{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T22:17:56Z","timestamp":1778624276038,"version":"3.51.4"},"reference-count":58,"publisher":"The Royal Society","issue":"1363","license":[{"start":{"date-parts":[[1997,12,29]],"date-time":"1997-12-29T00:00:00Z","timestamp":883353600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/royalsociety.org\/journals\/ethics-policies\/data-sharing-mining\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Phil. Trans. R. Soc. Lond. B"],"published-print":{"date-parts":[[1997,12,29]]},"abstract":"<jats:p>Genetics offers a powerful approach to the elucidation of mechanisms underlying specific components of the senescent phenotype of our species. Perhaps thousands of gene variations have escaped the force of natural selection and thus play roles in the genesis of different patterns of ageing in man. It is possible that a subset of these genes may be of particular importance in how most people age. While variations at the Werner helicase locus could be one such example, several lines of evidence suggest that mutation at that locus leads to a \u2018private\u2019 mechanism of ageing. It will be important, however, to investigate polymorphisms underlying the regulation of expression of this gene in the general population. Polymorphisms (normally occurring variants of a gene, or sequence of DNA), rather than mutations, may also prove to be more relevant to our understanding of the differing susceptibilities of people to common disorders such as late onset Alzheimer's disease. Polymorphic forms of the Apolipoprotein E gene is a good example. It remains to be seen if the pathogenetic framework (beta amyloidosis) derived from studies of the several rare mutations responsible for early onset familial forms of the disease proves relevant to the pathogenesis of the vastly more prevalent sporadic forms of the disorder. In contrast to the satisfying progress on the genetics of the diseases of ageing, research on the genetic basis for unusually robust retention of structure and function in old age has been neglected and requires a higher priority for the future. Such research should include studies of environmental agents and should address mechanisms of \u2018sageing\u2019, a stage in the life course characterized by an extensive utilization of behavioural and physiological adaptations to compensate for functional declines. For the genetics of longevity, we have to turn to genetically tractable organisms such as nematodes and fruit flies. Such studies have provided significant support for the oxidative stress theory of ageing. It will be important to learn more about the age\u2013related pathologies and pathophysiologies of these organisms.<\/jats:p>","DOI":"10.1098\/rstb.1997.0161","type":"journal-article","created":{"date-parts":[[2002,10,1]],"date-time":"2002-10-01T13:23:02Z","timestamp":1033478582000},"page":"1773-1780","source":"Crossref","is-referenced-by-count":51,"title":["Genetics and the pathobiology of ageing"],"prefix":"10.1098","volume":"352","author":[{"given":"George M.","family":"Martin","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Washington, Seattle, WA 98195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"175","published-online":{"date-parts":[[1997,12,29]]},"reference":[{"key":"p_1","doi-asserted-by":"crossref","unstructured":"Benditt E. P. & Benditt J. M. 1973 Evidence for a monoclonal origin of human atherosclerotic plaques. Proc. Natn. Acad. Sci. USA 70 1753^1756.","DOI":"10.1073\/pnas.70.6.1753"},{"key":"p_2","unstructured":"Bird T. D. Lampe T. H. Nemens E. J. Sumi S. M. Nochlin D. Schellenberg G. D. & Wijsman E. M. 1989 Characteristics of familial Alzheimer's disease in nine kindreds of Volga German ancestry. Prog. Clin. Biol. Res. 317 229^234."},{"key":"p_3","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/55.6.1222S"},{"key":"p_4","first-page":"87","article-title":"Neuronal plasticity in normal aging and de\u00a2cient plasticity in Alzheimer's disease: a proposed intercellular signal cascade","volume":"86","author":"Coleman P. D.","year":"1990","journal-title":"Prog. Brain Res."