Abstract
Various models for ageing, each focussing on different biochemical and/or cellular pathways have been proposed. This has resulted in a complex and non-coherent portrayal of ageing. Here, we describe a concise and comprehensive model for the biochemistry of ageing consisting of three interacting signalling hubs. These are the nuclear factor kappa B complex (NFκB), controlling the innate immune system, the mammalian target for rapamycin complex, controlling cell growth, and the integrated stress responses, controlling homeostasis. This model provides a framework for most other, more detailed, biochemical pathways involved in ageing, and explains why ageing involves chronic inflammation, cellular senescence, and vulnerability to environmental stress, while starting with the spontaneous formation of advanced glycation end products. The totality of data underlying this model suggest that the gradual inhibition of the AMPK-ISR probably determines the maximal lifespan. Based on this model, anti-ageing drugs in general, are expected to show hormetic dose response curves. This complicates the process of dose-optimization. Due to its specific mechanism of action, the anti-aging drug alkaline phosphatase is an exception to this rule, because it probably exhibits saturation kinetics.
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References
Abu Shelbayeh O, Arroum T, Morris S, Busch KB (2023) PGC-1α is a Master Regulator of mitochondrial lifecycle and ROS stress response. Antioxidants 12(5):1075. https://doi.org/10.3390/antiox12051075
Alkhoury F, Malo MS, Mozumder M, Mostafa G, Hodin RA (2005) Differential regulation of intestinal alkaline phosphatase gene expression by Cdx1 and Cdx2. Am J Physiology-Gastrointestinal Liver Physiol 289(2):G285–G290. https://doi.org/10.1152/ajpgi.00037.2005
Aragonès G, Rowan S, Francisco SG, Whitcomb EA, Yang W, Perini-Villanueva G, … and, Bejarano E (2021) The glyoxalase system in age-related diseases: nutritional intervention as anti-ageing strategy. Cells 10(8):1852. https://doi.org/10.3390/cells10081852
Balistreri CR, Candore G, Accardi G, Colonna-Romano G, Lio D (2013) NF-κB pathway activators as potential ageing biomarkers: targets for new therapeutic strategies. Immun Ageing 10(1):1–16. https://doi.org/10.1186/1742-4933-10-24
Bender A, Beckers J, Schneider I, Hölter SM, Haack T, Ruthsatz T, … and, Klopstock T (2008) Creatine improves health and survival of mice. Neurobiol Aging 29(9):1404–1411. https://doi.org/10.1016/j.neurobiolaging.2007.03.001
Biran A, Zada L, Karam A, Vadai P, Roitman E, Ovadya L, Y., … and, Krizhanovsky V (2017) Quantitative identification of senescent cells in aging and disease. Aging Cell 16(4):661–671. https://doi.org/10.1111/acel.12592
Blagosklonny MV (2022) Cell senescence, rapamycin and hyperfunction theory of aging. Cell Cycle 21(14):1456–1467. https://doi.org/10.1080/15384101.2022.2054636
Blagosklonny MV (2023) Cellular senescence: when growth stimulation meets cell cycle arrest. Aging 15(4):905. https://doi.org/10.18632/aging.204543
Calabrese EJ, Dhawan G, Kapoor R, Iavicoli I, Calabrese V (2015) What is hormesis and its relevance to healthy aging and longevity? Biogerontology 16:693–707. https://doi.org/10.1007/s10522-015-9601-0
Calabrese EJ, Osakabe N, Di Paola R, Siracusa R, Fusco R, D’Amico R, Calabrese V (2023) Hormesis defines the limits of lifespan. Ageing Res Rev. https://doi.org/10.1016/j.arr.2023.102074
