The Aging Epigenome and The Rejuvenation Strategies

Anna Meiliana, Nurrani Mustika Dewi, Andi Wijaya

Abstract


BACKGROUND: Aging is an unavoidable part of life, defined by a gradual loss in tissue and organ function and an increasing chance of death. Current studies of aging connected the genetic and epigenetic changes to cause this process.

CONTENT: When the aging-related epigenetic alterations is accumulated, it may result in irregulated gene expression, metabolic instability, stem cell senescence and exhaustion, and imbalance of tissue homeostasis, which all accelerate the aging process. Altered epigenetic gene regulatory mechanisms  such as DNA methylation,  histone modification and chromatin remodeling, and non-coding RNAs can induce aging process, thus manipulating these processes give a chance for the success of age-delaying interventions.

SUMMARY: Given updated tools and technologies to investigate the epigenetic regulation affecting aging processes, new therapeutic strategies to delay this process can be developed to increase longevity and improve quality of life.

KEYWORDS: aging, epigenetic, senescence, autophagy, mitochondria, metabolism, rejuvenation


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References


Benayoun BA, Pollina EA, Brunet A. Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nat Rev Mol Cell Biol. 2015; 16(10): 593–610, CrossRef.

Zhang W, Qu J, Liu GH, Belmonte JCI. The ageing epigenome and its rejuvenation. Nat Rev Mol Cell Biol. 2020; 21(3): 137–50, CrossRef.

Sen P, Shah PP, Nativio R, Berger SL. Epigenetic mechanisms of longevity and aging. Cell. 2016; 166(4): 822–39, CrossRef.

Zhang W, Song M, Qu J, Liu GH. Epigenetic modifications in cardiovascular aging and diseases. Circ Res. 2018; 123(7): 773–86, CrossRef.

Trojer P, Reinberg D. Facultative heterochromatin: is there a distinctive molecular signature? Mol Cell. 2007; 28(1): 1–13, CrossRef.

Allshire RC, Madhani HD. Ten principles of heterochromatin formation and function. Nat Rev Mol Cell Biol. 2018; 19(4): 229–44, CrossRef.

Feser J, Truong D, Das C, Carson JJ, Kieft J, Harkness T, et al. Elevated histone expression promotes life span extension. Mol Cell. 2010; 39(5): 724–35, CrossRef.

Mahmoudi S, Xu L, Brunet A. Turning back time with emerging rejuvenation strategies. Nat Cell Biol. 2019; 21(1): 32–43, CrossRef.

Sidler C, Kovalchuk O, Kovalchuk I. Epigenetic regulation of cellular senescence and aging. Front Genet. 2017; 8: 138, CrossRef.

Fraga MF, Esteller M. Epigenetics and aging: the targets and the marks. Trends Genet. 2007; 23(8): 413–8, CrossRef.

Pal S, Tyler JK. Epigenetics and aging. Sci Adv. 2016; 2(7): e1600584, CrossRef.

Xie K, Ryan DP, Pearson BL, Henzel KS, Neff F, Vidal RO, et al. Epigenetic alterations in longevity regulators, reduced life span, and exacerbated aging-related pathology in old father offspring mice. PNAS. 2018; 115(10): E2348–57, CrossRef.

Feil R, Fraga MF. Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet. 2012; 13(2): 97–109, CrossRef.

Li CCY, Cropley JE, Cowley MJ, Preiss T, Martin DIK, Suter CM. A sustained dietary change increases epigenetic variation in isogenic mice. PLOS Genetics. 2011; 7(4): e1001380, CrossRef.

Brodin P, Davis MM. Human immune system variation. Nat Rev Immunol. 2017; 17(1): 21–9, CrossRef.

Jones MJ, Goodman SJ, Kobor MS. DNA methylation and healthy human aging. Aging Cell. 2015; 14(6): 924–32, CrossRef.

Voisin S, Eynon N, Yan X, Bishop DJ. Exercise training and DNA methylation in humans. Acta Physiol (Oxf). 2015; 213(1): 39–59, CrossRef.

Azzi A, Dallmann R, Casserly A, Rehrauer H, Patrignani A, Maier B, et al. Circadian behavior is light-reprogrammed by plastic DNA methylation. Nat Neurosci. 2014; 17(3): 377–82, CrossRef.

Ecker S, Pancaldi V, Valencia A, Beck S, Paul DS. Epigenetic and transcriptional variability shape phenotypic plasticity. BioEssays. 2018; 40(2): 1700148, CrossRef.

Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012; 150(1): 12–27, CrossRef.

Jin B, Li Y, Robertson KD. DNA methylation: superior or subordinate in the epigenetic hierarchy? Genes Cancer. 2011; 2(6): 607–17, CrossRef.

Luo C, Hajkova P, Ecker JR. Dynamic DNA methylation: In the right place at the right time. Science. 2018; 361(6409): 1336–40, CrossRef.

