;209:520-3. 16.Satoh A, Tsuji S, Okada Y, et al.Preliminary clinical evaluation of toxicity and efcacy of a new astaxanthin-rich Haematococcus pluvialis extract.J Clin Biochem Nutr.2009;44:280-4. 17.Kajita M, Tsukahara H, Kato M.The efects of a dietary supplement containing astaxanthin on the accommodation function of the eye in middle-aged and older people.Med Consult New Rem.2009;46:89-93. 18.Nagaki Y, Hayasaka S, Yamada T, et al.Efects of astaxanthin on accom-modation, critical ficker fusion, and pattern visual evoked potential in visual display terminal workers.J Tradit Med.2002;19:170-3. 19.Comhaire FH, Garem EL, Mahmoud A, Eertmans F, Schoonjans F.Com-bined conventional/antioxidant "Astaxanthin" treatment for male infer-tility:a double blind, randomized trial.Asian J Androl.2005;7:257-62. 20.Kupcinskas L, Lafolie P, Lignell A, et al.Efcacy of the natural antioxidant astaxanthin in the treatment of functional dyspepsia in patients with or without Helicobacter pylori infection:a prospective, randomized, dou-ble blind, and placebo-controlled study.Phytomedicine.2008;15:391-9. 21.Satoh A, Ishikura M, Murakami N, et al.In:Bagchi D, Lau FC, Ghosh DK, editors.Biotechnology in functional foods and nutraceuticals.Boca Raton:CRC Press; 2010.p.313-30 22.Brendler T, Williamson EM.Astaxanthin:how much is too much? A safety review.Phytother Res.2019;33:3090-111. 23.Feng T, Su J, Ding ZH, Zheng YT, Li Y, Leng Y, Liu JK.Chemical con-stituents and their bioactivities of "Tongling White Ginger" (Zingiber ofcinale).J Agric Food Chem.2011;59:11690-5. 24.Kotha RR, Luthria DL.Curcumin:biological, pharmaceutical, nutraceu-tical, and analytical aspects.Molecules.2019;24:2930-56. 25.Priyadarsini KI.The chemistry of curcumin:from extraction to thera-peutic agent.Molecules.2014;19:20091-112. 26.Kitani K, Osawa T, Yokozawa T.The efects of tetrahydrocurcumin and green tea polyphenol on the survival of male C57BL/6 mice.Biogerontology.2007;8:567-73. 27.Kim SJ, Son TG, Park HR, et al.Curcumin stimulates proliferation of embryonic neural progenitor cells and neurogenesis in the adult hippocampus.J Biol Chem.2008;283:14497-505. 28.He Y, Wang P, Wei P, et al.Efects of curcumin on synapses in APPswe/PS1dE9 mice.Int J Immunopathol Pharmacol.2016;29:217-25. 29.Wang C, Zhang X, Teng Z, Zhang T, Li Y.Downregulation of PI3K/Akt/mTOR signaling pathway in curcumin-induced autophagy in APP/PS1 double transgenic mice.Eur J Pharmacol.2014;740:312-20. 30.Nelson KM, Dahlin JL, Bisson J, Graham J, Pauli GF, Walters MA.The essential medicinal chemistry of curcumin.J Med Chem.2017;60:1620-37. 31.Dubiley TA, Rushkevich YE, Koshel NM, Voitenko VP, Vaiserman AM.Life span extension in Drosophila melanogaster induced by mor-phine.Biogerontology.2011;12:179-84. 32.Dubiley TA, Rushkevich YE, Pishel IN.Efect of agonist of opioid recep-tors upon lifespan of old mice.Probl Aging Longvity.2000;9:331-2 (in Russian). 33.Chen QQ.Nordihydroguaiaretic acid analogues:their chemical syn-thesis and biological activities.Curr Top Med Chem.2009;9:1636-59. 34.Strong R, Miller RA, Astle CM, et al.Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice.Aging Cell.2008;7:641-50. 35.Siddique YH, Ali F.Protective efect of nordihydroguaiaretic acid (NDGA) on the transgenic Drosophila model of Alzheimer's disease.Chem Biol Interact.2017;269:59-66. 36.Yamada M, Ono K, Hamaguchi T.Natural phenolic compounds as therapeutic and preventive agents for cerebral amyloidosis.Adv Exp Med Biol.2015;863:79-94. 37.Billinsky JL, Marcoux MR, Krol ES.Oxidation of the lignan nordihy-droguaiaretic acid.Chem Res Toxicol.2007;20:1352-8. 38.Saxton RA, Sabatini DM.mTOR signaling in growth, metabolism, and disease.Cell.2017;168:960-76. 39.Apelo SIA, Lamming DW.Rapamycin:an inhibiTOR of aging emerges from the soil of Easter Island.J Gerontol Biol Sci.2016;71:841-9. 40.Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Mueller F.Genetics:infuence of TOR kinase on lifespan in C.elegans.Nature.2003;426:620. 41.Kaeberlein M, Power RW III, Stefen KK, et al.Regulation of yeast rep-licative life span by TOR and Sch9 in response to nutrients.Science.2005;310:1193-6. 42.Bjedov I, Toivonen JM, Kerr F, et al.Mechanisms of life span extension by rapamycin in the fruit fy Drosophila melanogaster.Cell Metab.2010;11:35-46. 43.Harrison DE, Strong R, Sharp ZD, et al.Rapamycin fed late in life extends lifespan in genetically heterogeneous mice.Nature.2009;460:392-5. 44.Miller RA, Harrison DE, Astle CM, et al.Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction.Aging Cell.2014;13:468-77. 45.Swindell WR.Rapamycin in mice.Aging (Albany NY).2017;9:1941-2. 46.Ehninger D, Nef F, Xie K.Longevity, aging and rapamycin.Cell Mol Life Sci.2014;71:4325-46. 47.Johnson SC, Martinez F, Bitto A, et al.mTOR inhibitors may beneft kidney transplant recipients with mitochondrial diseases.Kidney Int.2019;95:455-66. 48.Kaeberlein M, Galvan V.Rapamycin and Alzheimer's disease:time for a clinical trial? Sci Transl Med.2019;11(476):eaar4289. 49.Bove J, Martinez-Vicente M, Vila M.Fighting neurodegeneration with rapamycin:mechanistic insights.Nat Rev Neurosci.2011;12:437-52. 50.Abu-Amero KK, Kondkar AA, Chalam KV.Resveratrol and ophthalmic diseases.Nutrients.2016;8:200.https://doi.org/10.3390/nu8040200. 51.Jang M, Cai L, Udeani GO, et al.Cancer chemopreventive activ-ity of resveratrol, a natural product derived from grapes.Science.1997;275:218-20. 52.Kim S, Benguria A, Lai CY, Jazwinski SM.Modulation of life-span by histone deacetylase genes in Saccharomyces cerevisiae.Mol Biol Cell.1999;10:3125-36. 53.Li YR, Li SM, Lin CC.Efect of resveratrol and pterostilbene on aging and longevity.BioFactors.2018;44:69-82. 54.Howitz KT, Bitterman KJ, Cohan HY, et al.Small molecule activa-tors of sirtuins extend Saccharomyces cerevisiae lifespan.Nature.2003;425:191-6. 55.Rascon B, Hubbard BP, Sinclair DA, Amdam GV.The lifespan extension efects of resveratrol are conserved in the honey bee and may be driven by a mechanism related to caloric restriction.Aging (Albany NY).2012;4:499-508. 56.Valenzano DR, Terzibasi E, Genade T, et al.Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate.Curr Biol.2006;16:296-300. 