Carosi JM, Fourrier C, Bensalem J, Sargeant TJ (2022) The mTOR–lysosome axis at the centre of ageing. FEBS Open Bio 12(4):739–757. https://doi.org/10.1002/2211-5463.13347
Chaudhuri J, Bains Y, Guha S, Kahn A, Hall D, Bose N, … and, Kapahi P (2018) The role of advanced glycation end products in aging and metabolic diseases: bridging association and causality. Cell Metabol 28(3):337–352. https://doi.org/10.1016/j.cmet.2018.08.014
Chen KT, Malo MS, Moss AK, Zeller S, Johnson P, Ebrahimi F, … and, Hodin RA (2010) Identification of specific targets for the gut mucosal defense factor intestinal alkaline phosphatase. Am J Physiology-Gastrointestinal Liver Physiol 299(2):G467–G475. https://doi.org/10.1152/ajpgi.00364.2009
Costa-Mattioli M, Walter P (2020) The integrated stress response: from mechanism to disease. Science 368(6489):eaat5314. https://doi.org/10.1126/science.aat5314
Deng J, Lu PD, Zhang Y, Scheuner D, Kaufman RJ, Sonenberg N, Ron D (2004) Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2. Mol Cell Biol 24(23):10161–10168. https://doi.org/10.1128/MCB.24.23.10161-10168.2004
Derisbourg MJ, Hartman MD, Denzel MS (2021) Modulating the integrated stress response to slow aging and ameliorate age-related pathology. Nature Aging 1(9):760–768
Gao C, Koko MYF, Ding M, Hong W, Li J, Dong N, Hui M (2022) Intestinal alkaline phosphatase (IAP, IAP enhancer) attenuates intestinal inflammation and alleviates insulin resistance. Front Immunol 13:927272. https://doi.org/10.3389/fimmu.2022.927272
George M, Tharakan M, Culberson J, Reddy AP, Reddy PH (2022) Role of Nrf2 in aging, Alzheimer’s and other neurodegenerative diseases. Ageing Res Rev. https://doi.org/10.1016/j.arr.2022.101756
Gordon HA, Bruckner-kardoss E, Wostmann BS (1966) Aging in germ-free mice: life tables and lesions observed at natural death. J Gerontol 21(3):380–387. https://doi.org/10.1093/geronj/21.3.380
Gugliucci A (2009) Blinding of AMP-dependent kinase by methylglyoxal: a mechanism that allows perpetuation of hepatic insulin resistance? Med Hypotheses 73(6):921–924. https://doi.org/10.1016/j.mehy.2009.06.044
Gureev AP, Shaforostova EA, Popov VN (2019) Regulation of mitochondrial biogenesis as a way for active longevity: interaction between the Nrf2 and PGC-1α signaling pathways. Front Genet 10:435. https://doi.org/10.3389/fgene.2019.00435
Hindupur SK, González A, Hall MN (2015) The opposing actions of target of rapamycin and AMP-activated protein kinase in cell growth control. Cold Spring Harb Perspect Biol 7(8):a019141. https://doi.org/10.1101/cshperspect.a019141
Huang J, Manning BD (2008) The TSC1–TSC2 complex: a molecular switchboard controlling cell growth. Biochem J 412(2):179–190. https://doi.org/10.1042/BJ20080281
Imseng S, Aylett CH, Maier T (2018) Architecture and activation of phosphatidylinositol 3-kinase related kinases. Curr Opin Struct Biol 49:177–189. https://doi.org/10.1016/j.sbi.2018.03.010
Kauppinen A, Suuronen T, Ojala J, Kaarniranta K, Salminen A (2013) Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders. Cell Signal 25(10):1939–1948. https://doi.org/10.1016/j.cellsig.2013.06.007
Keizer HG, Brands R, Seinen W (2023) An AMP kinase-pathway dependent integrated stress response regulates ageing and longevity. Biogerontology, pp 1–13. https://doi.org/10.1007/s10522-023-10024-3