Stojković V, Fujimori DG. Mutations in RNA methylating enzymes in disease. Curr Opin Chem Biol. 2017; 41: 20–7, CrossRef.

Xie P, Zang LQ, Li XK, Shu Q. An epigenetic view of developmental diseases: new targets, new therapies. World J Pediatr. 2016; 12(3): 291–7, CrossRef.

Kohli RM, Zhang Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature. 2013; 502(7472): 472–9, CrossRef.

Deguchi T, Barchas J. Inhibition of transmethylations of biogenic amines by S-adenosylhomocysteine. Enhancement of transmethylation by adenosylhomocysteinase. J Biol Chem. 1971; 246(10): 3175–81, PMID.

Wang Y, Sun Z, Szyf M. S-adenosyl-methionine (SAM) alters the transcriptome and methylome and specifically blocks growth and invasiveness of liver cancer cells. Oncotarget. 2017; 8(67): 111866–81, CrossRef.

Michalak EM, Burr ML, Bannister AJ, Dawson MA. The roles of DNA, RNA and histone methylation in ageing and cancer. Nat Rev Mol Cell Biol. 2019; 20(10): 573–89, CrossRef.

Shah PP, Donahue G, Otte GL, Capell BC, Nelson DM, Cao K, et al. Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. Genes Dev. 2013; 27(16): 1787–99, CrossRef.

Ni Z, Ebata A, Alipanahiramandi E, Lee SS. Two SET domain containing genes link epigenetic changes and aging in Caenorhabditis elegans. Aging Cell. 2012; 11(2): 315–25, CrossRef.

Pu M, Ni Z, Wang M, Wang X, Wood JG, Helfand SL, et al. Trimethylation of Lys36 on H3 restricts gene expression change during aging and impacts life span. Genes Dev. 2015; 29(7): 718–31, CrossRef.

Wilson ID. Drugs, bugs, and personalized medicine: pharmacometabonomics enters the ring. Proc Natl Acad Sci USA. 2009; 106(34): 14187–8, CrossRef.

Unnikrishnan A, Hadad N, Masser DR, Jackson J, Freeman WM, Richardson A. Revisiting the genomic hypomethylation hypothesis of aging. Ann NY Acad Sci. 2018; 1418(1): 69–79, CrossRef.

De Cecco M, Criscione SW, Peterson AL, Neretti N, Sedivy JM, Kreiling JA. Transposable elements become active and mobile in the genomes of aging mammalian somatic tissues. Aging (Albany NY). 2013; 5(12): 867–83, CrossRef.

Belgnaoui SM, Gosden RG, Semmes OJ, Haoudi A. Human LINE-1 retrotransposon induces DNA damage and apoptosis in cancer cells. Cancer Cell Int. 2006; 6(1): 13, CrossRef.

Gasior SL, Wakeman TP, Xu B, Deininger PL. The human LINE-1 retrotransposon creates DNA double-strand breaks. J Mol Biol. 2006; 357(5): 1383–93, CrossRef.

Belancio VP, Deininger PL, Roy-Engel AM. LINE dancing in the human genome: transposable elements and disease. Genome Med. 2009; 1(10): 97, CrossRef.

Tan L, Ke Z, Tombline G, Macoretta N, Hayes K, Tian X, et al. Naked mole rat cells have a stable epigenome that resists iPSC reprogramming. Stem Cell Rep. 2017; 9(5): 1721–34, CrossRef.

Beerman I, Bock C, Garrison BS, Smith ZD, Gu H, Meissner A, et al. Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell Stem Cell. 2013; 12(4): 413–25, CrossRef.

Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, Sadda S, et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell. 2013; 49(2): 359–67, CrossRef.

Field AE, Robertson NA, Wang T, Havas A, Ideker T, Adams PD. DNA methylation clocks in aging: categories, causes, and consequences. Mol Cell. 2018; 71(6): 882–95, CrossRef.

Horvath S, Raj K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet. 2018; 19(6): 371–84, CrossRef.

Marioni RE, Shah S, McRae AF, Chen BH, Colicino E, Harris SE, et al. DNA methylation age of blood predicts all-cause mortality in later life. Genome Biol. 2015; 16(1): 25, CrossRef.

Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015; 126(1): 9–16, CrossRef.

Chen BH, Marioni RE, Colicino E, Peters MJ, Ward-Caviness CK, Tsai PC, et al. DNA methylation-based measures of biological age: meta-analysis predicting time to death. Aging (Albany NY). 2016; 8(9): 1844–65, CrossRef.

Bratic A, Larsson NG. The role of mitochondria in aging. J Clin Invest. 2013; 123(3): 951–7, CrossRef.

Riera CE, Dillin A. Tipping the metabolic scales towards increased longevity in mammals. Nat Cell Biol. 2015; 17(3): 196–203, CrossRef.

Speakman JR, Mitchell SE. Caloric restriction. Mol Aspects Med. 2011; 32(3): 159–221, CrossRef.

