New England Centenarian Study

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Welcome to the largest and most comprehensive study of centenarians and their families in the world!

To Discover the Secrets of A Long Healthy and Happy Life…

Our two major studies are the New England Centenarian Study and the multi-center Long Life Family Study (Boston Medical Center is one of 5 study sites). 

We are actively seeking subjects to be in the New England Centenarian Study. The criteria are simply subjects age 105+ years old and their family members.  

If you would like to contact the study, please call us at 888-333-6327 where you will hear a menu to contact a member of the research staff. You can also email the study manager, Stacy Andersen at stacy@bu.edu or the Principal Investigator, Thomas Perls MD, MPH at thperls@bu.edu.

The New England Centenarain Study is funded by:

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THE GLENN FOUNDATION FOR MEDICAL RESEARCH


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The Long Life Family Study successfully enrolled and collected data from nearly 5,000 subjects belonging to about 850 families that demonstrate extreme clustering for exceptional longevity. The study is currently closed to further enrollment while the investigators collect followup data on existing subjects and analyze data. The Long Life Family Study is funded by and collaborates closely with The National Institute on Aging.


 

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The New England Centenarian Study at Boston Medical Center (BMC) is a supporting organization of a newly announced research prize, the Archon Genomics X Prize sponsored by Medco. The goal of the prize is to sequence the genomes of 100 centenarians (people over the age of 100) in an accurate, timely and cost-effective way so that medical-grade genetic information can eventually be used to personalize medical decisions based upon a person’s own genetic information. Sequencing the genomes of centenarians will give scientists an unprecedented opportunity to identify “rare genes” that protect against diseases, while giving researchers valuable clues to health and longevity.

At the Archon Genomics X Prize press conference held at the New York Academy of Medicine, Dr. Thomas Perls, the Director of the New England Centenarian Study stated, “This competition brings us one step closer to realizing the promise of truly personalized medicine. With the selection of centenarians as the genomic pioneers, this competition emphasizes the tremendous opportunity to discover ‘wellness’ genes and therefore learn how to prevent disease and live a long, healthy life.”

To learn more about this project, please also visit http://genomics.xprize.org/medco-100-over-100. The competition is now accepting nominations from centenarians and their family members to participate in a research project. You can call Dr. Thomas Perls toll-free at 888-333-6327 or email him at thperls@bu.edu.


               Our Recent Discoveries & Publications

Genetic Signatures of Exceptional Longevity in Humans

We published in January of this year the corrected version of our paper that originally came out in Science last year: Genetic Signatures of Exceptional Longevity in Humans. The major scientific findings were generally the same, but there were substantial technical differences that merited publication of the corrected version in another journal, PLoS ONE. The major (but many) findings of our research were:

  • Genes play a critical and complex role in facilitating exceptional longevity
  • Because many genes are involved, one needs to include many different genes at once (rather than rely on single genes, one at a time) to predict who is a centenarian, using genetic data alone.
  • We found 281 genetic markers that are 61% accurate in predicting who is 100 years old, 73% accurate in predicting who is 102 years old or older and 85% accurate in predicting who is 105 years old or older. In other words the prediction gets better with older and older ages beyond 100 which goes along with our hypothesis that the genetic component of exceptional longevity gets greater and greater with older and older age.
  • These markers point to at least 130 genes, many of which have been shown to play roles in Alzheimer’s, diabetes, heart disease, cancers, high blood pressure, and basic biological mechanisms of aging.
  • Centenarians have just as many genetic variants that are associated with increased risk for age-related diseases (like Alzheimer’s, heart disease, stroke, diabetes and cancer) as people in the general population. Therefore, their tremendous survival advantage may in great part be due to the existence of longevity associated genetic variants.
  • People have genetic profiles that can be constructed from these 281 genetic markers (each of which has 3 variations) and these in turn are associated with specific probabilities of achieving very old age. Very interestingly, subjects in both the control groups and the centenarian group have profiles in common that we call genetic signatures. Ninety percent of the 801 centenarians in the New England Centenarian Study could be grouped into one of 27 genetic signatures.
  • These genetic signatures are also associated with different predispositions to subgroups of centenarians such as those that completely escape heart disease, or those that delay Alzheimer’s disease until the last 5% of their very long lives. We believe that method for producing these signatures will be very useful for better understanding the underlying genetics of protection from age-related diseases and for the field of personal genomics.

Citation: Paola Sebastiani, Nadia Solovieff, Andrew T. DeWan, Kyle M. Walsh, Annibale Puca, Stephen W. Hartley, Efthymia Melista, Stacy Andersen, Daniel A. Dworkis, Jemma B. Wilk, Richard H. Myers, Martin H. Steinberg, Monty Montano, Clinton T. Baldwin, Josephine Hoh, Thomas T. Perls Genetic Signatures of Exceptional Longevity in Humans. PloS ONE 2012. DOI: 10.1371/journal.pone.0029848.  

Compression of Morbidity in Supercentenarians:

In another paper published this January, we have produced perhaps some of our most exciting findings to date. Early in our studies (The New England Centenarian Study began in 1995), we thought that centenarians had to markedly delay or even escape age-related diseases like heart attacks, stroke, diabetes and Alzheimer’s, or else they would never be able to get to their very old ages. In fact, in 1980, a Stanford researcher named James Fries proposed the “Compression of Morbidity” hypothesis which states that as one approaches the limit of human life span, they must compress the time that they develop diseases towards the very end of their life and he proposed that people around the age of 100 do this. However, in 2003 we found that many of our centenarian subjects had age related diseases even before the age of 80 (about 43%, and whom we called “survivors”), after the age of 80 (about 42% and whom we called “delayers”) and lastly, those who had no mortality-associated diseases at age 100 (about 15% and whom we called escapers). The key though was that 90% of all of the centenarians were still independently functioning at the average age of 93 years. Somehow, despite the presence of diseases, people who become centenarians don’t die from those diseases, but rather they are able to deal with them much better than other people and remain independently functioning more than 30 years beyond the age of 60.