57.Kim E, Ansell CM, Dudycha JL.Resveratrol and food efects on lifespan and reproduction in the model crustacean Daphnia.J Exp Zool A Ecol Genet Physiol.2014;321:48-56. 58.Baur JA, Pearson KJ, Price NL, et al.Resveratrol improves health and survival of mice on a high-calorie diet.Nature.2006;444:337-42. 59.Ochiai A, Kuroda K.Preconception resveratrol intake against infertility:friend or foe? Reprod Med Biol.2020;19:107-13. 60.Gambini J, Inglés M, Olaso G.Properties of resveratrol:in vitro and in vivo studies about metabolism, bioavailability, and biologi-cal efects in animal models and humans.Oxid Med Cell Longev.2015;2015:837042. 61.Shaito A, Posadino AM, Younes N, et al.Potential adverse efects of resveratrol:a literature review.Int J Mol Sci.2020;21:2084. 62.Zhao JW, Zhu A, Sun YQ, et al.Benefcial efects of sappanone A on lifes-pan and thermotolerance in Caenorhabditis elegans.Eur J Pharmacol.2020;888:173558. 63.de Cabo R, Carmona-Gutierrez D, Bernier FM, Hall MN, Madeo F.The search for antiaging interventions:from elixirs to fasting regimens.Cell.2014;157:1515-26. 64.Kiechl S, Pechlaner R, Willeit P, et al.Higher spermidine intake is linked to lower mortality:a prospective population-based study.Am J Clin Nutr.2018;108:371-80. 65.Atiya AM, Poorvliet E, Stromberg R, Yngve A.Polyamines in foods:devel-opment of a food database.Food Nutr Res.2011;55:5572. 66.Madeo F, Eisenberg T, Pietrocola F, Kroemer G.Spermidine in health and disease.Science.2018;359:6374. 67.Gupta VK, Scheunemann L, Eisenberg T, et al.Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner.Nat Neurosci.2013;16:1453-60. 68.Jamwal S, Singh S, Kaur N, Kumar P.Protective efect of spermidine against excitotoxic neuronal death induced by quinolinic acid in rats:possible neurotransmitters and neuroinfammatory mechanism.Neuro-tox Res.2015;28:171-84. 69.Velloso NA, Dalmolin GD, Gomes GM, et al.Spermine improves recognition memory defcit in a rodent model of Huntington's disease.Neurobiol Learn Mem.2009;92:574-80. 70.Schwarz C, Stekovic S, Wirth M, et al.Safety and tolerability of spermi-dine supplementation in mice and older adults with subjective cogni-tive decline.Aging (Albany NY).2018;10:19-33. 71.Eisenberg T, Abdellatif M, Schroeder S, et al.Cardioprotection and lifespan extension by the natural polyamine spermidine.Nat Med.2016;22:1428-38. 72.Pandey T, Sammi SR, Nooreen Z, et al.Anti-ageing and anti-Par-kinsonian efects of natural favonol, tambulin from Zanthoxyllum aramatum promotes longevity in Caenorhabditis elegans.Exp Gerontol.2019;120:50-61. 73.Djedjibegovic J, Marjanovic A, Panieri E, Saso L.Ellagic Acid-derived urolithins as modulators of oxidative stress.Oxid Med Cell Longev.2020;2020:5194508. 74.Liu CF, Li XL, Zhang ZL, et al.Antiaging efects of urolithin A on replicative senescent human skin fbroblasts.Rejuvenation Res.2019;22:191-200. 75.Hasheminezhad SH, Boozari M, Iranshahi M, et al.A mechanistic insight into the biological activities of urolithins as gut microbial metabolites of ellagitannins.Phytother Res.2022;36:112-46. 76.Shen S, Zhang Y, Zhang R, Tu X, Gong X.Ursolic acid induces autophagy in U87MG cells via ROS-dependent endoplasmic reticu-lum stress.Chem Biol Interact.2014;218:28-41. 77.Jia Y, Kim S, Kim J, Kim B, et al.Ursolic acid improves lipid and glucose metabolism in high-fat-fed C57BL/6J mice by activating peroxisome proliferator-activated receptor alpha and hepatic autophagy.Mol Nutr Food Res.2015;59:344-54. 78.Ebert SM, Dyle MC, Bullard SA, et al.Identifcation and small molecule inhibition of an activating transcription factor 4 (ATF4)-dependent pathway to age-related skeletal muscle weakness and atrophy.J Biol Chem.2015;290:25497-511. 79.Bahrami SA, Bakhtiari N.Ursolic acid regulates aging process through enhancing of metabolic sensor proteins level.Biomed Pharmaother.2016;82:8-14. 80.Bakhtiari N, Hosseinkhani S, Tashakor A, Hemmati R.Ursolic acid ame-liorates aging-metabolic phenotype through promoting of skeletal muscle rejuvenation.Med Hypothe.2015;85:1-6. 81.Negi H, Shukla A, Khan F, Pandey R.3β-Hydroxy-urs-12-en-28-oic acid prolongs lifespan in C.elegans by modulating JNK-1.Biochem Biophys Res Commun.2016;480:539-43. 82.Negi H, Saikia SK, Pandey R.3β-Hydroxy-urs-12-en-28-oic acid modu-lates dietary restriction mediated longevity and ameliorates toxic protein aggregation in C.elegans.J Gerontol Biol Sci.2017;72:1614-9. 83.Staats S, Wagner AE, Lueersen K, et al.Dietary ursolic acid improves health span and life span in male Drosophila melanogaster.BioFac-tors.2019;45:169-86. 84.Nukui K, Yamagishi T, Miyawaki H, et al.Blood CoQ10 levels and safety profle after single-dose or chronic administration of PureSorb-Q40:animal and human studies.BioFactors.2008;32:209-19. 85.Shults CW, Oakes MD, Kieburtz K, et al.Efects of coenzyme Q10 in early Parkinson disease:evidence of slowing of the functional decline.Arch Neurol.2002;59:1541-50. 86.Weber C, Byste A, Holmer G.Coenzyme Q10 in the diet- daily intake and relative bioavailability.Molec Aspects Med.1997;18(Suppl):S251-254. 87.Berg S, Javed S, Kohli K.Bioavailability enhancement of coenzyme Q10:an extensive review of patents.Recent Pat Drug Deliv Formul.2010;4:245-55. 88.Zmitek K, Zmitek J, Butina MR, Pogacnik T.Efects of a combination of water-soluble coenzyme Q10 and collagen on skin parameters and condition:results of a randomised, placebo-controlled, double-blind study.Nutrients.2020;12:618. 89.Muthukumaran K, Leahy S, Harrison K, et al.Orally delivered water soluble coenzyme Q10 (Ubisol-Q10) blocks on-going neurodegen-eration in rats exposed to paraquat:potential for therapeutic applica-tion in Parkinson's disease.BMC Neurosci.2014;15:21. 90.Guastini L, Mora R, Dellepiane M, et al.Water-soluble coenzyme Q10 formulation in presbycusis:long-term efects.Acta Otolaryngol.2011;131:512-7. 91.Salami A, Mora R, Dellepiane M, et al.Water-soluble coenzyme Q10 formulation (Q-TER(®)) in the treatment of presbycusis.Acta Otolar-yngol.2010;130:1154-62. 92.Hernandez-Camacho JD, Bernier M, Lopez-Lluch G, Navas P.Coen-zyme Q 10 supplementation in aging and disease.Front Physiol.2018;9:44. 