Therapeutic Antiaging Strategies
Abstract
:1. Introduction
2. Anti-Inflammatory Drugs Used as an Antiaging Approach
3. Antioxidant Activity
4. Telomere Reactivation
5. Antiaging Approaches Using Epigenetic Drugs
6. Activation of Chaperons and the Proteolytic System against Aging
7. Mitophagy Activators as an Antiaging Approach
8. Inhibition of mTOR and Insulin/IGF-1 Signaling (IIS) as an Antiaging Approach
9. Activation of AMPK and Sirtuin Signaling as an Antiaging Approach
10. Clearance of Senescent Cells
11. Stem Cell-Based Therapies
12. Role of the Microbiome in Aging and Potential Antiaging Therapeutics
13. Role of Noncoding RNAs in Aging and Their Potential Therapeutics
14. Conclusions
Expert Opinion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Rojo, L.E.; Fernández, J.A.; Maccioni, A.A.; Jimenez, J.M.; Maccioni, R.B. Neuroin flammation: Implications for the Pathogenesis and Molecular Diagnosis of Alzheimer’s Disease. Arch. Med. Res. 2008, 39, 1–16. [Google Scholar] [CrossRef]
- López-Otín, C.; Blasco, M.A.; Partridge, L.; Serrano, M.; Kroemer, G. The Hallmarks of Aging. Cell 2013, 153, 1194–1217. [Google Scholar] [CrossRef] [Green Version]
- de Magalhães, J.P. Programmatic features of aging originating in development: Aging mechanisms beyond molecular damage? FASEB J. 2012, 26, 4821–4826. [Google Scholar] [CrossRef] [PubMed]
- Kenyon, C.J. The genetics of ageing. Nature 2010, 464, 504–512. [Google Scholar] [CrossRef]
- Tacutu, R.; Craig, T.; Budovsky, A.; Wuttke, D.; Lehmann, G.; Taranukha, D.; Costa, J.; Fraifeld, V.E.; de Magalhaes, J.P. Human Ageing Genomic Resources: Integrated Databases and Tools for the Biology and Genetics Of Ageing. Nucleic Acids Res. 2012, 41, D1027–D1033. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shetty, A.K.; Kodali, M.; Upadhya, R.; Madhu, L.N. Emerging Anti-Aging Strategies—Scientific Basis and Efficacy. Aging Dis. 2018, 9, 1165–1184. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Helfand, S.L.; de Cabo, R. Evidence that overnight fasting could extend healthy lifespan. Nature 2021, 598, 265–266. [Google Scholar] [CrossRef]
- Franceschi, C.; Campisi, J. Chronic Inflammation (Inflammaging) and Its Potential Contribution to Age-Associated Diseases. J. Gerontol. Ser. A 2014, 69, S4–S9. [Google Scholar] [CrossRef] [PubMed]
- Howcroft, T.K.; Campisi, J.; Louis, G.B.; Smith, M.T.; Wise, B.; Wyss-Coray, T.; Augustine, A.D.; McElhaney, J.E.; Kohanski, R.; Sierra, F. The role of inflammation in age-related disease. Aging 2013, 5, 84–93. [Google Scholar] [CrossRef] [Green Version]
- De Magalhães, J.P.; Curado, J.; Church, G. Meta-analysis of age-related gene expression profiles identifies common signatures of aging. Bioinformatics 2009, 25, 875–881. [Google Scholar] [CrossRef] [PubMed]
- Kriete, A.; Mayo, K.L.; Yalamanchili, N.; Beggs, W.; Bender, P.; Kari, C.; Rodeck, U. Cell autonomous expression of inflammatory genes in biologically aged fibroblasts associated with elevated NF-kappaB activity. Immun. Ageing 2008, 5, 5. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Minciullo, P.L.; Catalano, A.; Mandraffino, G.; Casciaro, M.; Crucitti, A.; Maltese, G.; Morabito, N.; Lasco, A.; Gangemi, S.; Basile, G. Inflammaging and Anti-Inflammaging: The Role of Cytokines in Extreme Longevity. Arch. Immunol. Ther. Exp. 2016, 64, 111–126. [Google Scholar] [CrossRef] [PubMed]
- Ventura, M.T.; Casciaro, M.; Gangemi, S.; Buquicchio, R. Immunosenescence in aging: Between immune cells depletion and cytokines up-regulation. Clin. Mol. Allergy 2017, 15, 21. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rea, I.M.; Gibson, D.S.; McGilligan, V.; McNerlan, S.E.; Alexander, H.D.; Ross, O.A. Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines. Front. Immunol. 2018, 9, 586. [Google Scholar] [CrossRef] [PubMed]
- Sanada, F.; Taniyama, Y.; Muratsu, J.; Otsu, R.; Shimizu, H.; Rakugi, H.; Morishita, R. Source of Chronic Inflammation in Aging. Front. Cardiovasc. Med. 2018, 5, 12. [Google Scholar] [CrossRef] [Green Version]
- Chung, H.Y.; Ki, W.C.; Lee, E.K.; Chung, K.W.; Chung, S.; Lee, B.; Seo, A.Y.; Chung, J.H.; Jung, Y.S.; Im, E.; et al. Redefining Chronic Inflammation in Aging and Age-Related Diseases: Proposal of the Senoinflammation Concept. Aging Dis. 2019, 10, 367–382. [Google Scholar] [CrossRef] [Green Version]
- Neves, J.M.; Sousa-Victor, P. Regulation of inflammation as an anti-aging intervention. FEBS J. 2020, 287, 43–52. [Google Scholar] [CrossRef] [Green Version]
- Coppé, J.-P.; Desprez, P.-Y.; Krtolica, A.; Campisi, J. The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression. Annu. Rev. Pathol. Mech. Dis. 2010, 5, 99–118. [Google Scholar] [CrossRef] [Green Version]
- Jurk, D.; Wilson, C.; Passos, J.F.; Oakley, F.; Correia-Melo, C.; Greaves, L.; Saretzki, G.; Fox, C.; Lawless, C.; Anderson, R.; et al. Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nat. Commun. 2014, 5, 4172. [Google Scholar] [CrossRef] [Green Version]
- Vitale, G.; Salvioli, S.; Franceschi, C. Oxidative stress and the ageing endocrine system. Nat. Rev. Endocrinol. 2013, 9, 228–240. [Google Scholar] [CrossRef]
- Youm, Y.-H.; Grant, R.W.; McCabe, L.R.; Albarado, D.C.; Nguyen, K.Y.; Ravussin, A.; Pistell, P.; Newman, S.; Carter, R.; Laque, A.; et al. Canonical Nlrp3 Inflammasome Links Systemic Low-Grade Inflammation to Functional Decline in Aging. Cell Metab. 2013, 18, 519–532. [Google Scholar] [CrossRef] [Green Version]
- He, C.; Tsuchiyama, S.K.; Nguyen, Q.T.; Plyusnina, E.N.; Terrill, S.R.; Sahibzada, S.; Patel, B.; Faulkner, A.R.; Shaposhnikov, M.; Tian, R.; et al. Enhanced Longevity by Ibuprofen, Conserved in Multiple Species, Occurs in Yeast through Inhibition of Tryptophan Import. PLoS Genet. 2014, 10, e1004860. [Google Scholar] [CrossRef] [Green Version]
- Ching, T.-T.; Chiang, W.-C.; Chen, C.-S.; Hsu, A.-L. Celecoxib extends C. elegans lifespan via inhibition of insulin-like signaling but not cyclooxygenase-2 activity. Aging Cell 2011, 10, 506–519. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Strong, R.; Miller, R.A.; Astle, C.M.; Floyd, R.A.; Flurkey, K.; Hensley, K.L.; Javors, M.A.; Leeuwenburgh, C.; Nelson, J.F.; Ongini, E.; et al. Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice. Aging Cell 2008, 7, 641–650. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lee, M.E.; Kim, S.R.; Lee, S.; Jung, Y.-J.; Choi, S.S.; Kim, W.J.; Han, J.A. Cyclooxygenase-2 inhibitors modulate skin aging in a catalytic activity-independent manner. Exp. Mol. Med. 2012, 44, 536–544. [Google Scholar] [CrossRef] [PubMed]
- Kalonia, H.; Kumar, P.; Kumar, A. Licofelone attenuates quinolinic acid induced Huntington like symptoms: Possible behavioral, biochemical and cellular alterations. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2011, 35, 607–615. [Google Scholar] [CrossRef] [PubMed]
- Asanuma, M.; Miyazaki, I.; Diaz-Corrales, F.J.; Ogawa, N. Quinone formation as dopaminergic neuron-specific oxidative stress in the pathogenesis of sporadic Parkinson’s disease and neurotoxin-induced parkinsonism. Acta Medica Okayama 2004, 58, 221–233. [Google Scholar] [PubMed]
- Black, P.H. Stress and the inflammatory response: A review of neurogenic inflammation. Brain Behav. Immun. 2002, 16, 622–653. [Google Scholar] [CrossRef]
- Choi, S.H.; Aid, S.; Caracciolo, L.; Sakura Minami, S.; Niikura, T.; Matsuoka, Y.; Turner, R.S.; Mattson, M.P.; Bosetti, F. Cyclooxygenase-1 inhibition reduces amyloid pathology and improves memory deficits in a mouse model of Alzheimer’s disease. J. Neurochem. 2013, 124, 59–68. [Google Scholar] [CrossRef] [Green Version]
- Calfio, C.; Gonzalez, A.; Singh, S.K.; Rojo, L.E.; Maccioni, R.B. The Emerging Role of Nutraceuticals and Phytochemicals in the Prevention and Treatment of Alzheimer’s Disease. J. Alzheimer’s Dis. 2020, 77, 33–51. [Google Scholar] [CrossRef]
- Veurink, G.; Perry, G.; Singh, S.K. Role of antioxidants and a nutrient rich diet in Alzheimer’s disease. Open Biol. 2020, 10, 200084. [Google Scholar] [CrossRef]
- Minois, N. Molecular Basis of the ‘Anti-Aging’ Effect of Spermidine and Other Natural Polyamines—A Mini-Review. Gerontology 2014, 60, 319–326. [Google Scholar] [CrossRef]
- Madeo, F.; Carmona-Gutierrez, D.; Kepp, O.; Kroemer, G. Spermidine delays aging in humans. Aging 2018, 10, 2209–2211. [Google Scholar] [CrossRef]
- Phillips, T.; Leeuwenburgh, C. Lifelong Aspirin Supplementation as a Means to Extending Life Span. Rejuvenation Res. 2004, 7, 243–252. [Google Scholar] [CrossRef]