     In this current paper though, titled Health span approximates life span among many supercentenarians: Compression of morbidity at the approximate limit of life span, we have found that we just weren’t looking at old enough subjects when investi-gating Jim Fries’ hypothesis. After all, the oldest person ever was 122 years old (she died in 1997) and people who live to 110+ years occur in the population at the rate of about one per 5 million, while people who live to 100 are much more common at the rate of one per 5,000. So, surviving to age 100 is very special relative to the general population and surviving to 110+  years is very special relative to people who live to around 100.     As some of you know, over the past few years we have been working hard on recruiting and enrolling the most extreme old, supercentenarians who are people that live to 110 years and older. Once we enrolled our hundredth super-centenarian (by far the largest collection of supers in the world), we were able to investigate whether or not people who truly approach the limit of human lifespan actually compress their morbidity towards the end of their lives.     In comparing controls, nonagenarians (subjects in their nineties), centenarians (ages 100-104), semi-supercentenarians (ages 105-109) and supercentenarians(ages 110+), the subjects had a progressively shorter periods of their lives spent with age-related diseases, from 17.9% of their lives in the controls, to 9.4% in the nonagenarians, down to 5.2% in the supercentenarians. These findings support the compression of morbidity hypothesis and the idea that there truly is a limit to human life span and that this limit is around 110-125 years. Also the supercentenarians were much more alike in terms of the markedly delayed age of onset of age-related diseases compared to the subjects age 100-104. That homogeneity indicates they must have some factors (presumably genetic) in common that allow them to be so similar.

Citation: Andersen SL, Sebastiani P, Dworkis DA, Feldman L, Perls T. Health span approximates life span among many supercentenarians: Compression of morbidity at the approximate limit of life span J Gerontol A Biol Sci Med Sci 2012;doi:10.1093/gerona/ glr223.

Whole Genome Sequences of 2 Supercentenarians

The New England Centenarian Study, along with collaborators at the Scripps Institute and the University of Florida, Gainesville, performed and  published the first-ever whole genome sequencing of a supercentenarian –and actually not one super, but two, both over the age of 114 years and one was a man and the other a woman. As with our paper on the genetic signatures of exceptional longevity, we found here as well that centenarians have just as many genetic variants associated with diseases as the general population. However, they likely also have longevity-associated variants that counteract such disease genes thus allowing for slower aging and increased resistance to age-related diseases. In this paper we also found several genes that occurred in our published genetic prediction model which had coding regions that led to differences in gene function. These findings support the validity of the genetic prediction model. The New England Centenarian Study has posted or will very soon have the whole genome sequences of these two subjects on a data repository (called dbGaP) based at the National Institutes of Health. This will allow researchers from around the world to access all of the data and use them for their own research. Our hope is that these data will lead to important discoveries about genes that help delay or allow the escape from age related diseases like Alzheimer’s disease.

Citation: Sebastiani P, Riva A, Montano M, Pham P, Torkamani A, Scherba E, Benson G, Milton JN, Baldwin CT, Andersen S, Schork NJ, Steinberg MH, Perls T. Whole genome sequences of a male and female super-centenarian, ages greater than 114 years. Frontiers in Genetics of Aging 2012;2.  

Recent Media Coverage

 

Alice Park February 11, 2010

 

                    

 

  



Key Peer-Reviewed Publications (this list includes articles covering human longevity and “anti-aging”). From list of ~100 articles.

Newman AB, Glynn NW, Taylor CA, Sebastiani P, Perls TT, Mayeux R, Christensen K, Zmuda JM, Barral S, Lee JH, Simonsick EM, Walston JD, Yashin AI, Hadley E. Health and function of participants in the Long Life Family Study: A comparison with other cohorts. Aging (Albany NY). 2011 Jan 11. PMID: 21258136

Perls T, Barzilai, N. 100 Semi-supercentenarians and older as a proposed sample set for the Archon Genomics X PRIZE Validation Protocol. Nature Precedings. 2011. http://dx.doi.org/10.1038/npre.2011.5756.1

Young RD, Desjardins B, McLaughlin K, Poulain M, Perls T. Typologies of Extreme Longevity Myths. Current Gerontology and Geriatrics Research 2010; doi:10.1155/2010/423087 http://www.hindawi.com/journals/cggr/2010/423087/

Kulminski AM, Arbeev KG, Christensen K, Mayeux R, Newman AB, Province MA, Hadley EC, Rossi W, Perls TT, Elo IT, Yashin AI. Do gender, disability, and morbidity affect aging rate in the LLFS? Application of indices of cumulative deficits. Mech Ageing Dev. 2011 Apr;132(4):195-201.

Solovieff N, Hartley SW, Baldwin CT, Perls TT, Steinberg MH, Sebastiani P. Clustering by genetic ancestry using genome-wide SNP data. BMC Genet. 2010 Dec 9;11:108. 

Barral S, Cosentino S, Costa R, Matteini A, Christensen K, Andersen SL, Glynn NW, Newman AB, Mayeux R. Cognitive function in families with exceptional survival. Neurobiol Aging. 2012 Mar 33;3:619.

Stern RA, Andersen SL, Gavett BE (2011). Executive functioning.  In A. E. Budson & N. W. Kowall (Eds.), The handbook of Alzheimer’s Disease and other dementias (pp 369-415). : West Sussex, UK: Wiley-Blackwell.

Givens JL, Frederick M, Silverman L, Anderson S, Senville J, Silver M, Sebastiani P, Terry DF, Costa PT, Perls TT. Personality traits of centenarians’ offspring. J Am Geriatr Soc. 2009 Apr;57(4):683-5. PMID: 19392961

Sebastiani P, Hadley EC,   Province M, Christensen K, Rossi W, Perls T, Ash AS. A family longevity selection score: ranking sibships by their longevity, size, and availability for study. Am J Epidemiol. 2009 Dec 15;170(12):1555-62. Epub 2009 Nov 12.PMID: 19910380.

