The new science of ageing
2010; Royal Society; Volume: 366; Issue: 1561 Linguagem: Inglês
10.1098/rstb.2010.0298
ISSN1471-2970
AutoresLinda Partridge, Janet M. Thornton, Gillian P. Bates,
Tópico(s)Aging and Gerontology Research
ResumoYou have accessMoreSectionsView PDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InRedditEmail Cite this article Partridge Linda, Thornton Janet and Bates Gillian 2011The new science of ageingPhil. Trans. R. Soc. B3666–8http://doi.org/10.1098/rstb.2010.0298SectionYou have accessIntroductionThe new science of ageing Linda Partridge Linda Partridge Department of Genetics, Evolution and Environment, Darwin Building, University College London, Gower Street, London WC1E 6BT, UK [email protected] Google Scholar Find this author on PubMed Search for more papers by this author , Janet Thornton Janet Thornton European Bioinformatics Institute, Hinxton, Cambridge, UK Google Scholar Find this author on PubMed Search for more papers by this author and Gillian Bates Gillian Bates Department of Medical and Molecular Genetics, Kings College London School of Medicine, London, UK Google Scholar Find this author on PubMed Search for more papers by this author Linda Partridge Linda Partridge Department of Genetics, Evolution and Environment, Darwin Building, University College London, Gower Street, London WC1E 6BT, UK [email protected] Google Scholar Find this author on PubMed , Janet Thornton Janet Thornton European Bioinformatics Institute, Hinxton, Cambridge, UK Google Scholar Find this author on PubMed and Gillian Bates Gillian Bates Department of Medical and Molecular Genetics, Kings College London School of Medicine, London, UK Google Scholar Find this author on PubMed Published:12 January 2011https://doi.org/10.1098/rstb.2010.0298This article has a CorrectionCorrectionThe new science of ageinghttps://doi.org/10.1098/rstb.2015.0249 Linda Partridge, Janet Thornton and Gillian Bates volume 370issue 1676journalTitle Philosophical Transactions of the Royal Society B: Biological Sciences05 September 2015Thanks to improvements in hygiene and healthcare, human life expectancy in developed countries has been increasing at a steady rate of about 2.5 years per decade since the middle of the nineteenth century [1]. People are staying healthier as they go through middle and older age and, as a result, they are living longer. Although this crowning achievement of human civilisation should be celebrated as such, it is receiving a decidedly mixed press. The reason is that more people are now living long enough to experience the loss of function and diseases of older age. Ageing is the major risk factor for all of the predominant killer diseases, including cardiovascular disease, cancer and neurodegeneration, and the main burden of ill health is now falling on the older section of the population. However, until recently, the complexity of the ageing process has made it appear an unpromising target for experimental analysis or medical intervention. At best, a piecemeal approach to the problems of ageing has seemed feasible [2].Research into ageing has undergone a revolution in recent years, with the discovery that mutations in single genes can increase lifespan in laboratory animals. Rather than simply extending the moribund period at the end of life, these genetic interventions often keep the animals in a state of youthful health and vigour for longer, and in mice they produce a broad-spectrum maintenance of function and freedom from disease as the animals age. Mechanisms of ageing also show strong evolutionary conservation, with mutations in related genes extending the lifespan of distantly related organisms, such as budding yeast, nematode worms, fruit flies and rodents [3,4]. These striking findings suggest that protecting against the ageing process can increase healthy lifespan and they have opened up the prospect of a broad-spectrum, preventative medicine for the diseases of ageing in humans [5]. The aim of the Discussion Meeting 'The new science of ageing' was to explore these new findings, with an emphasis on identifying key areas for future research.Cynthia Kenyon [4] opened with the history of the discovery of the first long-lived mutants in the nematode worm Caenorhabditis elegans, and the finding that the genes involved encoded an insulin/insulin-like growth factor signalling (IIS) pathway. This effect of IIS is conserved during evolution, because similar mutants in fruit flies and mice have subsequently been shown to extend lifespan [4,6]. IIS matches nutrient-consuming processes, such