Klaus S, Ost M (2020) Mitochondrial uncoupling and longevity–a role for mitokines? Exp Gerontol 130:110796. https://doi.org/10.1016/j.exger.2019.110796
Kroemer G, Mariño G, Levine B (2010) Autophagy and the integrated stress response. Mol cell 40(2):280–293
Kühn F, Adiliaghdam F, Cavallaro PM, Hamarneh SR, Tsurumi A, Hoda RS, Hodin RA (2020) Intestinal alkaline phosphatase targets the gut barrier to prevent aging. JCI insight. https://doi.org/10.1172/jci.insight.134049
Laplante M, Sabatini DM (2009) mTOR signaling at a glance. J Cell Sci 122(20):3589–3594. https://doi.org/10.1242/jcs.051011
Licastro F, Candore G, Lio D, Porcellini E, Colonna-Romano G, Franceschi C, Caruso C (2005) Innate immunity and inflammation in ageing: a key for understanding age-related diseases. Immun Ageing 2:1–14. https://doi.org/10.1186/1742-4933-2-8
Liu Y, Li J, Han Y, Chen Y, Liu L, Lang J, … and, Ning J (2020) Advanced glycation end-products suppress autophagy by AMPK/mTOR signaling pathway to promote vascular calcification. Mol Cell Biochem 471:91–100. https://doi.org/10.1007/s11010-020-03769-9
Ma L, Sun P, Zhang JC, Zhang Q, Yao SL (2017) Proinflammatory effects of S100A8/A9 via TLR4 and RAGE signaling pathways in BV-2 microglial cells. Int J Mol Med 40(1):31–38. https://doi.org/10.3892/ijmm.2017.2987
Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, … and, De Cabo R (2013) Metformin improves healthspan and lifespan in mice. Nat Commun 4(1):2192. https://doi.org/10.1038/ncomms3192
Matzinger M, Fischhuber K, Pölöske D, Mechtler K, Heiss EH (2020) AMPK leads to phosphorylation of the transcription factor Nrf2, tuning transactivation of selected target genes. Redox Biol 29:101393
McConnell RE, Higginbotham JN, Shifrin DA Jr, Tabb DL, Coffey RJ, Tyska MJ (2009) The enterocyte microvillus is a vesicle-generating organelle. J Cell Biol 185(7):1285–1298. https://doi.org/10.1083/jcb.200902147
Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, De Cabo R, … and, Strong R (2011) Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. Journals Gerontol Ser A: Biomedical Sci Med Sci 66(2):191–201. https://doi.org/10.1093/gerona/glq178
Mitchell SJ, Martin-Montalvo A, Mercken EM, Palacios HH, Ward TM, Abulwerdi G, … and, De Cabo R (2014) The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet. Cell Rep 6(5):836–843. https://doi.org/10.1016/j.celrep.2014.01.031
Mitchell S, Tsui R, Tan ZC, Pack A, Hoffmann A (2023) The NF-κB multidimer system model: a knowledge base to explore diverse biological contexts. Sci Signal 16(776):eabo2838. https://doi.org/10.1126/scisignal.abo2838
Moskalev A, Shaposhnikov M (2011) Pharmacological inhibition of NF-κB prolongs lifespan of Drosophila melanogaster. Aging 3(4):391. https://doi.org/10.18632/aging.100314
Mota-Martorell N, Jove M, Pradas I, Berdún R, Sanchez I, Naudi A, … and, Pamplona R (2020) Gene expression and regulatory factors of the mechanistic target of rapamycin (mTOR) complex 1 predict mammalian longevity. Geroscience 42:1157–1173. https://doi.org/10.1007/s11357-020-00210-3
Mylonas A, O’Loghlen A (2022) Cellular senescence and ageing: mechanisms and interventions. Front Aging 3:866718. https://doi.org/10.3389/fragi.2022.866718
Navarro A, Gomez C, López-Cepero JM, Boveris A (2004) Beneficial effects of moderate exercise on mice aging: survival, behavior, oxidative stress, and mitochondrial electron transfer. Am J physiology-regulatory Integr Comp Physiol 286(3):R505–R511. https://doi.org/10.1152/ajpregu.00208.2003