93.Takahashi M, Takahashi K.Water-soluble CoQ10 as A promising anti-aging agent for neurological dysfunction in brain mitochondria.Antioxidants (Basel).2019;8:61.https://doi.org/10.3390/antiox8030061. 94.Kua CH.Dietary lipophilic antioxidants:implications and signifcance in the aging process.Crit Rev Food Sci Nutr.2010;50:931-7. 95.Pietsch K, Saul N, Chakrabarti S, et al.Hormetins, antioxidants and prooxidants:defning quercetin-, cafeic acid-and rosmarinic acid-mediated life extension in C.elegans.Biogerontology.2011;12:329-47. 96.Warnsmann V, Hainbuch S, Osiewacz HD.Quercetin-induced lifespan extension in Podospora anserina requires methylation of the favonoid by the O-methyltransferase PaMTH1.Front Genet.2018;9:160. 97.Lee EB, Ahb D, Kim BJ, et al.Genistein from Vigna angularis extends lifespan in Caenorhabditis elegans.Biomol Ther.2015;23:77-83. 98.Soukup ST, Spanier B, Gruenz G, et al.Formation of phosphoglycosides in Caenorhabditis elegans:a novel biotransformation pathway.PLoS ONE.2012;7:e46914. 99.Abbas S, Wink M.Epigallocatechin gallate from green tea (Camellia sinensis) increases lifespan and stress resistance in Caenorhabditis elegans.Planta Med.2009;75:216-21. 100.Li YM, Chan HYE, Huang Y, Chen ZY.Green tea catechins upregulate superoxide dismutase and catalase in fruit fies.Mol Nutr Food Res.2007;51:546-54. 101.Niu Y, Na L, Feng R, et al.The phytochemical, EGCG, extends lifespan by reducing liver and kidney function damage and improving age-associated infammation and oxidative stress in healthy rats.Aging Cell.2013;12:1041-9. 102.Lopez T, Schriner SE, Okoro M, et al.Green tea polyphenols extend the lifespan of male Drosophila melanogaster while impairing reproductive ftness.J Med Food.2014;17:1314-21. 103.Zhang LZ, Jie GL, Zhang JJ, Zhao BL.Signifcant longevity-extending efects of EGCG on Caenorhabditis elegans under stress.Free Radic Biol Med.2009;46:414-21. 104.Velmurugan K, Alam J, McCord JM, Pugazhenthi S.Synergistic induction of heme oxygenase-1 by the components of the antioxidant supple-ment Protandim.Free Radic Biol Med.2009;46:430-40. 105.Nelson SK, Bose SK, Grunwald GK, et al.The induction of human super-oxide dismutase and catalase in vivo:a fundamentally new approach to antioxidant therapy.Free Radic Biol Med.2006;40:341-7. 106.Strong R, Miller RA, Antebi A, et al.Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer.Aging Cell.2016;15:872-84. 107.Schlernitzauer A, Oiry C, Hamad R, et al.Chicoric acid is an antioxidant molecule that stimulates AMP kinase pathway in L6 myotubes and extends lifespan in Caenorhabditis elegans.PLoS ONE.2013;8:e78788. 108.Canuelo A, Esteban FJ, Peragon J.Gene profling to investi-gate tyrosol-induced lifespan extension in Caenorhabditis elegans.Eur J Nutr.2016;55:639-50. 109.Singh S, Garg G, Singh AK, et al.Fisetin, a potential caloric restriction mimetic, attenuates senescence biomarkers in rat erythrocytes.Bio-chem Cell Biol.2019;97:480-7. 110.Yousefzadeh MJ, Zhu Y, McGowan SJ, et al.Fisetin is a senotherapeutic that extends health and lifespan.EBioMedicine.2018;36:18-28. 111.Blagosklonny MV.Anti-aging:senolytics or gerostatics (unconventional view).Oncotarget.2021;12:1821-35. 112.Harley CB, Liu W, Blasco M, et al.A natural product telomerase activa-tor as part of a health maintenance program.Rejuvenation Res.2011;14:45-56. 113.De Jesus BB, Schneeberger K, Vera E, et al.The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence.Aging Cell.2011;10:604-21. 114.Dow CT, Harley CB.Evaluation of an oral telomerase activator for early age-related macular degeneration-a pilot study.Clin Ophthalmol.2016;10:243-9. 115.Sunagawa T, Shimizu T, Kanda T, et al.Procyanidins from apples (Malus pumila Mill.) extend the lifespan of Caenorhabditis elegans.Planta Med.2011;77:122-7. 116.Xu Q, Fu Q, Li Z, et al.The favonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice.Nat Metab.2021;3:1706-26. 117.Bayliak MM, Lushchak VI.Pleiotropic efects of alpha-ketoglutarate as a potential anti-ageing agent.Aging Res Rev.2021;66:101237. 118.Martinez-Reyes I, Chandel NS.Mitochondrial TCA cycle metabolites control physiology and disease.Nat Commun.2020;11:102. 119.Chin RM, Fu X, Pai MY, et al.The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR.Nature.2014;510:397-401. 120.Su Y, Wang T, Wu N, et al.Alpha-ketoglutarate extends Drosophila lifespan by inhibiting mTOR and activating AMPK.Aging (Albany, NY).2019;11:4183-97. 121.Burdyliuk N, Bayliak M.Efects of long-term cultivation on medium with alpha-ketoglutarate supplementation on metabolic processes of Saccharomyces cerevisiae.J Aging Res.2017;2017:8754879. 122.Shahmirzadi AA, Edger D, Liao C, et al.Alpha-ketoglutarate, an endog-enous metabolite, extends lifespan and compresses morbidity in aging mice.Cell Metab.2020;32:447-56. 123.Salminen A, Kauppinen A, Hiltunen M, Kaarniranta K.Krebs cycle intermediates regulate DNA and histone methylation:epigenetic impact on the aging process.Aging Res Rev.2014;16:45-65. 124.Williams DS, Cash A, Hamadani L, Diemer T.Oxaloacetate supplemen-tation increases lifespan in Caenorhabditis elegans through an AMPK/FOXO-dependent pathway.Aging Cell.2009;8:765-8. 125.Sahu P, Gidwani B, Dhongade HJ.Pharmacological activities of dehy-droepiandrosterone:a review.Steroids.2020;153:108507. 126.Dykens JA, Moos WH, Howell N.Development of 17alpha-estradiol as a neuroprotective therapeutic agent:rationale and results from a phase I clinical study.Ann N Y Acad Sci.2005;1052:116-35. 127.Cascella R, Evangelisti E, Zampagni M, et al.S-linolenoyl glutathione intake extends life-span and stress resistance via Sir-2.1 upregulation in Caenorhabditis elegans.Free Radic Biol Med.2014;73:127-35. 128.Izmaylov DM, Obukhova LK.Geroprotector efectiveness of mela-tonin:investigation of lifespan of Drosophila melanogaster.Mech Aging Dev.1999;106:233-40. 129.Bonilla E, Medina-Leendertz S, Diaz S.Extension of life span and stress resistance of Drosophila melanogaster by long-term supplementation with melatonin.Exp Gerontol.2002;37:629-38. 130.Anisimov V.Dose-dependent efect of melatonin on life span and spontaneous tumor incidence in female SHR mice.Exp Gerontol.2003;38:449-61. 