Finkel T. The metabolic regulation of aging. Nat Med. 2015; 21(12): 1416–23, CrossRef.

Albert V, Hall MN. mTOR signaling in cellular and organismal energetics. Curr Opin Cell Biol. 2015; 33: 55–66,

Hirschey MD, Zhao Y. Metabolic regulation by lysine malonylation, succinylation, and glutarylation. Mol Cell Proteom. 2015; 14(9): 2308–15, CrossRef.

Lin SJ, Defossez PA, Guarente L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science. 2000; 289(5487): 2126–8, CrossRef.

Rogina B, Helfand SL. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. PNAS. 2004; 101(45): 15998–6003, CrossRef.

Hardie DG. AMPK: positive and negative regulation, and its role in whole-body energy homeostasis. Curr Opin Cell Biol. 2015; 33: 1–7, CrossRef.

Ulgherait M, Rana A, Rera M, Graniel J, Walker DW. AMPK modulates tissue and organismal aging in a non-cell-autonomous manner. Cell Rep. 2014; 8(6): 1767–80, CrossRef.

Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R. A C. elegans mutant that lives twice as long as wild type. Nature. 1993; 366(6454): 461–4, CrossRef.

Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science. 1997; 277(5328): 942–6, CrossRef.

Suh Y, Atzmon G, Cho M-O, Hwang D, Liu B, Leahy DJ, et al. Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci USA. 2008; 105(9): 3438–42, CrossRef.

Wheeler HE, Kim SK. Genetics and genomics of human ageing. Philos Trans R Soc Lond B Biol Sci. 2011; 366(1561): 43–50, CrossRef.

Brown-Borg HM. The somatotropic axis and longevity in mice. Am J Physiol Endocrinol Metab. 2015; 309(6): E503–10, CrossRef.

Satoh A, Brace CS, Rensing N, Clifton P, Wozniak DF, Herzog ED, 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(3): 416–30, CrossRef.

Zhang G, Li J, Purkayastha S, Tang Y, Zhang H, Yin Y, et al. Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature. 2013; 497(7448): 211–6, CrossRef.

Gräff J, Tsai LH. Histone acetylation: molecular mnemonics on the chromatin. Nat Rev Neurosci. 2013; 14(2): 97–111,

Peleg S, Feller C, Ladurner AG, Imhof A. The Metabolic impact on histone acetylation and transcription in ageing. Trends Biochem Sci. 2016; 41(8): 700–11, CrossRef.

Verdin E. NAD+ in aging, metabolism, and neurodegeneration. Science. 2015; 350(6265): 1208–13, CrossRef.

Guarente L. Sir2 links chromatin silencing, metabolism, and aging. Genes Dev. 2000; 14(9): 1021–6, CrossRef.

Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens GH, et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 2011; 14(5): 612–22, CrossRef.

Burnett C, Valentini S, Cabreiro F, Goss M, Somogyvári M, Piper MD, et al. Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature. 2011; 477(7365): 482–5, CrossRef.

Partridge L, Gems D. Benchmarks for ageing studies. Nature. 2007; 450(7167): 165–7, CrossRef.

Fan J, Krautkramer KA, Feldman JL, Denu JM. Metabolic regulation of histone post-translational modifications. ACS Chem Biol. 2015; 10(1): 95–108, CrossRef.

Wellen KE, Hatzivassiliou G, Sachdeva UM, Bui TV, Cross JR, Thompson CB. ATP-citrate lyase links cellular metabolism to histone acetylation. Science. 2009; 324(5930): 1076–80, CrossRef.

Everett JR. Pharmacometabonomics in humans: a new tool for personalized medicine. Pharmacogenomics. 2015; 16(7): 737–54, CrossRef.

Sutendra G, Kinnaird A, Dromparis P, Paulin R, Stenson TH, Haromy A, et al. A nuclear pyruvate dehydrogenase complex is important for the generation of acetyl-CoA and histone acetylation. Cell. 2014; 158(1): 84–97, CrossRef.

Katada S, Imhof A, Sassone-Corsi P. Connecting threads: epigenetics and metabolism. Cell. 2012; 148(1): 24–8, CrossRef.

Peleg S, Feller C, Forne I, Schiller E, Sévin DC, Schauer T, et al. Life span extension by targeting a link between metabolism and histone acetylation in Drosophila. EMBO Rep. 2016; 17(3): 455–69, CrossRef.

Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003; 425(6954): 191–6, CrossRef.

Dang W. The controversial world of sirtuins. Drug Discov Today Technol. 2014; 12: e9–17, CrossRef.

Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell. 2006; 127(6): 1109–22, CrossRef.

Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending lifespan. Cell Metab. 2008; 8(2): 157–68, CrossRef.

Jimenez-Gomez Y, Mattison JA, Pearson KJ, Martin-Montalvo A, Palacios HH, Sossong AM, et al. Resveratrol improves adipose insulin signaling and reduces the inflammatory response in adipose tissue of rhesus monkeys on high-fat, high-sugar diet. Cell Metab. 2013; 18(4): 533–45, CrossRef.