Sebastiani P, Timofeev N, Dworkis DA, Perls TT, Steinberg MH. Genome-wide association studies and the genetic dissection of complex traits. Am J Hematol. 2009 Aug;84(8):504-15. Review. PMID: 19569043

Sebastiani P, Montano M, Puca A, Solovieff N, Kojima T, Wang MC, Melista E, Meltzer M, Fischer SE, Andersen S, Hartley SH, Sedgewick A, Arai Y, Bergman A, Barzilai N, Terry DF, Riva A, Anselmi CV, Malovini A, Kitamoto A, Sawabe M, Arai T, Gondo Y, Steinberg MH, Hirose N, Atzmon G, Ruvkun G, Baldwin CT, Perls TT. RNA editing genes associated with extreme old age in humans and with lifespan in C. elegans. PLoS One;4(12):e8210.PMID: 20011587

Perls T. Health and disease in people over 85. BMJ. 2009 Dec 22;339:b4715. doi: 10.1136/bmj.b4715

Sebastiani P, Perls TT. Prediction models that include genetic data. Circ Cardiovasc Genet. 2010 Feb 1;3(1):1-2. No abstract available. PMID: 20160188 [PubMed - indexed for MEDLINE]

Growth hormone and anabolic steroids: athletes are the tip of the iceberg. 

Perls TT. Drug Test Anal. 2009 Sep;1(9-10):419-25.

Abstract: Professional Athletes’ misuse of anabolic steroids, growth hormone and other drugs are the tip of a very large, mostly ignored iceberg, made up of people who receive these drugs for such non-medical uses as body-building, school sports and “anti-aging”. Although these drugs are often used in combination, this article focuses on growth hormone. Fuelling the demand for these drugs are drug manufacturers, pharmacies, websites, clinics and their doctors.

PMID: 20355224 Related citations

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 Prediction models that include genetic data. 

 Sebastiani P, Perls TT. Circ Cardiovasc Genet. 2010 Feb 1;3(1):1-2.

PMID: 20160188 [PubMed - indexed for MEDLINE] Related citations

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Antiaging medicine: what should we tell our patients?

Perls T. Aging Health April 2010, Vol. 6, No. 2, Pages 149-154 , DOI 10.2217/ahe.10.11 (doi:10.2217/ahe.10.11)

 future medicineAging Health [FREE ARTICLE]

 

Health and disease in people over 85.

Perls T. BMJ. 2009 Dec 22;339:b4715. doi: 10.1136/bmj.b4715. Comment on: BMJ. 2009;339:b4904.

 PMID: 20028776 [PubMed - indexed for MEDLINE] Related citations

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RNA editing genes associated with extreme old age in humans and with lifespan in C. elegans.

Sebastiani P, Montano M, Puca A, Solovieff N, Kojima T, Wang MC, Melista E, Meltzer M, Fischer SE, Andersen S, Hartley SH, Sedgewick A, Arai Y, Bergman A, Barzilai N, Terry DF, Riva A, Anselmi CV, Malovini A, Kitamoto A, Sawabe M, Arai T, Gondo Y, Steinberg MH, Hirose N, Atzmon G, Ruvkun G, Baldwin CT, Perls TT. PLoS One. 2009 Dec 14;4(12):e8210.

Abstract: BACKGROUND: The strong familiality of living to extreme ages suggests that human longevity is genetically regulated. The majority of genes found thus far to be associated with longevity primarily function in lipoprotein metabolism and insulin/IGF-1 signaling. There are likely many more genetic modifiers of human longevity that remain to be discovered. METHODOLOGY/PRINCIPAL FINDINGS: Here, we first show that 18 single nucleotide polymorphisms (SNPs) in the RNA editing genes ADARB1 and ADARB2 are associated with extreme old age in a U.S. based study of centenarians, the New England Centenarian Study. We describe replications of these findings in three independently conducted centenarian studies with different genetic backgrounds (Italian, Ashkenazi Jewish and Japanese) that collectively support an association of ADARB1 and ADARB2 with longevity. Some SNPs in ADARB2 replicate consistently in the four populations and suggest a strong effect that is independent of the different genetic backgrounds and environments. To evaluate the functional association of these genes with lifespan, we demonstrate that inactivation of their orthologues adr-1 and adr-2 in C. elegans reduces median survival by 50%. We further demonstrate that inactivation of the argonaute gene, rde-1, a critical regulator of RNA interference, completely restores lifespan to normal levels in the context of adr-1 and adr-2 loss of function. CONCLUSIONS/SIGNIFICANCE: Our results suggest that RNA editors may be an important regulator of aging in humans and that, when evaluated in C. elegans, this pathway may interact with the RNA interference machinery to regulate lifespan.

PMID: 20011587 [PubMed - indexed for MEDLINE]PMCID: PMC2788130Free PMC Article Related citations

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A family longevity selection score: ranking sibships by their longevity, size, and availability for study.

Sebastiani P, Hadley EC, Province M, Christensen K, Rossi W, Perls TT, Ash AS. Am J Epidemiol. 2009 Dec 15;170(12):1555-62. Epub 2009 Nov 12.

Abstract: Family studies of exceptional longevity can potentially identify genetic and other factors contributing to long life and healthy aging. Although such studies seek families that are exceptionally long lived, they also need living members who can provide DNA and phenotype information. On the basis of these considerations, the authors developed a metric to rank families for selection into a family study of longevity. Their measure, the family longevity selection score (FLoSS), is the sum of 2 components: 1) an estimated family longevity score built from birth-, gender-, and nation-specific cohort survival probabilities and 2) a bonus for older living siblings. The authors examined properties of FLoSS-based family rankings by using data from 3 ongoing studies: the New England Centenarian Study, the Framingham Heart Study, and screenees for the Long Life Family Study. FLoSS-based selection yields families with exceptional longevity, satisfactory sibship sizes and numbers of living siblings, and high ages. Parameters in the FLoSS formula can be tailored for studies of specific populations or age ranges or with different conditions. The first component of the FLoSS also provides a conceptually sound survival measure to characterize exceptional longevity in individuals or families in various types of studies and correlates well with later-observed longevity.