131.Vaiserman A, Koliada A, Lushchak O, Castillo MJ.Repurposing drugs to fght aging:the difcult path from bench to bedside.Med Res Rev.2021;41:1676-700. 132.Scheibye-Knudsen M, Mitchell SJ, Fang EF, et al.A high-fat diet and NAD+ activate Sirt1 to rescue premature aging in cockayne syn-drome.Cell Metab.2014;20:840-55. 133.Fang EF, Lautrup S, Hou Y, et al.NAD+ in aging:molecular mechanisms and translational implications.Trends Mol Med.2017;23:899-916. 134.Braidy N, Berg J, Clement J, et al.Role of nicotinamide adenine dinu-cleotide and related precursors as therapeutic targets for age-related degenerative diseases:rationale, biochemistry, pharmacokinetics, and outcomes.Antioxid Redox Signal.2019;30:251-94. 135.Bonkowski MS, Sinclair DA.Slowing ageing by design:the rise of NAD + and sirtuin-activating compounds.Nat Rev Mol Cell Biol.2016;17:679-90. 136.Satoh A, Imai SI, Guarente L.The brain, sirtuins, and ageing.Nat Rev Neurosci.2017;18:362-74. 137.Trammell SA, Schmit MS, Weidemann BJ, et al.Nicotinamide riboside is uniquely and orally bioavailable in mice and humans.Nat Com-mun.2016;7:12948. 138.Ratajczak J, Jofraud M, Trammell SA, et al.NRK1 controls nicotina-mide mononucleotide and nicotinamide riboside metabolism in mammalian cells.Nat Commun.2016;7:13103. 139.Canto C, Houtkooper RH, Pirinen E, et al.The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity.Cell Metab.2012;15:838-47. 140.Schoendorf DC, Ivanyuk D, Baden P, et al.The NAD+ precursor nicotinamide riboside rescues mitochondrial defects and neu-ronal loss in iPSC and Fly models of Parkinson's disease.Cell Rep.2018;23:2976-88. 141.Hou Y, Lautrup S, Cordonnier S, et al.NAD+ supplementation normal-izes key Alzheimer's features and DNA damage responses in a new AD mouse model with introduced DNA repair defciency.Proc Natl Acad Sci USA.2018;115:E1876-85. 142.Fang EF.Mitophagy and NAD+ inhibit Alzheimer disease.Autophagy.2019;15:1112-4. 143.Fang EF, Hou Y, Palikaras K, et al.Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive defcits in models of Alzheimer's disease.Nat Neurosci.2019;22:401-12. 144.Wang X, Hu X, Yang Y, et al.Nicotinamide mononucleotide protects against β-amyloid oligomer-induced cognitive impairment and neu-ronal death.Brain Res.2016;1643:1-9. 145.Harrison DE, Strong R, Allison DB.Acarbose, 17-α-estradiol, and nordihy-droguaiaretic acid extend mouse lifespan preferentially in males.Aging Cell.2014;13:273-82. 146.Harrison DE, Strong R, Alavez S, et al.Acarbose improves health and lifespan in aging HET3 mice.Aging Cell.2019;18:e12898. 147.Robbins PD, Niedernhofer LJ.Advances in therapeutic approaches to extend healthspan:a perspective from the 2nd scripps symposium on the biology of aging.Aging Cell.2017;16:610-4. 148.Khalili N, Safavipour A.Evaluation of the efects of acarbose on weight and metabolic, infammatory, and cardiovascular markers in patients with obesity and overweigh.Int J Prev Med.2020;11:140. 149.Sagagurski M, Cady G, Miller RA.Anti-aging drugs reduce hypothalamic infammation in a sex-specifc manner.Aging Cell.2017;16:652-60. 150.Yan WW, Chen GH, Wang F, et al.Long-term acarbose administration alleviating the impairment of spatial learning and memory in the SAMP8 mice was associated with alleviated reduction of insulin system and acetylated H4K8.Brain Res.2015;1603:22-31. 151.Miller RA, Harrison DE, Astle CM, et al.An aging interventions testing program:study design and interim report.Aging Cell.2007;6:565-75. 152.Ayyadevara S, Bharill P, Dandapat A, et al.Aspirin inhibits oxidant stress, reduces age-associated functional declines, and extends lifespan of Caenorhabditis elegans.Antioxid Redox Signal.2013;18:481-90. 153.Wan QL, Zheng SQ, Wu GS, Luo HR.Aspirin extends the lifespan of Caenorhabditis elegans via AMPK and DAF-16/FOXO in dietary restriction pathway.Exp Gerontol.2013;48:499-506. 154.Kitani K, Minami C, Isobe K, et al.Why (-)deprenyl prolongs survivals of experimental animals:increase of anti-oxidant enzymes in brain and other body tissues as well as mobilization of various humoral factors may lead to systemic anti-aging efects.Mech Aging Dev.2002;123:1087-100. 155.Soukas AA, Hao HB, Wu LF.Metformin as anti-aging therapy:is it for everyone? Trends Endocrinol Metab.2019;30:745-55. 156.Bailey CJ.Metformin:historical overview.Diabetologia.2017;60:1566-76. 157.Werner A, Bell J.Metformin and related biguanide compounds synthe-sis.J Chem Soc Trans.1922;121:1790-4. 158.Campbell JM, et al.Metformin reduces all-cause mortality and diseases of ageing independent of its efect on diabetes control:a systematic review and meta-analysis.Aging Res Rev.2017;40:31-44. 159.Castillo-Quan JI, Blackwell TK.Metformin:restraining nucleocytoplasmic shuttling to fght cancer and aging.Cell.2016;167:1670-1. 160.Barzilai N, et al.Metformin as a tool to target aging.Cell Metab.2016;23:1060-5. 161.Vancura A, et al.Metformin as an anticancer agent.Trends Pharmacol Sci.2018;39:867-78. 162.Onken B, Driscoll M.Metformin induces a dietary restriction-like state and the oxidative stress response to extend C elegans healthspan via AMPK, LKB1, and SKN-1.PLoS ONE.2010;5:e8758. 163.Anisimov VN, et al.If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice.Aging (Albany NY).2011;3:148-57. 164.Martin-Montalvo A, et al.Metformin improves healthspan and lifespan in mice.Nat Commun.2013;4:2192. 165.Cuyas E, et al.Metformin is a direct SIRT1-activating compound:computational modeling and experimental validation.Front Endocrinol (Lausanne).2018;9:657. 166.Bridgeman SC, et al.Epigenetic efects of metformin:from molecu-lar mechanisms to clinical implications.Diabetes Obes Metab.2018;20:1553-62. 167.Cabreiro F, et al.Metformin retards aging in C.elegans by altering micro-bial folate and methionine metabolism.Cell.2013;153:228-39. 168.Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA.Metformin as a tool to target aging.Cell Metab.2016;23:1060-5. 169.Oxenkrug G, Navrotskaya V, Vorobyova L, Summergrad P.Minocycline efect on life and health span of Drosophila melanogaster.Aging Dis.2012;3:352-9. 170.Mora M, Medina-Leendertz SJ, Bonilla E, et al.Minocycline, but not ascorbic acid, increases motor activity and extends the life span of Drosophila melanogaster.Invest Clin.2013;54:161-70. 