Mattison JA, Wang M, Bernier M, Zhang J, Park SS, Maudsley S, et al. Resveratrol prevents high fat/sucrose diet-induced central arterial wall inflammation and stiffening in nonhuman primates. Cell Metab. 2014; 20(1): 183–90, CrossRef.

Meidenbauer JJ, Ta N, Seyfried TN. Influence of a ketogenic diet, fish-oil, and calorie restriction on plasma metabolites and lipids in C57BL/6J mice. Nutr Metab. 2014; 11(1): 23, CrossRef.

Roberts MN, Wallace MA, Tomilov AA, Zhou Z, Marcotte GR, Tran D, et al. A ketogenic diet extends longevity and healthspan in adult mice. Cell Metab. 2017; 26(3): 539-46.e5, CrossRef.

Cantó C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y, et al. The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet induced obesity. Cell Metab. 2012; 15(6): 838–47, CrossRef.

Gomes AP, Price NL, Ling AJY, Moslehi JJ, Montgomery MK, Rajman L, et al. Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013; 155(7): 1624–38, CrossRef.

Mouchiroud L, Houtkooper RH, Moullan N, Katsyuba E, Ryu D, Cantó C, et al. The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell. 2013; 154(2): 430–41, CrossRef.

Yoshino J, Mills KF, Yoon MJ, Imai S. Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011; 14(4): 528–36, CrossRef.

Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 2014; 24(8): 464–71, CrossRef.

Wallace DC, Fan W, Procaccio V. Mitochondrial energetics and therapeutics. Annu Rev Pathol Mech Dis. 2010; 5(1): 297–348, CrossRef.

Koopman WJH, Willems PHGM, Smeitink JAM. Monogenic mitochondrial disorders. N Engl J Med. 2012; 366(12): 1132–41, CrossRef.

Sun N, Youle RJ, Finkel T. The mitochondrial basis of aging. Mol Cell. 2016; 61(5): 654–66, CrossRef.

Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature. 2004; 429(6990): 417–23, CrossRef.

Jiang N, Yan X, Zhou W, Zhang Q, Chen H, Zhang Y, et al. NMR-based metabonomic investigations into the metabolic profile of the senescence-accelerated mouse. J Proteome Res. 2008; 7(9): 3678–86, CrossRef.

Joseph AM, Adhihetty PJ, Buford TW, Wohlgemuth SE, Lees HA, Nguyen LMD, et al. The impact of aging on mitochondrial function and biogenesis pathways in skeletal muscle of sedentary high- and low-functioning elderly individuals. Aging Cell. 2012; 11(5): 801–9, CrossRef.

Longo VD, Antebi A, Bartke A, Barzilai N, Brown-Borg HM, Caruso C, et al. Interventions to slow aging in humans: are we ready? Aging Cell. 2015; 14(4): 497–510, CrossRef.

Correia-Melo C, Marques FDM, Anderson R, Hewitt G, Hewitt R, Cole J, et al. Mitochondria are required for pro-ageing features of the senescent phenotype. EMBO J. 2016; 35(7): 724–42, CrossRef.

Dillin A, Hsu AL, Arantes-Oliveira N, Lehrer-Graiwer J, Hsin H, Fraser AG, et al. Rates of behavior and aging specified by mitochondrial function during development. Science. 2002; 298(5602): 2398–401, CrossRef.

Lee SS, Lee RYN, Fraser AG, Kamath RS, Ahringer J, Ruvkun G. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nat Genet. 2003; 33(1): 40–8, CrossRef.

Short KR, Bigelow ML, Kahl J, Singh R, Coenen-Schimke J, Raghavakaimal S, et al. Decline in skeletal muscle mitochondrial function with aging in humans. PNAS. 2005; 102(15): 5618–23. https://doi.org/10.1073/pnas.0501559102">CrossRef.

Merkwirth C, Jovaisaite V, Durieux J, Matilainen O, Jordan SD, Quiros PM, et al. Two conserved histone demethylases regulate mitochondrial stress-induced longevity. Cell. 2016; 165(5): 1209–23, CrossRef.

Tian Y, Garcia G, Bian Q, Steffen KK, Joe L, Wolff S, et al. Mitochondrial stress induces chromatin reorganization to promote longevity and UPRmt. Cell. 2016; 165(5): 1197–208, CrossRef.

Tatar M, Sedivy JM. Mitochondria: masters of epigenetics. Cell. 2016; 165(5): 1052–4, CrossRef.

Couvillion MT, Soto IC, Shipkovenska G, Churchman LS. Synchronized mitochondrial and cytosolic translation programs. Nature. 2016; 533(7604): 499–503, CrossRef.

Richter-Dennerlein R, Oeljeklaus S, Lorenzi I, Ronsör C, Bareth B, Schendzielorz AB, et al. Mitochondrial protein synthesis adapts to influx of nuclear-encoded protein. Cell. 2016; 167(2): 471–83.e10, CrossRef.