- Ayyadevara, S.; Bharill, P.; Dandapat, A.; Hu, C.; Khaidakov, M.; Mitra, S.; Shmookler Reis, R.J.; Mehta, J.L. Aspirin inhibits oxidant stress, reduces age-associated functional declines, and extends lifespan of Caenorhabditis elegans. Antioxid. Redox Signal. 2013, 18, 481–490. [Google Scholar] [CrossRef]
- Nadon, N.L.; Strong, R.; Miller, R.A.; Harrison, D.E. NIA Interventions Testing Program: Investigating Putative Aging Intervention Agents in a Genetically Heterogeneous Mouse Model. eBioMedicine 2017, 21, 3–4. [Google Scholar] [CrossRef] [Green Version]
- Orhan, H.; Doğruer, D.; Cakir, B.; Şahin, G.; Şahin, M. The in vitro effects of new non-steroidal antiinflammatory compounds on antioxidant system of human erythrocytes. Exp. Toxicol. Pathol. 1999, 51, 397–402. [Google Scholar] [CrossRef]
- Danilov, A.; Shaposhnikov, M.; Shevchenko, O.; Zemskaya, N.; Zhavoronkov, A.; Moskalev, A. Influence of non-steroidal anti-inflammatory drugs on Drosophila melanogaster longevity. Oncotarget 2015, 6, 19428–19444. [Google Scholar] [CrossRef] [Green Version]
- Hosseini, S.; Abdollahi, M.; Azizi, G.; Fattahi, M.J.; Rastkari, N.; Zavareh, F.T.; Aghazadeh, Z.; Mirshafiey, A. Anti-aging effects of M2000 (β-D-mannuronic acid) as a novel immunosuppressive drug on the enzymatic and non-enzymatic oxidative stress parameters in an experimental model. J. Basic Clin. Physiol. Pharmacol. 2017, 28, 249–255. [Google Scholar] [CrossRef] [PubMed]
- Waditee-Sirisattha, R.; Kageyama, H. Protective effects of mycosporine-like amino acid-containing emulsions on UV-treated mouse ear tissue from the viewpoints of antioxidation and antiglycation. J. Photochem. Photobiol. B 2021, 223, 112296. [Google Scholar] [CrossRef]
- Kageyama, H.; Waditee-Sirisattha, R. Antioxidative, Anti-Inflammatory, and Anti-Aging Properties of Mycosporine-Like Amino Acids: Molecular and Cellular Mechanisms in the Protection of Skin-Aging. Mar. Drugs 2019, 17, 222. [Google Scholar] [CrossRef] [Green Version]
- Kumar Singh, S.; Barreto, G.E.; Aliev, G.; Echeverria, V. Ginkgo biloba as an Alternative Medicine in the Treatment of Anxiety in Dementia and other Psychiatric Disorders. Curr. Drug. Metab. 2017, 18, 112–119. [Google Scholar] [CrossRef]
- Singh, S.K.; Srikrishna, S.; Castellani, R.J.; Perry, G. Antioxidants in the prevention and treatment of alzheimer’s disease. In Nutritional Antioxidant Therapies: Treatments and Perspectives; Springer International Publishing: Berlin/Heidelberg, Germany, 2018; pp. 523–553. [Google Scholar] [CrossRef]
- Singh, S.K.; Srivastav, S.; Castellani, R.J.; Plascencia-Villa, G.; Perry, G. Neuroprotective and Antioxidant Effect of Ginkgo biloba Extract Against AD and Other Neurological Disorders. Neurotherapeutics 2019, 16, 666–674. [Google Scholar] [CrossRef]
- Mishra, S.; Mishra, S.K.; Singh, S.K. Ayurveda and Yoga practices: A synergistic approach for the treatment of Alzheimer’s disease. Eur. J. Biol. Res. 2020, 11, 65–74. [Google Scholar]
- Pietta, P.G. Flavonoids as Antioxidants. J. Nat. Prod. 2000, 63, 1035–1042. [Google Scholar] [CrossRef]
- Lobo, V.; Patil, A.; Phatak, A.; Chandra, N. Free radicals, antioxidants and functional foods: Impact on human health. Pharmacogn. Rev. 2010, 4, 118–126. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kampkötter, A.; Timpel, C.; Zurawski, R.F.; Ruhl, S.; Chovolou, Y.; Proksch, P.; Wätjen, W. Increase of stress resistance and lifespan of Caenorhabditis elegans by quercetin. Comp. Biochem. Physiol. Part B Biochem. Mol. Biol. 2008, 149, 314–323. [Google Scholar] [CrossRef]
- Sugawara, T.; Sakamoto, K. Quercetin enhances motility in aged and heat-stressed Caenorhabditis elegans nematodes by modulating both HSF-1 activity, and insulin-like and p38-MAPK signalling. PLoS ONE 2020, 15, e0238528. [Google Scholar] [CrossRef]
- Pietsch, K.; Saul, N.; Swain, S.C.; Menzel, R.; Steinberg, C.E.; Stürzenbaum, S.R. Meta-analysis of global transcriptomics suggests that conserved genetic pathways are responsible for quercetin and tannic acid mediated longevity in C. elegans. Front. Genet. 2012, 3, 48. [Google Scholar] [CrossRef] [Green Version]
- Proshkina, E.; Lashmanova, E.; Dobrovolskaya, E.; Zemskaya, N.; Kudryavtseva, A.; Shaposhnikov, M.; Moskalev, A. Geroprotective and Radioprotective Activity of Quercetin, (-)-Epicatechin, and Ibuprofen in Drosophila melanogaster. Front. Pharmacol. 2016, 7, 505. [Google Scholar] [CrossRef]
- Končič, M.; Rajić, Z.; Petrič, N.; Zorc, B. Antioxidant activity of NSAID hydroxamic acids. Acta Pharm. 2009, 59, 235–242. [Google Scholar] [CrossRef] [PubMed]
- Orhan, H.; Şahin, G. In vitro effects of NSAIDS and paracetamolon oxidative stress-related parameters of human erythrocytes. Exp. Toxicol. Pathol. 2001, 53, 133–140. [Google Scholar] [CrossRef]
- Peng, C.; Wang, X.; Chen, J.; Jiao, R.; Wang, L.; Li, Y.M.; Zuo, Y.; Liu, Y.; Lei, L.; Ma, K.Y.; et al. Biology of Ageing and Role of Dietary Antioxidants. BioMed Res. Int. 2014, 2014, 831841. [Google Scholar] [CrossRef] [Green Version]
- O’Sullivan, R.J.; Karlseder, J. Telomeres: Protecting chromosomes against genome instability. Nat. Rev. Mol. Cell Biol. 2010, 11, 171–181. [Google Scholar] [CrossRef] [Green Version]
- Lingner, J.; Cooper, J.P.; Cech, T.R. Telomerase and DNA end replication: No longer a lagging strand problem? Science 1995, 269, 1533–1534. [Google Scholar] [CrossRef]
- Greider, C.W. Telomerase is processive. Mol. Cell. Biol. 1991, 11, 4572–4580. [Google Scholar]
- Cesare, A.J.; Reddel, R.R. Alternative lengthening of telomeres: Models, mechanisms and implications. Nat. Rev. Genet. 2010, 11, 319–330. [Google Scholar] [CrossRef] [PubMed]
- Victorelli, S.; Passos, J.F. Telomeres and Cell Senescence—Size Matters Not. eBioMedicine 2017, 21, 14–20. [Google Scholar] [CrossRef] [Green Version]
- Dodig, S.; Čepelak, I.; Pavić, I. Hallmarks of senescence and aging. Biochem. Med. 2019, 29, 483–497. [Google Scholar] [CrossRef] [PubMed]
- Cassidy, A.; De Vivo, I.; Liu, Y.; Han, J.; Prescott, J.; Hunter, D.J.; Rimm, E.B. Associations between diet, lifestyle factors, and telomere length in women. Am. J. Clin. Nutr. 2010, 91, 1273–1280. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Prescott, J.; Kraft, P.; Chasman, D.I.; Savage, S.A.; Mirabello, L.; Berndt, S.I.; Weissfeld, J.L.; Han, J.; Hayes, R.B.; Chanock, S.J.; et al. Genome-Wide Association Study of Relative Telomere Length. PLoS ONE 2011, 6, e19635. [Google Scholar] [CrossRef]
- Song, S.; Johnson, F.B. Epigenetic Mechanisms Impacting Aging: A Focus on Histone Levels and Telomeres. Genes 2018, 9, 201. [Google Scholar] [CrossRef] [Green Version]
- Kuszel, L.; Trzeciak, T.; Richter, M.; Czarny-Ratajczak, M. Osteoarthritis and telomere shortening. J. Appl. Genet. 2015, 56, 169–176. [Google Scholar] [CrossRef] [Green Version]
- Carlquist, J.F.; Knight, S.; Cawthon, R.M.; Le, V.; Bunch, T.J.; Horne, B.D.; Rollo, J.S.; Huntinghouse, J.A.; Muhlestein, J.B.; Anderson, J.L. Shortened telomere length is associated with paroxysmal atrial fibrillation among cardiovascular patients enrolled in the Intermountain Heart Collaborative Study. Hear. Rhythm 2016, 13, 21–27. [Google Scholar] [CrossRef]
- Hunt, S.C.; Kimura, M.; Hopkins, P.N.; Carr, J.J.; Heiss, G.; Province, M.A.; Aviv, A. Leukocyte Telomere Length and Coronary Artery Calcium. Am. J. Cardiol. 2015, 116, 214–218. [Google Scholar] [CrossRef] [Green Version]
- Blasco, M.A. Telomere length, stem cells and aging. Nat. Chem. Biol. 2007, 3, 640–649. [Google Scholar] [CrossRef]
- Pereira, B.; Ferreira, M.G. Sowing the seeds of cancer: Telomeres and age-associated tumorigenesis. Curr. Opin. Oncol. 2013, 25, 93–98. [Google Scholar] [CrossRef]
- Wang, S.; Madu, C.O.; Lu, Y. Telomere and Its Role in Diseases. Oncomedicine 2019, 4, 1–9. [Google Scholar] [CrossRef] [Green Version]
- Bernades de Jesus, B.; Schneeberger, K.; Vera, E.; Tejera, A.; Harley, C.B.; Blasco, M.A. The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence. Aging Cell 2011, 10, 604–621. [Google Scholar] [CrossRef] [Green Version]
- Bär, C.; Huber, N.; Beier, F.; Blasco, M.A. Therapeutic effect of androgen therapy in a mouse model of aplastic anemia produced by short telomeres. Haematologica 2015, 100, 1267–1274. [Google Scholar] [CrossRef] [Green Version]
- Calado, R.T.; Yewdell, W.T.; Wilkerson, K.L.; Regal, J.A.; Kajigaya, S.; Stratakis, C.A.; Young, N.S. Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells. Blood J. Am. Soc. Hematol. 2009, 114, 2236–2243. [Google Scholar] [CrossRef]
- de Jesus, B.B.; Vera, E.; Schneeberger, K.; Tejera, A.M.; Ayuso, E.; Bosch, F.; Blasco, M.A. Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Mol. Med. 2012, 4, 691–704. [Google Scholar] [CrossRef]