Nguyen LS, Vautier M, Allenbach Y, Zahr N, Benveniste O, Funck-Brentano C, Salem JE (2019) Sirolimus and mTOR inhibitors: a review of side effects and specific management in solid organ transplantation. Drug Saf 42:813–825. https://doi.org/10.1007/s40264-019-00810-9
Nicolae CM, O’Connor MJ, Constantin D, Moldovan GL (2018) NFκB regulates p21 expression and controls DNA damage-induced leukemic differentiation. Oncogene 37(27):3647–3656. https://doi.org/10.1038/s41388-018-0219-y
Osorio FG, Soria-Valles C, Santiago-Fernández O, Freije JMP, López-Otín C (2016) NF-κB signaling as a driver of ageing. Int Rev cell Mol Biology 326:133–174. https://doi.org/10.1016/bs.ircmb.2016.04.003
Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman AM (2016) The integrated stress response. EMBO Rep 17(10):1374–1395. https://doi.org/10.15252/embr.201642195
Pandolfi F, Altamura S, Frosali S, Conti P (2016) Key role of DAMP in inflammation, cancer, and tissue repair. Clin Ther 38(5):1017–1028. https://doi.org/10.1016/j.clinthera.2016.02.028
Pardo PS, Boriek AM (2020) SIRT1 regulation in ageing and obesity. Mech Ageing Dev 188:111249. https://doi.org/10.1016/j.mad.2020.111249
Postnikoff SD, Johnson JE, Tyler JK (2017) The integrated stress response in budding yeast lifespan extension. Microb Cell 4(11):368. https://doi.org/10.15698/mic2017.11.597
Puzianowska-Kuźnicka M, Owczarz M, Wieczorowska-Tobis K, Nadrowski P, Chudek J, Slusarczyk P, … and, Mossakowska M (2016) Interleukin-6 and C-reactive protein, successful aging, and mortality: the PolSenior study. Immun Ageing 13:1–12. https://doi.org/10.1186/s12979-016-0076-x
Rabbani N, Thornalley PJ (2018) Advanced glycation end products in the pathogenesis of chronic kidney disease. Kidney Int 93(4):803–813. https://doi.org/10.1016/j.kint.2017.11.034
Rabbani N, Xue M, Thornalley PJ (2016) Dicarbonyls and glyoxalase in disease mechanisms and clinical therapeutics. Glycoconj J 33:513–525. https://doi.org/10.1007/s10719-016-9705-z
Rahman MM, McFadden G (2011) Modulation of NF-κB signalling by microbial pathogens. Nat Rev Microbiol 9(4):291–306. https://doi.org/10.1038/nrmicro2539
Rattan SI (2007) Homeostasis, homeodynamics, and aging. Encyclopedia of Gerontology. 2nd edition ed. UK: Elsevier Inc, 696-9
Rattan SI (2024) Seven knowledge gaps in modern biogerontology. Biogerontology. https://doi.org/10.1007/s10522-023-10089-0
Rosner M, Hanneder M, Siegel N, Valli A, Fuchs C, Hengstschläger M (2008) The mTOR pathway and its role in human genetic diseases. Mutat Research/reviews Mutat Res 659(3):284–292. https://doi.org/10.1016/j.mrrev.2008.06.001
Rowart P, Wu J, Caplan MJ, Jouret F (2018) Implications of AMPK in the formation of epithelial tight junctions. Int J Mol Sci. https://doi.org/10.3390/ijms19072040
Salminen A, Kaarniranta K (2012) AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev 11(2):230–241. https://doi.org/10.1016/j.arr.2011.12.005
Salminen A, Huuskonen J, Ojala J, Kauppinen A, Kaarniranta K, Suuronen T (2008) Activation of innate immunity system during aging: NF-kB signaling is the molecular culprit of inflamm-aging. Ageing Res Rev 7(2):83–105. https://doi.org/10.1016/j.arr.2007.09.002
Saoudaoui S, Bernard M, Cardin GB, Malaquin N, Christopoulos A, Rodier F (2021) mTOR as a senescence manipulation target: a forked road. Adv Cancer Res 150:335–363. https://doi.org/10.1016/bs.acr.2021.02.002
