P.M. Zorkii, A.E. Razumaeva and V.K. Belsky- The Systematization of Molecular Crystal Structures
Implications for Clinical Trials of Therapies to Extend ... · Daniel W. Belsky, PhD Assistant...
Transcript of Implications for Clinical Trials of Therapies to Extend ... · Daniel W. Belsky, PhD Assistant...
Quantification of Biological Aging
Daniel W. Belsky, PhD Assistant Professor of Population Health ScienceDuke University School of Medicine
Implications for Clinical Trials of Therapies to Extend Healthy Lifespan
[email protected]:/sites.duke.edu/danbelsky
U24AG047121 (Kraus, Peiper)P30 AG028716 (Schmader, Morey)P30AG034424 (O’Rand)R01 AG032282 (Moffitt)R21AG054846 (Belsky)
Outline
IntroductionBiological aging is a treatment target for healthspan extension
Part 1. Human trials of geroprotectorsChallenges & opportunities
Part 2. Quantification of biological aging in young adults
Part 3. Testing biological aging in a geroprotector trial
Conclusion
4
The global population is aging
Strategies are needed to extend healthy lifespan
5https://www.nimh.nih.gov/health/statistics/disability/us-leading-disease-disorder-categories-by-age.shtml
Aging itself is a leading risk factor for many diseases
6
Kennedyetal.2014Cell
Agingisabiologicalprocessagradualandprogressivedeclineinsystemintegrity
Lopez-Otin etal.2013Cell
7
GeroprotectiveIntervention?
8
Evolving theoretical models of aging
AcceleratedAging
Diseaseà Disability/Frailtyà Death
Early-lifeAdversity
Belsky etal.2015PNASMoffittetal.2016JGeron AMedSci
9
Evolving theoretical models of aging
AcceleratedAging
Diseaseà Disability/Frailtyà Death
Early-lifeAdversity
Belsky etal.2015PNASMoffittetal.2016JGeron AMedSci
10
Evolving theoretical models of aging
AcceleratedAging
Diseaseà Disability/Frailtyà Death
Early-lifeAdversity
Belsky etal.2015PNASMoffittetal.2016JGeron AMedSci
20 30 40 50 60 70 80 90 100DecadeofLife
Morbidityà
RisingMorbidity withAdvancingAge
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• Exposures accumulate from early life • Changes to physiology precede disease onset• Preventive intervention must begin early
Belsky 2017
20 30 40 50 60 70 80 90 100DecadeofLife
Morbidityà
RisingMorbidity withAdvancingAge
GeroprotectiveIntervention
12
• Exposures accumulate from early life • Changes to physiology precede disease onset• Preventive intervention must begin early
Belsky 2017
20 30 40 50 60 70 80 90 100DecadeofLife
Morbidityà
RisingMorbidity withAdvancingAge
GeroprotectiveIntervention
13
• Exposures accumulate from early life • Changes to physiology precede disease onset• Preventive intervention must begin early
Belsky 2017
Outline
IntroductionBiological aging is a treatment target for healthspan extension
Part 1. Human trials of geroprotectorsChallenges & opportunities
Part 2. Quantification of biological aging in young adults
Part 3. Testing biological aging in a geroprotector trial
Conclusion
15
Ideal Geroprotector Trial Design
Rx
Control
HealthspanExtension
Belsky 2017
16
Ideal Geroprotector Trial Design
Rx
Control
HealthspanExtension
Rx
Control
HealthspanExtension
Belsky 2017
17
Ideal Geroprotector Trial Design
Rx
Control
HealthspanExtension
Rx
Control
HealthspanExtension
Months
Belsky 2017
18
Ideal Geroprotector Trial Design
Rx
Control
HealthspanExtension
Rx
Control
HealthspanExtension
Months Decades
Belsky 2017
19
Problem: Healthspan follow-up from midlife prevention takes too long
20 30 40 50 60 70 80 90 100DecadeofLife
Morbidityà
RisingMorbidity withAdvancingAge
GeroprotectiveIntervention
Belsky 2017
20
Solution: Measure aging processes as healthspansurrogate endpoint for trial
20 30 40 50 60 70 80 90 100DecadeofLife
Morbidityà
RisingMorbidity withAdvancingAge
GeroprotectiveIntervention
Belsky 2017
21
Alternative Geroprotector Trial Design
Rx
Control
SlowerPaceofAging
NormalPaceofAging
Years
Belsky 2017
22
Alternative Geroprotector Trial Design
Biologica
lAge
Y1 Y2 Y3
Control
Treatment
Rx
Control
SlowerPaceofAging
NormalPaceofAging
Years
23
Alternative Geroprotector Trial Design
Biologica
lAge
Y1 Y2 Y3
Control
Treatment
Rx
Control
SlowerPaceofAging
NormalPaceofAging
Years
Belsky 2017
24
Part 1 Summary
• Biological aging may be a modifiable risk factor for age-related disease and disability
• New (and old) therapies to slow biological aging now have proof-of-concept in animal models, and more are on the way
• Translation of midlife geroprotective interventions to humans faces a barrier – follow-up takes too long
• Translation to humans can be accelerated using study designs that measure biological aging as a surrogate endpoint for healthspanextension
Outline
IntroductionBiological aging is a treatment target for healthspan extension
Part 1. Human trials of geroprotectorsChallenges & opportunities
Part 2. Quantification of biological aging in young adults
Part 3. Testing biological aging in a geroprotector trial
Conclusion
26
27
www.moffittcaspi.com
28
The Dunedin Longitudinal Study
*Percentassessed,ofthosewhowerealiveateachage.
Age Year Number Percent*
Birth 1972-733 1975-76 1037 100%5 1977-78 991 967 1979-80 954 929 1981-82 955 9211 1983-84 925 9013 1985-86 850 8215 1987-88 976 9518 1990-91 993 9721 1993-94 992 9726 1998-99 980 9632 2004-05 972 96
38 2010-12 961 95%45 2017-18 ?? ??
29
The Dunedin Longitudinal Study
*Percentassessed,ofthosewhowerealiveateachage.
Age Year Number Percent*
Birth 1972-733 1975-76 1037 100%5 1977-78 991 967 1979-80 954 929 1981-82 955 9211 1983-84 925 9013 1985-86 850 8215 1987-88 976 9518 1990-91 993 9721 1993-94 992 9726 1998-99 980 9632 2004-05 972 96
38 2010-12 961 95%45 2017-18 ?? ??
30
Can we measure the rate of aging in young, healthy humans?
31
The Pace of Aging
Quantification of biological aging in young adultsDaniel W. Belskya,b,1, Avshalom Caspic,d,e,f, Renate Houtsc, Harvey J. Cohena, David L. Corcorane, Andrea Danesef,g,HonaLee Harringtonc, Salomon Israelh, Morgan E. Levinei, Jonathan D. Schaeferc, Karen Sugdenc, Ben Williamsc,Anatoli I. Yashinb, Richie Poultonj, and Terrie E. Moffittc,d,e,f
aDepartment of Medicine, Duke University School of Medicine, Durham, NC 27710; bSocial Science Research Institute, Duke University, Durham, NC 27708;cDepartment of Psychology & Neuroscience, Duke University, Durham, NC 27708; dDepartment of Psychiatry & Behavioral Sciences, Duke UniversitySchool of Medicine, Durham, NC 27708; eCenter for Genomic and Computational Biology, Duke University, Durham, NC 27708; fSocial, Genetic, &Developmental Psychiatry Research Centre, Institute of Psychiatry, Kings College London, London SE5 8AF, United Kingdom; gDepartment of Child &Adolescent Psychiatry, Institute of Psychiatry, King’s College London, London SE5 8AF, United Kingdom; hDepartment of Psychology, The HebrewUniversity of Jerusalem, Jerusalem 91905, Israel; iDepartment of Human Genetics, Gonda Research Center, David Geffen School of Medicine, University ofCalifornia, Los Angeles, CA 90095; and jDepartment of Psychology, University of Otago, Dunedin 9016, New Zealand
Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved June 1, 2015 (received for review March 30, 2015)
Antiaging therapies show promise in model organism research.Translation to humans is needed to address the challenges of anaging global population. Interventions to slow human aging willneed to be applied to still-young individuals. However, most humanaging research examines older adults, manywith chronic disease. Asa result, little is known about aging in young humans. We studiedaging in 954 young humans, the Dunedin Study birth cohort,tracking multiple biomarkers across three time points spanningtheir third and fourth decades of life. We developed and validatedtwo methods by which aging can be measured in young adults,one cross-sectional and one longitudinal. Our longitudinal mea-sure allows quantification of the pace of coordinated physiologicaldeterioration across multiple organ systems (e.g., pulmonary,periodontal, cardiovascular, renal, hepatic, and immune function).We applied these methods to assess biological aging in younghumans who had not yet developed age-related diseases. Youngindividuals of the same chronological age varied in their “biologicalaging” (declining integrity of multiple organ systems). Already,before midlife, individuals who were aging more rapidly were lessphysically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biologicalaging in young adults can be used to identify causes of agingand evaluate rejuvenation therapies.
