Determinants of Successful Aging: Developing an Integrated Research Agenda for the 21st Century
2 September 2003

Understanding the Determinants of Exceptional Longevity

Publication: Annals of Internal Medicine
Volume 139, Number 5_Part_2


Centenarians represent an extreme of life expectancy. They achieve their exceptional longevity in part by lacking genetic variations linked to premature death. Pedigree studies have shown a substantial familial component in the ability to survive to extreme old age, and a recent study demonstrated a locus on chromosome 4 linked to exceptional longevity, indicating the likely existence of at least one longevity-enabling gene in humans. The children of centenarians have markedly reduced relative risks for age-related diseases, particularly heart disease, hypertension, and diabetes, and are a promising model for genetic and phenotypic studies of 1) aging slowly relative to the general population and 2) the delay of and perhaps escape from important age-related diseases. These studies and those of other mammals and lower organisms show great promise for the delineation of important environmental and genetic determinants of aging well.

Get full access to this article

View all available purchase options and get full access to this article.


Martin GM. Keynote: mechanisms of senescencecomplificationists versus simplificationists. Mech Ageing Dev. 2002;123:65-73, discussion 75-9. [PMID: 11718800]
Ljungquist BBerg SLanke JMcClearn GEPedersen NL. The effect of genetic factors for longevity: a comparison of identical and fraternal twins in the Swedish Twin Registry. J Gerontol A Biol Sci Med Sci. 1998;53:M441-6. [PMID: 9823748]
Fraser GEShavlik DJ. Ten years of life: is it a matter of choice? Arch Intern Med. 2001;161:1645-52. [PMID: 11434797]
Fontaine KRRedden DTWang CWestfall AOAllison DB. Years of life lost due to obesity. JAMA. 2003;289:187-93. [PMID: 12517229]
Wechsler HRigotti NAGledhill-Hoyt JLee H. Increased levels of cigarette use among college students: a cause for national concern. JAMA. 1998;280:1673-8. [PMID: 9831998]
Wei MKampert JBBarlow CENichaman MZGibbons LWPaffenbarger RS Jr . Relationship between low cardiorespiratory fitness and mortality in normal-weight, overweight, and obese men. JAMA. 1999;282:1547-53. [PMID: 10546694]
Yu CEOshima JFu YHWijsman EMHisama FAlisch R . Positional cloning of the Werner's syndrome gene. Science. 1996;272:258-62. [PMID: 8602509]
Eriksson MBrown WTGordon LBGlynn MWSinger JScott L . Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature. 2003;423:293-8. [PMID: 12714972]
De Sandre-Giovannoli A, Bernard R, Cau P, Navarro C, Amiel J, Boccaccio I, et al. Lamin A truncation in Hutchinson-Gilford progeria. Science. 17 April 2003. [ 12702809]
Schachter FFaure-Delanef LGuanot FRouger HFroguel PLesueur-Ginot L . Genetic associations with human longevity at the APOE and ACE loci. Nat Genet. 1994;6:29-32. [PMID: 8136829]
Cutler RG. Evolution of human longevity and the genetic complexity governing aging rate. Proc Natl Acad Sci U S A. 1975;72:4664-8. [PMID: 812099]
Schachter F. Causes, effects, and constraints in the genetics of human longevity. Am J Hum Genet. 1998;62:1008-14. [PMID: 9545419]
Perls TKunkel LMPuca AA. The genetics of exceptional human longevity. J Am Geriatr Soc. 2002;50:359-68. [PMID: 12028221]
Perls TTWilmoth JLevenson RDrinkwater MCohen MBogan H . Life-long sustained mortality advantage of siblings of centenarians. Proc Natl Acad Sci U S A. 2002;99:8442-7. [PMID: 12060785]
Perls T, Fretts R. Why women live longer than men. Scientific American Presents. 1998; 100-7.
Kannel WBHjortland MCMcNamara PMGordon T. Menopause and risk of cardiovascular disease: the Framingham study. Ann Intern Med. 1976;85:447-52. [PMID: 970770]
Sullivan JL. The iron paradigm of ischemic heart disease. Am Heart J. 1989;117:1177-88. [PMID: 2653014]
Stohs SJBagchi D. Oxidative mechanisms in the toxicity of metal ions. Free Radic Biol Med. 1995;18:321-36. [PMID: 7744317]
Sullivan JL. Iron and the sex difference in heart disease risk. Lancet. 1981;1:1293-4. [PMID: 6112609]
Salonen JTKorpela HNyyssonen KPorkkala ETuomainen TPBelcher JD . Lowering of body iron stores by blood letting and oxidation resistance of serum lipoproteins: a randomized cross-over trial in male smokers. J Intern Med. 1995;237:161-8. [PMID: 7852918]
Klipstein-Grobusch KGrobbee DEden Breeijen JHBoeing HHofman AWitteman JC. Dietary iron and risk of myocardial infarction in the Rotterdam Study. Am J Epidemiol. 1999;149:421-8. [PMID: 10067901]
McCarthy MIKruglyak LLander ES. Sib-pair collection strategies for complex diseases. Genet Epidemiol. 1998;15:317-40. [PMID: 9671984]
Puca AADaly MJBrewster SJMatise TCBarrett JShea-Drinkwater M . A genome-wide scan for linkage to human exceptional longevity identifies a locus on chromosome 4. Proc Natl Acad Sci U S A. 2001;98:10505-8. [PMID: 11526246]
Hitt RYoung-Xu YSilver MPerls T. Centenarians: the older you get, the healthier you have been [Letter]. Lancet. 1999;354:652. [PMID: 10466675]
Lee CKKlopp RGWeindruch RProlla TA. Gene expression profile of aging and its retardation by caloric restriction. Science. 1999;285:1390-3. [PMID: 10464095]
Vita AJTerry RBHubert HBFries JF. Aging, health risks, and cumulative disability. N Engl J Med. 1998;338:1035-41. [PMID: 9535669]
Perls T. Genetic and phenotypic markers among centenarians. Journal of Gerontology: Medical Sciences. 2000;56A:M1-4.
Evert J, Lawler E, Bogan H, Perls T. Morbidity profiles of centenarians: survivors, delayers and escapers. Journal of Gerontology: Medical Sciences. [In press.]
Terry DF, Wilcox M, McCormick MA, Lawler E, Perls TT. Cardiovascular advantages among the offspring of centenarians. Journal of Gerontology: Medical Sciences. [In press.]
Barzilai NGabriely IGabriely MIankowitz NSorkin JD. Offspring of centenarians have a favorable lipid profile. J Am Geriatr Soc. 2001;49:76-9. [PMID: 11207846]