as growth, metabolism and reproduction, to nutrient availability. It acts systemically in multicellular organisms, and may indeed have evolved with the advent of multicellularity. The closely connected Target of Rapamycin (TOR) pathway, which is present in yeast as well as in multicellular animals, senses amino acids, and also plays an evolutionarily conserved role in ageing [7]. Rapamycin, a potent and specific inhibitor of TOR, has recently been shown to extend lifespan in mice, a clear proof of principle for the use of pharmacological intervention into the ageing process [8]. Brian Kennedy discussed how mutations in TOR signalling extend lifespan in yeast, nematodes, fruit flies and mice [9], exploring the downstream signalling and effector mechanisms at work, including altered AMPK activity and translation, AMPK activity, autophagy, mitochondrial function and stress response. As with IIS, elucidating the precise modulation of TOR signalling, the tissues in which altered signalling is important and the combination of downstream effectors that act to extend lifespan will be a challenge requiring both incisive experiments and integrated modelling approaches. In mice, many of the mutations that extend lifespan alter growth hormone (GH) and IGF-1 signalling. Andrzej Bartke [10] pointed out that extension of lifespan is most robust in mice mutant for GH signalling itself. As with IIS and TOR signalling, the potential downstream effectors are numerous and include stress resistance, antioxidant defence, alterations to insulin, IGF or TOR signalling, reduced inflammation and altered mitochondrial function. These pathways have highly pleiotropic effects, not all of them desirable (for instance, reduced IIS can both impair wound healing and cause diabetes), and it will be important to understand the extent to which these different effects can be separated from each other by intervention at a suitable level in the signalling networks.Work on the role of these pathways in human ageing is in its infancy, but developing rapidly. Eline Slagboom et al. [11], Heather Wheeler & Stuart Kim [12] and Nir Barzilai et al. [13] described work on both the phenotypes and genotypes associated with exceptional longevity in human study cohorts. Intriguingly, long-lived humans show a phenotypic resemblance to animals subject to dietary restriction and have a particularly low incidence of diabetes. Although genetic influences on human lifespan are small, at least some of the genes involved are human orthologues of ones shown to be important in animal lifespan, particularly the key IIS effector FoxO forkhead transcription factor. Interestingly, genes that affect lifespan seem in general to be different from those that confer susceptibility to specific ageing-related diseases.A systems level approach to ageing has barely begun, but already functional genomic approaches are yielding new insights. For instance, gene expression profiles change with age in the human kidney, and individuals with youthful expression profiles for their chronological age also have youthful looking kidneys [14]. For these kinds of functional genomic approaches to reach their full potential, extensive databases and powerful methods of bioinformatic analysis will be needed, issues addressed by Janet Thornton [15]. Tom Kirkwood [16] addressed the challenge of applying a systems approach to the complexity of the ageing phenotype and its modification during extension of lifespan, illustrated by modelling of the interplay between mitochondrial dysfunction, telomere shortening and DNA damage in cellular senescence.One of the most remarkable phenomena of ageing is that rejuvenated offspring are produced by ageing parents. The processes of spatial quality control that cause damaged cellular components to be retained in the parent, thus rejuvenating the offspring but causing the parent to age, were discussed by Thomas Nyström [17]. Great strides have been made, particularly in budding yeast in identifying damaged molecules that undergo asymmetrical segregation and the genes and mechanisms involved. The role of cellular senescence in organismal ageing was addressed by Maria Blasco [18], who considered the role of telomeres. In normal mice, artificially driven expression of telomerase leads to a slightly increased incidence of cancer. By contrast, if telomerase is similarly expressed in mice where resistance to cancer is augmented by over-expression of tumour suppressors, lifespan is extended, and this extension depends upon the catalytic activity of telomerase. This