biological aging | cognitive aging | aging | healthspan | geroscience
By 2050, the world population aged 80 y and above will morethan triple, approaching 400 million individuals (1, 2). As the
population ages, the global burden of disease and disability isrising (3). From the fifth decade of life, advancing age is asso-ciated with an exponential increase in burden from many differentchronic conditions (Fig. 1). The most effective means to reducedisease burden and control costs is to delay this progression byextending healthspan, years of life lived free of disease and dis-ability (4). A key to extending healthspan is addressing the prob-lem of aging itself (5–8).At present, much research on aging is being carried out with
animals and older humans. Paradoxically, these seemingly sen-sible strategies pose translational difficulties. The difficulty withstudying aging in old humans is that many of them already haveage-related diseases (9–11). Age-related changes to physiologyaccumulate from early life, affecting organ systems years beforedisease diagnosis (12–15). Thus, intervention to reverse or delaythe march toward age-related diseases must be scheduled whilepeople are still young (16). Early interventions to slow aging canbe tested in model organisms (17, 18). The difficulty with thesenonhuman models is that they do not typically capture thecomplex multifactorial risks and exposures that shape humanaging. Moreover, whereas animals’ brief lives make it feasible tostudy animal aging in the laboratory, humans’ lives span manyyears. A solution is to study human aging in the first half of thelife course, when individuals are starting to diverge in their aging
trajectories, before most diseases (and regimens to managethem) become established. The main obstacle to studying agingbefore old age—and before the onset of age-related diseases—is the absence of methods to quantify the Pace of Aging inyoung humans.We studied aging in a population-representative 1972–1973 birth
cohort of 1,037 young adults followed from birth to age 38 y with95% retention: the Dunedin Study (SI Appendix). When they were38 y old, we examined their physiologies to test whether this youngpopulation would show evidence of individual variation in agingdespite remaining free of age-related disease. We next tested thehypothesis that cohort members with “older” physiologies at age 38had actually been aging faster than their same chronologically agedpeers who retained “younger” physiologies; specifically, we testedwhether indicators of the integrity of their cardiovascular, meta-bolic, and immune systems, their kidneys, livers, gums, and lungs,and their DNA had deteriorated more rapidly according to mea-surements taken repeatedly since a baseline 12 y earlier at age 26.We further tested whether, by midlife, young adults who wereaging more rapidly already exhibited deficits in their physicalfunctioning, showed signs of early cognitive decline, and lookedolder to independent observers.
ResultsAre Young Adults Aging at Different Rates? Measuring the aging pro-cess is controversial. Candidate biomarkers of aging are numerous,
Significance
The global population is aging, driving up age-related diseasemorbidity. Antiaging interventions are needed to reduce theburden of disease and protect population productivity. Youngpeople are the most attractive targets for therapies to extendhealthspan (because it is still possible to prevent disease in theyoung). However, there is skepticism about whether agingprocesses can be detected in young adults who do not yet havechronic diseases. Our findings indicate that aging processes canbe quantified in people still young enough for prevention ofage-related disease, opening a new door for antiaging thera-pies. The science of healthspan extension may be focused onthe wrong end of the lifespan; rather than only studying oldhumans, geroscience should also study the young.
Author contributions: D.W.B., A.C., R.P., and T.E.M. designed research; D.W.B., A.C., R.H.,H.J.C., D.L.C., A.D., H.H., S.I., M.E.L., J.D.S., K.S., B.W., A.I.Y., R.P., and T.E.M. performedresearch; M.E.L. contributed new reagents/analytic tools; D.W.B., A.C., R.H., H.H., andT.E.M. analyzed data; and D.W.B., A.C., and T.E.M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Freely available online through the PNAS open access option.1To whom correspondence should be addressed. Email: [email protected].
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1506264112/-/DCSupplemental.
www.pnas.org/cgi/doi/10.1073/pnas.1506264112 PNAS Early Edition | 1 of 7
MED
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SPS
YCHO
LOGICALAND
COGNITIVESC
IENCE
SPN
ASPL
US
Belsky et al. 2015 PNAS
Agingischaracterizedbyagradualandprogressivedeclineinsystemintegrity
Therateofagingcanbeinferredfromtherateofdeclineinintegrityacrossmultipleorgansystems
32
The Pace of Aging
Quantification of biological aging in young adultsDaniel W. Belskya,b,1, Avshalom Caspic,d,e,f, Renate Houtsc, Harvey J. Cohena, David L. Corcorane, Andrea Danesef,g,HonaLee Harringtonc, Salomon Israelh, Morgan E. Levinei, Jonathan D. Schaeferc, Karen Sugdenc, Ben Williamsc,Anatoli I. Yashinb, Richie Poultonj, and Terrie E. Moffittc,d,e,f
aDepartment of Medicine, Duke University School of Medicine, Durham, NC 27710; bSocial Science Research Institute, Duke University, Durham, NC 27708;cDepartment of Psychology & Neuroscience, Duke University, Durham, NC 27708; dDepartment of Psychiatry & Behavioral Sciences, Duke UniversitySchool of Medicine, Durham, NC 27708; eCenter for Genomic and Computational Biology, Duke University, Durham, NC 27708; fSocial, Genetic, &Developmental Psychiatry Research Centre, Institute of Psychiatry, Kings College London, London SE5 8AF, United Kingdom; gDepartment of Child &Adolescent Psychiatry, Institute of Psychiatry, King’s College London, London SE5 8AF, United Kingdom; hDepartment of Psychology, The HebrewUniversity of Jerusalem, Jerusalem 91905, Israel; iDepartment of Human Genetics, Gonda Research Center, David Geffen School of Medicine, University ofCalifornia, Los Angeles, CA 90095; and jDepartment of Psychology, University of Otago, Dunedin 9016, New Zealand
Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved June 1, 2015 (received for review March 30, 2015)
Antiaging therapies show promise in model organism research.Translation to humans is needed to address the challenges of anaging global population. Interventions to slow human aging willneed to be applied to still-young individuals. However, most humanaging research examines older adults, manywith chronic disease. Asa result, little is known about aging in young humans. We studiedaging in 954 young humans, the Dunedin Study birth cohort,tracking multiple biomarkers across three time points spanningtheir third and fourth decades of life. We developed and validatedtwo methods by which aging can be measured in young adults,one cross-sectional and one longitudinal. Our longitudinal mea-sure allows quantification of the pace of coordinated physiologicaldeterioration across multiple organ systems (e.g., pulmonary,periodontal, cardiovascular, renal, hepatic, and immune function).We applied these methods to assess biological aging in younghumans who had not yet developed age-related diseases. Youngindividuals of the same chronological age varied in their “biologicalaging” (declining integrity of multiple organ systems). Already,before midlife, individuals who were aging more rapidly were lessphysically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biologicalaging in young adults can be used to identify causes of agingand evaluate rejuvenation therapies.
biological aging | cognitive aging | aging | healthspan | geroscience
By 2050, the world population aged 80 y and above will morethan triple, approaching 400 million individuals (1, 2). As the
population ages, the global burden of disease and disability isrising (3). From the fifth decade of life, advancing age is asso-ciated with an exponential increase in burden from many differentchronic conditions (Fig. 1). The most effective means to reducedisease burden and control costs is to delay this progression byextending healthspan, years of life lived free of disease and dis-ability (4). A key to extending healthspan is addressing the prob-lem of aging itself (5–8).At present, much research on aging is being carried out with
animals and older humans. Paradoxically, these seemingly sen-sible strategies pose translational difficulties. The difficulty withstudying aging in old humans is that many of them already haveage-related diseases (9–11). Age-related changes to physiologyaccumulate from early life, affecting organ systems years beforedisease diagnosis (12–15). Thus, intervention to reverse or delaythe march toward age-related diseases must be scheduled whilepeople are still young (16). Early interventions to slow aging canbe tested in model organisms (17, 18). The difficulty with thesenonhuman models is that they do not typically capture thecomplex multifactorial risks and exposures that shape humanaging. Moreover, whereas animals’ brief lives make it feasible tostudy animal aging in the laboratory, humans’ lives span manyyears. A solution is to study human aging in the first half of thelife course, when individuals are starting to diverge in their aging
trajectories, before most diseases (and regimens to managethem) become established. The main obstacle to studying agingbefore old age—and before the onset of age-related diseases—is the absence of methods to quantify the Pace of Aging inyoung humans.We studied aging in a population-representative 1972–1973 birth
cohort of 1,037 young adults followed from birth to age 38 y with95% retention: the Dunedin Study (SI Appendix). When they were38 y old, we examined their physiologies to test whether this youngpopulation would show evidence of individual variation in agingdespite remaining free of age-related disease. We next tested thehypothesis that cohort members with “older” physiologies at age 38had actually been aging faster than their same chronologically agedpeers who retained “younger” physiologies; specifically, we testedwhether indicators of the integrity of their cardiovascular, meta-bolic, and immune systems, their kidneys, livers, gums, and lungs,and their DNA had deteriorated more rapidly according to mea-surements taken repeatedly since a baseline 12 y earlier at age 26.We further tested whether, by midlife, young adults who wereaging more rapidly already exhibited deficits in their physicalfunctioning, showed signs of early cognitive decline, and lookedolder to independent observers.