- Raghavan, P.R. Metadichol®: A Novel Nanolipid Formulation That Inhibits SARS-CoV-2 and a Multitude of Pathological Viruses In Vitro. BioMed Res. Int. 2020. [Google Scholar] [CrossRef]
- Tsoukalas, D.; Fragkiadaki, P.; Docea, A.O.; Alegakis, A.K.; Sarandi, E.; Thanasoula, M.; Spandidos, D.A.; Tsatsakis, A.; Razgonova, M.P.; Calina, D. Discovery of potent telomerase activators: Unfolding new therapeutic and anti-aging perspectives. Mol. Med. Rep. 2019, 20, 3701–3708. [Google Scholar] [CrossRef] [Green Version]
- Shay, J.W. Role of Telomeres and Telomerase in Aging and Cancer. Cancer Discov. 2016, 6, 584–593. [Google Scholar] [CrossRef] [Green Version]
- Sedivy, J.M.; Banumathy, G.; Adams, P.D. Aging by epigenetics—A consequence of chromatin damage? Exp. Cell. Res. 2008, 314, 1909–1917. [Google Scholar] [CrossRef] [Green Version]
- Feser, J.; Tyler, J. Chromatin structure as a mediator of aging. FEBS Lett. 2011, 585, 2041–2048. [Google Scholar] [CrossRef] [Green Version]
- O’Sullivan, R.J.; Karlseder, J. The great unravelling: Chromatin as a modulator of the aging process. Trends Biochem. Sci. 2012, 37, 466–476. [Google Scholar] [CrossRef] [Green Version]
- Imai, S.-I.; Armstrong, C.M.; Kaeberlein, M.; Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 2000, 403, 795–800. [Google Scholar] [CrossRef]
- Longo, V.D. Linking sirtuins, IGF-I signaling, and starvation. Exp. Gerontol. 2009, 44, 70–74. [Google Scholar] [CrossRef]
- Zhang, L.; Xie, W.J.; Liu, S.; Meng, L.; Gu, C.; Gao, Y.Q. DNA Methylation Landscape Reflects the Spatial Organization of Chromatin in Different Cells. Biophys. J. 2017, 113, 1395–1404. [Google Scholar] [CrossRef]
- McClay, J.L.; Aberg, K.A.; Clark, S.L.; Nerella, S.; Kumar, G.; Xie, L.Y.; Hudson, A.D.; Harada, A.; Hultman, C.M.; Magnusson, P.K.; et al. A methylome-wide study of aging using massively parallel sequencing of the methyl-CpG-enriched genomic fraction from blood in over 700 subjects. Hum. Mol. Genet. 2014, 23, 1175–1185. [Google Scholar] [CrossRef] [Green Version]
- Teschendorff, A.E.; Menon, U.; Gentry-Maharaj, A.; Ramus, S.J.; Weisenberger, D.J.; Shen, H.; Campan, M.; Noushmehr, H.; Bell, C.G.; Maxwell, A.P.; et al. Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Res. 2010, 20, 440–446. [Google Scholar] [CrossRef] [Green Version]
- Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol. 2013, 14, R115. [Google Scholar] [CrossRef] [Green Version]
- Pal, S.; Tyler, J.K. Epigenetics and aging. Sci. Adv. 2016, 2. [Google Scholar] [CrossRef] [Green Version]
- Jylhava, J. Determinants of longevity: Genetics, biomarkers and therapeutic approaches. Current Pharmaceutical Design 2014, 20, 6058–6070. [Google Scholar] [CrossRef]
- Morselli, E.; Mariño, G.; Bennetzen, M.V.; Eisenberg, T.; Megalou, E.; Schroeder, S.; Cabrera, S.; Bénit, P.; Rustin, P.; Criollo, A.; et al. Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome. J. Cell Biol. 2011, 192, 615–629. [Google Scholar] [CrossRef] [Green Version]
- Pasyukova, E.G.; Vaiserman, A.M. HDAC inhibitors: A new promising drug class in anti-aging research. Mech. Ageing Dev. 2017, 166, 6–15. [Google Scholar] [CrossRef]
- McIntyre, R.L.; Daniels, E.G.; Molenaars, M.; Houtkooper, R.H.; Janssens, G.E. From molecular promise to preclinical results: HDAC inhibitors in the race for healthy aging drugs. EMBO Mol. Med. 2019, 11, e9854. [Google Scholar] [CrossRef]
- Hetz, C.; Chevet, E.; Oakes, S.A. Proteostasis control by the unfolded protein response. Nat. Cell Biol. 2015, 17, 829–838. [Google Scholar] [CrossRef] [Green Version]
- Cannizzo, E.S.; Clement, C.C.; Morozova, K.; Valdor, R.; Kaushik, S.; Almeida, L.N.; Follo, C.; Sahu, R.; Cuervo, A.M.; Macian, F.; et al. Age-Related Oxidative Stress Compromises Endosomal Proteostasis. Cell Rep. 2012, 2, 136–149. [Google Scholar] [CrossRef]
- Brehm, A.; Krüger, E. Dysfunction in protein clearance by the proteasome: Impact on autoinflammatory diseases. Semin. Immunopathol. 2015, 37, 323–333. [Google Scholar] [CrossRef]
- Dai, D.-F.; Karunadharma, P.P.; Chiao, Y.A.; Basisty, N.; Crispin, D.; Hsieh, E.J.; Chen, T.; Gu, H.; Djukovic, D.; Raftery, D.; et al. Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart. Aging Cell 2014, 13, 529–539. [Google Scholar] [CrossRef]
- Gong, Z.; Tasset, I. Humanin enhances the cellular response to stress by activation of chaperone-mediated autophagy. Oncotarget 2018, 9, 10832–10833. [Google Scholar] [CrossRef]
- Amm, I.; Sommer, T.; Wolf, D.H. Protein quality control and elimination of protein waste: The role of the ubiquitin–proteasome system. Biochim. Biophys. Acta BBA—Mol. Cell Res. 2013, 1843, 182–196. [Google Scholar] [CrossRef] [Green Version]
- Koga, H.; Kaushik, S.; Cuervo, A.M. Protein homeostasis and aging: The importance of exquisite quality control. Ageing Res. Rev. 2011, 10, 205–215. [Google Scholar] [CrossRef] [Green Version]
- Calderwood, S.K.; Murshid, A.; Prince, T. The Shock of Aging: Molecular Chaperones and the Heat Shock Response in Longevity and Aging—A Mini-Review. Gerontology 2009, 55, 550–558. [Google Scholar] [CrossRef] [Green Version]
- Morrow, G.; Samson, M.; Michaud, S.; Tanguay, R.M. Overexpression of the small mitochondrial Hsp22 extends Drosophila life span and increases resistance to oxidative stress. FASEB J. 2004, 18, 598–599. [Google Scholar] [CrossRef] [Green Version]
- Walker, G.A.; Lithgow, G.J. Lifespan extension in C. elegans by a molecular chaperone dependent upon insulin-like signals. Aging Cell 2003, 2, 131–139. [Google Scholar] [CrossRef] [Green Version]
- Chiang, W.C.; Ching, T.T.; Lee, H.C.; Mousigian, C.; Hsu, A.L. HSF-1 Regulators DDL-1/2 Link Insulin-like Signaling to Heat-Shock Responses and Modulation of Longevity. Cell 2012, 148, 322–334. [Google Scholar] [CrossRef] [Green Version]
- Hsu, A.-L.; Murphy, C.T.; Kenyon, C. Regulation of Aging and Age-Related Disease by DAF-16 and Heat-Shock Factor. Science 2003, 300, 1142–1145. [Google Scholar] [CrossRef]
- Ünal, E.; Kinde, B.; Amon, A. Gametogenesis Eliminates Age-Induced Cellular Damage and Resets Life Span in Yeast. Science 2011, 332, 1554–1557. [Google Scholar] [CrossRef] [Green Version]
- Erjavec, N.; Larsson, L.; Grantham, J.; Nyström, T. Accelerated aging and failure to segregate damaged proteins in Sir2 mutants can be suppressed by overproducing the protein aggregation-remodeling factor Hsp104p. Genes Dev. 2007, 21, 2410–2421. [Google Scholar] [CrossRef] [Green Version]
- Kaeberlein, M.; Kirkland, K.T.; Fields, S.; Kennedy, B.K. Genes determining yeast replicative life span in a long-lived genetic background. Mech. Ageing Dev. 2005, 126, 491–504. [Google Scholar] [CrossRef]
- Andersson, V.; Hanzén, S.; Liu, B.; Molin, M.; Nyström, T. Enhancing protein disaggregation restores proteasome activity in aged cells. Aging 2013, 5, 802–812. [Google Scholar] [CrossRef] [Green Version]
- Press, M.; Jung, T.; König, J.; Grune, T.; Höhn, A. Protein aggregates and proteostasis in aging: Amylin and β-cell function. Mech. Ageing Dev. 2019, 177, 46–54. [Google Scholar] [CrossRef]
- Moreno, D.; Jenkins, K.; Morlot, S.; Charvin, G.; Csikasz-Nagy, A.; Aldea, M. Proteostasis collapse, a hallmark of aging, hinders the chaperone-Start network and arrests cells in G1. eLife 2019, 8, 48240. [Google Scholar] [CrossRef] [PubMed]
- Chondrogianni, N.; Georgila, K.; Kourtis, N.; Tavernarakis, N.; Gonos, E.S. 20S proteasome activation promotes life span extension and resistance to proteotoxicity in Caenorhabditis elegans. FASEB J. 2015, 29, 611–622. [Google Scholar] [CrossRef] [Green Version]
- Chondrogianni, N.; Tzavelas, C.; Pemberton, A.J.; Nezis, I.P.; Rivett, A.J.; Gonos, E.S. Overexpression of Proteasome β5 Assembled Subunit Increases the Amount of Proteasome and Confers Ameliorated Response to Oxidative Stress and Higher Survival Rates*[boxs]. J. Biol. Chem. 2005, 280, 11840–11850. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tonoki, A.; Kuranaga, E.; Tomioka, T.; Hamazaki, J.; Murata, S.; Tanaka, K.; Miura, M. Genetic Evidence Linking Age-Dependent Attenuation of the 26S Proteasome with the Aging Process. Mol. Cell. Biol. 2009, 29, 1095–1106. [Google Scholar] [CrossRef] [Green Version]
- Papaevgeniou, N.; Sakellari, M.; Jha, S.; Tavernarakis, N.; Holmberg, C.I.; Gonos, E.S.; Chondrogianni, N. 18α-Glycyrrhetinic acid proteasome activator decelerates aging and Alzheimer’s disease progression in Caenorhabditis elegans and neuronal cultures. Antioxid. Redox Signal. 2016, 25, 855–869. [Google Scholar] [CrossRef]
- Eisenberg, T.; Knauer, H.; Schauer, A.; Büttner, S.; Ruckenstuhl, C.; Carmona-Gutierrez, D.; Ring, J.; Schroeder, S.; Magnes, C.; Antonacci, L.; et al. Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 2009, 11, 1305–1314. [Google Scholar] [CrossRef]