171.Lee GJ, Lim JJ, Hyun S.Minocycline treatment increases resistance to oxidative stress and extends lifespan in Drosophila via FOXO.Onco-target.2017;8:87878-90. 172.Spindler SR, Li R, Dhahbi JM, et al.Statin treatment increases lifespan and improves cardiac health in Drosophila by decreasing specifc protein prenylation.PLoS ONE.2012;7:e39581. 173.Kennedy BK, Pennypacker JK.Drugs that modulate aging:the prom-ising yet difcult path ahead.Transl Res.2014;163:456-65. 174.Olivieri F, Mazzanti I, Abbatecola A, et al.Telomere/Telomerase sys-tem:a new target of statins pleiotropic efect? Curr Vasc Pharmacol.2012;10:216-24. 175.Fang SC, Xie H, Chen F, et al.Simvastatin ameliorates memory impair-ment and neurotoxicity in streptozotocin-induced diabetic mice.Neuroscience.2017;355:200-11. 176.Wang C, Chen T, Li G, et al.Simvastatin prevents β-amyloid(25-35)-impaired neurogenesis in hippocampal dentate gyrus through α7nAChR-dependent cascading PI3K-Akt and increasing BDNF via reduction of farnesyl pyrophosphate.Neuropharmacology.2015;97:122-32. 177.Tong XK, Nicolakakis N, Fernandes P, et al.Simvastatin improves cerebrovascular function and counters soluble amyloid-beta, infammation and oxidative stress in aged APP mice.Neurobiol Dis.2009;35:406-14. 178.Power MC, Weuve J, Sharrett AR, Blacker D.Statins, cognition, and dementia-systematic review and methodological commentary.Nat Rev Neurol.2015;11:220-9. 179.Li G, Larson EB, Sonnen JA, et al.Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease.Neurology.2007;69:878-85. 180.Mehta JL, Bursac Z, Hauer-Jensen M, et al.Comparison of mortality rates in statin users versus nonstatin users in a United States veteran population.Am J Cardiol.2006;98:923-8. 181.Jacobs JM, Cohen A, Ein-Mor E, Stessman J.Cholesterol, statins, and longevity from age 70 to 90 years.J Am Med Dir Assoc.2013;14:883-8. 182.Houtkooper RH, Mouchiroud L, Ryu D, et al.Mitonuclear protein imbal-ance as a conserved longevity mechanism.Nature.2013;497:451-7. 183.Ye X, Linton JM, Shork NJ, et al.A pharmacological network for lifespan extension in Caenorhabditis elegans.Aging Cell.2014;13:206-15. 184.Bonilla E, Contreras R, Medina-Leendertz S, Mora M, Villalobos V, Bravo Y.Minocycline increases the life span and motor activity and decreases lipid peroxidation in manganese treated Drosophila melanogaster.Toxicology.2012;294:50-3. 185.Santos EL, de PicoliSouza K, da Silva ED, et al.Long term treatment with ACE inhibitor enalapril decreases body weight gain and increases life span in rats.Biochem Pharmacol.2009;78:951-8. 186.Spindler SR, Mote PL, Li R, et al.β1-Adrenergic receptor blockade extends the life span of Drosophila and long-lived mice.Age (Dordr).2013;35:2099-109. 187.Floyd RA, Hensley K, Forster MJ, et al.Nitrones, their value as therapeutics and probes to understand aging.Mech Aging Dev.2002;123:1021-31. 188.Forster MJ, Lal H.Within-subject behavioral analysis of recent memory in aging mice.Behav Pharm.1992;3:337-49. 189.Floyd RA, Hensley K, Forster MJ, Kelleher-Andersson JA, Wood PL.Nitrones, their value as therapeutics and probes to understand aging.Mech Aging Dev.2002;123:1021-31. 190.Sayed AAR, El-Shaieb KM, Mourad AFE.Life span extension of Caenorhabditis elegans by novel pyridoperimidine derivative.Arch Pharm Res.2012;35:69-76. 191.Lamichane S, Baek SH, Kim YJ, et al.MHY2233 attenuates replicative cellular senescence in human endothelial progenitor cells via SIRT1 signaling.Oxid Med Cell Longev.2019;2019:6492029. 192.Koufaki M, Fotopoulou T, Kapetanou M, et al.Microwave-assisted synthesis of 3,5-disubstituted isoxazoles and evaluation of their anti-ageing activity.Eur J Med Chem.2014;83:508-15. 193. Klass MR. A method for the isolation of longevity mutants in the nematode Caenorhabditis elegans and initial results. Mech Aging Dev. 1983;22:279-86. 194. Friedman DB, Johnson TE. Three mutants that extend both mean and maximum life span of the nematode, Caenorhabditis elegans, defne the age-1 gene. J Gerontol. 1988;43:B102-9. 195. Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang RA. A C. elegans mutant that lives twice as long as wild type. Nature. 1993;366:461-4. 196. Tissenbaum HA. Genetics, life span, health span, and the aging process in Caenorhabditis elegans. J Gerontol A Biol Sci Med Sci. 2012;67A:503-10. 197. Fitzgerald K, Tertyshnikova S, Moore L, et al. Chemical genetics reveals an RGS/G-protein role in the action of a compound. PLoS Genet. 2006;2:e57. 198. Lucanic M, Lithgow GJ, Alavez S. Pharmacological lifespan extension of invertebrates. Aging Res Rev. 2013;12:445-58. 199. Jafari M. Drosophila melanogaster as a model system for the evalua-tion of anti-aging compounds. Fly. 2010;4:253-7. 200. Ladiges W, Remmen HV, Strong R, et al. Lifespan extension in geneti-cally modifed mice. Aging Cell. 2009;8:346-52. 201. Nakamura S, Yoshimori T. Autophagy and longevity. Mol Cells. 2018;41:65-72. 202. Pyo JO, Yoo SM, Jung YK. The interplay between autophagy and aging. Diabetes Metab J. 2013;37:333-9. 203. Gelino S, Hansen M. Autophagy-an emerging anti-aging mecha-nism. J Clin Exp Pathol Suppl. 2012;4:006. 204. Yamaguchi O, Otsu K. Role of autophagy in aging. J Cardiovasc Phar-macol. 2012;60:242-7. 205. Rubinsztein DC, Marino G, Kroemer G. Autophagy and aging. Cell. 2011;148:682-95. 206. Darzynkiewicz Z, Zhao H, Halicka HD, et al. In search of antiaging modalities:evaluation of mTOR-and ROS/DNA damage-signaling by cytometry. Cytometry A. 2014;85:386-99. 207. Varghese N, Werner S, Grimm A, Eckert A. Dietary mitophagy enhancer:a strategy for healthy brain aging? Antioxidants (Basel). 2020;9:932. 208. Madeo F, Zimmermann A, Maiuri MC, Kroemer G. Essential role for autophagy in life span extension. J Clin Invest. 2015;125:85-93. 209. McCay CM, Maynard LA, Sperling G, Barnes RL. Retarded growth, life span, ultimate body size and age changes in the albino rat after feed-ing diets restricted in calories. J Nutr. 1939;18:1-13. 210. Masoro EJ. Overview of caloric restriction and ageing. Mech Ageing Dev. 2005;126:913-22. 211. Lin SJ, Kaeberlein M, Andrelis AA, et al. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature. 2002;418:344-8. 212. Partridge L, Piper MDW, Mair W. Dietary restriction in Drosophila. Mech Ageing Dev. 2005;126:938-50. 213. Masoro EJ. Caloric restriction-induced life extension of rats and mice:a critique of proposed mechanisms. Biochim Biophy Acta. 2009;1790:1040-8. 214. Roth GS, Ingram DK, Lane MA. Caloric restriction in primates and relevance to humans. Ann N Y Acad Sci. 2001;928:305-15. 215. Fontana L, Meyer TE, Klein S, Holloszy JO. Long-term calorie restric-tion is highly efective in reducing the risk for atherosclerosis in humans. Proc Natl Acad Sci USA. 2004;101:6659-63. 216. Colman RJ, Anderson RM, Johnson SC, et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science. 2009;325:201-4. 217. Mattison JA, Roth GS, Beasley TM, et al. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature. 2012;489:318-21. 218. Mattison JA, Colman RJ, Beasley TM, et al. Caloric restriction improves health and survival of rhesus monkeys. Nat Commun. 2017;8:14063. 219. Martin CK, Bhapkar M, Pittas AG, et al. Efect of calorie restriction on mood, quality of life, sleep, and sexual function in healthy non-obese adults:the CALERIE 2 randomized clinical trial. JAMA Int Med. 2016;176:743-52. 220. Redman LM, Smith SR, Burton JH, et al. Metabolic slowing and reduced oxidative damage with sustained caloric restriction support the rate of living and oxidative damage theories of aging. Cell Metab. 2018;27:805-15. 221. Lane MA, Ingram DK, Roth GS. D-Deoxy-D-glucose feeding in rats mimics physiologic efects of calorie restriction. J Anti-Aging Med. 1998;1:327-37. 222. Shintani H, Shintani T, Ashida H, Sato M. Calorie restriction mimetics:upstream-type compounds for modulating glucose metabolism. Nutrients. 2018;10:1821. 223. Weimer S, Priebs J, Kuhlow D, et al. D-Glucosamine supplementation extends life span of nematodes and of ageing mice. Nat Commun. 2014;5:3563. 224. Katoh A, Kai H, Harada H, et al. Oral administration of glucosamine improves vascular endothelial function by modulating intracellular redox state. Int Heart J. 2017;58:926-32. 225. Pocobelli G, Kristal AR, Patterson RE, et al. Total mortality risk in rela-tion to use of less-common dietary supplements. Am J Clin Nutr. 2010;91:1791-800. 226. Shintani T, Sakoguchi H, Yoshihara A, et al. D-Allose, a stereoisomer of D-glucose, extends the lifespan of Caenorhabditis elegans via sirtuin and insulin signaling. J Appl Glycosci. 2019;66:139-42. 227. Shintani T, Kosuge Y, Ashida H. Glucosamine extends the lifespan of Caenorhabditis elegans via autophagy induction. J Appl Glycosci. 2018;65:37-43. 228. Benayoun BA, Pollina EA, Brunet A. Epigenetic regulation of ageing:linking environmental inputs to genomic stability. Nat Rev Mol Cell Biol. 2015;16:593-610. 229. Booth LN, Brunet A. The aging epigenome. Mol Cell. 2016;62:728-44. 230. Li X, Wang J, Wang L, et al. Impaired lipid metabolism by age-depend-ent DNA methylation alterations accelerates aging. Proc Nat Acad Sci USA. 2020;117:4328-36. 231. Gensous N, Bacalini MG, Pirazzini C, et al. The epigenetic landscape of age-related diseases:the geroscience perspective. Biogerontology. 2017;8:549-59. 232. Dor Y, Cedar H. Principles of DNA methylation and their implications for biology and medicine. Lancet. 2018;392:777-86. 233. Horvath S, Raj K. DNA methylation-based biomarkers and the epige-netic clock theory of ageing. Nat Rev Gen. 2018;19:371-84. 234. Jiang S, Guo Y. Epigenetic clock:DNA methylation in aging. Stem Cells Int. 2020;2020:1047896. 235. Maegawa S, Lu Y, Tahara T, et al. Caloric restriction delays age-related methylation drift. Nat Commun. 2017;8:539. 236. Fahy GM, Brooke RT, Watson JP, et al. Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell. 2019;18:e13028. 237. Wood JG, Helfand SL. Chromatin structure and transposable elements in organismal aging. Front Genet. 2013;4:274. 238. Jylhava J. Determinants of longevity:genetics, biomarkers and thera-peutic approaches. Curr Pharm Des. 2015;20:6058-70. 239. Edwards C, Canfeld J, Copes N, et al. D-beta-hydroxybutyrate extends lifespan in C. elegans. Aging (Albany NY). 2014;6:621-44. 240. Kang HL, Benzer S, Min KT. Life extension in Drosophila by feeding a drug. Proc Natl Acad Sci USA. 2002;99:838-43. 241. Zhao YM, Sun H, Lu J, et al. Lifespan extension and elevated hsp gene in Drosophila caused by histone deacetylase inhibitors. J Exp Biol. 2005;208:697-705. 242. McDonald P, Maizi BM, Arking R. Chemical regulation of mid-and late-life longevities in Drosophila. Exp Gerontol. 2013;48:240-9. 243. Laurent RS, O'Brien LM, Ahmad ST. Sodium butyrate improves locomo-tor impairment and early mortality in a rotenone-induced Drosophila model of Parkinson's disease. Neuroscience. 2013;246:382-90. 244. Vaiserman AM, et al. Determination of geroprotective potential of sodium butyrate in Drosophila melanogaster:long-term efects. Adv Gerontol. 2013;26:111-6. 245. Tao D, Lu J, Sun H, et al. Trichostatin A extends the lifespan of Drosophila melanogaster by elevating hsp22 . Acta Biochim Biophys Sin. 2004;36:618-22. 246. Pasyukova EG, Vaiserman AM. HDAC inhibitors:a new promising drug class in anti-aging research. Mech Aging Dev. 2017;106:6-15. 247. Dzakah EE, Waqas A, Wei S, et al. Loss of miR-83 extends lifespan and afects target gene in an age-dependent manner in Caenorhabditis elegans. J Genet Genom. 2018;45:651-62. 248. Wang N, Liu J, Xie F, et al. miR-124/ATF-6, a novel lifespan extension pathway of Astragalus polysaccharide in Caenorhabditis elegans. J Cell Biochem. 2015;116:242-51. 249. Gendron CM, Pleatcher SD. MicroRNAs mir-184 and let-7 alter Dros-ophila metabolism and longevity. Aging Cell. 2017;16:1434-8. 250. Zhang YP, Zhang WH, Dong MQ. Science China, The miR-58 microRNA family is regulated by insulin signaling and contributes to lifespan regulation in Caenorhabditis elegans. Life Sci. 2018;61:1060-70. 251. Pinto S, Sato VN, De-Souza EA, et al. Enoxacin extends lifespan of C elegans by inhibiting miR-34-5p and promoting mitohormesis. Rodox Biol. 2018;18:84-92. 252. Cohen-Berkman M, Dudkevich R, Ben-Hamo S, et al. Endogenous siRNAs promote proteostasis and longevity in germline-less Caenorhabditis elegans. Elife. 