ResultsAre Young Adults Aging at Different Rates? Measuring the aging pro-cess is controversial. Candidate biomarkers of aging are numerous,
Significance
The global population is aging, driving up age-related diseasemorbidity. Antiaging interventions are needed to reduce theburden of disease and protect population productivity. Youngpeople are the most attractive targets for therapies to extendhealthspan (because it is still possible to prevent disease in theyoung). However, there is skepticism about whether agingprocesses can be detected in young adults who do not yet havechronic diseases. Our findings indicate that aging processes canbe quantified in people still young enough for prevention ofage-related disease, opening a new door for antiaging thera-pies. The science of healthspan extension may be focused onthe wrong end of the lifespan; rather than only studying oldhumans, geroscience should also study the young.
Author contributions: D.W.B., A.C., R.P., and T.E.M. designed research; D.W.B., A.C., R.H.,H.J.C., D.L.C., A.D., H.H., S.I., M.E.L., J.D.S., K.S., B.W., A.I.Y., R.P., and T.E.M. performedresearch; M.E.L. contributed new reagents/analytic tools; D.W.B., A.C., R.H., H.H., andT.E.M. analyzed data; and D.W.B., A.C., and T.E.M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Freely available online through the PNAS open access option.1To whom correspondence should be addressed. Email: [email protected].
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1506264112/-/DCSupplemental.
www.pnas.org/cgi/doi/10.1073/pnas.1506264112 PNAS Early Edition | 1 of 7
MED
ICALSC
IENCE
SPS
YCHO
LOGICALAND
COGNITIVESC
IENCE
SPN
ASPL
US
Belsky et al. 2015 PNAS
GingivalRecession
LTLWBCCRP
VO2max
CreatinineBUN
BMI,WHR
FEV1FEV1/FVC
TotCholesterolHDL,TriglyceridesLipoprotein(a)ApoB100/ApoA1
HbA1C
MeanArterialPressure
33
The Pace of Aging
Quantification of biological aging in young adultsDaniel W. Belskya,b,1, Avshalom Caspic,d,e,f, Renate Houtsc, Harvey J. Cohena, David L. Corcorane, Andrea Danesef,g,HonaLee Harringtonc, Salomon Israelh, Morgan E. Levinei, Jonathan D. Schaeferc, Karen Sugdenc, Ben Williamsc,Anatoli I. Yashinb, Richie Poultonj, and Terrie E. Moffittc,d,e,f
aDepartment of Medicine, Duke University School of Medicine, Durham, NC 27710; bSocial Science Research Institute, Duke University, Durham, NC 27708;cDepartment of Psychology & Neuroscience, Duke University, Durham, NC 27708; dDepartment of Psychiatry & Behavioral Sciences, Duke UniversitySchool of Medicine, Durham, NC 27708; eCenter for Genomic and Computational Biology, Duke University, Durham, NC 27708; fSocial, Genetic, &Developmental Psychiatry Research Centre, Institute of Psychiatry, Kings College London, London SE5 8AF, United Kingdom; gDepartment of Child &Adolescent Psychiatry, Institute of Psychiatry, King’s College London, London SE5 8AF, United Kingdom; hDepartment of Psychology, The HebrewUniversity of Jerusalem, Jerusalem 91905, Israel; iDepartment of Human Genetics, Gonda Research Center, David Geffen School of Medicine, University ofCalifornia, Los Angeles, CA 90095; and jDepartment of Psychology, University of Otago, Dunedin 9016, New Zealand
Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved June 1, 2015 (received for review March 30, 2015)
Antiaging therapies show promise in model organism research.Translation to humans is needed to address the challenges of anaging global population. Interventions to slow human aging willneed to be applied to still-young individuals. However, most humanaging research examines older adults, manywith chronic disease. Asa result, little is known about aging in young humans. We studiedaging in 954 young humans, the Dunedin Study birth cohort,tracking multiple biomarkers across three time points spanningtheir third and fourth decades of life. We developed and validatedtwo methods by which aging can be measured in young adults,one cross-sectional and one longitudinal. Our longitudinal mea-sure allows quantification of the pace of coordinated physiologicaldeterioration across multiple organ systems (e.g., pulmonary,periodontal, cardiovascular, renal, hepatic, and immune function).We applied these methods to assess biological aging in younghumans who had not yet developed age-related diseases. Youngindividuals of the same chronological age varied in their “biologicalaging” (declining integrity of multiple organ systems). Already,before midlife, individuals who were aging more rapidly were lessphysically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biologicalaging in young adults can be used to identify causes of agingand evaluate rejuvenation therapies.
biological aging | cognitive aging | aging | healthspan | geroscience
By 2050, the world population aged 80 y and above will morethan triple, approaching 400 million individuals (1, 2). As the
population ages, the global burden of disease and disability isrising (3). From the fifth decade of life, advancing age is asso-ciated with an exponential increase in burden from many differentchronic conditions (Fig. 1). The most effective means to reducedisease burden and control costs is to delay this progression byextending healthspan, years of life lived free of disease and dis-ability (4). A key to extending healthspan is addressing the prob-lem of aging itself (5–8).At present, much research on aging is being carried out with
animals and older humans. Paradoxically, these seemingly sen-sible strategies pose translational difficulties. The difficulty withstudying aging in old humans is that many of them already haveage-related diseases (9–11). Age-related changes to physiologyaccumulate from early life, affecting organ systems years beforedisease diagnosis (12–15). Thus, intervention to reverse or delaythe march toward age-related diseases must be scheduled whilepeople are still young (16). Early interventions to slow aging canbe tested in model organisms (17, 18). The difficulty with thesenonhuman models is that they do not typically capture thecomplex multifactorial risks and exposures that shape humanaging. Moreover, whereas animals’ brief lives make it feasible tostudy animal aging in the laboratory, humans’ lives span manyyears. A solution is to study human aging in the first half of thelife course, when individuals are starting to diverge in their aging
trajectories, before most diseases (and regimens to managethem) become established. The main obstacle to studying agingbefore old age—and before the onset of age-related diseases—is the absence of methods to quantify the Pace of Aging inyoung humans.We studied aging in a population-representative 1972–1973 birth
cohort of 1,037 young adults followed from birth to age 38 y with95% retention: the Dunedin Study (SI Appendix). When they were38 y old, we examined their physiologies to test whether this youngpopulation would show evidence of individual variation in agingdespite remaining free of age-related disease. We next tested thehypothesis that cohort members with “older” physiologies at age 38had actually been aging faster than their same chronologically agedpeers who retained “younger” physiologies; specifically, we testedwhether indicators of the integrity of their cardiovascular, meta-bolic, and immune systems, their kidneys, livers, gums, and lungs,and their DNA had deteriorated more rapidly according to mea-surements taken repeatedly since a baseline 12 y earlier at age 26.We further tested whether, by midlife, young adults who wereaging more rapidly already exhibited deficits in their physicalfunctioning, showed signs of early cognitive decline, and lookedolder to independent observers.
ResultsAre Young Adults Aging at Different Rates? Measuring the aging pro-cess is controversial. Candidate biomarkers of aging are numerous,
Significance
The global population is aging, driving up age-related diseasemorbidity. Antiaging interventions are needed to reduce theburden of disease and protect population productivity. Youngpeople are the most attractive targets for therapies to extendhealthspan (because it is still possible to prevent disease in theyoung). However, there is skepticism about whether agingprocesses can be detected in young adults who do not yet havechronic diseases. Our findings indicate that aging processes canbe quantified in people still young enough for prevention ofage-related disease, opening a new door for antiaging thera-pies. The science of healthspan extension may be focused onthe wrong end of the lifespan; rather than only studying oldhumans, geroscience should also study the young.
Author contributions: D.W.B., A.C., R.P., and T.E.M. designed research; D.W.B., A.C., R.H.,H.J.C., D.L.C., A.D., H.H., S.I., M.E.L., J.D.S., K.S., B.W., A.I.Y., R.P., and T.E.M. performedresearch; M.E.L. contributed new reagents/analytic tools; D.W.B., A.C., R.H., H.H., andT.E.M. analyzed data; and D.W.B., A.C., and T.E.M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Freely available online through the PNAS open access option.1To whom correspondence should be addressed. Email: [email protected].