- Kim, E.J.E.; Lee, S.-J.V. Recent progresses on anti-aging compounds and their targets in Caenorhabditis elegans. Transl. Med. Aging 2019, 3, 121–124. [Google Scholar] [CrossRef]
- Cheng, J.; North, B.J.; Zhang, T.; Dai, X.; Tao, K.; Guo, J.; Wei, W. The emerging roles of protein homeostasis-governing pathways in Alzheimer’s disease. Aging Cell 2018, 17, e12801. [Google Scholar] [CrossRef] [Green Version]
- Höhn, A.; Tramutola, A.; Cascella, R. Proteostasis Failure in Neurodegenerative Diseases: Focus on Oxidative Stress. Oxidative Med. Cell. Longev. 2020, 2020, 5497046. [Google Scholar] [CrossRef] [Green Version]
- Sigurdson, C.J.; Bartz, J.C.; Glatzel, M. Cellular and Molecular Mechanisms of Prion Disease. Annu. Rev. Pathol. Mech. Dis. 2019, 14, 497–516. [Google Scholar] [CrossRef]
- Wickner, R.B.; Bezsonov, E.E.; Son, M.; Ducatez, M.; DeWilde, M.; Edskes, H.K. Anti-Prion Systems in Yeast and Inositol Polyphosphates. Biochemistry 2018, 57, 1285–1292. [Google Scholar] [CrossRef]
- Lin, M.T.; Beal, M.F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006, 443, 787–795. [Google Scholar] [CrossRef]
- Fang, E.F.; Scheibye-Knudsen, M.; Chua, K.F.; Mattson, M.P.; Croteau, D.L.; Bohr, V.A. Nuclear DNA damage signalling to mitochondria in ageing. Nat. Rev. Mol. Cell Biol. 2016, 17, 308–321. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Babbar, M.; Basu, S.; Yang, B.; Croteau, D.L.; Bohr, V.A. Mitophagy and DNA damage signaling in human aging. Mech. Ageing Dev. 2020, 186, 111207. [Google Scholar] [CrossRef]
- Knuppertz, L.; Warnsmann, V.; Hamann, A.; Grimm, C.; Osiewacz, H.D. Stress-dependent opposing roles for mitophagy in aging of the ascomycete Podospora anserina. Autophagy 2017, 13, 1037–1052. [Google Scholar] [CrossRef] [PubMed]
- Jin, S.M.; Youle, R.J. PINK1- and Parkin-mediated mitophagy at a glance. J. Cell Sci. 2012, 125, 795–799. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Greene, J.C.; Whitworth, A.J.; Kuo, I.; Andrews, L.A.; Feany, M.B.; Pallanck, L.J. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc. Natl. Acad. Sci. USA 2003, 100, 4078–4083. [Google Scholar] [CrossRef] [Green Version]
- Rana, A.; Rera, M.; Walker, D.W. Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan. Proc. Natl. Acad. Sci. USA 2013, 110, 8638–8643. [Google Scholar] [CrossRef] [Green Version]
- López-Armada, M.J.; Riveiro-Naveira, R.R.; Vaamonde-García, C.; Valcárcel-Ares, M.N. Mitochondrial dysfunction and the inflammatory response. Mitochondrion 2013, 13, 106–118. [Google Scholar] [CrossRef]
- Hashemzaei, M.; Heravi, R.E.; Rezaee, R.; Roohbakhsh, A.; Karimi, G. Regulation of autophagy by some natural products as a potential therapeutic strategy for cardiovascular disorders. Eur. J. Pharmacol. 2017, 802, 44–51. [Google Scholar] [CrossRef]
- Yoshino, J.; Mills, K.F.; Yoon, M.J.; Imai, S.-I. Nicotinamide Mononucleotide, a Key NAD+ Intermediate, Treats the Pathophysiology of Diet- and Age-Induced Diabetes in Mice. Cell Metab. 2011, 14, 528–536. [Google Scholar] [CrossRef] [Green Version]
- Mouchiroud, L.; Houtkooper, R.H.; Moullan, N.; Katsyuba, E.; Ryu, D.; Cantó, C.; Mottis, A.; Jo, Y.S.; Viswanathan, M.; Schoonjans, K.; et al. The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 2013, 154, 430–441. [Google Scholar] [CrossRef] [Green Version]
- Bonkowski, M.S.; Sinclair, D.A. Slowing ageing by design: The rise of NAD+ and sirtuin-activating compounds. Nat. Rev. Mol. Cell Biol. 2016, 17, 679–690. [Google Scholar] [CrossRef]
- Feige, J.N.; Lagouge, M.; Canto, C.; Strehle, A.; Houten, S.M.; Milne, J.C.; Lambert, P.D.; Mataki, C.; Elliott, P.J.; Auwerx, J. Specific SIRT1 Activation Mimics Low Energy Levels and Protects against Diet-Induced Metabolic Disorders by Enhancing Fat Oxidation. Cell Metab. 2008, 8, 347–358. [Google Scholar] [CrossRef]
- Canto, C.; Auwerx, J. PGC-1α, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr. Opin. Lipidol. 2009, 20, 98–105. [Google Scholar] [CrossRef] [PubMed]
- Park, D.; Jeong, H.; Lee, M.N.; Koh, A.; Kwon, O.; Yang, Y.R.; Noh, J.; Suh, P.-G.; Park, H.; Ryu, S.H. Resveratrol induces autophagy by directly inhibiting mTOR through ATP competition. Sci. Rep. 2016, 6, 21772. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kuno, A.; Hosoda, R.; Sebori, R.; Hayashi, T.; Sakuragi, H.; Tanabe, M.; Horio, Y. Resveratrol Ameliorates Mitophagy Disturbance and Improves Cardiac Pathophysiology of Dystrophin-deficient mdx Mice. Sci. Rep. 2018, 8, 1–12. [Google Scholar] [CrossRef] [Green Version]
- Cao, S.; Shen, Z.; Wang, C.; Zhang, Q.; Hong, Q.; He, Y.; Hu, C. Resveratrol improves intestinal barrier function, alleviates mitochondrial dysfunction and induces mitophagy in diquat challenged piglets 1. Food Funct. 2019, 10, 344–354. [Google Scholar] [CrossRef]
- Pearson, K.J.; Baur, J.A.; Lewis, K.N.; Peshkin, L.; Price, N.L.; Labinskyy, N.; Swindell, W.R.; Kamara, D.; Minor, R.K.; Perez, E.; et al. Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span. Cell Metab. 2008, 8, 157–168. [Google Scholar] [CrossRef] [Green Version]
- Zarse, K.; Schmeisser, S.; Birringer, M.; Falk, E.; Schmoll, D.; Ristow, M. Differential Effects of Resveratrol and SRT1720 on Lifespan of Adult Caenorhabditis elegans. Horm. Metab. Res. 2010, 42, 837–839. [Google Scholar] [CrossRef]
- Poulsen, M.M.; Vestergaard, P.F.; Clasen, B.F.; Radko, Y.; Christensen, L.P.; Stødkilde-Jørgensen, H.; Møller, N.; Jessen, N.; Pedersen, S.B.; Jørgensen, J.O. High-dose resveratrol supplementation in obese men: An investigator-initiated, randomized, placebo-controlled clinical trial of substrate metabolism, insulin sensitivity, and body composition. Diabetes 2013, 62, 1186–1195. [Google Scholar] [CrossRef] [Green Version]
- Eisenberg, T.; Abdellatif, M.; Schroeder, S.; Primessnig, U.; Stekovic, S.; Pendl, T.; Harger, A.; Schipke, J.; Zimmermann, A.; Schmidt, A.; et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat. Med. 2016, 22, 1428–1438. [Google Scholar] [CrossRef]
- Ryu, D.; Mouchiroud, L.; Andreux, P.A.; Katsyuba, E.; Moullan, N.; Nicolet-Dit-Félix, A.A.; Williams, E.G.; Jha, P.; Lo Sasso, G.; Huzard, D.; et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat. Med. 2016, 22, 879–888. [Google Scholar] [CrossRef]
- Andreux, P.A.; Blanco-Bose, W.; Ryu, D.; Burdet, F.; Ibberson, M.; Aebischer, P.; Auwerx, J.; Singh, A.; Rinsch, C. The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans. Nat. Metab. 2019, 1, 595–603. [Google Scholar] [CrossRef]
- Fang, E.F.; Waltz, T.B.; Kassahun, H.; Lu, Q.; Kerr, J.S.; Morevati, M.; Fivenson, E.M.; Wollman, B.N.; Marosi, K.; Wilson, M.A.; et al. Tomatidine enhances lifespan and healthspan in C. elegans through mitophagy induction via the SKN-1/Nrf2 pathway. Sci. Rep. 2017, 7, 46208. [Google Scholar] [CrossRef] [PubMed]
- Richter, U.; Lahtinen, T.; Marttinen, P.; Myöhänen, M.; Greco, D.; Cannino, G.; Jacobs, H.T.; Lietzén, N.; Nyman, T.A.; Battersby, B.J. A Mitochondrial Ribosomal and RNA Decay Pathway Blocks Cell Proliferation. Curr. Biol. 2013, 23, 535–541. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sun, N.; Yun, J.; Liu, J.; Malide, D.; Liu, C.; Rovira, I.I.; Holmström, K.M.; Fergusson, M.M.; Yoo, Y.H.; Combs, C.A.; et al. Measuring In Vivo Mitophagy. Mol. Cell 2015, 60, 685–696. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Xing, Y.; Liqi, Z.; Jian, L.; Qinghua, Y.; Qian, Y. Doxycycline Induces Mitophagy and Suppresses Production of Interferon-β in IPEC-J2 Cells. Front. Cell. Infect. Microbiol. 2017, 7, 21. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kujoth, G.C.; Bradshaw, P.C.; Haroon, S.; Prolla, T.A. The Role of Mitochondrial DNA Mutations in Mammalian Aging. PLoS Genet. 2007, 3, e24. [Google Scholar] [CrossRef] [Green Version]
- DeBalsi, K.L.; Hoff, K.E.; Copeland, W.C. Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases. Ageing Res. Rev. 2017, 33, 89–104. [Google Scholar] [CrossRef] [Green Version]
- Morita, M.; Gravel, S.-P.; Chénard, V.; Sikström, K.; Zheng, L.; Alain, T.; Gandin, V.; Avizonis, D.; Arguello, M.; Zakaria, C.; et al. mTORC1 Controls Mitochondrial Activity and Biogenesis through 4E-BP-Dependent Translational Regulation. Cell Metab. 2013, 18, 698–711. [Google Scholar] [CrossRef] [Green Version]
- Bartolomé, A.; García-Aguilar, A.; Asahara, S.-I.; Kido, Y.; Guillén, C.; Pajvani, U.B.; Benito, M. MTORC1 Regulates both General Autophagy and Mitophagy Induction after Oxidative Phosphorylation Uncoupling. Mol. Cell. Biol. 2017, 37, e00441-17. [Google Scholar] [CrossRef] [Green Version]