PMID: 19910380 [PubMed - indexed for MEDLINE]PMCID: PMC2800272 [Available on 2010/12/15] Related citations

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Genome-wide association studies and the genetic dissection of complex traits.

Sebastiani P, Timofeev N, Dworkis DA, Perls TT, Steinberg MH. Am J Hematol. 2009 Aug;84(8):504-15.

Abstract: The availability of affordable high throughput technology for parallel genotyping has opened the field of genetics to genome-wide association studies (GWAS), and in the last few years hundreds of articles reporting results of GWAS for a variety of heritable traits have been published. What do these results tell us? Although GWAS have discovered a few hundred reproducible associations, this number is underwhelming in relation to the huge amount of data produced, and challenges the conjecture that common variants may be the genetic causes of common diseases. We argue that the massive amount of genetic data that result from these studies remains largely unexplored and unexploited because of the challenge of mining and modeling enormous data sets, the difficulty of using nontraditional computational techniques and the focus of accepted statistical analyses on controlling the false positive rate rather than limiting the false negative rate. In this article, we will review the common approach to analysis of GWAS data and then discuss options to learn more from these data. We will use examples from our ongoing studies of sickle cell anemia and also GWAS in multigenic traits.

PMID: 19569043 [PubMed - indexed for MEDLINE] Related citations

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Personality traits of centenarians’ offspring.

Givens JL, Frederick M, Silverman L, Anderson S, Senville J, Silver M, Sebastiani P, Terry DF, Costa PT, Perls TT.J Am Geriatr Soc. 2009 Apr;57(4):683-5.

Abstract: OBJECTIVES: To determine whether the offspring of centenarians have personality characteristics that are distinct from the general population. DESIGN: Case-control. SETTING: Nationwide U.S. sample. PARTICIPANTS: Unrelated offspring of centenarians (n=246, mean age 75) were compared with published norms. MEASUREMENTS: Using the NEO-Five-Factor Inventory (NEO-FFI) questionnaire, measures of the personality traits neuroticism, extraversion, openness, agreeableness, and conscientiousness were obtained. T-scores and percentiles were calculated according to sex and used to interpret the results. RESULTS: Male and female offspring of centenarians scored in the low range of published norms for neuroticism and in the high range for extraversion. The women also scored comparatively high in agreeableness. Otherwise, both sexes scored within normal range for conscientiousness and openness, and the men scored within normal range for agreeableness. CONCLUSION: Specific personality traits may be important to the relative successful aging demonstrated by the offspring of centenarians. Similarities across four of the five domains between male and female offspring is noteworthy and may relate to their successful aging. Measures of personality are an important phenotype to include in studies that assess genetic and environmental influences of longevity and successful aging.

PMID: 19392961 [PubMed - indexed for MEDLINE] Related citations

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Centenarian offspring: start healthier and stay healthier.

Adams ER, Nolan VG, Andersen SL, Perls TT, Terry DF. J Am Geriatr Soc. 2008 Nov;56(11):2089-92. Epub 2008 Sep 22.

Abstract: OBJECTIVES: To assess the relative incidence of age-related diseases in a group of centenarian offspring who have thus far been considered to be predisposed to “healthy” aging. DESIGN: Longitudinal study. SETTING: Nationwide sample. PARTICIPANTS: Four hundred forty centenarian offspring and 192 referent cohort subjects who met inclusion criteria of having initial and follow-up health questionnaire data available. Median age of both cohorts was 72 at the initial health questionnaire. MEASUREMENTS: Initial health questionnaires were collected from 1997 to 2006. Follow-up questionnaires were collected from 2004 to 2007. The mean period of follow-up was 3.5+/-1.7 years for the centenarian offspring and 3.9+/-2.2 years for the referent cohort. RESULTS: During the follow-up period, centenarian offspring had a 78% lower risk of myocardial infarction (P<.04), 83% lower risk of stroke (P<.004), and 86% lower risk of developing diabetes mellitus (P<.005) than the referent cohort. There were no significant differences in new onset of other age-related diseases. Additionally, centenarian offspring were 81% less likely to die (P<.01) than the referent cohort during the follow-up. CONCLUSION: These findings suggest that centenarian offspring retain some important cardiovascular advantages over time over similarly aged referent cohort subjects. These findings reinforce the notion that there may be physiological reasons that longevity runs in families and that centenarian offspring are more likely to age in better cardiovascular health and with a lower mortality than their peers.

PMID: 18811609 [PubMed - indexed for MEDLINE] Related citations

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New developments in the illegal provision of growth hormone for “anti-aging” and bodybuilding.

Olshansky SJ, Perls TT. JAMA. 2008 Jun 18;299(23):2792-4.

PMID: 18560007 [PubMed - indexed for MEDLINE] Related citations

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Disentangling the roles of disability and morbidity in survival to exceptional old age.

Terry DF, Sebastiani P, Andersen SL, Perls TT. Arch Intern Med. 2008 Feb 11;168(3):277-83.