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1506264112/-/DCSupplemental.
www.pnas.org/cgi/doi/10.1073/pnas.1506264112 PNAS Early Edition | 1 of 7
MED
ICALSC
IENCE
SPS
YCHO
LOGICALAND
COGNITIVESC
IENCE
SPN
ASPL
US
Belsky et al. 2015 PNAS
GingivalRecession
LTLWBCCRP
VO2max
CreatinineBUN
BMI,WHR
FEV1FEV1/FVC
TotCholesterolHDL,TriglyceridesLipoprotein(a)ApoB100/ApoA1
HbA1C
MeanArterialPressure
34
The Pace of Aging
Quantification of biological aging in young adultsDaniel W. Belskya,b,1, Avshalom Caspic,d,e,f, Renate Houtsc, Harvey J. Cohena, David L. Corcorane, Andrea Danesef,g,HonaLee Harringtonc, Salomon Israelh, Morgan E. Levinei, Jonathan D. Schaeferc, Karen Sugdenc, Ben Williamsc,Anatoli I. Yashinb, Richie Poultonj, and Terrie E. Moffittc,d,e,f
aDepartment of Medicine, Duke University School of Medicine, Durham, NC 27710; bSocial Science Research Institute, Duke University, Durham, NC 27708;cDepartment of Psychology & Neuroscience, Duke University, Durham, NC 27708; dDepartment of Psychiatry & Behavioral Sciences, Duke UniversitySchool of Medicine, Durham, NC 27708; eCenter for Genomic and Computational Biology, Duke University, Durham, NC 27708; fSocial, Genetic, &Developmental Psychiatry Research Centre, Institute of Psychiatry, Kings College London, London SE5 8AF, United Kingdom; gDepartment of Child &Adolescent Psychiatry, Institute of Psychiatry, King’s College London, London SE5 8AF, United Kingdom; hDepartment of Psychology, The HebrewUniversity of Jerusalem, Jerusalem 91905, Israel; iDepartment of Human Genetics, Gonda Research Center, David Geffen School of Medicine, University ofCalifornia, Los Angeles, CA 90095; and jDepartment of Psychology, University of Otago, Dunedin 9016, New Zealand
Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved June 1, 2015 (received for review March 30, 2015)
Antiaging therapies show promise in model organism research.Translation to humans is needed to address the challenges of anaging global population. Interventions to slow human aging willneed to be applied to still-young individuals. However, most humanaging research examines older adults, manywith chronic disease. Asa result, little is known about aging in young humans. We studiedaging in 954 young humans, the Dunedin Study birth cohort,tracking multiple biomarkers across three time points spanningtheir third and fourth decades of life. We developed and validatedtwo methods by which aging can be measured in young adults,one cross-sectional and one longitudinal. Our longitudinal mea-sure allows quantification of the pace of coordinated physiologicaldeterioration across multiple organ systems (e.g., pulmonary,periodontal, cardiovascular, renal, hepatic, and immune function).We applied these methods to assess biological aging in younghumans who had not yet developed age-related diseases. Youngindividuals of the same chronological age varied in their “biologicalaging” (declining integrity of multiple organ systems). Already,before midlife, individuals who were aging more rapidly were lessphysically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biologicalaging in young adults can be used to identify causes of agingand evaluate rejuvenation therapies.
biological aging | cognitive aging | aging | healthspan | geroscience
By 2050, the world population aged 80 y and above will morethan triple, approaching 400 million individuals (1, 2). As the
population ages, the global burden of disease and disability isrising (3). From the fifth decade of life, advancing age is asso-ciated with an exponential increase in burden from many differentchronic conditions (Fig. 1). The most effective means to reducedisease burden and control costs is to delay this progression byextending healthspan, years of life lived free of disease and dis-ability (4). A key to extending healthspan is addressing the prob-lem of aging itself (5–8).At present, much research on aging is being carried out with
animals and older humans. Paradoxically, these seemingly sen-sible strategies pose translational difficulties. The difficulty withstudying aging in old humans is that many of them already haveage-related diseases (9–11). Age-related changes to physiologyaccumulate from early life, affecting organ systems years beforedisease diagnosis (12–15). Thus, intervention to reverse or delaythe march toward age-related diseases must be scheduled whilepeople are still young (16). Early interventions to slow aging canbe tested in model organisms (17, 18). The difficulty with thesenonhuman models is that they do not typically capture thecomplex multifactorial risks and exposures that shape humanaging. Moreover, whereas animals’ brief lives make it feasible tostudy animal aging in the laboratory, humans’ lives span manyyears. A solution is to study human aging in the first half of thelife course, when individuals are starting to diverge in their aging
trajectories, before most diseases (and regimens to managethem) become established. The main obstacle to studying agingbefore old age—and before the onset of age-related diseases—is the absence of methods to quantify the Pace of Aging inyoung humans.We studied aging in a population-representative 1972–1973 birth
cohort of 1,037 young adults followed from birth to age 38 y with95% retention: the Dunedin Study (SI Appendix). When they were38 y old, we examined their physiologies to test whether this youngpopulation would show evidence of individual variation in agingdespite remaining free of age-related disease. We next tested thehypothesis that cohort members with “older” physiologies at age 38had actually been aging faster than their same chronologically agedpeers who retained “younger” physiologies; specifically, we testedwhether indicators of the integrity of their cardiovascular, meta-bolic, and immune systems, their kidneys, livers, gums, and lungs,and their DNA had deteriorated more rapidly according to mea-surements taken repeatedly since a baseline 12 y earlier at age 26.We further tested whether, by midlife, young adults who wereaging more rapidly already exhibited deficits in their physicalfunctioning, showed signs of early cognitive decline, and lookedolder to independent observers.
ResultsAre Young Adults Aging at Different Rates? Measuring the aging pro-cess is controversial. Candidate biomarkers of aging are numerous,
Significance
The global population is aging, driving up age-related diseasemorbidity. Antiaging interventions are needed to reduce theburden of disease and protect population productivity. Youngpeople are the most attractive targets for therapies to extendhealthspan (because it is still possible to prevent disease in theyoung). However, there is skepticism about whether agingprocesses can be detected in young adults who do not yet havechronic diseases. Our findings indicate that aging processes canbe quantified in people still young enough for prevention ofage-related disease, opening a new door for antiaging thera-pies. The science of healthspan extension may be focused onthe wrong end of the lifespan; rather than only studying oldhumans, geroscience should also study the young.
Author contributions: D.W.B., A.C., R.P., and T.E.M. designed research; D.W.B., A.C., R.H.,H.J.C., D.L.C., A.D., H.H., S.I., M.E.L., J.D.S., K.S., B.W., A.I.Y., R.P., and T.E.M. performedresearch; M.E.L. contributed new reagents/analytic tools; D.W.B., A.C., R.H., H.H., andT.E.M. analyzed data; and D.W.B., A.C., and T.E.M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Freely available online through the PNAS open access option.1To whom correspondence should be addressed. Email: [email protected].
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1506264112/-/DCSupplemental.
www.pnas.org/cgi/doi/10.1073/pnas.1506264112 PNAS Early Edition | 1 of 7
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Belsky et al. 2015 PNAS
GingivalRecession
LTLWBCCRP
VO2max
CreatinineBUN
BMI,WHR
FEV1FEV1/FVC
TotCholesterolHDL,TriglyceridesLipoprotein(a)ApoB100/ApoA1
HbA1C
MeanArterialPressure
35
The Pace of Aging
Quantification of biological aging in young adultsDaniel W. Belskya,b,1, Avshalom Caspic,d,e,f, Renate Houtsc, Harvey J. Cohena, David L. Corcorane, Andrea Danesef,g,HonaLee Harringtonc, Salomon Israelh, Morgan E. Levinei, Jonathan D. Schaeferc, Karen Sugdenc, Ben Williamsc,Anatoli I. Yashinb, Richie Poultonj, and Terrie E. Moffittc,d,e,f
aDepartment of Medicine, Duke University School of Medicine, Durham, NC 27710; bSocial Science Research Institute, Duke University, Durham, NC 27708;cDepartment of Psychology & Neuroscience, Duke University, Durham, NC 27708; dDepartment of Psychiatry & Behavioral Sciences, Duke UniversitySchool of Medicine, Durham, NC 27708; eCenter for Genomic and Computational Biology, Duke University, Durham, NC 27708; fSocial, Genetic, &Developmental Psychiatry Research Centre, Institute of Psychiatry, Kings College London, London SE5 8AF, United Kingdom; gDepartment of Child &Adolescent Psychiatry, Institute of Psychiatry, King’s College London, London SE5 8AF, United Kingdom; hDepartment of Psychology, The HebrewUniversity of Jerusalem, Jerusalem 91905, Israel; iDepartment of Human Genetics, Gonda Research Center, David Geffen School of Medicine, University ofCalifornia, Los Angeles, CA 90095; and jDepartment of Psychology, University of Otago, Dunedin 9016, New Zealand
Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved June 1, 2015 (received for review March 30, 2015)
Antiaging therapies show promise in model organism research.Translation to humans is needed to address the challenges of anaging global population. Interventions to slow human aging willneed to be applied to still-young individuals. However, most humanaging research examines older adults, manywith chronic disease. Asa result, little is known about aging in young humans. We studiedaging in 954 young humans, the Dunedin Study birth cohort,tracking multiple biomarkers across three time points spanningtheir third and fourth decades of life. We developed and validatedtwo methods by which aging can be measured in young adults,one cross-sectional and one longitudinal. Our longitudinal mea-sure allows quantification of the pace of coordinated physiologicaldeterioration across multiple organ systems (e.g., pulmonary,periodontal, cardiovascular, renal, hepatic, and immune function).We applied these methods to assess biological aging in younghumans who had not yet developed age-related diseases. Youngindividuals of the same chronological age varied in their “biologicalaging” (declining integrity of multiple organ systems). Already,before midlife, individuals who were aging more rapidly were lessphysically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biologicalaging in young adults can be used to identify causes of agingand evaluate rejuvenation therapies.