- Narita, M.; Young, A.R.J.; Arakawa, S.; Samarajiwa, S.A.; Nakashima, T.; Yoshida, S.; Hong, S.; Berry, L.S.; Reichelt, S.; Ferreira, M.; et al. Spatial Coupling of mTOR and Autophagy Augments Secretory Phenotypes. Science 2011, 332, 966–970. [Google Scholar] [CrossRef] [Green Version]
- Iglesias-Bartolome, R.; Patel, V.; Cotrim, A.; Leelahavanichkul, K.; Molinolo, A.A.; Mitchell, J.B.; Gutkind, J.S. mTOR Inhibition Prevents Epithelial Stem Cell Senescence and Protects from Radiation-Induced Mucositis. Cell Stem Cell 2012, 11, 401–414. [Google Scholar] [CrossRef] [Green Version]
- Kolesnichenko, M.; Hong, L.; Liao, R.; Vogt, P.K.; Sun, P. Attenuation of TORC1 signaling delays replicative and oncogenic RAS-induced senescence. Cell Cycle 2012, 11, 2391–2401. [Google Scholar] [CrossRef] [PubMed]
- Vellai, T.; Takacs-Vellai, K.; Zhang, Y.; Kovacs, A.L.; Orosz, L.; Müller, F. Influence of TOR kinase on lifespan in C. elegans. Nature 2003, 426, 620. [Google Scholar] [CrossRef] [PubMed]
- Kapahi, P.; Zid, B.M.; Harper, T.; Koslover, D.; Sapin, V.; Benzer, S. Regulation of Lifespan in Drosophila by Modulation of Genes in the TOR Signaling Pathway. Curr. Biol. 2004, 14, 885–890. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bai, H.; Post, S.; Kang, P.; Tatar, M. Drosophila Longevity Assurance Conferred by Reduced Insulin Receptor Substrate Chico Partially Requires d4eBP. PLoS ONE 2015, 10, e0134415. [Google Scholar] [CrossRef] [Green Version]
- Kaeberlein, M.; Powers, R.W., III; Steffen, K.K.; Westman, E.A.; Hu, D.; Dang, N.; Kerr, E.O.; Kirkland, K.T.; Fields, S.; Kennedy, B.K. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 2005, 310, 1193–1196. [Google Scholar] [CrossRef] [Green Version]
- Deprez, M.-A.; Eskes, E.; Winderickx, J.; Wilms, T. The TORC1-Sch9 pathway as a crucial mediator of chronological lifespan in the yeast Saccharomyces cerevisiae. FEMS Yeast Res. 2018, 18, 48. [Google Scholar] [CrossRef]
- Wu, J.J.; Liu, J.; Chen, E.B.; Wang, J.J.; Cao, L.; Narayan, N.; Fergusson, M.M.; Rovira, I.I.; Allen, M.; Springer, D.A.; et al. Increased Mammalian Lifespan and a Segmental and Tissue-Specific Slowing of Aging after Genetic Reduction of mTOR Expression. Cell Rep. 2013, 4, 913–920. [Google Scholar] [CrossRef] [Green Version]
- Powers, R.W.; Kaeberlein, M.; Caldwell, S.D.; Kennedy, B.K.; Fields, S. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev. 2006, 20, 174–184. [Google Scholar] [CrossRef] [Green Version]
- Bjedov, I.; Toivonen, J.M.; Kerr, F.; Slack, C.; Jacobson, J.; Foley, A.; Partridge, L. Mechanisms of Life Span Extension by Rapamycin in the Fruit Fly Drosophila melanogaster. Cell Metab. 2010, 11, 35–46. [Google Scholar] [CrossRef] [Green Version]
- Scialo, F.; Sriram, A.; Naudi, A.; Ayala, V.; Jové, M.; Pamplona, R.; Sanz, A. Target of rapamycin activation predicts lifespan in fruit flies. Cell Cycle 2015, 14, 2949–2958. [Google Scholar] [CrossRef] [Green Version]
- Moskalev, A.; Shaposhnikov, M. Pharmacological Inhibition of Phosphoinositide 3 and TOR Kinases Improves Survival of Drosophila melanogaster. Rejuvenation Res. 2010, 13, 246–247. [Google Scholar] [CrossRef]
- Danilov, A.; Shaposhnikov, M.; Plyusnina, E.; Kogan, V.; Fedichev, P.; Moskalev, A. Selective anticancer agents suppress aging in Drosophila. Oncotarget 2013, 4, 1507–1526. [Google Scholar] [CrossRef] [Green Version]
- Fan, X.; Liang, Q.; Lian, T.; Wu, Q.; Gaur, U.; Li, D.; Yang, D.; Mao, X.; Jin, Z.; Li, Y.; et al. Rapamycin preserves gut homeostasis during Drosophila aging. Oncotarget 2015, 6, 35274–35283. [Google Scholar] [CrossRef] [Green Version]
- Robida-Stubbs, S.; Glover-Cutter, K.; Lamming, D.W.; Mizunuma, M.; Narasimhan, S.D.; Neumann-Haefelin, E.; Sabatini, D.M.; Blackwell, T.K. TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab. 2012, 15, 713–724. [Google Scholar] [CrossRef] [Green Version]
- Harrison, D.E.; Strong, R.; Sharp, Z.D.; Nelson, J.F.; Astle, C.M.; Flurkey, K.; Nadon, N.L.; Wilkinson, J.E.; Frenkel, K.; Carter, C.S.; et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009, 460, 392–395. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Anisimov, V.N.; Zabezhinski, M.A.; Popovich, I.G.; Piskunova, T.S.; Semenchenko, A.V.; Tyndyk, M.L.; Yurova, M.; Antoch, M.P.; Blagosklonny, M.V. Rapamycin Extends Maximal Lifespan in Cancer-Prone Mice. Am. J. Pathol. 2010, 176, 2092–2097. [Google Scholar] [CrossRef]
- Anisimov, V.N.; Zabezhinski, M.A.; Popovich, I.G.; Piskunova, T.S.; Semenchenko, A.V.; Tyndyk, M.L.; Yurova, M.; Rosenfeld, S.V.; Blagosklonny, M.V. Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle 2011, 10, 4230–4236. [Google Scholar] [CrossRef] [PubMed]
- Wilkinson, J.E.; Burmeister, L.; Brooks, S.V.; Chan, C.-C.; Friedline, S.; Harrison, D.E.; Hejtmancik, J.F.; Nadon, N.; Strong, R.; Wood, L.K.; et al. Rapamycin slows aging in mice. Aging Cell 2012, 11, 675–682. [Google Scholar] [CrossRef] [Green Version]
- Comas, M.; Toshkov, I.; Kuropatwinski, K.K.; Chernova, O.B.; Polinsky, A.; Blagosklonny, M.V.; Gudkov, A.V.; Antoch, M.P. New nanoformulation of rapamycin Rapatar extends lifespan in homozygous p53−/− mice by delaying carcinogenesis. Aging 2012, 4, 715–722. [Google Scholar] [CrossRef] [PubMed]
- Komarova, E.A.; Antoch, M.P.; Novototskaya, L.R.; Chernova, O.B.; Paszkiewicz, G.; Leontieva, O.V.; Blagosklonny, M.V.; Gudkov, A.V. Rapamycin extends lifespan and delays tumorigenesis in heterozygous p53+/− mice. Aging 2012, 4, 709. [Google Scholar] [CrossRef]
- Ramos, F.J.; Chen, S.C.; Garelick, M.G.; Dai, D.F.; Liao, C.Y.; Schreiber, K.H.; MacKay, V.L.; An, E.H.; Strong, R.; Ladiges, W.C.; et al. Rapamycin reverses elevated mTORC1 signaling in lamin A/C–deficient mice, rescues cardiac and skeletal muscle function, and extends survival. Sci. Transl. Med. 2012, 4, 144ra103. [Google Scholar] [CrossRef]
- Livi, C.B.; Hardman, R.L.; Christy, B.A.; Dodds, S.G.; Jones, D.; Williams, C.; Strong, R.; Bokov, A.; Javors, M.A.; Ikeno, Y.; et al. Rapamycin extends life span of Rb1+/− mice by inhibiting neuroendocrine tumors. Aging 2013, 5, 100. [Google Scholar] [CrossRef] [Green Version]
- Miller, R.A.; Harrison, D.E.; Astle, C.M.; Fernandez, E.; Flurkey, K.; Han, M.; Javors, M.A.; Li, X.; Nadon, N.L.; Nelson, J.F.; et al. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell 2014, 13, 468–477. [Google Scholar] [CrossRef] [PubMed]
- Popovich, I.G.; Anisimov, V.N.; Zabezhinski, M.A.; Semenchenko, A.V.; Tyndyk, M.L.; Yurova, M.N.; Blagosklonny, M.V. Lifespan extension and cancer prevention in HER-2/neu transgenic mice treated with low intermittent doses of rapamycin. Cancer Biol. Ther. 2014, 15, 586–592. [Google Scholar] [CrossRef] [Green Version]
- Zhang, Y.; Bokov, A.; Gelfond, J.; Soto, V.; Ikeno, Y.; Hubbard, G.; Diaz, V.; Sloane, L.; Maslin, K.; Treaster, S.; et al. Rapamycin extends life and health in C57BL/6 mice. J. Gerontol. Ser. A Biomed. Sci. Med. Sci. 2014, 69, 119–130. [Google Scholar] [CrossRef] [Green Version]
- Fok, W.C.Y.; Chen, Y.; Bokov, A.; Zhang, Y.; Salmon, A.; Diaz, V.; Javors, M.; Wood, W.H.; Zhang, Y.; Becker, K.; et al. Mice Fed Rapamycin Have an Increase in Lifespan Associated with Major Changes in the Liver Transcriptome. PLoS ONE 2014, 9, e83988. [Google Scholar] [CrossRef]
- Leontieva, O.V.; Paszkiewicz, G.M.; Blagosklonny, M.V. Weekly administration of rapamycin improves survival and biomarkers in obese male mice on high-fat diet. Aging Cell 2014, 13, 616–622. [Google Scholar] [CrossRef]
- Hasty, P.; Livi, C.B.; Dodds, S.G.; Jones, D.; Strong, R.; Javors, M.; Fischer, K.E.; Sloane, L.; Murthy, K.; Hubbard, G.; et al. eRapa Restores a Normal Life Span in a FAP Mouse ModelFAP Mice Can Live a Long Healthy Life. Cancer Prev. Res. 2014, 7, 169–178. [Google Scholar] [CrossRef] [Green Version]
- Fischer, K.E.; Gelfond, J.A.L.; Soto, V.Y.; Han, C.; Someya, S.; Richardson, A.; Austad, S.N. Health Effects of Long-Term Rapamycin Treatment: The Impact on Mouse Health of Enteric Rapamycin Treatment from Four Months of Age throughout Life. PLoS ONE 2015, 10, e0126644. [Google Scholar] [CrossRef]
- Ye, L.; Widlund, A.L.; Sims, C.A.; Lamming, D.W.; Guan, Y.; Davis, J.G.; Harrison, D.E.; Vang, O.; Baur, J.A.; Sabatini, D. Rapamycin doses sufficient to extend lifespan do not compromise muscle mitochondrial content or endurance. Aging 2013, 5, 7. [Google Scholar] [CrossRef] [Green Version]
- Johnson, S.C.; Yanos, M.E.; Kayser, E.-B.; Quintana, A.; Sangesland, M.; Castanza, A.; Uhde, L.; Hui, J.; Wall, V.Z.; Gagnidze, A.; et al. mTOR Inhibition Alleviates Mitochondrial Disease in a Mouse Model of Leigh Syndrome. Science 2013, 342, 1524–1528. [Google Scholar] [CrossRef] [PubMed]