Abstract BACKGROUND: Although it is commonly held that survival to age 100 years entails markedly delaying or escaping age-related morbidities, nearly one-third of centenarians have age-related morbidities for 15 or more years. Yet, we have previously observed that many centenarians compress disability toward the end of their lives. Therefore, we hypothesize that for some centenarians, compression of disability rather than morbidity is a key feature for survival to old age. METHODS: This cross-sectional, nationwide study included 523 women and 216 men 97 years or older. The participants were stratified by sex and age at onset (age <85 years [termed survivors] and age >or=85 years [termed delayers]) of chronic obstructive pulmonary disease, dementia, diabetes, heart disease, hypertension, osteoporosis, Parkinson disease, and stroke. Dependent variables were the Barthel Activities of Daily Living Index (Barthel Index) and the Information-Memory-Concentration test of the Blessed Dementia Scale. RESULTS: Thirty-two percent of the participants were survivors. For men with hypertension and/or heart disease for 15 or more years, the median Barthel Index score was 90 (independence range, 80-100). For female survivors with hypertension, heart disease, and/or osteoporosis, the median Barthel Index score was 65 (minimal assistance range, 60-79). Generally, men had better function than women: 60% of male survivors had Barthel Index scores of 90 or higher compared with 18% of female survivors (P < .001) and 50% of male delayers had Barthel Index scores of 90 or higher compared with 27% of females delayers (P < .001). CONCLUSIONS: Whereas the compression of both morbidity and disability are essential features of survival to old age for some centenarians, for others, the compression of disability alone may be the key prerequisite. Though far fewer in number, male centenarians tend to have significantly better cognition and physical function than their female counterparts.

PMID: 18268168 [PubMed - indexed for MEDLINE]Free Article Related citations

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A hierarchical and modular approach to the discovery of robust associations in genome-wide association studies from pooled DNA samples.

Sebastiani P, Zhao Z, Abad-Grau MM, Riva A, Hartley SW, Sedgewick AE, Doria A, Montano M, Melista E, Terry D, Perls TT, Steinberg MH, Baldwin CT. BMC Genet. 2008 Jan 14;9:6.

Abstract: BACKGROUND: One of the challenges of the analysis of pooling-based genome wide association studies is to identify authentic associations among potentially thousands of false positive associations. RESULTS: We present a hierarchical and modular approach to the analysis of genome wide genotype data that incorporates quality control, linkage disequilibrium, physical distance and gene ontology to identify authentic associations among those found by statistical association tests. The method is developed for the allelic association analysis of pooled DNA samples, but it can be easily generalized to the analysis of individually genotyped samples. We evaluate the approach using data sets from diverse genome wide association studies including fetal hemoglobin levels in sickle cell anemia and a sample of centenarians and show that the approach is highly reproducible and allows for discovery at different levels of synthesis. CONCLUSION: Results from the integration of Bayesian tests and other machine learning techniques with linkage disequilibrium data suggest that we do not need to use too stringent thresholds to reduce the number of false positive associations. This method yields increased power even with relatively small samples. In fact, our evaluation shows that the method can reach almost 70% sensitivity with samples of only 100 subjects.

PMID: 18194558 [PubMed - indexed for MEDLINE]PMCID: PMC2248205Free PMC Article Related citations

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Survival of parents and siblings of supercentenarians.

Perls T, Kohler IV, Andersen S, Schoenhofen E, Pennington J, Young R, Terry D, Elo IT. J Gerontol A Biol Sci Med Sci. 2007 Sep;62(9):1028-34.

Abstract: BACKGROUND: Given previous evidence of familial predisposition for longevity, we hypothesized that siblings and parents of supercentenarians (age >or= 110 years) were predisposed to survival to very old age and that, relative to their birth cohorts, their relative survival probabilities (RSPs) are even higher than what has been observed for the siblings of centenarians. METHODS: Mean age at death conditional upon survival to ages 20 and 50 and survival probabilities from ages 20 and 50 to higher ages were determined for 50 male and 56 female siblings and 54 parents of 29 supercentenarians. These estimates were contrasted with comparable estimates based on birth cohort-specific mortality experience for the United States and Sweden. RESULTS: Conditional on survival to age 20 years, mean age at death of supercentenarians’ siblings was approximately 81 years for men and women. Compared with respective Swedish and U.S. birth cohorts, these estimates were 17%-20% (12-14 years) higher for the brothers and 11%-14% (8-10 years) higher for the sisters. Sisters had a 2.9 times greater probability and brothers had a 4.3 times greater probability of survival from age 20 to age 90. Mothers of supercentenarians had a 5.8 times greater probability of surviving from age 50 to age 90. Fathers also experienced an increased survival probability from age 50 to age 90 of 2.7, but it failed to attain statistical significance. CONCLUSIONS: The RSPs of siblings and mothers of supercentenarians revealed a substantial survival advantage and were most pronounced at the oldest ages. The RSP to age 90 for siblings of supercentenarians was approximately the same as that reported for siblings of centenarians. It is possible that greater RSPs are observed for reaching even higher ages such as 100 years, but a larger sample of supercentenarians and their siblings and parents is needed to investigate this possibility.

PMID: 17895443 [PubMed - indexed for MEDLINE] Related citations

Hope drives antiaging hype.

Perls TT. Cleve Clin J Med. 2006 Dec;73(12):1039-40, 1044.

Comment on: Cleve Clin J Med. 2006 Dec;73(12):1049-56, 1058.

 PMID: 17190307 [PubMed - indexed for MEDLINE]Free Article Related citations

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Characteristics of 32 supercentenarians.

Schoenhofen EA, Wyszynski DF, Andersen S, Pennington J, Young R, Terry DF, Perls TT. J Am Geriatr Soc. 2006 Aug;54(8):1237-40.

Abstract: OBJECTIVES: To report phenotypic characteristics of 32 age-validated supercentenarians. DESIGN: Case series. SETTING: U.S.-based recruitment effort. PARTICIPANTS: Thirty-two supercentenarians. MEASUREMENTS: Multiple forms of proof were used to validate age claims. Sociodemographic, activities of daily living, and medical history data were collected. RESULTS: Age range was 110 to 119. Fifty-nine percent had Barthel Index scores in the partially to totally dependent range, whereas 41% required minimal assistance or were independent. Few subjects had a history of clinically evident vascular-related diseases, including myocardial infarction (n=2, 6%) and stroke (n=4, 13%). Twenty-two percent (n=7) were taking medications for hypertension. Twenty-five percent (n=8) had a history of cancer (all cured). Diabetes mellitus (n=1, 3%) and Parkinson’s disease (n=1, 3%) were rare. Osteoporosis (n=14, 44%) and cataract history (n=28, 88%) were common. CONCLUSION: Data collected thus far suggest that supercentenarians markedly delay and even escape clinical expression of vascular disease toward the end of their exceptionally long lives. A surprisingly substantial proportion of these individuals were still functionally independent or required minimal assistance.