biological aging | cognitive aging | aging | healthspan | geroscience
By 2050, the world population aged 80 y and above will morethan triple, approaching 400 million individuals (1, 2). As the
population ages, the global burden of disease and disability isrising (3). From the fifth decade of life, advancing age is asso-ciated with an exponential increase in burden from many differentchronic conditions (Fig. 1). The most effective means to reducedisease burden and control costs is to delay this progression byextending healthspan, years of life lived free of disease and dis-ability (4). A key to extending healthspan is addressing the prob-lem of aging itself (5–8).At present, much research on aging is being carried out with
animals and older humans. Paradoxically, these seemingly sen-sible strategies pose translational difficulties. The difficulty withstudying aging in old humans is that many of them already haveage-related diseases (9–11). Age-related changes to physiologyaccumulate from early life, affecting organ systems years beforedisease diagnosis (12–15). Thus, intervention to reverse or delaythe march toward age-related diseases must be scheduled whilepeople are still young (16). Early interventions to slow aging canbe tested in model organisms (17, 18). The difficulty with thesenonhuman models is that they do not typically capture thecomplex multifactorial risks and exposures that shape humanaging. Moreover, whereas animals’ brief lives make it feasible tostudy animal aging in the laboratory, humans’ lives span manyyears. A solution is to study human aging in the first half of thelife course, when individuals are starting to diverge in their aging
trajectories, before most diseases (and regimens to managethem) become established. The main obstacle to studying agingbefore old age—and before the onset of age-related diseases—is the absence of methods to quantify the Pace of Aging inyoung humans.We studied aging in a population-representative 1972–1973 birth
cohort of 1,037 young adults followed from birth to age 38 y with95% retention: the Dunedin Study (SI Appendix). When they were38 y old, we examined their physiologies to test whether this youngpopulation would show evidence of individual variation in agingdespite remaining free of age-related disease. We next tested thehypothesis that cohort members with “older” physiologies at age 38had actually been aging faster than their same chronologically agedpeers who retained “younger” physiologies; specifically, we testedwhether indicators of the integrity of their cardiovascular, meta-bolic, and immune systems, their kidneys, livers, gums, and lungs,and their DNA had deteriorated more rapidly according to mea-surements taken repeatedly since a baseline 12 y earlier at age 26.We further tested whether, by midlife, young adults who wereaging more rapidly already exhibited deficits in their physicalfunctioning, showed signs of early cognitive decline, and lookedolder to independent observers.
ResultsAre Young Adults Aging at Different Rates? Measuring the aging pro-cess is controversial. Candidate biomarkers of aging are numerous,
Significance
The global population is aging, driving up age-related diseasemorbidity. Antiaging interventions are needed to reduce theburden of disease and protect population productivity. Youngpeople are the most attractive targets for therapies to extendhealthspan (because it is still possible to prevent disease in theyoung). However, there is skepticism about whether agingprocesses can be detected in young adults who do not yet havechronic diseases. Our findings indicate that aging processes canbe quantified in people still young enough for prevention ofage-related disease, opening a new door for antiaging thera-pies. The science of healthspan extension may be focused onthe wrong end of the lifespan; rather than only studying oldhumans, geroscience should also study the young.
Author contributions: D.W.B., A.C., R.P., and T.E.M. designed research; D.W.B., A.C., R.H.,H.J.C., D.L.C., A.D., H.H., S.I., M.E.L., J.D.S., K.S., B.W., A.I.Y., R.P., and T.E.M. performedresearch; M.E.L. contributed new reagents/analytic tools; D.W.B., A.C., R.H., H.H., andT.E.M. analyzed data; and D.W.B., A.C., and T.E.M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Freely available online through the PNAS open access option.1To whom correspondence should be addressed. Email: [email protected].
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1506264112/-/DCSupplemental.
www.pnas.org/cgi/doi/10.1073/pnas.1506264112 PNAS Early Edition | 1 of 7
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COGNITIVESC
IENCE
SPN
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Belsky et al. 2015 PNAS
GingivalRecession
LTLWBCCRP
VO2max
CreatinineBUN
BMI,WHR
FEV1FEV1/FVC
TotCholesterolHDL,TriglyceridesLipoprotein(a)ApoB100/ApoA1
HbA1C
MeanArterialPressure
0
5
10
15
Perc
ent
0.0 0.5 1.0 1.5 2.0Years of Physiological Change Per One Chronological Year
Pace of Aging 26-38
36
The Pace of Aging
Quantification of biological aging in young adultsDaniel W. Belskya,b,1, Avshalom Caspic,d,e,f, Renate Houtsc, Harvey J. Cohena, David L. Corcorane, Andrea Danesef,g,HonaLee Harringtonc, Salomon Israelh, Morgan E. Levinei, Jonathan D. Schaeferc, Karen Sugdenc, Ben Williamsc,Anatoli I. Yashinb, Richie Poultonj, and Terrie E. Moffittc,d,e,f
aDepartment of Medicine, Duke University School of Medicine, Durham, NC 27710; bSocial Science Research Institute, Duke University, Durham, NC 27708;cDepartment of Psychology & Neuroscience, Duke University, Durham, NC 27708; dDepartment of Psychiatry & Behavioral Sciences, Duke UniversitySchool of Medicine, Durham, NC 27708; eCenter for Genomic and Computational Biology, Duke University, Durham, NC 27708; fSocial, Genetic, &Developmental Psychiatry Research Centre, Institute of Psychiatry, Kings College London, London SE5 8AF, United Kingdom; gDepartment of Child &Adolescent Psychiatry, Institute of Psychiatry, King’s College London, London SE5 8AF, United Kingdom; hDepartment of Psychology, The HebrewUniversity of Jerusalem, Jerusalem 91905, Israel; iDepartment of Human Genetics, Gonda Research Center, David Geffen School of Medicine, University ofCalifornia, Los Angeles, CA 90095; and jDepartment of Psychology, University of Otago, Dunedin 9016, New Zealand
Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved June 1, 2015 (received for review March 30, 2015)
Antiaging therapies show promise in model organism research.Translation to humans is needed to address the challenges of anaging global population. Interventions to slow human aging willneed to be applied to still-young individuals. However, most humanaging research examines older adults, manywith chronic disease. Asa result, little is known about aging in young humans. We studiedaging in 954 young humans, the Dunedin Study birth cohort,tracking multiple biomarkers across three time points spanningtheir third and fourth decades of life. We developed and validatedtwo methods by which aging can be measured in young adults,one cross-sectional and one longitudinal. Our longitudinal mea-sure allows quantification of the pace of coordinated physiologicaldeterioration across multiple organ systems (e.g., pulmonary,periodontal, cardiovascular, renal, hepatic, and immune function).We applied these methods to assess biological aging in younghumans who had not yet developed age-related diseases. Youngindividuals of the same chronological age varied in their “biologicalaging” (declining integrity of multiple organ systems). Already,before midlife, individuals who were aging more rapidly were lessphysically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biologicalaging in young adults can be used to identify causes of agingand evaluate rejuvenation therapies.
biological aging | cognitive aging | aging | healthspan | geroscience
By 2050, the world population aged 80 y and above will morethan triple, approaching 400 million individuals (1, 2). As the
population ages, the global burden of disease and disability isrising (3). From the fifth decade of life, advancing age is asso-ciated with an exponential increase in burden from many differentchronic conditions (Fig. 1). The most effective means to reducedisease burden and control costs is to delay this progression byextending healthspan, years of life lived free of disease and dis-ability (4). A key to extending healthspan is addressing the prob-lem of aging itself (5–8).At present, much research on aging is being carried out with
animals and older humans. Paradoxically, these seemingly sen-sible strategies pose translational difficulties. The difficulty withstudying aging in old humans is that many of them already haveage-related diseases (9–11). Age-related changes to physiologyaccumulate from early life, affecting organ systems years beforedisease diagnosis (12–15). Thus, intervention to reverse or delaythe march toward age-related diseases must be scheduled whilepeople are still young (16). Early interventions to slow aging canbe tested in model organisms (17, 18). The difficulty with thesenonhuman models is that they do not typically capture thecomplex multifactorial risks and exposures that shape humanaging. Moreover, whereas animals’ brief lives make it feasible tostudy animal aging in the laboratory, humans’ lives span manyyears. A solution is to study human aging in the first half of thelife course, when individuals are starting to diverge in their aging
trajectories, before most diseases (and regimens to managethem) become established. The main obstacle to studying agingbefore old age—and before the onset of age-related diseases—is the absence of methods to quantify the Pace of Aging inyoung humans.We studied aging in a population-representative 1972–1973 birth
cohort of 1,037 young adults followed from birth to age 38 y with95% retention: the Dunedin Study (SI Appendix). When they were38 y old, we examined their physiologies to test whether this youngpopulation would show evidence of individual variation in agingdespite remaining free of age-related disease. We next tested thehypothesis that cohort members with “older” physiologies at age 38had actually been aging faster than their same chronologically agedpeers who retained “younger” physiologies; specifically, we testedwhether indicators of the integrity of their cardiovascular, meta-bolic, and immune systems, their kidneys, livers, gums, and lungs,and their DNA had deteriorated more rapidly according to mea-surements taken repeatedly since a baseline 12 y earlier at age 26.We further tested whether, by midlife, young adults who wereaging more rapidly already exhibited deficits in their physicalfunctioning, showed signs of early cognitive decline, and lookedolder to independent observers.