Quirós PM, Mottis A, Auwerx J. Mitonuclear communication in homeostasis and stress. Nat Rev Mol Cell Biol. 2016; 17(4): 213–26, CrossRef.

Matilainen O, Quirós PM, Auwerx J. Mitochondria and epigenetics – crosstalk in homeostasis and dtress. Trends Cell Biol. 2017; 27(6): 453–63, CrossRef.

Margueron R, Reinberg D. Chromatin structure and the inheritance of epigenetic information. Nat Rev Genet. 2010; 11(4): 285–96, CrossRef.

Menzies KJ, Zhang H, Katsyuba E, Auwerx J. Protein acetylation in metabolism — metabolites and cofactors. Nat Rev Endocrinol. 2016; 12(1): 43–60, CrossRef.

Pietrocola F, Galluzzi L, Bravo-San Pedro JM, Madeo F, Kroemer G. Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab. 2015; 21(6): 805–21, CrossRef.

Teperino R, Schoonjans K, Auwerx J. Histone methyl transferases and demethylases; can they link metabolism and transcription? Cell Metab. 2010; 12(4): 321–7, CrossRef.

Greer EL, Shi Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet. 2012; 13(5): 343–57, CrossRef.

López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013; 153(6): 1194–217, CrossRef.

Berger SL, Sassone-Corsi P. Metabolic dignaling to vhromatin. Cold Spring Harb Perspect Biol. 2016; 8(11): a019463, CrossRef.

Li X, Egervari G, Wang Y, Berger SL, Lu Z. Regulation of chromatin and gene expression by metabolic enzymes and metabolites. Nat Rev Mol Cell Biol. 2018; 19(9): 563–78, CrossRef.

Lu C, Thompson CB. Metabolic regulation of epigenetics. Cell Metab. 2012; 16(1): 9–17, CrossRef.

Finkel T, Deng CX, Mostoslavsky R. Recent progress in the biology and physiology of sirtuins. Nature. 2009; 460(7255): 587–91, CrossRef.

Chalkiadaki A, Guarente L. The multifaceted functions of sirtuins in cancer. Nat Rev Cancer. 2015; 15(10): 608–24, CrossRef.

Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000; 403(6771): 795–800, CrossRef.

Schwer B, Verdin E. Conserved metabolic regulatory functions of sirtuins. Cell Metab. 2008; 7(2): 104–12, CrossRef.

Landry J, Sutton A, Tafrov ST, Heller RC, Stebbins J, Pillus L, et al. The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. PNAS. 2000; 97(11): 5807–11, CrossRef.

Hansen M, Rubinsztein DC, Walker DW. Autophagy as a promoter of longevity: insights from model organisms. Nat Rev Mol Cell Biol. 2018; 19(9): 579–93, CrossRef.

Kalfalah F, Janke L, Schiavi A, Tigges J, Ix A, Ventura N, et al. Crosstalk of clock gene expression and autophagy in aging. Aging (Albany NY). 2016; 8(9): 1876–95, CrossRef.

Green DR, Galluzzi L, Kroemer G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science. 2011; 333(6046): 1109–12, CrossRef.

Palikaras K, Lionaki E, Tavernarakis N. Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans. Nature. 2015; 521(7553): 525–8, CrossRef.

Pickrell JA, Oehme FW. Invited response to definition of hormesis (EJ Calabrese and LA Baldwin). Hum Exp Toxicol. 2002; 21(2): 107–9, CrossRef.

Ashrafi G, Schwarz TL. The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ. 2013; 20(1): 31–42, CrossRef.

Youle RJ, Narendra DP. Mechanisms of mitophagy. Nat Rev Mol Cell Biol. 2011; 12(1): 9–14, CrossRef.

Dutta D, Calvani R, Bernabei R, Leeuwenburgh C, Marzetti E. Contribution of impaired mitochondrial autophagy to cardiac aging: mechanisms and therapeutic opportunities. Circ Res. 2012; 110(8): 1125–38, CrossRef.

Singh LP, Devi TS, Yumnamcha T. The role of Txnip in mitophagy dysregulation and inflammasome activation in diabetic retinopathy: a new perspective. JOJ Ophthalmol. 2017; 4(4): 1–11, CrossRef.

Pang L, Liu K, Liu D, Lv F, Zang Y, Xie F, et al. Differential effects of reticulophagy and mitophagy on nonalcoholic fatty liver disease. Cell Death Dis. 2018; 9(2): 90, CrossRef.

Marshall E. Metabolic research. Canadian group claims “unique” database. Science. 2007; 315(5812): 583–4, CrossRef.

Chen K, Dai H, Yuan J, Chen J, Lin L, Zhang W, et al. Optineurin-mediated mitophagy protects renal tubular epithelial cells against accelerated senescence in diabetic nephropathy. Cell Death Dis. 2018; 9(2): 105, CrossRef.