Saxton RA, Sabatini DM (2017) mTOR signaling in growth, metabolism, and disease. Cell 168(6):960–976. https://doi.org/10.1016/j.cell.2017.02.004
Shih VFS, Tsui R, Caldwell A, Hoffmann A (2011) A single NFκB system for both canonical and non-canonical signaling. Cell Res 21(1):86–102. https://doi.org/10.1038/cr.2010.161
Songkiatisak P, Rahman SMT, Aqdas M, Sung MH (2022) NF-κB, a culprit of both inflamm-ageing and declining immunity? Immun Ageing 19(1):20. https://doi.org/10.1186/s12979-022-00277-w
Spencer SL, Cappell SD, Tsai FC, Overton KW, Wang CL, Meyer T (2013) The proliferation-quiescence decision is controlled by a bifurcation in CDK2 activity at mitotic exit. Cell 155(2):369–383. https://doi.org/10.1016/j.cell.2013.08.062
Strong R, Miller RA, Astle CM, Floyd RA, Flurkey K, Hensley KL, … and, Harrison DE (2008) Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice. Aging Cell 7(5):641–650. https://doi.org/10.1111/j.1474-9726.2008.00414.x
Sun X, Yang Q, Rogers CJ, Du M, Zhu MJ (2017) AMPK improves gut epithelial differentiation and barrier function via regulating Cdx2 expression. Cell Death Differ 24(5):819–831. https://doi.org/10.1038/cdd.2017.14
Tavernarakis N, Pasparaki A, Tasdemir E, Maiuri MC, Kroemer G (2008) The effects of p53 on whole organism longevity are mediated by autophagy. Autophagy 4(7):870–873
Tazume S, Umehara K, Matzuzawa H, Aikawa H, Hashimoto K, Sasiki S (1991) Effects of germfree status and food restriction on longevity and growth of mice. Exp Anim 40(4):517–522. https://doi.org/10.1538/expanim1978.40.4_517
Trefts E, Shaw RJ (2021) AMPK: restoring metabolic homeostasis over space and time. Mol Cell 81(18):3677–3690. https://doi.org/10.1016/j.molcel.2021.08.015
van Beek JH, Kirkwood TB, Bassingthwaighte JB (2016) Understanding the physiology of the ageing individual: computational modelling of changes in metabolism and endurance. Interface Focus 6(2):20150079. https://doi.org/10.1098/rsfs.2015.0079
Vellai T (2009) Autophagy genes and ageing. Cell Death Differ 16(1):94–102. https://doi.org/10.1038/cdd.2008.126
Wenz T (2011) Mitochondria and PGC-1α in aging and age-associated diseases. J Aging Res. https://doi.org/10.4061/2011/810619
Xu J, Ji J, Yan XH (2012) Cross-talk between AMPK and mTOR in regulating energy balance. Crit Rev Food Sci Nutr 52(5):373–381. https://doi.org/10.1080/10408398.2010.500245
Yin D, Chen K (2005) The essential mechanisms of aging: irreparable damage accumulation of biochemical side-reactions. Exp Gerontol 40(6):455–465. https://doi.org/10.1016/j.exger.2005.03.012
Yu H, Lin L, Zhang Z, Zhang H, Hu H (2020) Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study. Signal Transduct Target Therapy 5(1):209. https://doi.org/10.1038/s41392-020-00312-6
Zhang G, Li J, Purkayastha S, Tang Y, Zhang H, Yin Y, … and, Cai D (2013) Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature 497(7448):211–216. https://doi.org/10.1038/nature12143
Zhu R, Lei Y, Shi F, Tian Q, Zhou X (2022) Arginine reduces glycation in γ2 subunit of AMPK and pathologies in Alzheimer’s Disease Model mice. Cells 11(21):3520
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Keizer, H.G., Brands, R., Oosting, R.S. et al. A comprehensive model for the biochemistry of ageing, senescence and longevity. Biogerontology (2024). https://doi.org/10.1007/s10522-024-10097-8
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DOI: https://doi.org/10.1007/s10522-024-10097-8