ResultsAre Young Adults Aging at Different Rates? Measuring the aging pro-cess is controversial. Candidate biomarkers of aging are numerous,
Significance
The global population is aging, driving up age-related diseasemorbidity. Antiaging interventions are needed to reduce theburden of disease and protect population productivity. Youngpeople are the most attractive targets for therapies to extendhealthspan (because it is still possible to prevent disease in theyoung). However, there is skepticism about whether agingprocesses can be detected in young adults who do not yet havechronic diseases. Our findings indicate that aging processes canbe quantified in people still young enough for prevention ofage-related disease, opening a new door for antiaging thera-pies. The science of healthspan extension may be focused onthe wrong end of the lifespan; rather than only studying oldhumans, geroscience should also study the young.
Author contributions: D.W.B., A.C., R.P., and T.E.M. designed research; D.W.B., A.C., R.H.,H.J.C., D.L.C., A.D., H.H., S.I., M.E.L., J.D.S., K.S., B.W., A.I.Y., R.P., and T.E.M. performedresearch; M.E.L. contributed new reagents/analytic tools; D.W.B., A.C., R.H., H.H., andT.E.M. analyzed data; and D.W.B., A.C., and T.E.M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Freely available online through the PNAS open access option.1To whom correspondence should be addressed. Email: [email protected].
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1506264112/-/DCSupplemental.
www.pnas.org/cgi/doi/10.1073/pnas.1506264112 PNAS Early Edition | 1 of 7
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LTLWBCCRP
VO2max
CreatinineBUN
BMI,WHR
FEV1FEV1/FVC
TotCholesterolHDL,TriglyceridesLipoprotein(a)ApoB100/ApoA1
HbA1C
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26 32 38Chronological Age
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AgingSlow
AgingFast
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Cross-sectional measurement of biological age
Quantification of biological aging in young adultsDaniel W. Belskya,b,1, Avshalom Caspic,d,e,f, Renate Houtsc, Harvey J. Cohena, David L. Corcorane, Andrea Danesef,g,HonaLee Harringtonc, Salomon Israelh, Morgan E. Levinei, Jonathan D. Schaeferc, Karen Sugdenc, Ben Williamsc,Anatoli I. Yashinb, Richie Poultonj, and Terrie E. Moffittc,d,e,f
aDepartment of Medicine, Duke University School of Medicine, Durham, NC 27710; bSocial Science Research Institute, Duke University, Durham, NC 27708;cDepartment of Psychology & Neuroscience, Duke University, Durham, NC 27708; dDepartment of Psychiatry & Behavioral Sciences, Duke UniversitySchool of Medicine, Durham, NC 27708; eCenter for Genomic and Computational Biology, Duke University, Durham, NC 27708; fSocial, Genetic, &Developmental Psychiatry Research Centre, Institute of Psychiatry, Kings College London, London SE5 8AF, United Kingdom; gDepartment of Child &Adolescent Psychiatry, Institute of Psychiatry, King’s College London, London SE5 8AF, United Kingdom; hDepartment of Psychology, The HebrewUniversity of Jerusalem, Jerusalem 91905, Israel; iDepartment of Human Genetics, Gonda Research Center, David Geffen School of Medicine, University ofCalifornia, Los Angeles, CA 90095; and jDepartment of Psychology, University of Otago, Dunedin 9016, New Zealand
Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved June 1, 2015 (received for review March 30, 2015)
Antiaging therapies show promise in model organism research.Translation to humans is needed to address the challenges of anaging global population. Interventions to slow human aging willneed to be applied to still-young individuals. However, most humanaging research examines older adults, manywith chronic disease. Asa result, little is known about aging in young humans. We studiedaging in 954 young humans, the Dunedin Study birth cohort,tracking multiple biomarkers across three time points spanningtheir third and fourth decades of life. We developed and validatedtwo methods by which aging can be measured in young adults,one cross-sectional and one longitudinal. Our longitudinal mea-sure allows quantification of the pace of coordinated physiologicaldeterioration across multiple organ systems (e.g., pulmonary,periodontal, cardiovascular, renal, hepatic, and immune function).We applied these methods to assess biological aging in younghumans who had not yet developed age-related diseases. Youngindividuals of the same chronological age varied in their “biologicalaging” (declining integrity of multiple organ systems). Already,before midlife, individuals who were aging more rapidly were lessphysically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biologicalaging in young adults can be used to identify causes of agingand evaluate rejuvenation therapies.
biological aging | cognitive aging | aging | healthspan | geroscience
By 2050, the world population aged 80 y and above will morethan triple, approaching 400 million individuals (1, 2). As the
population ages, the global burden of disease and disability isrising (3). From the fifth decade of life, advancing age is asso-ciated with an exponential increase in burden from many differentchronic conditions (Fig. 1). The most effective means to reducedisease burden and control costs is to delay this progression byextending healthspan, years of life lived free of disease and dis-ability (4). A key to extending healthspan is addressing the prob-lem of aging itself (5–8).At present, much research on aging is being carried out with
animals and older humans. Paradoxically, these seemingly sen-sible strategies pose translational difficulties. The difficulty withstudying aging in old humans is that many of them already haveage-related diseases (9–11). Age-related changes to physiologyaccumulate from early life, affecting organ systems years beforedisease diagnosis (12–15). Thus, intervention to reverse or delaythe march toward age-related diseases must be scheduled whilepeople are still young (16). Early interventions to slow aging canbe tested in model organisms (17, 18). The difficulty with thesenonhuman models is that they do not typically capture thecomplex multifactorial risks and exposures that shape humanaging. Moreover, whereas animals’ brief lives make it feasible tostudy animal aging in the laboratory, humans’ lives span manyyears. A solution is to study human aging in the first half of thelife course, when individuals are starting to diverge in their aging
trajectories, before most diseases (and regimens to managethem) become established. The main obstacle to studying agingbefore old age—and before the onset of age-related diseases—is the absence of methods to quantify the Pace of Aging inyoung humans.We studied aging in a population-representative 1972–1973 birth
cohort of 1,037 young adults followed from birth to age 38 y with95% retention: the Dunedin Study (SI Appendix). When they were38 y old, we examined their physiologies to test whether this youngpopulation would show evidence of individual variation in agingdespite remaining free of age-related disease. We next tested thehypothesis that cohort members with “older” physiologies at age 38had actually been aging faster than their same chronologically agedpeers who retained “younger” physiologies; specifically, we testedwhether indicators of the integrity of their cardiovascular, meta-bolic, and immune systems, their kidneys, livers, gums, and lungs,and their DNA had deteriorated more rapidly according to mea-surements taken repeatedly since a baseline 12 y earlier at age 26.We further tested whether, by midlife, young adults who wereaging more rapidly already exhibited deficits in their physicalfunctioning, showed signs of early cognitive decline, and lookedolder to independent observers.
ResultsAre Young Adults Aging at Different Rates? Measuring the aging pro-cess is controversial. Candidate biomarkers of aging are numerous,
Significance
The global population is aging, driving up age-related diseasemorbidity. Antiaging interventions are needed to reduce theburden of disease and protect population productivity. Youngpeople are the most attractive targets for therapies to extendhealthspan (because it is still possible to prevent disease in theyoung). However, there is skepticism about whether agingprocesses can be detected in young adults who do not yet havechronic diseases. Our findings indicate that aging processes canbe quantified in people still young enough for prevention ofage-related disease, opening a new door for antiaging thera-pies. The science of healthspan extension may be focused onthe wrong end of the lifespan; rather than only studying oldhumans, geroscience should also study the young.
Author contributions: D.W.B., A.C., R.P., and T.E.M. designed research; D.W.B., A.C., R.H.,H.J.C., D.L.C., A.D., H.H., S.I., M.E.L., J.D.S., K.S., B.W., A.I.Y., R.P., and T.E.M. performedresearch; M.E.L. contributed new reagents/analytic tools; D.W.B., A.C., R.H., H.H., andT.E.M. analyzed data; and D.W.B., A.C., and T.E.M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Freely available online through the PNAS open access option.1To whom correspondence should be addressed. Email: [email protected].