Hansen M, Flatt T, Aguilaniu H. Reproduction, fat metabolism, and life span: what is the connection? Cell Metab. 2013; 17(1): 10–9, CrossRef.

Schulze RJ, Sathyanarayan A, Mashek DG. Breaking fat: The regulation and mechanisms of lipophagy. Biochim Biophys Acta Mol Cell Biol Lipids. 2017; 1862(10 Pt B): 1178–87, CrossRef.

Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, et al. Autophagy regulates lipid metabolism. Nature. 2009; 458(7242): 1131–5, CrossRef.

Kaushik S, Cuervo AM. The coming of age of chaperone-mediated autophagy. Nat Rev Mol Cell Biol. 2018; 19(6): 365–81, CrossRef.

Singh R, Cuervo AM. Lipophagy: connecting autophagy and lipid metabolism. Int J Cell Biol. 2012; 2012: 282041, CrossRef.

Maan M, Peters JM, Dutta M, Patterson AD. Lipid metabolism and lipophagy in cancer. Biochem Biophys Res Commun. 2018; 504(3): 582–9, CrossRef.

Chen K, Yuan R, Zhang Y, Geng S, Li L. Tollip deficiency alters atherosclerosis and steatosis by disrupting lipophagy. J Am Heart Assoc. 2017; 6(4): e004078, CrossRef.

Ravikumar B, Duden R, Rubinsztein DC. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet. 2002; 11(9): 1107–17, CrossRef.

Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC. α-synuclein is degraded by both autophagy and the proteasome. J Biol Chem. 2003; 278(27): 25009–13, CrossRef.

Berger Z, Ravikumar B, Menzies FM, Oroz LG, Underwood BR, Pangalos MN, et al. Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum Mol Genet. 2006; 15(3): 433–42, CrossRef.

Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet. 2004; 36(6): 585–95, CrossRef.

Lopez A, Lee SE, Wojta K, Ramos EM, Klein E, Chen J, et al. A152T tau allele causes neurodegeneration that can be ameliorated in a zebrafish model by autophagy induction. Brain. 2017; 140(4): 1128–46, CrossRef.

Kumsta C, Chang JT, Schmalz J, Hansen M. Hormetic heat stress and HSF-1 induce autophagy to improve survival and proteostasis in C. elegans. Nat Commun. 2017; 8: 14337, CrossRef.

Menzies FM, Fleming A, Caricasole A, Bento CF, Andrews SP, Ashkenazi A, et al. Autophagy and neurodegeneration: pathogenic mechanisms and therapeutic opportunities. Neuron. 2017; 93(5): 1015–34, CrossRef.

Lopez-Otín C, Kroemer G. Decelerating ageing and biological clocks by autophagy. Nat Rev Mol Cell Biol. 2019; 20(7): 385–6, CrossRef.

Levy JMM, Towers CG, Thorburn A. Targeting autophagy in cancer. Nat Rev Cancer. 2017; 17(9): 528–42, CrossRef.

Galluzzi L, Bravo-San Pedro JM, Levine B, Green DR, Kroemer G. Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat Rev Drug Discov. 2017; 16(7): 487–511, CrossRef.

Galluzzi L, Pietrocola F, Levine B, Kroemer G. Metabolic control of autophagy. Cell. 2014; 159(6): 1263–76, CrossRef.

Kubben N, Misteli T. Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases. Nat Rev Mol Cell Biol. 2017; 18(10): 595–609, CrossRef.

Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res. 1965; 37(3): 614–36, CrossRef.

Herbig U. Cellular senescence in aging primates. Science. 2006; 311(5765): 1257, CrossRef.

Farr JN, Fraser DG, Wang H, Jaehn K, Ogrodnik MB, Weivoda MM, et al. Identification of senescent cells in the bone microenvironment: senescent in the bone microenvironment. J Bone Miner Res. 2016; 31(11): 1920–9, CrossRef.

Biran A, Zada L, Abou Karam P, Vadai E, Roitman L, Ovadya Y, et al. Quantitative identification of senescent cells in aging and disease. Aging Cell. 2017; 16(4): 661–71, CrossRef.

Huang S, Risques RA, Martin GM, Rabinovitch PS, Oshima J. Accelerated telomere shortening and replicative senescence in human fibroblasts overexpressing mutant and wild-type lamin A. Exp Cell Res. 2008; 314(1): 82–91, CrossRef.

van Deursen JM. The role of senescent cells in ageing. Nature. 2014; 509(7501): 439–46, CrossRef.

Chandra T, Kirschner K, Thuret J-Y, Pope BD, Ryba T, Newman S, et al. Independence of repressive histone marks and chromatin compaction during senescent heterochromatic layer formation. Mol Cell. 2012; 47(2): 203–14, CrossRef.

Zhang R, Chen W, Adams PD. Molecular dissection of formation of senescence-associated heterochromatin foci. Mol Cell Biol. 2007; 27(6): 2343–58, CrossRef.

