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Can we intervene in human ageing?

Published online by Cambridge University Press:  07 September 2009

Richard G.A. Faragher*
Affiliation:
School of Pharmacy and Biomolecular Science, University of Brighton, Brighton, BN2 4GJ, UK.
Angela N. Sheerin
Affiliation:
School of Pharmacy and Biomolecular Science, University of Brighton, Brighton, BN2 4GJ, UK.
Elizabeth L. Ostler
Affiliation:
School of Pharmacy and Biomolecular Science, University of Brighton, Brighton, BN2 4GJ, UK.
*
*Corresponding author: Richard G.A. Faragher, School of Pharmacy and Biomolecular Sciences, Cockcroft Building, University of Brighton, Brighton, East Sussex, BN2 4GJ, UK. Tel: +44 1273 642124; Fax: +44 1273 679333; E-mail: rgaf@brighton.ac.uk

Abstract

Ageing is a progressive failure of defence and repair processes that produces physiological frailty (the loss of organ reserve with age), loss of homeostasis and eventual death. Over the past ten years exceptional progress has been made in understanding both why the ageing process happens and the mechanisms that are responsible for it. The study of natural mutants that accelerate some, but not all, of the features of the human ageing process has now progressed to a degree that drug trials are either taking place or can be envisaged. Simultaneously, a series of mutations have been identified in different species that confer extended healthy life, indicating that the ageing process is much more malleable than might have been expected and that single interventions have the potential to delay the onset of multiple age-associated conditions. Data generated using these organisms have led to the formulation of a powerful new hypothesis, the ‘green theory’ of ageing. This proposes that a finite capacity to carry out broad-spectrum detoxification and recycling is the primary mechanistic limit on organismal lifespan. This is turn suggests important new experimental approaches and potential interventions designed to increase healthy lifespan.