2020;9:e50896. 253. Suh Y, Atzmon G, Cho MO, et al. Functionally signifcant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci USA. 2008;105:3438-42. 254. Milman S, Atzmon G, Hufman DM, et al. Low insulin-like growth factor-1 level predicts survival in humans with exceptional longevity. Aging Cell. 2014;13:769-71. 255. Zhou Y, Xu BC, Maheshwari HG, et al. A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse). Proc Natl Acad Sci. 1997;94:13215-20. 256. Shevah O, Laron Z. Patients with congenital defciency of IGF-I seem protected from the development of malignancies:a preliminary report. Growth Horm IGF Res. 2007;17:54-7. 257. Ikeno Y, Hubbard GB, Lee S, et al. Reduced incidence and delayed occurrence of fatal neoplastic diseases in growth hormone recep-tor/binding protein knockout mice. J Gerontol A Biol Sci Med Sci. 2009;64:522-9. 258. Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, et al. Growth hormone receptor defciency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Tansl Med. 2011;3:70ra13. 259. Steuerman R, Shevah O, Laron Z, et al. Congenital IGF1 defciency tends to confer protection against post-natal development of malignancies. Eur J Endocrinol. 2011;164:485-9. 260. Franceschi C, Campisi J. Chronic infammation (infammaging) and its potential contribution to age-associated disease. J Gerontol A Biol Sci Med Sci. 2014;69:S4-9. 261. Pinti M, Cevenini E, Nasi M, et al. Circulating mitochondrial DNA increases with age and is a familiar trait:Implications for "infamm-aging." Eur J Immunol. 2014;44:1552-62. 262. Dall'Olio F, Vanhooren V, Chen CC, et al. N-glycomic biomarkers of biological aging and longevity:a link with infammaging. Ageing Res Rev. 2012;12:685-98. 263. Lopez-Otin C, Blasco MA, Partridge L, et al. The hallmarks of aging. Cell. 2013;153:1194-217. 264. Bourque G, Burns KH, Gehring M, et al. Ten things you should know about transposable elements. Genome Biol. 2018;19:199. 265. Goodier JL. Restricting retrotransposons:a review. Mob DNA. 2016;7:16. 266. Saleh A, Macia A, Muotri AR. Transposable elements, infammation, and neurological disease. Front Neurol. 2019;10:894. 267. LaRocca TJ, Cavalier AN, Wahl D. Repetitive elements as a transcriptomic marker of aging:evidence in multiple datasets and models. Aging Cell. 2020;19:e13167. 268. Pasha M, Eider AH, Eid AA, et al. Sestrin2 as a novel biomarker and therapeutic target for various diseases. Oxid Med Cell Longev. 2017;2017:3296264. 269. Campisi J. Replicative senescence:an old lives' tale? Cell. 1996;84:497-500. 270. Borghesan M, Hoogaars WMH, Varela-Eirin M, et al. A senescence-centric view of aging:implications for longevity and disease. Trends Cell Biol. 2020;30:777-91. 271. Lagoumtzi SM, Chondrogianni N. Senolytics and senomorphics:natural and synthetic therapeutics in the treatment of aging and chronic diseases. Free Radic Biol Med. 2021;171:169-90. 272. Boccardi V, Mecocci P. Senotherapeutics:targeting senescent cells for the main age-related diseases. Mech Aging Dev. 2021;197:111526. 273. Kirkland JL, Tchkonia T, Zhu Y, et al. The clinical potential of senolytic drugs. J Am Geriatr Soc. 2017;65:2297-301. 274. Xu M, Pirtskhalava T, Farr JN, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med. 2018;24:1246-56. 275. Zhang P, Kishimoto Y, Grammatikakis I, et al. Senolytic therapy allevi-ates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive defcits in an Alzheimer's disease model. Nat Neurosci. 2019;22:719-28. 276. Munoz-Espín D, Canamero M, Maraver A, et al. Programmed cell senescence during mammalian embryonic development. Cell. 2013;155:1104. 277. Storer M, Mas A, Robert-Moreno A, et al. Senescence is a developmen-tal mechanism that contributes to embryonic growth and patterning. Cell. 2013;155:1119. 278. Demaria M, Ohtani N, Youssef SA, et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell. 2014;31:722-33. 279. Childs BG, Gluscevic M, Baker DJ, et al. Senescent cells:an emerging target for diseases of ageing. Nat Rev Drug Discov. 2017;16:718-32. 280. Iside C, Scafuro M, Nebbioso A, Altucci L. SIRT1 activation by natural phytochemicals:an overview. Front Pharmacol. 2020;11:1225. 281. Smith HJ, Mair WB. Metabolic communication and healthy aging:where should we focus our energy? Dev Cell. 2020;54:196-211. 282. Tissenbaum HA, Guarente SL. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature. 2001;410:227-30. 283. Rogina B, Helfand SL. Sir2 mediates longevity in the fy through a pathway related to calorie restriction. Proc Natl Acad Sci USA. 2004;101:15998-6003. 284. Kanf Y, Naiman S, Amir G, et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature. 2012;483:218-21. 285. Satoh A, Brace CS, Rensing N, et al. Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. Cell Metab. 2013;18:416-30. 286. Morris BJ. Seven sirtuins for seven deadly diseases of aging. Free Radic Biol Med. 2013;56:133-71. 287. Mostoslavsky R, Chua KF, Lombard DB, et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell. 2006;124:315-29. 288. Tsoukalas D, Fragkiadaki P, Docea AO, et al. Discovery of potent telomer-ase activators:unfolding new therapeutic and anti-aging perspectives. Mol Med Rep. 2019;20:3701-8. 289. Bai H, Liu R, Chen HL, et al. Enhanced antioxidant efect of cafeic acid phenethyl ester and Trolox in combination against radiation induced-oxidative stress. Chem Biol Interact. 2014;207:7-15. 290. Stefanska B, Salamé P, Bednarek A, Fabianowska-Majewska K. Compara-tive efects of retinoic acid, vitamin D and resveratrol alone and in combination with adenosine analogues on methylation and of phosphatase and tensin homologue tumour suppressor gene in breast cancer cells. Br J Nutr. 2012;107:781-90. 291. Bernardes de Jesus B, Blasco MA. Telomerase at the intersection of cancer and aging. Trends Genet. 2013;29:513-20. 292. Bernardes de Jesus B, Vera E, Schneeberger K, et al. Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Mol Med. 2012;4:691-704. 293. Serrano M, Blasco M. Cancer and ageing:convergent and divergent mechanisms. Nat Rev Mol Cell Biol. 2007;8:715-22. 294. Lamming DM, Ye L, Katajisto P, et al. Rapamycin-induced insulin resist-ance is mediated by mTORC2 loss and uncoupled from longevity. Science. 