PMID: 16913991 [PubMed - indexed for MEDLINE] Related citations

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The different paths to age one hundred.

Perls T. Ann N Y Acad Sci. 2005 Dec;1055:13-25.

Abstract: Attaining age 100 is a rare event in industrialized nations, occurring in 1 person per 10,000 in the population. Becoming a centenarian does not appear to be rare because the individual genetic or behavioral factors (such as specific genetic polymorphisms or lack of specific toxic exposures) that enable such longevity are rare, but rather because having the adequate combination of these factors is rare.

PMID: 16387714 [PubMed - indexed for MEDLINE] Related citations

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Provision or distribution of growth hormone for “antiaging”: clinical and legal issues.

Perls TT, Reisman NR, Olshansky SJ. JAMA. 2005 Oct 26;294(16):2086-90.

 PMID: 16249424 [PubMed - indexed for MEDLINE] Related citations

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Cancer in the oldest old.

Andersen SL, Terry DF, Wilcox MA, Babineau T, Malek K, Perls TT. Mech Ageing Dev. 2005 Feb;126(2):263-7.

Abstract: Our previous work revealed that 88% of centenarians delay or escape the age-related lethal diseases cardiac disease, stroke and diabetes. In the cases of those having a history of cancer we have observed anecdotes of centenarians presenting with large primary tumors that would have otherwise been expected to have metastasized and to have been lethal. However, these tumors were removed without consequence. To better understand the relationship between cancer and exceptional longevity, we quantified age of cancer diagnoses, life-time clinically evident cancer prevalence, tobacco use and family histories through medical record review and interviews. One thousand one hundred and forty-three subjects were studied revealing 20% (N=152) of female and 22% (N=80) of male centenarians with a history of non-skin cancer. The most common cancers were prostate (11.7% of males), breast (8.2% of females), and colon (5.7%). The average age of diagnosis was 80.5 years compared to 63.2 years in the general population according to National Cancer Institute SEER data. Similar delays were noted when age of onset was examined according to specific type of cancer. In conclusion, the age of diagnosis of cancer is relatively delayed in those who live to 100 years. Some cancers are very rare among these individuals suggesting that there are certain cancers that may be incompatible with survival to extreme old age.

PMID: 15621206 [PubMed - indexed for MEDLINE] Related citations

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Dementia-free centenarians.

Perls T. Exp Gerontol. 2004 Nov-Dec;39(11-12):1587-93.

Abstract: BACKGROUND: A small percentage of centenarians, about 15-25%, are functionally cognitively intact. Among those who are not cognitively intact at 100, approximately 90% delayed the onset of clinically evident impairment at least until the average age of 92 yr. OBJECTIVE: To review current and past findings related to the prevalence and incidence of dementia amongst the exceptionally long-lived. METHODS: Findings from the various centenarian studies, world-wide, are reviewed. RESULTS: Neuropsychological and neuropathological correlations thus far suggest that there are centenarians who demonstrate no evidence of neurodegenerative disease. There also appear to be centenarians who despite the substantial presence of neuropathological markers of Alzheimer’s disease did not meet clinical criteria for having dementia, thus suggesting the existence of cognitive reserve. Epigenic studies suggest a significant familial component to these survival advantages. CONCLUSION: Centenarians are of scientific interest as a human model of relative resistance to dementia.

PMID: 15582273 [PubMed - indexed for MEDLINE] Related citations

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Lower all-cause, cardiovascular, and cancer mortality in centenarians’ offspring.

Terry DF, Wilcox MA, McCormick MA, Pennington JY, Schoenhofen EA, Andersen SL, Perls TT. J Am Geriatr Soc. 2004 Dec;52(12):2074-6.

Abstract: OBJECTIVES: To assess the cause of death for centenarians’ offspring and controls. DESIGN: Cross-sectional study. SETTING: Community-based, nationwide sample. PARTICIPANTS: Family pedigree information was collected on 295 offspring of centenarians (from 106 families with a parent already enrolled in the nationwide New England Centenarian Study) and on 276 controls (from 82 control families) from 1997 to 2000. Controls were individuals whose parents were born in the same year as the centenarians but at least one of whom died at the average life expectancy. MEASUREMENTS: Age at death and cause of death. RESULTS: Centenarians’ offspring had a 62% lower risk of all-cause mortality (P<.001), a 71% lower risk of cancer-specific mortality (P=.002), and an 85% lower risk of coronary heart disease-specific mortality (P<.001). Significant differences were not found for other causes of death. However of those who died centenarian offsprings dead at a significantly younger age than controls. CONCLUSION: These findings suggest that centenarians’ offspring have lower all-cause mortality rates and cause-specific mortality rates for cancer and coronary heart disease. These results suggest that mechanisms for survival to exceptional old age may go beyond the avoidance or delay of cardiovascular disease and also include the avoidance or delay of cancer. Moreover survival advantage of centenarian offsprings may not be due to factors related to childhood mortality. Ultimately, survival to exceptional old age may involve lower susceptibility to a broad range of age-related diseases, perhaps secondary to inhibition of basic mechanisms of aging.

PMID: 15571545 [PubMed - indexed for MEDLINE] Related citations

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Anti-aging quackery: human growth hormone and tricks of the trade–more dangerous than ever.

Perls TT. J Gerontol A Biol Sci Med Sci. 2004 Jul;59(7):682-91.