Freund A, Laberge RM, Demaria M, Campisi J. Lamin B1 loss is a senescence-associated biomarker. Mol Biol Cell. 2012; 23(11): 2066–75, CrossRef.

Shimi T, Butin-Israeli V, Adam SA, Hamanaka RB, Goldman AE, Lucas CA, et al. The role of nuclear lamin B1 in cell proliferation and senescence. Genes Dev. 2011; 25(24): 2579–93, CrossRef.

Dou Z, Xu C, Donahue G, Shimi T, Pan JA, Zhu J, et al. Autophagy mediates degradation of nuclear lamina. Nature. 2015; 527(7576): 105–9, CrossRef.

Rai TS, Cole JJ, Nelson DM, Dikovskaya D, Faller WJ, Vizioli MG, et al. HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia. Genes Dev. 2014; 28(24): 2712–25, CrossRef.

Lundblad V, Szostak JW. A mutant with a defect in telomere elongation leads to senescence in yeast. Cell. 1989; 57(4): 633–43, CrossRef.

Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature. 1990; 345(6274): 458–60, CrossRef.

Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science. 1996; 273(5271): 59–63, CrossRef.

Vaziri H, Benchimol S. From telomere loss to p53 induction and activation of a DNA-damage pathway at senescence: the telomere loss/DNA damage model of cell aging. Exp Gerontol. 1996; 31(1–2): 295–301, CrossRef.

Sedelnikova OA, Horikawa I, Zimonjic DB, Popescu NC, Bonner WM, Barrett JC. Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nat Cell Biol. 2004; 6(2): 168–70, CrossRef.

Seluanov A, Mittelman D, Pereira-Smith OM, Wilson JH, Gorbunova V. DNA end joining becomes less efficient and more error-prone during cellular senescence. Proc Natl Acad Sci USA. 2004; 101(20): 7624–9, CrossRef.

Sfeir A, de Lange T. Removal of shelterin reveals the telomere end-protection problem. Science. 2012; 336(6081): 593–7, CrossRef.

Sedivy JM, Banumathy G, Adams PD. Aging by epigenetics—A consequence of chromatin damage? Exp Cell Res. 2008; 314(9): 1909–17, CrossRef.

Feser J, Tyler J. Chromatin structure as a mediator of aging. FEBS Letters. 2011; 585(13): 2041–8, CrossRef.

O’Sullivan RJ, Karlseder J. The great unravelling: chromatin as a modulator of the aging process. Trends Biochem Sci. 2012; 37(11): 466–76, CrossRef.

Tchkonia T, Zhu Y, van Deursen J, Campisi J, Kirkland JL. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest. 2013; 123(3): 966–72, CrossRef.

Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, et al. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature. 2006; 443(7110): 453–7, CrossRef.

Baumann K. Rejuvenating senolytics. Nat Rev Mol Cell Biol. 2018; 19(9): 543, CrossRef.

Kenyon CJ. The genetics of ageing. Nature. 2010; 464(7288): 504–12, CrossRef.

Gems D, Partridge L. Genetics of longevity in model organisms: debates and paradigm shifts. Annu Rev Physiol. 2013; 75: 621–44, CrossRef.

Brandhorst S, Choi IY, Wei M, Cheng CW, Sedrakyan S, Navarrete G, et al. A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan. Cell Metab. 2015; 22(1): 86–99, CrossRef.

Cheng CW, Villani V, Buono R, Wei M, Kumar S, Yilmaz OH, et al. Fasting-mimicking diet promotes Ngn3-driven β-cell regeneration to reverse diabetes. Cell. 2017; 168(5): 775-788.e12, CrossRef.

Cerletti M, Jang YC, Finley LWS, Haigis MC, Wagers AJ. Short-term calorie restriction enhances skeletal muscle stem cell function. Cell Stem Cell. 2012; 10(5): 515–9, CrossRef.

Newman JC, Covarrubias AJ, Zhao M, Yu X, Gut P, Ng CP, et al. Ketogenic diet reduces midlife mortality and improves memory in aging mice. Cell Metab. 2017; 26(3): 547–57.e8, CrossRef.

Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009; 460(7253): 392–5, CrossRef.

de Cabo R, Carmona-Gutierrez D, Bernier M, Hall MN, Madeo F. The search for antiaging interventions: from elixirs to fasting regimens. Cell. 2014; 157(7): 1515–26, CrossRef.

Conboy MJ, Conboy IM, Rando TA. Heterochronic parabiosis: historical perspective and methodological considerations for studies of aging and longevity. Aging Cell. 2013; 12(3): 525–30, CrossRef.

de Keizer PLJ. The fountain of youth by targeting Senescent cells? Trends Mol Med. 2017; 23(1): 6–17, CrossRef.

Mahmoudi S, Brunet A. Aging and reprogramming: a two-way street. Curr Opin Cell Biol. 2012; 24(6): 744–56, CrossRef.