Type
Review Article
Copyright
Copyright © Cambridge University Press 2009

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References

References

1Khaw, K. (1999) How many, how old, how soon? British Medical Journal 319, 1350-1352CrossRefGoogle ScholarPubMed
2NHS National Statistics (2008) Prescriptions Dispensed in the Community – Statistics for 1997 to 2007: England (Bulletin IC 2008 10; ISBN 978-1-84636-223-1), The Information Centre (Government Statistical Service), UKGoogle Scholar
3Seshamani, M. and Gray, A. (2004) Ageing and health-care expenditure: the red herring argument revisited. Health Economics 13, 303-314Google Scholar
4Fries, J.F. (1980) Aging, natural death, and the compression of morbidity. New England Journal of Medicine 303, 130-135CrossRefGoogle ScholarPubMed
5Fries, J.F. (2003) Measuring and monitoring success in compressing morbidity. Annals of Internal Medicine 139, 455-459CrossRefGoogle ScholarPubMed
6Bowling, A. and Dieppe, P. (2005) What is successful ageing and who should define it? British Medical Journal 331, 1548-1551Google Scholar
7Strawbridge, W.J., Wallhagen, M.I. and Cohen, R.D. (2002) Successful aging and well-being: self-rated compared with Rowe and Kahn. Gerontologist 42, 727-733Google Scholar
8Strehler, B.L. and Mildvan, A.S. (1960) General theory of mortality and aging. Science 132, 14-21CrossRefGoogle ScholarPubMed
9Powell, C.D., Quain, D.E. and Smart, K.A. (2003) Chitin scar breaks in aged Saccharomyces cerevisiae. Microbiology 149, 3129-3137Google Scholar
10Kale, S.P. and Jazwinski, S.M. (1996) Differential response to UV stress and DNA damage during the yeast replicative life span. Developmental Genetics 18, 154-160Google Scholar
11Meyer, K.C. (2004) Lung infections and aging. Ageing Research Reviews 3, 55-67CrossRefGoogle ScholarPubMed
12Mercer, J.B. (2003) Cold - an underrated risk factor for health. Environmental Research 92, 8-13Google Scholar
13Bocquet-Appel, J.P. and Bacro, J.N. (1997) Brief communication: estimates of some demographic parameters in a Neolithic rock-cut chamber (approximately 2000 BC) using iterative techniques for aging and demographic estimators. American Journal of Physical Anthropology 102, 569-575Google Scholar
14Pietrusewsky, M. et al. (1997) An assessment of health and disease in the prehistoric inhabitants of the Mariana Islands. American Journal of Physical Anthropology 104, 315-3423.0.CO;2-U>CrossRefGoogle ScholarPubMed
15Williams, G.C. (1957) Pleiotropy, natural selection and the evolution of senescence. Evolution 11, 398-411CrossRefGoogle Scholar
16Kirkwood, T.B. and Holliday, R. (1979) The evolution of ageing and longevity. Proceedings of the Royal Society of London. Series B, Biological Sciences 205, 531-546Google Scholar
17Ligthart, G.H. (2001) The SENIEUR protocol after 16 years: the next step is to study the interaction of ageing and disease. Mechanisms of Ageing and Development 122, 136-140CrossRefGoogle Scholar
18Ershler, W.B. (2001) The value of the SENIEUR protocol: distinction between “ideal ageing” and clinical reality. Mechanisms of Ageing and Development 122, 134-136Google Scholar
19Martin, G.M., Sprague, C.A. and Epstein, C.J. (1970) Replicative life-span of cultivated human cells. Effects of donor's age, tissue, and genotype. Laboratory Investigation 23, 86-92Google ScholarPubMed
20Goldstein, S. et al. (1978) Chronologic and physiologic age affect replicative life-span of fibroblasts from diabetic, prediabetic, and normal donors. Science 199, 781-782Google Scholar
21Cristofalo, V.J. et al. (1998) Relationship between donor age and the replicative lifespan of human cells in culture: a reevaluation. Proceedings of the National Academy of Sciences of the United States of America 95, 10614-10619Google Scholar
22Houthoofd, K. and Vanfleteren, J.R. (2006) The longevity effect of dietary restriction in Caenorhabditis elegans. Experimental Gerontology 41, 1026-1031Google Scholar
23Harman, D. (1991) The aging process: major risk factor for disease and death. Proceedings of the National Academy of Sciences of the United States of America 88, 5360-5363Google Scholar
24Pérez, V.I. et al. (2009) Is the oxidative stress theory of aging dead? Biochimica et Biophysica Acta Jun 11; [Epub ahead of print]CrossRefGoogle ScholarPubMed
25Doonan, R. et al. (2008) Against the oxidative damage theory of aging: superoxide dismutases protect against oxidative stress but have little or no effect on life span in Caenorhabditis elegans. Genes and Development 22, 3236-3241Google Scholar
26Kaberlein, M. and Powers, R.W. (2007) Sir2 and calorie restriction in yeast: a sceptical perspective. Ageing Research Reviews 6, 128-140Google Scholar
27Falcon, A.A. and Aris, J.P. (2003) Plasmid accumulation reduces life span in Saccharomyces cerevisiae. Journal of Biological Chemistry 278, 41607-41617Google Scholar