2012;335:1638-43. 295. Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature. 2013;493:338-45. 296. Schreiber KH, Ortiz D, Academia EC, et al. Rapamycin-mediated mTORC2 inhibition is determined by the relative of FK506-binding proteins. Aging Cell. 2015;14:265-73. 297. Kaeberlein M. mTOR inhibition:from aging to autism and beyond. Scientifca. 2013;2013:849186. 298. Wrighton KH. Ageing:staying alive without CRTC-1. Nat Rev Mol Cell Biol. 2011;12:206-7. 299. Pazoki-Toroudi H, Amani H, Ajami M, et al. Targeting mTOR signaling by polyphenols:a new therapeutic target for ageing. Aging Res Rev. 2016;31:55-66. 300. Castillo-Quan JI, Kinghorn KJ, Bjedov I. Genetics and pharmacology of longevity:the road to therapeutics for healthy aging. Adv Genet. 2015;90:1-101. 301. Blagsklonny MV. From rapalogs to anti-aging formula. Oncotarget. 2017;8:35492-507. 302. Martel J, Ojcius DM, Ko YF, et al. Antiaging efects of bioactive mol-ecules isolated from plants and fungi. Med Res Rev. 2019;39:1515-52. 303. Ding AJ, Zheng SQ, Huang XB, et al. Current perspective in the discov-ery of anti-aging agents from natural products. Nat Prod Bioprospect. 2017;7:335-404. 304. Wu JY, Siu KC, Geng P. Bioactive ingredients and medicinal values of Grifola frondosa (Maitake). Foods. 2021;10:95. 305. Zhang C, Gao Z, Hu CL, et al. Antioxidant, antibacterial and anti-aging activities of intracellular zinc polysaccharides from Grifola frondosa SH-05. Int J Biol Macromol. 2017;95:778-87. 306. Wang J, Cao B, Zhao HP, Feng J. Emerging roles of Ganoderma lucidum in anti-aging. Aging Dis. 2017;8:691-707. 307. Liu XY, Liu D, Chen YH, et al. Physicochemical characterization of a poly-saccharide from Agrocybe aegirita and its anti-ageing activity. Carbohyd Polym. 2020;236:116056. 308. Liu P, Zhao HP, Luo YM. Anti-aging implications of Astragalus membranaceus (Huangqi):a well-known Chinese tonic. Aging Dis. 2017;8:868-86. 309. Zhou HT, Ding SS, Sun CX, et al. Lycium barbarum extracts extend lifes-pan and alleviate proteotoxicity in Caenorhabditis elegans. Front Nutr. 2022;8:815947. 310. Yuan YY, Kang NX, Li QX, et al. Study of the efect of neutral polysaccha-rides from Rehmannia glutinosa on lifespan of Caenorhabditis elegans. Molecules. 2019;24:4592.

[1]	Hesham R. El-Seedi, Mohamed S. Refaey, Nizar Elias, Mohamed F. El-Mallah, Faisal M. K. Albaqami, Ismail Dergaa, Ming Du, Mohamed F. Salem, Haroon Elrasheid Tahir, Maria Dagliaa, Nermeen Yosri, Hongcheng Zhang, Awg H. El-Seedi, Zhiming Guo, Shaden A. M. Khalifa. Marine natural products as a source of novel anticancer drugs: an updated review (2019-2023) [J]. Natural Products and Bioprospecting, 2025, 15(2): 13-13.
[2]	María I. Osella, Mario O. Salazar, Carlos M. Solís, Ricardo L. E. Furlan. New semisynthetic α-glucosidase inhibitor from a doubly-chemically engineered extract [J]. Natural Products and Bioprospecting, 2025, 15(1): 4-4.
[3]	Ahmed H. Elbanna, Xinhui Kou, Dilip V. Prajapati, Surasree Rakshit, Rebecca A. Butcher. Discovery of a parallel family of euglenatide analogs in Euglena gracilis [J]. Natural Products and Bioprospecting, 2025, 15(1): 10-10.
[4]	Song-Yu Hou, Bing-Chao Yan, Han-Dong Sun, Pema-Tenzin Puno. Recent advances in the application of [2+2] cycloaddition in the chemical synthesis of cyclobutane-containing natural products [J]. Natural Products and Bioprospecting, 2024, 14(5): 37-37.
[5]	Felaine Anne Sumang, Alan Ward, Jeff Errington, Yousef Dashti. Hibiscus acid and hydroxycitric acid dimethyl esters from Hibiscus flowers induce production of dithiolopyrrolone antibiotics by Streptomyces Strain MBN2-2 [J]. Natural Products and Bioprospecting, 2024, 14(5): 40-40.
[6]	Chunsong Hu. Marine natural products and human immunity: novel biomedical resources for anti-infection of SARS-CoV-2 and related cardiovascular disease [J]. Natural Products and Bioprospecting, 2024, 14(2): 2-2.
[7]	Shohreh Ariaeenejad, Javad Gharechahi, Mehdi Foroozandeh Shahraki, Fereshteh Fallah Atanaki, Jian-Lin Han, Xue-Zhi Ding, Falk Hildebrand, Mohammad Bahram, Kaveh Kavousi, Ghasem Hosseini Salekdeh. Precision enzyme discovery through targeted mining of metagenomic data [J]. Natural Products and Bioprospecting, 2024, 14(1): 7-7.
[8]	Daniel W. Armstrong, Alain Berthod. Occurrence of D-amino acids in natural products [J]. Natural Products and Bioprospecting, 2023, 13(6): 47-47.
[9]	Dalila Carbone, Carmela Gallo, Genoveffa Nuzzo, Giusi Barra, Mario Dell'Isola, Mario Affuso, Olimpia Follero, Federica Albiani, Clementina Sansone, Emiliano Manzo, Giuliana d'Ippolito, Angelo Fontana. Marine natural product lepadin A as a novel inducer of immunogenic cell death via CD91-dependent pathway [J]. Natural Products and Bioprospecting, 2023, 13(5): 34-34.
[10]	Phanankosi Moyo, Luke Invernizzi, Sephora M. Mianda, Wiehan Rudolph, Warren A. Andayi, Mingxun Wang, Neil R. Crouch, Vinesh J. Maharaj. Leveraging off higher plant phylogenetic insights for antiplasmodial drug discovery [J]. Natural Products and Bioprospecting, 2023, 13(5): 35-35.
[11]	Phanankosi Moyo, Luke Invernizzi, Sephora M. Mianda, Wiehan Rudolph, Andrew W. Andayi, Mingxun Wang, Neil R. Crouch, Vinesh J. Maharaj. Prioritised identification of structural classes of natural products from higher plants in the expedition of antimalarial drug discovery [J]. Natural Products and Bioprospecting, 2023, 13(5): 37-37.
[12]	Ji-Kai Liu. Natural products in cosmetics [J]. Natural Products and Bioprospecting, 2022, 12(6): 40-40.
[13]	Si-Yuan Luo, Jun-Yu Zhu, Ming-Feng Zou, Sheng Yin, Gui-Hua Tang. Mulberry Diels–Alder-type adducts: isolation, structure, bioactivity, and synthesis [J]. Natural Products and Bioprospecting, 2022, 12(5): 31-31.
[14]	Yulian Lv, Tian Tian, Yong-Jiang Wang, Jian-Ping Huang, Sheng-Xiong Huang. Advances in chemistry and bioactivity of the genus Erythroxylum [J]. Natural Products and Bioprospecting, 2022, 12(3): 15-15.
[15]	Ghodsi Mohammadi Ziarani, Negar Jamasbi, Fatemeh Mohajer. Recent advances on the synthesis of natural pyrrolizidine alkaloids: alexine, and its stereoisomers [J]. Natural Products and Bioprospecting, 2022, 12(1): 1-15.