Abstract: To assess the presence of quackery in the anti-aging industry, the Internet was surveyed for web sites marketing anti-aging products as well as those providing consumer advice regarding quackery and hucksterism. The United States Federal Food, Drug, and Cosmetic Act and its amendments were reviewed, particularly as they pertain to dietary supplements and human growth hormone. Anti-aging quackery and hucksterism are pervasive on the Internet and in clinics advertising anti-aging treatments. Review of the marketing techniques of the industry revealed 15 common ruses used by many in the industry to market their products. Federal law states that distributing or administering human growth hormone for anti-aging or age-related problems is illegal. Nonetheless, anti-aging clinics thrive, administering human growth hormone to thousands of gullible and oftentimes vulnerable patients. Anti-aging quackery has become a multimillion dollar industry exacting great monetary, health, and social costs. Consumers and health care providers alike are wise to educate themselves on how to recognize quackery. Congress must reassess the wisdom of the 1994 Dietary Supplements Health and Education Act, which facilitates and, in numerous cases, endangers Americans on a grand scale. In the case of some substances such as human growth hormone, adequate legal safeguards are impotent without adequate resources allocated to enforcement agencies.

PMID: 15304532 [PubMed - indexed for MEDLINE] Related citations

Understanding the determinants of exceptional longevity.

Perls T, Terry D. Ann Intern Med. 2003 Sep 2;139(5 Pt 2):445-9.

Abstract: 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.

PMID: 12965974 [PubMed - indexed for MEDLINE]Free Article Related citations

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Morbidity profiles of centenarians: survivors, delayers, and escapers.

Evert J, Lawler E, Bogan H, Perls T. J Gerontol A Biol Sci Med Sci. 2003 Mar;58(3):232-7.

Abstract: BACKGROUND: The compression of morbidity hypothesis predicts that, in order to achieve their extreme old age, centenarians markedly delay or even escape diseases that would otherwise be lethal at younger ages. Phenotypic studies have not adequately characterized the prevalence and timing of age-related illnesses among those who achieve exceptional old age. Thus, we conducted a retrospective cohort study of centenarians to explore the timing of such diseases among centenarians. METHODS: Health history questionnaires were completed by 424 centenarians (aged 97-119 years) or their proxies. Lifetime (to-date) diagnoses of 10 major lethal illnesses (hypertension, heart disease, diabetes, stroke, nonskin cancer, skin cancer, osteoporosis, thyroid condition, Parkinson’s disease, and chronic obstructive pulmonary disease) and one ocular disease (cataracts) that befall the elderly population, approximate age of diagnosis, level of alcohol and tobacco use, and presence or absence of cognitive impairment were assessed. Because of the retrospective nature of the study, the typically imprecise age of onset of cognitive impairment negated the ability to include age of onset of cognitive impairment in this aspect of the analyses. RESULTS: Examining the ages of onset for the 10 age-associated diseases and excluding cognitive impairment, we found that the centenarians fit into three morbidity profiles-Survivors, Delayers, and Escapers. 24% of male subjects and 43% of female subjects fit the Survivor profile, or those who had a diagnosis of an age-associated illness prior to the age of 80. Delayers were individuals who delayed the onset of age-associated illness until at least the age of 80, and 44% of male and 42% of female subjects fit this profile. Escapers were individuals who attained their 100th year of life without the diagnosis of common age-associated illnesses, and 32% of male and 15% of female subjects fit the Escaper profile. When examining only the most lethal diseases of the elderly population, heart disease, nonskin cancer, and stroke, we found that 87% of male and 83% of female subjects delayed or escaped these diseases. Subjects with and without cognitive impairment did not differ in terms of the profile to which they belonged. CONCLUSIONS: These results suggest there may be multiple routes to achieving exceptional longevity and that there are sex differences according to which route is taken. These routes represent different phenotypes and thus likely different genotypes of centenarians. The identification of three types of centenarians, Survivors, Delayers, and Escapers, provides direction for future study into the factors that determine exceptional longevity.

PMID: 12634289 [PubMed - indexed for MEDLINE] Related citations

Life-long sustained mortality advantage of siblings of centenarians.

Perls TT, Wilmoth J, Levenson R, Drinkwater M, Cohen M, Bogan H, Joyce E, Brewster S, Kunkel L, Puca A. Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8442-7.

 Abstract: Although survival to old age is known to have strong environmental and behavioral components, mortality differences between social groups tend to diminish or even disappear at older ages. Hypothesizing that surviving to extreme old age entails a substantial familial predisposition for longevity, we analyzed the pedigrees of 444 centenarian families in the United States. These pedigrees included 2,092 siblings of centenarians, whose survival was compared with 1900 birth cohort survival data from the U.S. Social Security Administration. Siblings of centenarians experienced a mortality advantage throughout their lives relative to the U.S. 1900 cohort. Female siblings had death rates at all ages about one-half the national level; male siblings had a similar advantage at most ages, although diminished somewhat during adolescence and young adulthood. Relative survival probabilities for these siblings increase markedly at older ages, reflecting the cumulative effect of their mortality advantage throughout life. Compared with the U.S. 1900 cohort, male siblings of centenarians were at least 17 times as likely to attain age 100 themselves, while female siblings were at least 8 times as likely.

PMID: 12060785 [PubMed - indexed for MEDLINE]PMCID: PMC123086Free PMC ArticleRelated citations

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The genetics of exceptional human longevity.

Perls T, Kunkel LM, Puca AA. J Am Geriatr Soc. 2002 Feb;50(2):359-68.

Abstract: There is a substantial distinction to be made between the genetics of aging and the genetics of exceptional longevity. Twin studies suggest that the average set of genetic variations facilitates the average human’s ability to live well into their octogenarian years. Other studies indicate that taking full advantage of this average set results in spending the majority of those years in good health. However, many people counteract such genetic endowment with poor health habits, resulting in a substantially lower average life expectancy and relatively more time spent in poor health. To live beyond the octogenarian years, life-span experiments in lower organisms and mammals and population and molecular genetic studies of centenarian sibships suggest that genetic factors play an important role in exceptional longevity. These factors are likely to influence basic mechanisms of aging, which in turn broadly influence susceptibility to age-related illnesses. Lacking genetic variations that predispose to disease, and having variations that confer disease resistance (longevity enabling genes), are probably both important to such a remarkable survival advantage. Recent studies indicate the likelihood that such factors will be elucidated in the near future.