28Jazwinski, S.M. (2004) Yeast replicative lifespan: the mitochondrial connection. FEMS Yeast Research 5, 119-125CrossRefGoogle ScholarPubMed
29Barnes, A.I. et al. (2008) Feeding, fecundity and lifespan in female Drosophila melanogaster. Proceedings. Biological sciences/The Royal Society 275, 1675-1683CrossRefGoogle ScholarPubMed
30Selman, C. et al. (2008) Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. FASEB Journal 22, 807-818Google Scholar
31Bartke, A. (2008) New findings in gene knockout, mutant and transgenic mice. Experimental Gerontology 43, 4-11CrossRefGoogle ScholarPubMed
32Piper, M.D. et al. (2008) Separating cause from effect: how does insulin/IGF signalling control lifespan in worms, flies and mice? Journal of Internal Medicine 263, 179-191Google Scholar
33McElwee, J.J. et al. (2007) Evolutionary conservation of regulated longevity assurance mechanisms. Genome Biology 8, R132CrossRefGoogle ScholarPubMed
34Gems, D. and McElwee, J.J. (2005) Broad spectrum detoxification: the major longevity assurance process regulated by insulin/IGF-1 signaling? Mechanisms of Ageing and Development 126, 381-387Google Scholar
35Gems, D. (2009) Ageing and oxidants in the nematode Caenorhabditis elegans. In Redox Metabolism and Longevity Relationships in Animals and Plants (SEB Experimental Biology Series Volume 62) (Faragher, R.G., Thornally, P. and Foyer, C.H., eds), pp. 31-47, Taylor & Francis Group, Abingdon, UKGoogle Scholar
36Chou, M.W. et al. (1993) Effect of caloric restriction on the metabolic activation of xenobiotics. Mutation Research 295, 223-235CrossRefGoogle ScholarPubMed
37Cho, C.G. et al. (2003) Modulation of glutathione and thioredoxin systems by calorie restriction during the aging process. Experimental Gerontology 38, 539-548Google Scholar
38Spindler, S.R. and Dhahbi, J.M. (2007) Conserved and tissue-specific genic and physiologic responses to caloric restriction and altered IGFI signaling in mitotic and postmitotic tissues. Annual Review of Nutrition 27, 193-217Google Scholar
39Tóth, M.L. et al. (2008) Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans. Autophagy 4, 330-338Google Scholar
40Tsuchiya, T. et al. (2004) Additive regulation of hepatic gene expression by dwarfism and caloric restriction. Physiological Genomics 17, 307-315CrossRefGoogle ScholarPubMed
41Mattison, J.A. et al. (2003) Calorie restriction in rhesus monkeys. Experimental Gerontology 38, 35-46Google Scholar
42Vellai, T. et al. (2003) Influence of TOR kinase on lifespan in C. elegans. Nature 426, 620Google Scholar
43Kapahi, P. et al. (2004) Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Current Biology 14, 885-890Google Scholar
44Ritz, B.W. and Gardner, E.M. (2006) Malnutrition and energy restriction differentially affect viral immunity. Journal of Nutrition 136, 1141-1144Google Scholar
45Ritz, B.W. et al. (2008) Energy restriction impairs natural killer cell function and increases the severity of influenza infection in young adult male C57BL/6 mice. Journal of Nutrition 138, 2269-2275Google Scholar
46Faragher, R.G.A. (2008) Senescent cells cause ageing: definitely maybe. Biochemist 30, 4-8Google Scholar
47Campisi, J. and Sedivy, J. (2009) How does proliferative homeostasis change with age? What causes it and how does it contribute to aging? Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 64, 164-166Google Scholar
48Coppé, J.P. et al. (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biology 6, 2853-2868CrossRefGoogle ScholarPubMed
49Kipling, D. et al. (2009) A transcriptomic analysis of the EK1.Br strain of human fibroblastoid keratocytes: the effects of growth, quiescence and senescence. Experimental Eye Research 88, 277-285Google Scholar
50Herbig, U. et al. (2006) Cellular senescence in aging primates. Science 311, 1257CrossRefGoogle ScholarPubMed
51Krizhanovsky, V. et al. (2009) Implications of cellular senescence in tissue damage response, tumor suppression, and stem cell biology. Cold Spring Harbor Symposia on Quantitative Biology 73, 513-522Google Scholar
52Effros, R.B. (2009) Kleemeier Award Lecture 2008—the canary in the coal mine: telomeres and human healthspan. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 64, 511-515Google Scholar
53Loeser, R.F. (2009) Aging and osteoarthritis: the role of chondrocyte senescence and aging changes in the cartilage matrix. Osteoarthritis and Cartilage Mar 12; [Epub ahead of print]Google Scholar
54Burton, D.G. (2009) Cellular senescence, ageing and disease. Age (Dordrecht, Netherlands) 31, 1-9CrossRefGoogle ScholarPubMed
55Krtolica, A. et al. (2001) Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proceedings of the National Academy of Sciences of the United States of America 98, 12072-12077CrossRefGoogle ScholarPubMed
56Cox, L.S. and Faragher, R.G. (2007) From old organisms to new molecules: integrative biology and therapeutic targets in accelerated human ageing. Cellular and Molecular Life Sciences 64, 2620-2641CrossRefGoogle ScholarPubMed