- Hurez, V.; Dao, V.; Liu, A.; Pandeswara, S.; Gelfond, J.; Sun, L.; Bergman, M.; Orihuela, C.J.; Galvan, V.; Padrón, Á.; et al. Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune-deficient mice. Aging Cell 2015, 14, 945–956. [Google Scholar] [CrossRef]
- Verlingue, L.; Dugourd, A.; Stoll, G.; Barillot, E.; Calzone, L.; Londoño-Vallejo, A. A comprehensive approach to the molecular determinants of lifespan using a Boolean model of geroconversion. Aging Cell 2016, 15, 1018–1026. [Google Scholar] [CrossRef]
- Johnson, S.C.; Yanos, M.E.; Bitto, A.; Castanza, A.; Gagnidze, A.; Gonzalez, B.; Gupta, K.; Hui, J.; Jarvie, C.; Johnson, B.M.; et al. Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice. Front. Genet. 2015, 6, 247. [Google Scholar] [CrossRef] [Green Version]
- Xue, Q.-L.; Yang, H.; Li, H.-F.; Abadir, P.M.; Burks, T.N.; Koch, L.G.; Britton, S.L.; Carlson, J.; Chen, L.; Walston, J.D.; et al. Rapamycin increases grip strength and attenuates age-related decline in maximal running distance in old low capacity runner rats. Aging 2016, 8, 769–776. [Google Scholar] [CrossRef] [Green Version]
- Bitto, A.; Ito, T.K.; Pineda, V.V.; Letexier, N.J.; Huang, H.; Sutlief, E.; Tung, H.; Vizzini, N.; Chen, B.; Smith, K.; et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. eLife 2016, 5, e16351. [Google Scholar] [CrossRef]
- Fang, Y.; Bartke, A. Prolonged Rapamycin treatment led to beneficial metabolic switch. Aging 2013, 5, 328–329. [Google Scholar] [CrossRef] [Green Version]
- Blagosklonny, M.V. Rapamycin extends life- and health span because it slows aging. Aging 2013, 5, 592–598. [Google Scholar] [CrossRef] [Green Version]
- Stanfel, M.N.; Shamieh, L.S.; Kaeberlein, M.; Kennedy, B.K. The TOR pathway comes of age. Biochim. Biophys. Acta BBA—Gen. Subj. 2009, 1790, 1067–1074. [Google Scholar] [CrossRef] [Green Version]
- Campistol, J.M.; Eris, J.; Oberbauer, R.; Friend, P.; Hutchison, B.; Morales, J.M.; Claesson, K.; Stallone, G.; Russ, G.; Rostaing, L.; et al. Sirolimus Therapy after Early Cyclosporine Withdrawal Reduces the Risk for Cancer in Adult Renal Transplantation. J. Am. Soc. Nephrol. 2006, 17, 581–589. [Google Scholar] [CrossRef] [Green Version]
- Kauffman, H.M.; Cherikh, W.S.; Cheng, Y.; Hanto, D.W.; Kahan, B.D. Maintenance Immunosuppression with Target-of-Rapamycin Inhibitors is Associated with a Reduced Incidence of De Novo Malignancies. Transplantation 2005, 80, 883–889. [Google Scholar] [CrossRef]
- Euvrard, S.; Morelon, E.; Rostaing, L.; Goffin, E.; Brocard, A.; Tromme, I.; Broeders, N.; del Marmol, V.; Chatelet, V.; Dompmartin, A.; et al. Sirolimus and Secondary Skin-Cancer Prevention in Kidney Transplantation. N. Engl. J. Med. 2012, 367, 329–339. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pedro, J.M.B.-S.; Senovilla, L. Immunostimulatory activity of lifespan-extending agents. Aging 2013, 5, 793–801. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mannick, J.B.; Del Giudice, G.; Lattanzi, M.; Valiante, N.M.; Praestgaard, J.; Huang, B.; Lonetto, M.A.; Maecker, H.T.; Kovarik, J.; Carson, S.; et al. mTOR inhibition improves immune function in the elderly. Sci. Transl. Med. 2014, 6, 268ra179. [Google Scholar] [CrossRef]
- Kennedy, B.K.; Pennypacker, J.K. Aging interventions get human. Oncotarget 2015, 6, 590–591. [Google Scholar] [CrossRef]
- Blagosklonny, M.V. Rejuvenating immunity: “Anti-aging drug today” eight years later. Oncotarget 2015, 6, 19405. [Google Scholar] [CrossRef] [Green Version]
- Ross, C.; Salmon, A.; Strong, R.; Fernandez, E.; Javors, M.; Richardson, A.; Tardif, S. Metabolic consequences of long-term rapamycin exposure on common marmoset monkeys (Callithrix jacchus). Aging 2015, 7, 964–973. [Google Scholar] [CrossRef] [Green Version]
- Zaseck, L.W.; Miller, R.A.; Brooks, S.V. Rapamycin Attenuates Age-associated Changes in Tibialis Anterior Tendon Viscoelastic Properties. J. Gerontol. Ser. A 2016, 71, 858–865. [Google Scholar] [CrossRef] [Green Version]
- Lelegren, M.; Liu, Y.; Ross, C.; Tardif, S.; Salmon, A.B. Pharmaceutical inhibition of mTOR in the common marmoset: Effect of rapamycin on regulators of proteostasis in a non-human primate. Pathobiol. Aging Age-Related Dis. 2016, 6, 31793. [Google Scholar] [CrossRef] [Green Version]
- Johnson, S.; Rabinovitch, P.S.; Kaeberlein, M. mTOR is a key modulator of ageing and age-related disease. Nat. 2013, 493, 338–345. [Google Scholar] [CrossRef] [Green Version]
- Lin, K.; Dorman, J.B.; Rodan, A.; Kenyon, C. daf-16: An HNF-3/forkhead Family Member That Can Function to Double the Life-Span of Caenorhabditis elegans. Science 1979, 278, 1319–1322. [Google Scholar] [CrossRef] [PubMed]
- Hwangbo, D.S.; Gersham, B.; Tu, M.-P.; Palmer, M.; Tatar, M. Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nat. 2004, 429, 562–566. [Google Scholar] [CrossRef] [PubMed]
- Tatar, M.; Kopelman, A.; Epstein, D.; Tu, M.-P.; Yin, C.-M.; Garofalo, R.S. A Mutant Drosophila Insulin Receptor Homolog That Extends Life-Span and Impairs Neuroendocrine Function. Science 2001, 292, 107–110. [Google Scholar] [CrossRef] [Green Version]
- Selman, C.; Lingard, S.; Choudhury, A.I.; Batterham, R.L.; Claret, M.; Clements, M.; Ramadani, F.; Okkenhaug, K.; Schuster, E.; Blanc, E.; et al. Evidence for lifespan extension and delayed age–related biomarkers in insulin receptor substrate 1 null mice. FASEB J. 2008, 22, 807–818. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Selman, C.; Partridge, L.; Withers, D. Replication of Extended Lifespan Phenotype in Mice with Deletion of Insulin Receptor Substrate 1. PLoS ONE 2011, 6, e16144. [Google Scholar] [CrossRef]
- Anderson, R.M.; le Couteur, D.G.; de Cabo, R. Caloric Restriction Research: New Perspectives on the Biology of Aging. J. Gerontol. Ser. A 2018, 73, 1–3. [Google Scholar] [CrossRef] [Green Version]
- Gems, D.; Partridge, L. Genetics of Longevity in Model Organisms: Debates and Paradigm Shifts. Annu. Rev. Physiol. 2013, 75, 621–644. [Google Scholar] [CrossRef] [Green Version]
- Mattison, J.A.; Colman, R.J.; Beasley, T.M.; Allison, D.B.; Kemnitz, J.W.; Roth, G.S.; Ingram, D.K.; Weindruch, R.; De Cabo, R.; Anderson, R.M. Caloric restriction improves health and survival of rhesus monkeys. Nat. Commun. 2017, 8, 14063. [Google Scholar] [CrossRef] [Green Version]
- Li, J.; Cui, X.; Wang, Z.; Li, Y. rBTI extends Caenorhabditis elegans lifespan by mimicking calorie restriction. Exp. Gerontol. 2015, 67, 62–71. [Google Scholar] [CrossRef]
- Jeon, H.; Cha, D.S. Anti-aging properties of Ribes fasciculatum in Caenorhabditis elegans. Chin. J. Nat. Med. 2016, 14, 335–342. [Google Scholar] [CrossRef]
- Wan, Q.L.; Fu, X.; Meng, X.; Luo, Z.; Dai, W.; Yang, J.; Wang, C.; Wang, H.; Zhou, Q. Hypotaurine promotes longevity and stress tolerance via the stress response factors DAF-16/FOXO and SKN-1/NRF2 in Caenorhabditis elegans. Food Funct. 2020, 11, 347–357. [Google Scholar] [CrossRef]
- Steinberg, G.R.; Kemp, B.E. AMPK in Health and Disease. Physiol. Rev. 2009, 89, 1025–1078. [Google Scholar] [CrossRef]
- Hardie, D.G. AMP-activated protein kinase—An energy sensor that regulates all aspects of cell function. Genes Dev. 2011, 25, 1895–1908. [Google Scholar] [CrossRef] [Green Version]
- Mihaylova, M.M.; Shaw, R.J. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat. Cell Biol. 2011, 13, 1016–1023. [Google Scholar] [CrossRef] [PubMed]
- Burnett, C.; Valentini, S.; Cabreiro, F.; Goss, M.; Somogyvári, M.; Piper, M.D.; Hoddinott, M.; Sutphin, G.L.; Leko, V.; McElwee, J.J.; et al. Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 2011, 477, 482–485. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kanfi, Y.; Naiman, S.; Amir, G.; Peshti, V.; Zinman, G.; Nahum, L.; Bar-Joseph, Z.; Cohen, H.Y. The sirtuin SIRT6 regulates lifespan in male mice. Nature 2012, 483, 218–221. [Google Scholar] [CrossRef] [PubMed]
- Kapahi, P.; Kaeberlein, M.; Hansen, M. Dietary restriction and lifespan: Lessons from invertebrate models. Ageing Res. Rev. 2017, 39, 3–14. [Google Scholar] [CrossRef]
- Satoh, A.; Brace, C.S.; Rensing, N.; Cliften, P.; Wozniak, D.F.; Herzog, E.D.; Yamada, K.A.; Imai, S.-I. 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, 416–430. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rogina, B.; Helfand, S.L. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc. Natl. Acad. Sci. USA 2004, 101, 15998–16003. [Google Scholar] [CrossRef] [Green Version]
- Kaeberlein, M.; McVey, M.; Guarente, L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 1999, 13, 2570–2580. [Google Scholar] [CrossRef] [Green Version]