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1506264112/-/DCSupplemental.
www.pnas.org/cgi/doi/10.1073/pnas.1506264112 PNAS Early Edition | 1 of 7
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IENCE
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Belsky et al. 2015 PNAS
AlbuminAlkalinePhosphataseBUNCreatinineCRPHbA1cSBPTotalcholesterolCMVFEV1
Klemera &Doubal 2006Mech AgDev
Levine2013JGeron A
Klemera-Doubal MethodBiologicalAge
38
Cross-sectional measurement reflects recent rate of change
Quantification of biological aging in young adultsDaniel W. Belskya,b,1, Avshalom Caspic,d,e,f, Renate Houtsc, Harvey J. Cohena, David L. Corcorane, Andrea Danesef,g,HonaLee Harringtonc, Salomon Israelh, Morgan E. Levinei, Jonathan D. Schaeferc, Karen Sugdenc, Ben Williamsc,Anatoli I. Yashinb, Richie Poultonj, and Terrie E. Moffittc,d,e,f
aDepartment of Medicine, Duke University School of Medicine, Durham, NC 27710; bSocial Science Research Institute, Duke University, Durham, NC 27708;cDepartment of Psychology & Neuroscience, Duke University, Durham, NC 27708; dDepartment of Psychiatry & Behavioral Sciences, Duke UniversitySchool of Medicine, Durham, NC 27708; eCenter for Genomic and Computational Biology, Duke University, Durham, NC 27708; fSocial, Genetic, &Developmental Psychiatry Research Centre, Institute of Psychiatry, Kings College London, London SE5 8AF, United Kingdom; gDepartment of Child &Adolescent Psychiatry, Institute of Psychiatry, King’s College London, London SE5 8AF, United Kingdom; hDepartment of Psychology, The HebrewUniversity of Jerusalem, Jerusalem 91905, Israel; iDepartment of Human Genetics, Gonda Research Center, David Geffen School of Medicine, University ofCalifornia, Los Angeles, CA 90095; and jDepartment of Psychology, University of Otago, Dunedin 9016, New Zealand
Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved June 1, 2015 (received for review March 30, 2015)
Antiaging therapies show promise in model organism research.Translation to humans is needed to address the challenges of anaging global population. Interventions to slow human aging willneed to be applied to still-young individuals. However, most humanaging research examines older adults, manywith chronic disease. Asa result, little is known about aging in young humans. We studiedaging in 954 young humans, the Dunedin Study birth cohort,tracking multiple biomarkers across three time points spanningtheir third and fourth decades of life. We developed and validatedtwo methods by which aging can be measured in young adults,one cross-sectional and one longitudinal. Our longitudinal mea-sure allows quantification of the pace of coordinated physiologicaldeterioration across multiple organ systems (e.g., pulmonary,periodontal, cardiovascular, renal, hepatic, and immune function).We applied these methods to assess biological aging in younghumans who had not yet developed age-related diseases. Youngindividuals of the same chronological age varied in their “biologicalaging” (declining integrity of multiple organ systems). Already,before midlife, individuals who were aging more rapidly were lessphysically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biologicalaging in young adults can be used to identify causes of agingand evaluate rejuvenation therapies.
biological aging | cognitive aging | aging | healthspan | geroscience
By 2050, the world population aged 80 y and above will morethan triple, approaching 400 million individuals (1, 2). As the
population ages, the global burden of disease and disability isrising (3). From the fifth decade of life, advancing age is asso-ciated with an exponential increase in burden from many differentchronic conditions (Fig. 1). The most effective means to reducedisease burden and control costs is to delay this progression byextending healthspan, years of life lived free of disease and dis-ability (4). A key to extending healthspan is addressing the prob-lem of aging itself (5–8).At present, much research on aging is being carried out with
animals and older humans. Paradoxically, these seemingly sen-sible strategies pose translational difficulties. The difficulty withstudying aging in old humans is that many of them already haveage-related diseases (9–11). Age-related changes to physiologyaccumulate from early life, affecting organ systems years beforedisease diagnosis (12–15). Thus, intervention to reverse or delaythe march toward age-related diseases must be scheduled whilepeople are still young (16). Early interventions to slow aging canbe tested in model organisms (17, 18). The difficulty with thesenonhuman models is that they do not typically capture thecomplex multifactorial risks and exposures that shape humanaging. Moreover, whereas animals’ brief lives make it feasible tostudy animal aging in the laboratory, humans’ lives span manyyears. A solution is to study human aging in the first half of thelife course, when individuals are starting to diverge in their aging
trajectories, before most diseases (and regimens to managethem) become established. The main obstacle to studying agingbefore old age—and before the onset of age-related diseases—is the absence of methods to quantify the Pace of Aging inyoung humans.We studied aging in a population-representative 1972–1973 birth
cohort of 1,037 young adults followed from birth to age 38 y with95% retention: the Dunedin Study (SI Appendix). When they were38 y old, we examined their physiologies to test whether this youngpopulation would show evidence of individual variation in agingdespite remaining free of age-related disease. We next tested thehypothesis that cohort members with “older” physiologies at age 38had actually been aging faster than their same chronologically agedpeers who retained “younger” physiologies; specifically, we testedwhether indicators of the integrity of their cardiovascular, meta-bolic, and immune systems, their kidneys, livers, gums, and lungs,and their DNA had deteriorated more rapidly according to mea-surements taken repeatedly since a baseline 12 y earlier at age 26.We further tested whether, by midlife, young adults who wereaging more rapidly already exhibited deficits in their physicalfunctioning, showed signs of early cognitive decline, and lookedolder to independent observers.
ResultsAre Young Adults Aging at Different Rates? Measuring the aging pro-cess is controversial. Candidate biomarkers of aging are numerous,
Significance
The global population is aging, driving up age-related diseasemorbidity. Antiaging interventions are needed to reduce theburden of disease and protect population productivity. Youngpeople are the most attractive targets for therapies to extendhealthspan (because it is still possible to prevent disease in theyoung). However, there is skepticism about whether agingprocesses can be detected in young adults who do not yet havechronic diseases. Our findings indicate that aging processes canbe quantified in people still young enough for prevention ofage-related disease, opening a new door for antiaging thera-pies. The science of healthspan extension may be focused onthe wrong end of the lifespan; rather than only studying oldhumans, geroscience should also study the young.
Author contributions: D.W.B., A.C., R.P., and T.E.M. designed research; D.W.B., A.C., R.H.,H.J.C., D.L.C., A.D., H.H., S.I., M.E.L., J.D.S., K.S., B.W., A.I.Y., R.P., and T.E.M. performedresearch; M.E.L. contributed new reagents/analytic tools; D.W.B., A.C., R.H., H.H., andT.E.M. analyzed data; and D.W.B., A.C., and T.E.M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Freely available online through the PNAS open access option.1To whom correspondence should be addressed. Email: [email protected].
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1506264112/-/DCSupplemental.
www.pnas.org/cgi/doi/10.1073/pnas.1506264112 PNAS Early Edition | 1 of 7
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AlbuminAlkalinePhosphataseBUNCreatinineCRPHbA1cSBPTotalcholesterolCMVFEV1
Klemera &Doubal 2006Mech AgDev
Levine2013JGeron A
Klemera-Doubal MethodBiologicalAge
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Does variation in rate of aging predict signs of aging?
40
Faster aging predicts poor physical function
Quantification of biological aging in young adultsDaniel W. Belskya,b,1, Avshalom Caspic,d,e,f, Renate Houtsc, Harvey J. Cohena, David L. Corcorane, Andrea Danesef,g,HonaLee Harringtonc, Salomon Israelh, Morgan E. Levinei, Jonathan D. Schaeferc, Karen Sugdenc, Ben Williamsc,Anatoli I. Yashinb, Richie Poultonj, and Terrie E. Moffittc,d,e,f
aDepartment of Medicine, Duke University School of Medicine, Durham, NC 27710; bSocial Science Research Institute, Duke University, Durham, NC 27708;cDepartment of Psychology & Neuroscience, Duke University, Durham, NC 27708; dDepartment of Psychiatry & Behavioral Sciences, Duke UniversitySchool of Medicine, Durham, NC 27708; eCenter for Genomic and Computational Biology, Duke University, Durham, NC 27708; fSocial, Genetic, &Developmental Psychiatry Research Centre, Institute of Psychiatry, Kings College London, London SE5 8AF, United Kingdom; gDepartment of Child &Adolescent Psychiatry, Institute of Psychiatry, King’s College London, London SE5 8AF, United Kingdom; hDepartment of Psychology, The HebrewUniversity of Jerusalem, Jerusalem 91905, Israel; iDepartment of Human Genetics, Gonda Research Center, David Geffen School of Medicine, University ofCalifornia, Los Angeles, CA 90095; and jDepartment of Psychology, University of Otago, Dunedin 9016, New Zealand
Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved June 1, 2015 (received for review March 30, 2015)
Antiaging therapies show promise in model organism research.Translation to humans is needed to address the challenges of anaging global population. Interventions to slow human aging willneed to be applied to still-young individuals. However, most humanaging research examines older adults, manywith chronic disease. Asa result, little is known about aging in young humans. We studiedaging in 954 young humans, the Dunedin Study birth cohort,tracking multiple biomarkers across three time points spanningtheir third and fourth decades of life. We developed and validatedtwo methods by which aging can be measured in young adults,one cross-sectional and one longitudinal. Our longitudinal mea-sure allows quantification of the pace of coordinated physiologicaldeterioration across multiple organ systems (e.g., pulmonary,periodontal, cardiovascular, renal, hepatic, and immune function).We applied these methods to assess biological aging in younghumans who had not yet developed age-related diseases. Youngindividuals of the same chronological age varied in their “biologicalaging” (declining integrity of multiple organ systems). Already,before midlife, individuals who were aging more rapidly were lessphysically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biologicalaging in young adults can be used to identify causes of agingand evaluate rejuvenation therapies.