},{"key":"p_5","doi-asserted-by":"crossref","unstructured":"Corder E. H. Saunders A. M. Strittmatter W. J. Schmechel D. E. Gaskell P. C. Small G. W. Roses A. D. & Haines J. L. 1993 Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261 921^923.","DOI":"10.1126\/science.8346443"},{"key":"p_6","doi-asserted-by":"crossref","unstructured":"Engel S. A. 1996 Looking into the black box: new directions in neuroimaging. Neuron 17 375^378.","DOI":"10.1016\/S0896-6273(00)80170-1"},{"key":"p_7","doi-asserted-by":"crossref","unstructured":"Epstein C. J. Martin G. M. Schultz A. L. & Motulsky A. G. 1966 Werner's syndrome a review of its symptomatology natural history pathologic features genetics and relationship to the natural aging process. Med. Baltimore 45 177^221.","DOI":"10.1097\/00005792-196605000-00001"},{"key":"p_8","doi-asserted-by":"crossref","unstructured":"Flood D. G. Buell S. J. De\u00a2ore C. H. Horwitz G. J. & Coleman P. D. 1985 Age-related dendritic growth in dentate gyrus of human brain is followed by regression in the oldest old. Brain Res. 345 366^368.","DOI":"10.1016\/0006-8993(85)91018-2"},{"key":"p_9","doi-asserted-by":"crossref","unstructured":"Fukuchi K. Martin G. M. & Monnat Jr R. J. 1989 Mutator phenotype of Werner syndrome is characterized by extensive deletions. Proc. Natn. Acad. Sci. USA 86 5893^5897.","DOI":"10.1073\/pnas.86.15.5893"},{"key":"p_10","doi-asserted-by":"crossref","unstructured":"Fukuchi K. Tanaka K. Kumahara Y. Marumo K. Prode M. B. Martin G. M. & Monnat Jr R. J. 1990 Increased frequency of 6-thioguanine-resistant peripheral blood lymphocytes in Werner syndrome patients. Hum. Genet. 84 249^252.","DOI":"10.1007\/BF00200569"},{"key":"p_11","doi-asserted-by":"crossref","unstructured":"Goate A. Chartier-Harlin M. C. Mullan M. Brown J. Crawford F. Fidani L. Giu\u00a1ra L. Haynes A. Irving N. & James L. 1991 Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349 704^706.","DOI":"10.1038\/349704a0"},{"key":"p_12","unstructured":"Goto M. Miller R. W. Ishikawa Y. & Sugano H. 1996 Excess of rare cancers in Werner syndrome (adult progeria). Cancer Epidemiol. Biomarkers Prev. 5 239^246."},{"key":"p_13","doi-asserted-by":"crossref","unstructured":"Goto M. Kindynis P. Resnick D. & Sartoris D. J. 1989 Osteosclerosis of the phalanges in Werner syndrome. Radiology 172 841^843.","DOI":"10.1148\/radiology.172.3.2772198"},{"key":"p_14","doi-asserted-by":"crossref","unstructured":"Goto M. Rubenstein M. Weber J. Woods K. & Drayna D. 1992 Genetic linkage of Werner's syndrome to \u00a2ve markers on chromosome 8. Nature 355 735^738.","DOI":"10.1038\/355735a0"},{"key":"p_15","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1111\/j.1399-0004.1981.tb00660.x","article-title":"Family analysis of Werner's syndrome: a survey of 42 Japanese families with a review of the literature","volume":"19","author":"Goto M.","year":"1981","journal-title":"Clin. Genet."},{"key":"p_16","doi-asserted-by":"crossref","unstructured":"Hardy J. 1997 Amyloid the presenilins and Alzheimer's disease.Trends Neurosci. 20 154^159.","DOI":"10.1016\/S0166-2236(96)01030-2"},{"key":"p_17","article-title":"Androgen receptor CAG repeat lengths in prostate cancer: correlation with age of onset","volume":"81","author":"Hardy D. O.","year":"1996","journal-title":"J. Clin. Endocr. Metab."},{"key":"p_18","article-title":"Finnish type of familial amyloidosis: consegregation of Asp187\u00f6Asn mutation of gelsolin with the disease in three large families","volume":"49","author":"Hiltunen T.","year":"1991","journal-title":"Am. J. Hum. Genet."},{"key":"p_19","first-page":"14","article-title":"On cataract in conjunction with scleroderma","volume":"190","author":"Hoehn H.","year":"1985","journal-title":"Adv. Exp. Med. Biol."},{"key":"p_20","doi-asserted-by":"crossref","unstructured":"Hoehn H. Bryant E. M. Au K. Norwood T. H. Boman H. & Martin G. M. 1975 Variegated translocation mosaicism in human skin \u00a2broblast cultures. Cytogenet. Cell Genet. 