Oh J, Lee YD, Wagers AJ. Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nat Med. 2014; 20(8): 870–80, CrossRef.

Galluzzi L, Yamazaki T, Kroemer G. Linking cellular stress responses to systemic homeostasis. Nat Rev Mol Cell Biol. 2018; 19(11): 731–45, CrossRef.

Weir HJ, Yao P, Huynh FK, Escoubas CC, Goncalves RL, Burkewitz K, et al. Dietary restriction and AMPK increase lifespan via mitochondrial network and peroxisome remodeling. Cell Metab. 2017; 26(6): 884–96.e5, CrossRef.

Labbadia J, Brielmann RM, Neto MF, Lin YF, Haynes CM, Morimoto RI. Mitochondrial stress restores the heat shock response and prevents proteostasis collapse during aging. Cell Rep. 2017; 21(6): 1481–94, CrossRef.

Guarente L. Mitochondria—a nexus for aging, calorie restriction, and sirtuins? Cell. 2008; 132(2): 171–6, CrossRef.

Masotti A, Celluzzi A, Petrini S, Bertini E, Zanni G, Compagnucci C. Aged iPSCs display an uncommon mitochondrial appearance and fail to undergo in vitro neurogenesis. Aging (Albany NY). 2014; 6(12): 1094–108, CrossRef.

Sinha I, Sinha-Hikim AP, Wagers AJ, Sinha-Hikim I. Testosterone is essential for skeletal muscle growth in aged mice in a heterochronic parabiosis model. Cell Tissue Res. 2014; 357(3): 815–21, CrossRef.

Ren R, Ocampo A, Liu GH, Izpisua Belmonte JC. Regulation of stem cell aging by metabolism and epigenetics. Cell Metab. 2017; 26(3): 460–74, CrossRef.

Zhang H, Ryu D, Wu Y, Gariani K, Wang X, Luan P, et al. NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. 2016; 352(6292): 1436–43, CrossRef.

Igarashi M, Miura M, Williams E, Jaksch F, Kadowaki T, Yamauchi T, et al. NAD+ supplementation rejuvenates aged gut adult stem cells. Aging Cell. 2019; 18(3): e12935, CrossRef.

Rajman L, Chwalek K, Sinclair DA. Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell Metab. 2018; 27(3): 529–47, CrossRef.

Yoshino J, Baur JA, Imai SI. NAD+ intermediates: the biology and therapeutic potential of NMN and NR. Cell Metab. 2018; 27(3): 513–28, CrossRef.

Mitchell SJ, Bernier M, Aon MA, Cortassa S, Kim EY, Fang EF, et al. Nicotinamide improves aspects of healthspan, but not lifespan, in mice. Cell Metab. 2018; 27(3): 667–76.e4, CrossRef.

Saini JS, Corneo B, Miller JD, Kiehl TR, Wang Q, Boles NC, et al. Nicotinamide ameliorates disease phenotypes in a human iPSC model of age-related macular degeneration. Cell Stem Cell. 2017; 20(5): 635–47.e7, CrossRef.

Saint-Geniez M, Rosales MAB. Eyeing the fountain of youth. Cell Stem Cell. 2017; 20(5): 583–4, CrossRef.

Katsyuba E, Mottis A, Zietak M, De Franco F, van der Velpen V, Gariani K, et al. De novo NAD+ synthesis enhances mitochondrial function and improves health. Nature. 2018; 563(7731): 354–9, CrossRef.

Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun. 2018; 9(1): 1286, CrossRef.

Narita M, Nuñez S, Heard E, Narita M, Lin AW, Hearn SA, et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell. 2003; 113(6): 703–16, CrossRef.

Foran E, Garrity-Park MM, Mureau C, Newell J, Smyrk TC, Limburg PJ, et al. Upregulation of DNA methyltransferase-mediated gene silencing, anchorage-independent growth, and migration of colon cancer cells by interleukin-6. Mol Cancer Res. 2010; 8(4): 471–81, CrossRef.

Hodge DR, Xiao W, Clausen PA, Heidecker G, Szyf M, Farrar WL. Interleukin-6 regulation of the human DNA methyltransferase (HDNMT) gene in human erythroleukemia cells. J Biol Chem. 2001; 276(43): 39508–11, CrossRef.

Ocampo A, Reddy P, Martinez-Redondo P, Platero-Luengo A, Hatanaka F, Hishida T, et al. In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell. 2016; 167(7): 1719–33.e12, CrossRef.

Hahn O, Grönke S, Stubbs TM, Ficz G, Hendrich O, Krueger F, et al. Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism. Genome Biol. 2017; 18(1): 56, CrossRef.

Rando TA, Chang HY. Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. Cell. 2012; 148(1): 46–57, CrossRef.

Greer EL, Maures TJ, Hauswirth AG, Green EM, Leeman DS, Maro GS, et al. Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature. 2010; 466(7304): 383–7, CrossRef.




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