PMID: 12028221 [PubMed - indexed for MEDLINE] Related citations

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Distinguishing between neurodegenerative disease and disease-free aging: correlating neuropsychological evaluations and neuropathological studies in centenarians.

Silver MH, Newell K, Brady C, Hedley-White ET, Perls TT. Psychosom Med. 2002 May-Jun;64(3):493-501.

Abstract: OBJECTIVE: In an examination of disease-free aging and neurodegenerative disease in 100-year-olds, the New England Centenarian Study compared data from neuropsychological evaluations with postmortem brain studies of fourteen 100-year-olds to ascertain if the presence or absence of Alzheimer disease changes correlated with measured cognitive abilities. METHODS: Fourteen of 74 centenarians who underwent annual extensive neuropsychological evaluation proceeded to postmortem neuropathological examination. CERAD criteria, emphasizing neuritic amyloid plaques and Braak and Braak staging of neurofibrillary tangles were used to assess the 14 brains. RESULTS: Neuropsychological and neuropathological findings correlated well for four subjects with no dementia on testing (CDR = 0) and for six subjects with CDR scores in the dementia range (CDR = 1-5). In the latter group, Alzheimer’s disease was diagnosed in four brains; Pick’s disease was an etiological factor in the fifth and hippocampal sclerosis in the sixth. Correlation was low for four subjects: two subjects with no dementia on neuropsychological testing met CERAD neuropathological criteria for possible AD; two subjects with dementia on testing did not meet CERAD criteria for definite Alzheimer’s disease and had otherwise minimal changes to correlate with the cognitive findings. CONCLUSIONS: Lack of correlation between level of cognitive functioning and brain pathology in two subjects with no dementia raised the question of whether a functional reserve delayed the functional expression of pathological changes. For two subjects with dementia on testing, there appeared to be no sufficient pathological explanation for the extent of the cognitive changes; depression and such factors as environment, sensory impairment, and medical illness may all have played a role. There may also have been neuropathologic changes not detected by current methods.

PMID: 12021423 [PubMed - indexed for MEDLINE]Free Article Related citations

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Genetic and environmental influences on exceptional longevity and the AGE nomogram.

Perls T. Ann N Y Acad Sci. 2002 Apr;959:1-13.

Abstract: To live beyond the octogenarian years, population and molecular genetic studies of centenarian sibships indicate that genetic factors play an increasingly important role as the limit of life span is approached. These factors are likely to influence basic mechanisms of aging that in turn broadly influence susceptibility to age-related illnesses. Lacking genetic variations that predispose to disease as well as having variations that confer disease resistance (longevity enabling genes) are probably both important to achieving exceptional old age. The AGE (aging, genetics, environment) nomogram is introduced as an illustrative construct for understanding the influence of environmental and genetic factors on survival to various ages, depending on variations in the hypothesized relative importance of genes and environment to longevity. The rapid rise in the incidence of centenarians could indicate that many more people than we originally thought have the optimal set of genetic factors necessary to get to 100 and beyond. Recent studies indicate the likelihood that such factors will be elucidated in the near future.

PMID: 11976180 [PubMed - indexed for MEDLINE] Related citations

A genome-wide scan for linkage to human exceptional longevity identifies a locus on chromosome 4.

Puca AA, Daly MJ, Brewster SJ, Matise TC, Barrett J, Shea-Drinkwater M, Kang S, Joyce E, Nicoli J, Benson E, Kunkel LM, Perls T. Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10505-8. Epub 2001 Aug 27.

Abstract: Substantial evidence supports the familial aggregation of exceptional longevity. The existence of rare families demonstrating clustering for this phenotype suggests that a genetic etiology may be an important component. Previous attempts at localizing loci predisposing for exceptional longevity have been limited to association studies of candidate gene polymorphisms. In this study, a genome-wide scan for such predisposing loci was conducted by using 308 individuals belonging to 137 sibships demonstrating exceptional longevity. By using nonparametric analysis, significant evidence for linkage was noted for chromosome 4 at D4S1564 with a MLS of 3.65 (P = 0.044). The analysis was corroborated by a parametric analysis (P = 0.052). These linkage results indicate the likelihood that there exists a gene, or genes, that exerts a substantial influence on the ability to achieve exceptional old age. Identification of the genes in humans that allow certain individuals to live to extreme old age should lead to insights on cellular pathways that are important to the aging process.

PMID: 11526246 [PubMed - indexed for MEDLINE]PMCID: PMC56990Free PMC Article Related citations

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The evolution of menopause and human life span.

Perls TT, Fretts RC. Ann Hum Biol. 2001 May-Jun;28(3):237-45.

Abstract: Noteworthy data is emerging to support the existence of longevity-enabling genes. Our observations of the relationship between reproductive fitness and longevity among centenarians support theories that posit strong selective forces in the determination of how fast humans age and their susceptibility to diseases associated with ageing. Current data support the idea that there is no selective advantage for humans to have a lifespan of approximately 100 years. Rather, getting to such a very old age may be a by-product of longevity-enabling genes that maximize the length of time during which women can bear children, and during which they can increase the survival probabilities of their children and grandchildren. We thus review the literature pertaining to the relationship between reproductive fitness and longevity.

PMID: 11393331 [PubMed - indexed for MEDLINE] Related citations

Siblings of centenarians live longer. 

Perls TT, Bubrick E, Wager CG, Vijg J, Kruglyak L. Lancet. 1998 May 23;351(9115):1560. PMID: 10326548 [PubMed - indexed for MEDLINE] Related citations

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Middle-aged mothers live longer. 

Perls TT, Alpert L, Fretts RC. Nature. 1997 Sep 11;389(6647):133.PMID: 9296486 [PubMed - indexed for MEDLINE] Related citations

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