result implies that deficiencies in the maintenance of telomeres are normally limiting for mouse lifespan. Ageing of stem cells may be complex, and, in part, a consequence of ageing of the local and systemic environment, as well as of the stem cells themselves. Tom Rando [19] analysed the evidence for one mechanism by which stem cells may retain their regenerative potential in tissues, namely unequal partitioning of chromosomes at mitosis according to the age of their template DNA strands. Although the data broadly support the idea that stem and other progenitor cells retain the original DNA strand, with the new copy with its replication errors going to the offspring cell, the exact mechanisms and functional significance of the asymmetry await discovery. Little is known of the rate of accumulation of non-replicative errors on the parent DNA strand, which could be an important cause of damage in long-lived cells. Nor is it yet known whether lifespan-extending mutations modify the asymmetrical division of molecular damage or the maintenance of telomeres.Although so far it has only scratched the surface, experimental work with the model organisms is starting to reveal exactly how amelioration of the ageing process protects against the diseases of ageing. Andrew Dillin [20] discussed work in C. elegans and the mouse, demonstrating that animal mutants for IIS are protected against neurodegenerative disease by amelioration of their proteotoxic aetiology. Interestingly, mutations that reduce IIS with or without increasing lifespan can protect against neurodegenerative disease, and it will be important to understand the exact relationships between these two outputs of the pathway. Dominic Withers [21] discussed how reduced IIS and TOR signalling produce a broad-spectrum improvement in health during ageing in mice. For instance, several long-lived mouse mutants are protected against cognitive and motor decline, adiposity, cancer, bone loss and glucose intolerance; the last is particularly striking given that some of these mouse models are insulin resistant when young. Understanding how a single mutation can have such profound effects on health during ageing is a major challenge for research in this area.The aim of research into ageing is to improve the health of older humans. David Gems [22] considered the ethical implications of extending human lifespan, and concluded that the ethical imperative to free people from the diseases of ageing far outweighs the potential negative social consequences of increased lifespan. However, amelioration of ageing by medical intervention will require the development and testing of drugs that target the gene products that have this effect. Such an undertaking would pose major challenges for the pharmaceutical industry. William Evans [23] discussed some of these. Drug trials would have to be conducted over a long period and with older people, who often have complications from multiple chronic diseases and polypharmacy. Furthermore, a broad spectrum improvement in health is not an outcome that would currently motivate a drug trial and nor is frailty a recognised medical problem. In practice, these considerations may be the major obstacles to the translation of the science of ageing into improvements in the health of older people. However, pressure from the growing population of older people may nonetheless change the face of geriatric medicine in the not too distant future.AcknowledgementsWe would like to thank The Royal Society staff for their excellent support for the Discussion Meeting and the preparation of this volume, and we particularly thank Julie Black for her excellent organisational and editorial work on this volume.FootnotesOne contribution of 15 to a Discussion Meeting Issue 'The new science of ageing'.This Journal is © 2011 The Royal SocietyReferences1Oeppen J.& Vaupel J. W.. 2002Demography. Broken limits to life expectancy. Science 296, 1029–1031.doi:10.1126/science.1069675 (doi:10.1126/science.1069675). Crossref, PubMed, ISI, Google Scholar2Partridge L.& Gems D.. 2002Mechanisms of ageing: public or private?Nat. Rev. Genet. 3, 165–175.doi:10.1038/nrg753 (doi:10.1038/nrg753). Crossref, PubMed, ISI, Google Scholar3Fontana L., Partridge L.& Longo V. D.. 2010Extending healthy life span—from yeast to humans. Science 328, 321–326.doi:10.1126/science.1172539 (doi:10.1126/science.1172539). Crossref, PubMed, ISI, Google Scholar4Kenyon C. J.. 2010The genetics of ageing. Nature 464, 504–512.doi:10.1038/nature08980 (doi:10.1038/nature08980). Crossref, PubMed, ISI, Google Scholar5Partridge L.. 2010The new biology of ageing. Phil. Trans. R. Soc. B 365, 147–154.doi:10.1098/rstb.2009.0222 (doi:10.1098/rstb.2009.0222). Link, ISI, Google Scholar6Piper M. D., Selman C., McElwee J. J.