15 282^298.","DOI":"10.1159\/000130526"},{"key":"p_21","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/89.2.166"},{"key":"p_22","doi-asserted-by":"publisher","DOI":"10.1111\/j.1558-5646.1956.tb02852.x"},{"key":"p_23","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.1991.0028"},{"key":"p_24","article-title":"Parametric and nonparametric linkage analysis: a uni\u00a2ed multipoint approach","volume":"58","author":"Kruglyak L.","year":"1996","journal-title":"Am. J. Hum. Genet."},{"key":"p_25","unstructured":"Lakatta E. G. 1985 Heart and circulation. In Handbook of the biology of aging (ed. C. E. Finch & E. L. Schneider) pp. 377^413. New York: Van Nostrand Reinhold."},{"key":"p_26","unstructured":"Leopold A. C. 1978 The biological signi\u00a2cance of death implants. In The biology of aging (ed. J. A. Behnke C. E. Finch & G. B. Moment) New York: Plenum Press."},{"key":"p_27","doi-asserted-by":"crossref","unstructured":"Levy-Lahad E. Wasco W. Poorkaj P. Romano D. M. Oshima J. Pettingell W. H. Yu C.-E. Jondro P. D. Schmidt S. D. & Wang K. 1995 Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269 973^977.","DOI":"10.1126\/science.7638622"},{"key":"p_28","doi-asserted-by":"crossref","unstructured":"Marsden C. D. & Jenner P. G. 1987 The signi\u00a2cance of 1- methyl-4-phenyl-1 2 3 6-tetrahydropyridine. Ciba Found. Symp. 126 239^256.","DOI":"10.1002\/9780470513422.ch15"},{"key":"p_29","unstructured":"Martin G. M. 1982 Syndromes of accelerated aging. Natn. Cancer Inst. Monogr. 60 241^247."},{"key":"p_30","first-page":"80","article-title":"Interactions of aging and environmental agents: the gerontological perspective","volume":"228","author":"Martin G. M.","year":"1987","journal-title":"Prog. Clin. Bio. Res."},{"key":"p_31","doi-asserted-by":"publisher","DOI":"10.1038\/ng0596-25"},{"key":"p_32","first-page":"92","article-title":"Replicative life-span of cultivated human cells. E\u00a1ects of donors age, tissue, and genotype","volume":"23","author":"Martin G. M.","year":"1970","journal-title":"Lab. Invest."},{"key":"p_33","article-title":"Cortical and subcortical patterns of synaptophysin like immunoreactivity in Alzheimer's disease","volume":"138","author":"Masliah E.","year":"1991","journal-title":"Am. J. Pathol."},{"key":"p_34","doi-asserted-by":"crossref","unstructured":"Masoro E. J. 1995 Dietary restriction. Exp. Geron. 30 291^298.","DOI":"10.1016\/0531-5565(94)00028-2"},{"key":"p_35","first-page":"56","article-title":"Old age and natural death","volume":"1","author":"Medawar P. B.","year":"1946","journal-title":"Modern Quarterly"},{"key":"p_36","unstructured":"Medawar P. B. 1952 An unsolved problem of biology. London: H. K. Lewis."},{"key":"p_37","doi-asserted-by":"crossref","unstructured":"Medawar P. B. 1957 An unsolved problem of biology. In The uniqueness of the individual. London: Methuen & Co (reprint of Medawar 1952).","DOI":"10.5962\/bhl.title.4483"},{"key":"p_38","doi-asserted-by":"crossref","unstructured":"Meretoja J. 1973 Genetic aspects of familial amyloidosis with corneal lattice dystrophy and cranial neuropathy. Clin. Genet. 4 173^185.","DOI":"10.1111\/j.1399-0004.1973.tb01140.x"},{"key":"p_39","doi-asserted-by":"publisher","DOI":"10.1111\/j.1532-5415.1987.tb04641.x"},{"key":"p_40","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)64456-X"},{"key":"p_41","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1041620213"},{"key":"p_42","doi-asserted-by":"crossref","unstructured":"Oshima J. Yu C.-E. Piussan C. and 13 co-authors. 1996 Homozygous and compound heterozygous mutations at the Werner syndrome locus. Hum. Mol. Genet. 5 1909^ 1913.","DOI":"10.1093\/hmg\/5.12.1909"},{"key":"p_43","unstructured":"Polymeropoulos M. H. & Scha\u00a1er A. A. 1996 Scanning the genome with 1772 microsatellite markers in search of a bipolar disorder susceptibility gene. Molec. Psych. 1 404^ 407."