- Coughlan, K.A.; Valentine, R.J.; Ruderman, N.B.; Saha, A.K. AMPK activation: A therapeutic target for type 2 diabetes? Diabetes Metab. Syndr. Obes. 2014, 7, 241. [Google Scholar] [PubMed]
- Tissenbaum, H.A.; Guarente, L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 2001, 410, 227–230. [Google Scholar] [CrossRef] [PubMed]
- Wang, N.; Luo, Z.; Jin, M.; Sheng, W.; Wang, H.-T.; Long, X.; Wu, Y.; Hu, P.; Xu, H.; Zhang, X. Exploration of age-related mitochondrial dysfunction and the anti-aging effects of resveratrol in zebrafish retina. Aging 2019, 11, 3117–3137. [Google Scholar] [CrossRef] [PubMed]
- Hubbard, B.P.; Sinclair, D.A. Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol. Sci. 2014, 35, 146–154. [Google Scholar] [CrossRef] [Green Version]
- Minor, R.K.; Baur, J.A.; Gomes, A.P.; Ward, T.M.; Csiszar, A.; Mercken, E.M.; Abdelmohsen, K.; Shin, Y.-K.; Canto, C.; Scheibye-Knudsen, M.; et al. SRT1720 improves survival and healthspan of obese mice. Sci. Rep. 2011, 1, 70. [Google Scholar] [CrossRef] [Green Version]
- Milne, J.C.; Lambert, P.D.; Schenk, S.; Carney, D.P.; Smith, J.J.; Gagne, D.J.; Jin, L.; Boss, O.; Perni, R.B.; Vu, C.B.; et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 2007, 450, 712–716. [Google Scholar] [CrossRef] [Green Version]
- Ota, H.; Eto, M.; Kano, M.R.; Ogawa, S.; Iijima, K.; Akishita, M.; Ouchi, Y. Cilostazol Inhibits Oxidative Stress–Induced Premature Senescence Via Upregulation of Sirt1 in Human Endothelial Cells. Arter. Thromb. Vasc. Biol. 2008, 28, 1634–1639. [Google Scholar] [CrossRef] [Green Version]
- Jamal, J.; Mustafa, M.R.; Wong, P.-F. Paeonol protects against premature senescence in endothelial cells by modulating Sirtuin 1 pathway. J. Ethnopharmacol. 2014, 154, 428–436. [Google Scholar] [CrossRef]
- Ota, H.; Eto, M.; Kano, M.R.; Kahyo, T.; Setou, M.; Ogawa, S.; Iijima, K.; Akishita, M.; Ouchi, Y. Induction of Endothelial Nitric Oxide Synthase, SIRT1, and Catalase by Statins Inhibits Endothelial Senescence Through the Akt Pathway. Arter. Thromb. Vasc. Biol. 2010, 30, 2205–2211. [Google Scholar] [CrossRef] [Green Version]
- Zheng, M.; Qiao, W.; Cui, J.; Liu, L.; Liu, H.; Wang, Z.; Yan, C. Hydrogen sulfide delays nicotinamide-induced premature senescence via upregulation of SIRT1 in human umbilical vein endothelial cells. Mol. Cell. Biochem. 2014, 393, 59–67. [Google Scholar] [CrossRef]
- Lee, Y.A.; Cho, E.J.; Yokozawa, T. Protective Effect of Persimmon (Diospyros kaki) Peel Proanthocyanidin against Oxidative Damage under H2O2-Induced Cellular Senescence. Biol. Pharm. Bull. 2008, 31, 1265–1269. [Google Scholar] [CrossRef]
- Jayasena, T.; Poljak, A.; Smythe, G.; Braidy, N.; Muench, G.; Sachdev, P. The role of polyphenols in the modulation of sirtuins and other pathways involved in Alzheimer’s disease. Ageing Res. Rev. 2013, 12, 867–883. [Google Scholar] [CrossRef] [PubMed]
- Apfeld, J.; O’Connor, G.; McDonagh, T.; DiStefano, P.S.; Curtis, R. The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev. 2004, 18, 3004–3009. [Google Scholar] [CrossRef] [Green Version]
- 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. [Google Scholar] [CrossRef] [PubMed]
- Anisimov, V.N. Metformin for aging and cancer prevention. Aging 2010, 2, 760–774. [Google Scholar] [CrossRef] [Green Version]
- Funakoshi, M.; Tsuda, M.; Muramatsu, K.; Hatsuda, H.; Morishita, S.; Aigaki, T. A gain-of-function screen identifies wdb and lkb1 as lifespan-extending genes in Drosophila. Biochem. Biophys. Res. Commun. 2011, 405, 667–672. [Google Scholar] [CrossRef] [PubMed]
- Martin-Montalvo, A.; Mercken, E.M.; Mitchell, S.J.; Palacios, H.H.; Mote, P.L.; Scheibye-Knudsen, M.; Gomes, A.P.; Ward, T.M.; Minor, R.K.; Blouin, M.-J.; et al. Metformin improves healthspan and lifespan in mice. Nat. Commun. 2013, 4, 2192. [Google Scholar] [CrossRef] [Green Version]
- Cabreiro, F.; Au, C.; Leung, K.-Y.; Vergara-Irigaray, N.; Cochemé, H.M.; Noori, T.; Weinkove, D.; Schuster, E.; Greene, N.D.; Gems, D. Metformin Retards Aging in C. elegans by Altering Microbial Folate and Methionine Metabolism. Cell 2013, 153, 228–239. [Google Scholar] [CrossRef] [Green Version]
- Piskovatska, V.; Stefanyshyn, N.; Storey, K.B.; Vaiserman, A.M.; Lushchak, O. Metformin as a geroprotector: Experimental and clinical evidence. Biogerontology 2019, 20, 33–48. [Google Scholar] [CrossRef] [PubMed]
- Curtis, R.; O’Connor, G.; DiStefano, P.S. Aging networks in Caenorhabditis elegans: AMP-activated protein kinase (aak-2) links multiple aging and metabolism pathways. Aging Cell 2006, 5, 119–126. [Google Scholar] [CrossRef]
- Park, S.-K.; Seong, R.-K.; Kim, J.-A.; Son, S.-J.; Kim, Y.; Yokozawa, T.; Shin, O.S. Oligonol promotes anti-aging pathways via modulation of SIRT1-AMPK-Autophagy Pathway. Nutr. Res. Pract. 2016, 10, 3–10. [Google Scholar] [CrossRef]
- Campisi, J. Aging, Cellular Senescence, and Cancer. Annu. Rev. Physiol. 2013, 75, 685. [Google Scholar] [CrossRef] [Green Version]
- van Deursen, J.M. The role of senescent cells in ageing. Nature 2014, 509, 439–446. [Google Scholar] [CrossRef] [Green Version]
- Ogrodnik, M.; Miwa, S.; Tchkonia, T.; Tiniakos, D.; Wilson, C.L.; Lahat, A.; Day, C.P.; Burt, A.; Palmer, A.; Anstee, Q.M.; et al. Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 2017, 8, 15691. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Campisi, J.; Robert, L. Cell Senescence: Role in Aging and Age-Related Diseases. Aging Facts Theor. 2014, 39, 45–61. [Google Scholar] [CrossRef] [Green Version]
- Muñoz-Espín, D.; Serrano, M. Cellular senescence: From physiology to pathology. Nat. Rev. Mol. Cell Biol. 2014, 15, 482–496. [Google Scholar] [CrossRef]
- Farr, J.N.; Xu, M.; Weivoda, M.M.; Monroe, D.G.; Fraser, D.G.; Onken, J.L.; Negley, B.A.; Sfeir, J.G.; Ogrodnik, M.B.; Hachfeld, C.M.; et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med. 2017, 23, 1072–1079. [Google Scholar] [CrossRef] [Green Version]
- Childs, B.G.; Baker, D.J.; Wijshake, T.; Conover, C.A.; Campisi, J.; Van Deursen, J.M. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 2016, 354, 472–477. [Google Scholar] [CrossRef] [Green Version]
- Baker, D.J.; Childs, B.G.; Durik, M.; Wijers, M.E.; Sieben, C.J.; Zhong, J.; Saltness, R.A.; Jeganathan, K.B.; Verzosa, G.C.; Pezeshki, A.; et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 2016, 530, 184–189. [Google Scholar] [CrossRef] [Green Version]
- Baker, D.J.; Wijshake, T.; Tchkonia, T.; Lebrasseur, N.K.; Childs, B.G.; Van De Sluis, B.; Kirkland, J.L.; Van Deursen, J.M. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 2011, 479, 232–236. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sagiv, A.; Bar-Shai, A.; Levi, N.; Hatzav, M.; Zada, L.; Ovadya, Y.; Roitman, L.; Manella, G.; Regev, O.; Majewska, J.; et al. p53 in Bronchial Club Cells Facilitates Chronic Lung Inflammation by Promoting Senescence. Cell Rep. 2018, 22, 3468–3479. [Google Scholar] [CrossRef]
- Childs, B.G.; Gluscevic, M.; Baker, D.J.; Laberge, R.-M.; Marquess, D.; Dananberg, J.; Van Deursen, J.M. Senescent cells: An emerging target for diseases of ageing. Nat. Rev. Drug Discov. 2017, 16, 718–735. [Google Scholar] [CrossRef] [Green Version]
- von Kobbe, C. Targeting senescent cells: Approaches, opportunities, challenges. Aging 2019, 11, 12844. [Google Scholar] [CrossRef]
- Zhu, Y.I.; Tchkonia, T.; Pirtskhalava, T.; Gower, A.C.; Ding, H.; Giorgadze, N.; Palmer, A.K.; Ikeno, Y.; Hubbard, G.B.; Lenburg, M.; et al. The Achilles’ heel of senescent cells: From transcriptome to senolytic drugs. Aging Cell 2015, 14, 644–658. [Google Scholar] [CrossRef] [PubMed]
- Zhu, Y.; Doornebal, E.J.; Pirtskhalava, T.; Giorgadze, N.; Wentworth, M.; Fuhrmann-Stroissnigg, H.; Niedernhofer, L.J.; Robbins, P.D.; Tchkonia, T.; Kirkland, J.L. New agents that target senescent cells: The flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging 2017, 9, 955–963. [Google Scholar] [CrossRef] [Green Version]
- Baar, M.P.; Brandt, R.M.C.; Putavet, D.A.; Klein, J.D.D.; Derks, K.W.J.; Bourgeois, B.R.M.; Stryeck, S.; Rijksen, Y.; Van Willigenburg, H.; Feijtel, D.A.; et al. Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell 2017, 169, 132–147.e16. [Google Scholar] [CrossRef] [Green Version]
- Chang, J.; Wang, Y.; Shao, L.; Laberge, R.-M.; DeMaria, M.; Campisi, J.; Janakiraman, K.; Sharpless, N.E.; Ding, S.; Feng, W.; et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 2017, 22, 78–83. [Google Scholar] [CrossRef] [Green Version]
- Chung, C.L.; Lawrence, I.; Hoffman, M.; Elgindi, D.; Nadhan, K.; Potnis, M.; Jin, A.; Sershon, C.; Binnebose, R.; Lorenzini, A.; et al. Topical rapamycin reduces markers of senescence and aging in human skin: An exploratory, prospective, randomized trial. GeroScience 2019, 41, 861–869. [Google Scholar] [CrossRef] [Green Version]