Information & Authors


Published In

cover image Annals of Internal Medicine
Annals of Internal Medicine
Volume 139Number 5_Part_22 September 2003
Pages: 445 - 449


Published online: 2 September 2003
Published in issue: 2 September 2003




Thomas Perls, MD, MPH
From Boston University Medical Center, Boston, Massachusetts.
Dellara Terry, MD, MPH
From Boston University Medical Center, Boston, Massachusetts.
Acknowledgments: The authors thank the American Association of Retired Persons for assistance with participant recruitment and dissemination of findings, and the centenarians and their family members who participate in the New England Centenarian Study.
Grant Support: By the American Federation of Aging Research's and Alliance for Aging Research's Paul Beeson Faculty Scholar in Aging Research Award, the Ellison Medical Foundation, the Institute for the Study of Aging, the Alzheimer's Association, and the National Institute on Aging (grant RO1 AG18721).
Disclosures: None disclosed.
Corresponding Author: Thomas Perls, MD, MPH, Geriatrics Section, Boston University Medical Center, 88 East Newton Street, Boston, MA 02118; e-mail, [email protected].
Current Author Addresses: Drs. Perls and Terry: Geriatrics Section, Boston University Medical Center, 88 East Newton Street, Boston, MA 02118.

Metrics & Citations



If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. For an editable text file, please select Medlars format which will download as a .txt file. Simply select your manager software from the list below and click Download.

For more information or tips please see 'Downloading to a citation manager' in the Help menu.


Download article citation data for:
Thomas Perls, Dellara Terry. Understanding the Determinants of Exceptional Longevity. Ann Intern Med.2003;139:445-449. [Epub 2 September 2003]. doi:10.7326/0003-4819-139-5_Part_2-200309021-00013

View More

Get Access

Login Options:

You will be redirected to to sign-in to Annals to complete your purchase.

Create your Free Account

You will be redirected to to create an account that will provide access to Annals.

View options


View PDF/ePub

Related in ACP Journals

Full Text

View Full Text







Copy the content Link

Share on social media