},{"key":"p_44","doi-asserted-by":"crossref","unstructured":"Poot M. Hoehn H. Runger T. M. & Martin G. M. 1992 Impaired S-phase transit of Werner syndrome cells expressed in Iymphoblastoid cell lines. Expl Cell Res. 202 267^273.","DOI":"10.1016\/0014-4827(92)90074-I"},{"key":"p_45","article-title":"Mapping quantitative trait loci with extreme discordant sib pairs: sampling considerations","volume":"58","author":"Risch N. J.","year":"1996","journal-title":"Am. J. Hum. Genet."},{"key":"p_46","doi-asserted-by":"publisher","DOI":"10.1111\/1523-1747.ep12371730"},{"key":"p_47","doi-asserted-by":"publisher","DOI":"10.1159\/000131596"},{"key":"p_48","doi-asserted-by":"publisher","DOI":"10.1016\/0140-6736(92)91590-5"},{"key":"p_49","doi-asserted-by":"crossref","unstructured":"Schulz V. P. Zakian V. A. Ogburn C. E. McKay J. Jarzebowicz A. A. Edland S. D. & Martin G. M. 1996 Accelerated loss of telomeric repeats may not explain accelerated replicative decline of Werner syndrome cells. Hum. Genet. 97 750^754.","DOI":"10.1007\/BF02346184"},{"key":"p_50","doi-asserted-by":"publisher","DOI":"10.1038\/375754a0"},{"key":"p_51","unstructured":"Stanford J. L. Just J. J. Gibbs M. Wicklund K. G. Neal C. L. Blumenstein B. A. & Ostrander E. A. 1997 Polymorphic repeats in the androgen receptor gene: molecular markers of prostate cancer risk. Cancer Res. 57 1194^1198."},{"key":"p_52","doi-asserted-by":"crossref","unstructured":"Takeuchi F. Hanaoka F. Goto M. Yamada M. & Miyamoto T. 1982 Prolongation of S phase and whole cell cycle in Werner's syndrome \u00a2broblasts. Expl Gerontol. 17 473^480.","DOI":"10.1016\/S0531-5565(82)80009-0"},{"key":"p_53","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19970211)68:4<494::AID-AJMG30>3.0.CO;2-L"},{"key":"p_54","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1996.tb39047.x"},{"key":"p_55","doi-asserted-by":"crossref","unstructured":"Yu C.-E. Oshima J. Fu Y. H. & 10 co-authors. 1996 Positional cloning of the Werner syndrome gene. Science 272 258^262.","DOI":"10.1126\/science.272.5259.258"},{"key":"p_56","article-title":"Mutations in the consensus helicase domains of the Werner syndrome gene. Werner's Syndrome Collaborative Group","volume":"60","author":"Yu C.-E.","year":"1997","journal-title":"Am. J. Hum. Genet."},{"key":"p_57","article-title":"Mapping quantitative-trait loci in humans by use of extreme concordant sib pairs: selected sampling by parental phenotypes","volume":"59","author":"Zhang H.","year":"1996","journal-title":"Am. J. Hum. Genet."},{"key":"p_58","doi-asserted-by":"crossref","unstructured":"Williams G. C. 1957 Pleiotrophy natural selection and the evolution of senescence. Evolution 11 398^411.","DOI":"10.1111\/j.1558-5646.1957.tb02911.x"}],"container-title":["Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/royalsocietypublishing.org\/doi\/pdf\/10.1098\/rstb.1997.0161","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/royalsocietypublishing.org\/doi\/pdf\/10.1098\/rstb.1997.0161","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T21:21:51Z","timestamp":1778620911000},"score":1,"resource":{"primary":{"URL":"http:\/\/royalsocietypublishing.org\/rstb\/article\/352\/1363\/1773-1780\/19206"}},"subtitle":[],"editor":[{"given":"J. Grimley","family":"Evans","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]},{"given":"R.","family":"Holliday","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]},{"given":"T. B. L.","family":"Kirkwood","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]},{"given":"P.","family":"Laslett","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]},{"given":"L.","family":"Tyler","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[1997,12,29]]},"references-count":58,"journal-issue":{"issue":"1363","published-print":{"date-parts":[[1997,12,29]]}},"alternative-id":["10.1098\/rstb.1997.0161"],"URL":"https:\/\/doi.org\/10.1098\/rstb.1997.0161","relation":{},"ISSN":["0962-8436","1471-2970"],"issn-type":[{"value":"0962-8436","type":"print"},{"value":"1471-2970","type":"electronic"}],"subject":[],"published":{"date-parts":[[1997,12,29]]}}}