& Partridge L.. 2008Separating cause from effect: how does insulin/IGF signalling control lifespan in worms, flies and mice?J. Intern. Med. 263, 179–191.doi:10.1111/j.1365-2796.2007.01906.x (doi:10.1111/j.1365-2796.2007.01906.x). Crossref, PubMed, ISI, Google Scholar7Smith E. D., et al.2008Quantitative evidence for conserved longevity pathways between divergent eukaryotic species. Genome Res. 18, 564–570.doi:10.1101/gr.074724.107 (doi:10.1101/gr.074724.107). Crossref, PubMed, ISI, Google Scholar8Harrison D. E., et al.2009Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395.doi:10.1038/nature08221 (doi:10.1038/nature08221). Crossref, PubMed, ISI, Google Scholar9McCormick M. A., Tsai S.& Kennedy B. K.. 2011TOR and ageing: a complex pathway for a complex process. Phil. Trans. R. Soc. B 366, 17–27.doi:10.1098/rstb.2010.0198 (doi:10.1098/rstb.2010.0198). Link, ISI, Google Scholar10Bartke A.. 2011Single-gene mutations and healthy ageing in mammals. Phil. Trans. R. Soc. B 366, 28–34.doi:10.1098/rstb.2010.0281 (doi:10.1098/rstb.2010.0281). Link, ISI, Google Scholar11Slagboom P. E., et al.2011Genomics of human longevity. Phil. Trans. R. Soc. B 366, 35–42.doi:10.1098/rstb.2010.0284 (doi:10.1098/rstb.2010.0284). Link, ISI, Google Scholar12Wheeler H. E.& Kim S. K.. 2011Genetics and genomics of human ageing. Phil. Trans. R. Soc. B 366, 43–50.doi:10.1098/rstb.2010.0259 (doi:10.1098/rstb.2010.0259). Link, ISI, Google Scholar13Barzilai N., Suh Y., Rothenberg D., Bergman A.& Atzmon G.. 2011The promise of human genetics in preventing ageing-related disease. Phil. Trans. R. Soc. B 366.doi:10.1098/rstb.2010.0292 (doi:10.1098/rstb.2010.0292). Crossref, Google Scholar14Rodwell G. E., et al.2004A transcriptional profile of ageing in the human kidney. PLoS Biol. 2, e427.doi:10.1371/journal.pbio.0020427 (doi:10.1371/journal.pbio.0020427). Crossref, PubMed, ISI, Google Scholar15Wieser D., Papatheodorou I., Ziehm I.& Thornton J. M.. 2011Computational biology for ageing. Phil. Trans. R. Soc. B 366, 51–63.doi:10.1098/rstb.2010.0286 (doi:10.1098/rstb.2010.0286). Link, ISI, Google Scholar16Kirkwood T. B. L.. 2011Systems biology of ageing and longevity. Phil. Trans. R. Soc. B 366, 64–70.doi:10.1098/rstb.2010.0275 (doi:10.1098/rstb.2010.0275). Link, ISI, Google Scholar17Nyström T.. 2011Spatial protein quality control and the evolution of lineage-specific ageing. Phil. Trans. R. Soc. B 366, 71–75.doi:10.1098/rstb.2010.0282 (doi:10.1098/rstb.2010.0282). Link, ISI, Google Scholar18Donate L. E.& Blasco M. A.. 2011Telomeres in cancer and ageing. Phil. Trans. R. Soc. B 366, 76–84.doi:10.1098/rstb.2010.0291 (doi:10.1098/rstb.2010.0291). Link, ISI, Google Scholar19Charville G. W.& Rando T. A.. 2011Stem cell ageing and non-random chromosome segregation. Phil. Trans. R. Soc. B 366, 85–93.doi:10.1098/rstb.2010.0279 (doi:10.1098/rstb.2010.0279). Link, ISI, Google Scholar20Dillin A.& Cohen E.. 2011Ageing and protein aggregation-mediated disorders: from invertebrates to mammals. Phil. Trans. R. Soc. B 366, 94–98.doi:10.1098/rstb.2010.0271 (doi:10.1098/rstb.2010.0271). Link, ISI, Google Scholar21Selman C.& Withers D. J.. 2011Mammalian models of extended healthy lifespan. Phil. Trans. R. Soc. B 366, 99–107.doi:10.1098/rstb.2010.0243 (doi:10.1098/rstb.2010.0243). Link, ISI, Google Scholar22Gems D.. 2011Tragedy and delight: the ethics of decelerated ageing. Phil. Trans. R. Soc. B 366, 108–112.doi:10.1098/rstb.2010.0288 (doi:10.1098/rstb.2010.0288). Link, ISI, Google Scholar23Evans W. J.. 2011Drug discovery and development for ageing: opportunities and challenges. Phil. Trans. R. Soc. B 366, 113–119.doi:10.1098/rstb.2010.0287 (doi:10.1098/rstb.2010.0287). Link, ISI, Google Scholar Previous ArticleNext Article VIEW FULL TEXT DOWNLOAD PDF FiguresRelatedReferencesDetailsCited by Ehni H (2019) Medical Ethics Encyclopedia of Gerontology and Population Aging, 10.1007/978-3-319-69892-2_398-1, (1-10), . Zhao S, Tian J, Tai G, Gao X, Liu H, Du G, Liu X and Qin X (2019) 1H NMR-based metabolomics revealed the protective effects of Guilingji on the testicular dysfunction of aging rats, Journal of Ethnopharmacology, 10.1016/j.jep.2019.111839, 238, (111839), Online publication date: 1-Jun-2019. Partridge L (2016) Comments from the departing Editor, Philosophical Transactions of the Royal Society B: Biological Sciences, 371:1687, Online publication date: 5-Feb-2016. Aliper