57Merideth, M.A. et al. (2008) Phenotype and course of Hutchinson-Gilford progeria syndrome. New England Journal of Medicine 358, 592-604Google Scholar
58Meaburn, K.J. et al. (2007) Primary laminopathy fibroblasts display altered genome organization and apoptosis. Aging Cell 6, 139-153Google Scholar
59Bridger, J.M. and Kill, I.R. (2004) Aging of Hutchinson-Gilford progeria syndrome fibroblasts is characterised by hyperproliferation and increased apoptosis. Experimental Gerontology 39, 717-724Google Scholar
60Paradisi, M. et al. (2005) Dermal fibroblasts in Hutchinson-Gilford progeria syndrome with the lamin A G608G mutation have dysmorphic nuclei and are hypersensitive to heat stress. BMC Cell Biology 6, 27CrossRefGoogle ScholarPubMed
61Kipling, D. et al. (2004) What can progeroid syndromes tell us about human aging? Science 305, 1426-1431CrossRefGoogle ScholarPubMed
62Capell, B.C. et al. (2008) A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model. Proceedings of the National Academy of Sciences of the United States of America 105, 15902-15907Google Scholar
63Varela, I. et al. (2008) Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging. Nature Medicine 14, 767-772CrossRefGoogle Scholar
64Davis, T. et al. (2005) Prevention of accelerated cell aging in Werner syndrome using a p38 mitogen-activated protein kinase inhibitor. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 60, 1386-1393Google Scholar
65Bagley, M.C. et al. (2008) Microwave-assisted synthesis of 5-aminopyrazol-4-yl ketones and the p38(MAPK) inhibitor RO3 201195 for study in Werner syndrome cells. Bioorganic and Medicinal Chemistry Letters 18, 3745-3748CrossRefGoogle Scholar
66Bagley, M.C. et al. (2006) Microwave-assisted synthesis of N-pyrazole ureas and the p38alpha inhibitor BIRB 796 for study into accelerated cell ageing. Organic and Biomolecular Chemistry 4, 4158-4164Google Scholar
67Aspinall, R. and Mitchell, W. (2008) Reversal of age-associated thymic atrophy: treatments, delivery, and side effects. Experimental Gerontology 43, 700-705Google Scholar
68Koch, S. et al. (2007) Cytomegalovirus infection: a driving force in human T cell immunosenescence. Annals of the New York Academy of Sciences 1114, 23-35CrossRefGoogle ScholarPubMed
69van Baarle, D. et al. (2008) Progressive telomere shortening of Epstein-Barr virus-specific memory T cells during HIV infection: contributor to exhaustion? Journal of Infectious Diseases 198, 1353-1357CrossRefGoogle ScholarPubMed
70Pass, R.F. et al. (2009) Vaccine prevention of maternal cytomegalovirus infection. New England Journal of Medicine 360, 1191-1199Google Scholar
71Fauce, S.R. et al. (2008) Telomerase-based pharmacologic enhancement of antiviral function of human CD8+ T lymphocytes. Journal of Immunology 181, 7400-7406CrossRefGoogle ScholarPubMed
72Aspinall, R. et al. (2007) Old rhesus macaques treated with interleukin-7 show increased TREC levels and respond well to influenza vaccination. Rejuvenation Research 10, 5-17Google Scholar
73Willcox, B.J. et al. (2008) FOXO3A genotype is strongly associated with human longevity. Proceedings of the National Academy of Sciences of the United States of America 105, 13987-13992Google Scholar
74Daitoku, H. and Fukamizu, A. (2007) FOXO transcription factors in the regulatory networks of longevity. Journal of Biochemistry 141, 769-774CrossRefGoogle ScholarPubMed
75van Heemst, D. et al. (2005) Reduced insulin/IGF-1 signalling and human longevity. Aging Cell 4, 79-85Google Scholar
76Reznick, D. et al. (2006) The evolution of senescence and post-reproductive lifespan in guppies (Poecilia reticulata). PLoS Biology 4, e7Google Scholar
77Li, Y. et al. (1997) Long-term caloric restriction delays age-related decline in proliferation capacity of murine lens epithelial cells in vitro and in vivo. Investigative Ophthalmology and Visual Science 38, 100-107Google Scholar
78Bracken, A.P. et al. (2007) The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes and Development 21, 525-530Google Scholar
79Cánepa, E.T. et al. (2007) INK4 proteins, a family of mammalian CDK inhibitors with novel biological functions. IUBMB Life 59, 419-426CrossRefGoogle ScholarPubMed
80Fridman, A.L. and Tainsky, M.A. (2008) Critical pathways in cellular senescence and immortalization revealed by gene expression profiling. Oncogene 27, 5975-5987Google Scholar

Further reading, resources and contacts

Arking, R. (1996) The Biology of Aging: Observations and Principles (3rd edn), Oxford University Press, USAGoogle Scholar
http://www.americanaging.org/ (American Aging Association)Google Scholar
http://www.bsra.org.uk/ (British Society for Research on Ageing)Google Scholar
http://ageaction.ncl.ac.uk/ (proceedings of AGEACTION meeting)Google Scholar
http://www.sparc.ac.uk/ (Strategic Promotion of Ageing Research Capacity)Google Scholar