- Xu, M.; Tchkonia, T.; Ding, H.; Ogrodnik, M.; Lubbers, E.R.; Pirtskhalava, T.; White, T.A.; Johnson, K.O.; Stout, M.B.; Mezera, V.; et al. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc. Natl. Acad. Sci. USA 2015, 112, E6301–E6310. [Google Scholar] [CrossRef] [Green Version]
- Tilstra, J.S.; Robinson, A.R.; Wang, J.; Gregg, S.Q.; Clauson, C.L.; Reay, D.P.; Nasto, L.A.; St Croix, C.M.; Usas, A.; Vo, N.; et al. NF-κB inhibition delays DNA damage–induced senescence and aging in mice. J. Clin. Investig. 2012, 122, 2601–2612. [Google Scholar] [CrossRef] [Green Version]
- Ozsvari, B.; Nuttall, J.R.; Sotgia, F.; Lisanti, M.P. Azithromycin and Roxithromycin define a new family of “senolytic” drugs that target senescent human fibroblasts. Aging 2018, 10, 3294–3307. [Google Scholar] [CrossRef] [PubMed]
- Bielak-Zmijewska, A.; Grabowska, W.; Ciolko, A.; Bojko, A.; Mosieniak, G.; Bijoch, Ł.; Sikora, E. The Role of Curcumin in the Modulation of Ageing. Int. J. Mol. Sci. 2019, 20, 1239. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Conboy, I.M.; Rando, T.A. Heterochronic parabiosis for the study of the effects of aging on stem cells and their niches. Cell Cycle 2012, 11, 2260–2267. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gruber, R.; Koch, H.; Doll, B.A.; Tegtmeier, F.; Einhorn, T.A.; Hollinger, J.O. Fracture healing in the elderly patient. Exp. Gerontol. 2006, 41, 1080–1093. [Google Scholar] [CrossRef] [PubMed]
- Goodell, M.A.; Rando, T.A. Stem cells and healthy aging. Science 2015, 350, 1199–1204. [Google Scholar] [CrossRef] [PubMed]
- Rando, T.A. Stem cells, ageing and the quest for immortality. Nature 2006, 441, 1080–1086. [Google Scholar] [CrossRef]
- Molofsky, A.V.; Slutsky, S.G.; Joseph, N.M.; He, S.; Pardal, R.; Krishnamurthy, J.; Sharpless, N.; Morrison, S.J. Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 2006, 443, 448–452. [Google Scholar] [CrossRef] [Green Version]
- Lavasani, M.; Robinson, A.R.; Lu, A.; Song, M.; Feduska, J.M.; Ahani, B.; Tilstra, J.S.; Feldman, C.H.; Robbins, P.D.; Niedernhofer, L.J.; et al. Muscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model. Nat. Commun. 2012, 3, 608. [Google Scholar] [CrossRef] [Green Version]
- Rando, T.A.; Chang, H.Y. Aging, Rejuvenation, and Epigenetic Reprogramming: Resetting the Aging Clock. Cell 2012, 148, 46–57. [Google Scholar] [CrossRef] [Green Version]
- Rossi, D.J.; Bryder, D.; Seita, J.; Nussenzweig, A.; Hoeijmakers, J.; Weissman, I.L. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 2007, 447, 725–729. [Google Scholar] [CrossRef]
- Mertens, J.; Paquola, A.C.; Ku, M.; Hatch, E.; Böhnke, L.; Ladjevardi, S.; McGrath, S.; Campbell, B.; Lee, H.; Herdy, J.R.; et al. Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects. Cell Stem Cell 2015, 17, 705–718. [Google Scholar] [CrossRef] [PubMed]
- Wahlestedt, M.; Norddahl, G.L.; Sten, G.; Ugale, A.; Frisk, M.-A.M.; Mattsson, R.; Deierborg, T.; Sigvardsson, M.; Bryder, D. An epigenetic component of hematopoietic stem cell aging amenable to reprogramming into a young state. Blood 2013, 121, 4257–4264. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fatt, M.; Hsu, K.; He, L.; Wondisford, F.; Miller, F.D.; Kaplan, D.R.; Wang, J. Metformin Acts on Two Different Molecular Pathways to Enhance Adult Neural Precursor Proliferation/Self-Renewal and Differentiation. Stem Cell Rep. 2015, 5, 988–995. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Khorraminejad-Shirazi, M.; Farahmandnia, M.; Kardeh, B.; Estedlal, A.; Kardeh, S.; Monabati, A. Aging and stem cell therapy: AMPK as an applicable pharmacological target for rejuvenation of aged stem cells and achieving higher efficacy in stem cell therapy. Hematol. Stem Cell Ther. 2017, 11, 189–194. [Google Scholar] [CrossRef]
- Safaeinejad, Z.; Nabiuni, M.; Peymani, M.; Ghaedi, K.; Nasr-Esfahani, M.-H.; Baharvand, H. Resveratrol promotes human embryonic stem cells self-renewal by targeting SIRT1-ERK signaling pathway. Eur. J. Cell Biol. 2017, 96, 665–672. [Google Scholar] [CrossRef]
- Candela, M.; Biagi, E.; Brigidi, P.; O’Toole, P.W.; De Vos, W.M. Maintenance of a healthy trajectory of the intestinal microbiome during aging: A dietary approach. Mech. Ageing Dev. 2014, 136-137, 70–75. [Google Scholar] [CrossRef]
- Saraswati, S.; Sitaraman, R. Aging and the human gut microbiota—From correlation to causality. Front. Microbiol. 2014, 5, 764. [Google Scholar]
- O’Toole, P.W.; Jeffery, I.B. Gut microbiota and aging. Science 2015, 350, 1214–1215. [Google Scholar] [CrossRef]
- Biagi, E.; Nylund, L.; Candela, M.; Ostan, R.; Bucci, L.; Pini, E.; Nikkïla, J.; Monti, D.; Satokari, R.; Franceschi, C.; et al. Through ageing, and beyond: Gut microbiota and inflammatory status in seniors and centenarians. PLoS ONE 2010, 5, e10667. [Google Scholar] [CrossRef]
- Pérez Martínez, G.; Bäuerl, C.; Collado, M.C. Understanding gut microbiota in elderly’s health will enable intervention through probiotics. Benef. Microbes 2014, 5, 235–246. [Google Scholar] [CrossRef]
- Lowry, C.A.; Smith, D.G.; Siebler, P.H.; Schmidt, D.; Stamper, C.E.; Hassell, J.E.; Yamashita, P.S.; Fox, J.H.; Reber, S.O.; Brenner, L.A.; et al. The Microbiota, Immunoregulation, and Mental Health: Implications for Public Health. Curr. Environ. Health Rep. 2016, 3, 270–286. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nehra, V.; Allen, J.M.; Mailing, L.J.; Kashyap, P.C.; Woods, J.A. Gut Microbiota: Modulation of Host Physiology in Obesity. Physiology 2016, 31, 327–335. [Google Scholar] [CrossRef] [PubMed]
- Zhang, X.; Zheng, X.; Yuan, Y. Treatment of insulin resistance: Straight from the gut. Drug Discov. Today 2016, 21, 1284–1290. [Google Scholar] [CrossRef]
- Rivière, A.; Selak, M.; Lantin, D.; Leroy, F.; De Vuyst, L. Bifidobacteria and Butyrate-Producing Colon Bacteria: Importance and Strategies for Their Stimulation in the Human Gut. Front. Microbiol. 2016, 7, 979. [Google Scholar] [CrossRef] [Green Version]
- Patel, R.; Dupont, H.L. New Approaches for Bacteriotherapy: Prebiotics, New-Generation Probiotics, and Synbiotics. Clin. Infect. Dis. 2015, 60, S108–S121. [Google Scholar] [CrossRef]
- Vaiserman, A.M.; Koliada, A.K.; Marotta, F. Gut microbiota: A player in aging and a target for anti-aging intervention. Ageing Res. Rev. 2017, 35, 36–45. [Google Scholar] [CrossRef]
- Wu, M.; Luo, Q.; Nie, R.; Yang, X.; Tang, Z.; Chen, H. Potential implications of polyphenols on aging considering oxidative stress, inflammation, autophagy, and gut microbiota. Crit. Rev. Food Sci. Nutr. 2020, 61, 2175–2193. [Google Scholar] [CrossRef] [PubMed]
- Du, Y.; Gao, Y.; Zeng, B.; Fan, X.; Yang, D.; Yang, M. Effects of anti-aging interventions on intestinal microbiota. Gut Microbes 2021, 13, 1994835. [Google Scholar] [CrossRef]
- Yoon, J.-H.; Abdelmohsen, K.; Kim, J.; Yang, X.; Martindale, J.L.; Tominaga-Yamanaka, K.; White, E.J.; Orjalo, A.V.; Rinn, J.L.; Kreft, S.G.; et al. Scaffold function of long non-coding RNA HOTAIR in protein ubiquitination. Nat. Commun. 2013, 4, 2939. [Google Scholar] [CrossRef] [Green Version]
- Singh, D.K.; Prasanth, K.V. Functional insights into the role of nuclear-retained long noncoding RNAs in gene expression control in mammalian cells. Chromosom. Res. 2013, 21, 695–711. [Google Scholar] [CrossRef] [Green Version]
- Yoon, J.-H.; Abdelmohsen, K.; Gorospe, M. Posttranscriptional Gene Regulation by Long Noncoding RNA. J. Mol. Biol. 2013, 425, 3723–3730. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Grammatikakis, I.; Panda, A.C.; Abdelmohsen, K.; Gorospe, M. Long noncoding RNAs (lncRNAs) and the molecular hallmarks of aging. Aging 2014, 6, 992–1009. [Google Scholar] [CrossRef]
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Mishra, S.K.; Balendra, V.; Esposto, J.; Obaid, A.A.; Maccioni, R.B.; Jha, N.K.; Perry, G.; Moustafa, M.; Al-Shehri, M.; Singh, M.P.; et al. Therapeutic Antiaging Strategies. Biomedicines 2022, 10, 2515. https://doi.org/10.3390/biomedicines10102515
Mishra SK, Balendra V, Esposto J, Obaid AA, Maccioni RB, Jha NK, Perry G, Moustafa M, Al-Shehri M, Singh MP, et al. Therapeutic Antiaging Strategies. Biomedicines. 2022; 10(10):2515. https://doi.org/10.3390/biomedicines10102515
Chicago/Turabian StyleMishra, Shailendra Kumar, Vyshnavy Balendra, Josephine Esposto, Ahmad A. Obaid, Ricardo B. Maccioni, Niraj Kumar Jha, George Perry, Mahmoud Moustafa, Mohammed Al-Shehri, Mahendra P. Singh, and et al. 2022. "Therapeutic Antiaging Strategies" Biomedicines 10, no. 10: 2515. https://doi.org/10.3390/biomedicines10102515