A, Belikov A, Garazha A, Jellen L, Artemov A, Suntsova M, Ivanova A, Venkova L, Borisov N, Buzdin A, Mamoshina P, Putin E, Swick A, Moskalev A and Zhavoronkov A (2016) In search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state, Aging, 10.18632/aging.101047, 8:9, (2127-2152), Online publication date: 24-Sep-2016. Afschar S, Toivonen J, Hoffmann J, Tain L, Wieser D, Finlayson A, Driege Y, Alic N, Emran S, Stinn J, Froehlich J, Piper M and Partridge L (2016) Nuclear hormone receptor DHR96 mediates the resistance to xenobiotics but not the increased lifespan of insulin-mutant Drosophila , Proceedings of the National Academy of Sciences, 10.1073/pnas.1515137113, 113:5, (1321-1326), Online publication date: 2-Feb-2016. Lafontaine C (2016) Aging in the Era of Regenerative Medicine: Analysis of Aging-Related Representations among Canadian Researchers, The Sociological Quarterly, 10.1111/tsq.12083, 56:1, (62-79), Online publication date: 1-Feb-2015. Van Den Heuvel W (2015) Value Reorientation and Intergenerational Conflicts in Ageing Societies, Journal of Medicine and Philosophy, 10.1093/jmp/jhu079, 40:2, (201-220), Online publication date: 1-Apr-2015. Moskalev A, Aliper A, Smit-McBride Z, Buzdin A and Zhavoronkov A (2014) Genetics and epigenetics of aging and longevity, Cell Cycle, 10.4161/cc.28433, 13:7, (1063-1077), Online publication date: 1-Apr-2014. Ott S and Crowther D (2013) Animal Models of Amyloid Diseases Amyloid Fibrils and Prefibrillar Aggregates, 10.1002/9783527654185.ch12, (245-262) Sancho-Martinez I, Nivet E and Belmonte J (2013) On the Search for Reliable Human Aging Models: Understanding Aging by Nuclear Reprogramming Programmed Cells from Basic Neuroscience to Therapy, 10.1007/978-3-642-36648-2_11, (119-130), . Swann J, Spagou K, Lewis M, Nicholson J, Glei D, Seeman T, Coe C, Goldman N, Ryff C, Weinstein M and Holmes E (2013) Microbial–Mammalian Cometabolites Dominate the Age-associated Urinary Metabolic Phenotype in Taiwanese and American Populations, Journal of Proteome Research, 10.1021/pr4000152, 12:7, (3166-3180), Online publication date: 5-Jul-2013. Sethe S and de Magalhães J (2013) Ethical Perspectives in Biogerontology Ethics, Health Policy and (Anti-) Aging: Mixed Blessings, 10.1007/978-94-007-3870-6_13, (173-188), . Wijeyesekera A, Selman C, Barton R, Holmes E, Nicholson J and Withers D (2012) Metabotyping of Long-Lived Mice using 1 H NMR Spectroscopy , Journal of Proteome Research, 10.1021/pr2010154, 11:4, (2224-2235), Online publication date: 6-Apr-2012. Liu G, Ding Z and Izpisua Belmonte J (2012) iPSC technology to study human aging and aging-related disorders, Current Opinion in Cell Biology, 10.1016/j.ceb.2012.08.014, 24:6, (765-774), Online publication date: 1-Dec-2012. Yu Z, Zhai G, Singmann P, He Y, Xu T, Prehn C, Römisch‐Margl W, Lattka E, Gieger C, Soranzo N, Heinrich J, Standl M, Thiering E, Mittelstraß K, Wichmann H, Peters A, Suhre K, Li Y, Adamski J, Spector T, Illig T and Wang‐Sattler R (2012) Human serum metabolic profiles are age dependent, Aging Cell, 10.1111/j.1474-9726.2012.00865.x, 11:6, (960-967), Online publication date: 1-Dec-2012. Martin-Matthews A (2011) Ten Years of the CIHR Institute of Aging: Building on Strengths, Addressing Gaps, Shaping the Future, Canadian Journal on Aging / La Revue canadienne du vieillissement, 10.1017/S0714980811000134, 30:2, (285-290), Online publication date: 1-Jun-2011. Martin-Matthews A (2011) Les dix ans de l'Institut du vieillissement des IRSC : Tirer parti des points forts, combler les lacunes, façonner l'avenir, Canadian Journal on Aging / La Revue canadienne du vieillissement, 10.1017/S0714980811000183, 30:2, (291-297), Online publication date: 1-Jun-2011. Giacomello E and Toniolo L (2021) The Potential of Calorie Restriction and Calorie Restriction Mimetics in Delaying Aging: Focus on Experimental Models, Nutrients, 10.3390/nu13072346, 13:7, (2346) Related articlesThe new science of ageing05 September 2015Philosophical Transactions of the Royal Society B: Biological Sciences This Issue12 January 2011Volume 366Issue 1561Discussion Meeting issue 'The new science of ageing' organized and edited by Linda Partridge, Gillian Bates and Janet Thornton Article InformationDOI:https://doi.org/10.1098/rstb.2010.0298PubMed:21115524Published by:Royal SocietyPrint ISSN:0962-8436Online ISSN:1471-2970History: Published online12/01/2011Published in print12/01/2011 License:This Journal is © 2011 The Royal Society Citations and impact PDF Download Subjectscellular biologyevolutionmolecular biologysystems biology
Referência(s)