biological aging | cognitive aging | aging | healthspan | geroscience
By 2050, the world population aged 80 y and above will morethan triple, approaching 400 million individuals (1, 2). As the
population ages, the global burden of disease and disability isrising (3). From the fifth decade of life, advancing age is asso-ciated with an exponential increase in burden from many differentchronic conditions (Fig. 1). The most effective means to reducedisease burden and control costs is to delay this progression byextending healthspan, years of life lived free of disease and dis-ability (4). A key to extending healthspan is addressing the prob-lem of aging itself (5–8).At present, much research on aging is being carried out with
animals and older humans. Paradoxically, these seemingly sen-sible strategies pose translational difficulties. The difficulty withstudying aging in old humans is that many of them already haveage-related diseases (9–11). Age-related changes to physiologyaccumulate from early life, affecting organ systems years beforedisease diagnosis (12–15). Thus, intervention to reverse or delaythe march toward age-related diseases must be scheduled whilepeople are still young (16). Early interventions to slow aging canbe tested in model organisms (17, 18). The difficulty with thesenonhuman models is that they do not typically capture thecomplex multifactorial risks and exposures that shape humanaging. Moreover, whereas animals’ brief lives make it feasible tostudy animal aging in the laboratory, humans’ lives span manyyears. A solution is to study human aging in the first half of thelife course, when individuals are starting to diverge in their aging
trajectories, before most diseases (and regimens to managethem) become established. The main obstacle to studying agingbefore old age—and before the onset of age-related diseases—is the absence of methods to quantify the Pace of Aging inyoung humans.We studied aging in a population-representative 1972–1973 birth
cohort of 1,037 young adults followed from birth to age 38 y with95% retention: the Dunedin Study (SI Appendix). When they were38 y old, we examined their physiologies to test whether this youngpopulation would show evidence of individual variation in agingdespite remaining free of age-related disease. We next tested thehypothesis that cohort members with “older” physiologies at age 38had actually been aging faster than their same chronologically agedpeers who retained “younger” physiologies; specifically, we testedwhether indicators of the integrity of their cardiovascular, meta-bolic, and immune systems, their kidneys, livers, gums, and lungs,and their DNA had deteriorated more rapidly according to mea-surements taken repeatedly since a baseline 12 y earlier at age 26.We further tested whether, by midlife, young adults who wereaging more rapidly already exhibited deficits in their physicalfunctioning, showed signs of early cognitive decline, and lookedolder to independent observers.
ResultsAre Young Adults Aging at Different Rates? Measuring the aging pro-cess is controversial. Candidate biomarkers of aging are numerous,
Significance
The global population is aging, driving up age-related diseasemorbidity. Antiaging interventions are needed to reduce theburden of disease and protect population productivity. Youngpeople are the most attractive targets for therapies to extendhealthspan (because it is still possible to prevent disease in theyoung). However, there is skepticism about whether agingprocesses can be detected in young adults who do not yet havechronic diseases. Our findings indicate that aging processes canbe quantified in people still young enough for prevention ofage-related disease, opening a new door for antiaging thera-pies. The science of healthspan extension may be focused onthe wrong end of the lifespan; rather than only studying oldhumans, geroscience should also study the young.
Author contributions: D.W.B., A.C., R.P., and T.E.M. designed research; D.W.B., A.C., R.H.,H.J.C., D.L.C., A.D., H.H., S.I., M.E.L., J.D.S., K.S., B.W., A.I.Y., R.P., and T.E.M. performedresearch; M.E.L. contributed new reagents/analytic tools; D.W.B., A.C., R.H., H.H., andT.E.M. analyzed data; and D.W.B., A.C., and T.E.M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Freely available online through the PNAS open access option.1To whom correspondence should be addressed. Email: [email protected].
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1506264112/-/DCSupplemental.
www.pnas.org/cgi/doi/10.1073/pnas.1506264112 PNAS Early Edition | 1 of 7
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41
Faster aging predicts declining brain health
Quantification of biological aging in young adultsDaniel W. Belskya,b,1, Avshalom Caspic,d,e,f, Renate Houtsc, Harvey J. Cohena, David L. Corcorane, Andrea Danesef,g,HonaLee Harringtonc, Salomon Israelh, Morgan E. Levinei, Jonathan D. Schaeferc, Karen Sugdenc, Ben Williamsc,Anatoli I. Yashinb, Richie Poultonj, and Terrie E. Moffittc,d,e,f
aDepartment of Medicine, Duke University School of Medicine, Durham, NC 27710; bSocial Science Research Institute, Duke University, Durham, NC 27708;cDepartment of Psychology & Neuroscience, Duke University, Durham, NC 27708; dDepartment of Psychiatry & Behavioral Sciences, Duke UniversitySchool of Medicine, Durham, NC 27708; eCenter for Genomic and Computational Biology, Duke University, Durham, NC 27708; fSocial, Genetic, &Developmental Psychiatry Research Centre, Institute of Psychiatry, Kings College London, London SE5 8AF, United Kingdom; gDepartment of Child &Adolescent Psychiatry, Institute of Psychiatry, King’s College London, London SE5 8AF, United Kingdom; hDepartment of Psychology, The HebrewUniversity of Jerusalem, Jerusalem 91905, Israel; iDepartment of Human Genetics, Gonda Research Center, David Geffen School of Medicine, University ofCalifornia, Los Angeles, CA 90095; and jDepartment of Psychology, University of Otago, Dunedin 9016, New Zealand
Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved June 1, 2015 (received for review March 30, 2015)
Antiaging therapies show promise in model organism research.Translation to humans is needed to address the challenges of anaging global population. Interventions to slow human aging willneed to be applied to still-young individuals. However, most humanaging research examines older adults, manywith chronic disease. Asa result, little is known about aging in young humans. We studiedaging in 954 young humans, the Dunedin Study birth cohort,tracking multiple biomarkers across three time points spanningtheir third and fourth decades of life. We developed and validatedtwo methods by which aging can be measured in young adults,one cross-sectional and one longitudinal. Our longitudinal mea-sure allows quantification of the pace of coordinated physiologicaldeterioration across multiple organ systems (e.g., pulmonary,periodontal, cardiovascular, renal, hepatic, and immune function).We applied these methods to assess biological aging in younghumans who had not yet developed age-related diseases. Youngindividuals of the same chronological age varied in their “biologicalaging” (declining integrity of multiple organ systems). Already,before midlife, individuals who were aging more rapidly were lessphysically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biologicalaging in young adults can be used to identify causes of agingand evaluate rejuvenation therapies.
biological aging | cognitive aging | aging | healthspan | geroscience
By 2050, the world population aged 80 y and above will morethan triple, approaching 400 million individuals (1, 2). As the
population ages, the global burden of disease and disability isrising (3). From the fifth decade of life, advancing age is asso-ciated with an exponential increase in burden from many differentchronic conditions (Fig. 1). The most effective means to reducedisease burden and control costs is to delay this progression byextending healthspan, years of life lived free of disease and dis-ability (4). A key to extending healthspan is addressing the prob-lem of aging itself (5–8).At present, much research on aging is being carried out with
animals and older humans. Paradoxically, these seemingly sen-sible strategies pose translational difficulties. The difficulty withstudying aging in old humans is that many of them already haveage-related diseases (9–11). Age-related changes to physiologyaccumulate from early life, affecting organ systems years beforedisease diagnosis (12–15). Thus, intervention to reverse or delaythe march toward age-related diseases must be scheduled whilepeople are still young (16). Early interventions to slow aging canbe tested in model organisms (17, 18). The difficulty with thesenonhuman models is that they do not typically capture thecomplex multifactorial risks and exposures that shape humanaging. Moreover, whereas animals’ brief lives make it feasible tostudy animal aging in the laboratory, humans’ lives span manyyears. A solution is to study human aging in the first half of thelife course, when individuals are starting to diverge in their aging
trajectories, before most diseases (and regimens to managethem) become established. The main obstacle to studying agingbefore old age—and before the onset of age-related diseases—is the absence of methods to quantify the Pace of Aging inyoung humans.We studied aging in a population-representative 1972–1973 birth
cohort of 1,037 young adults followed from birth to age 38 y with95% retention: the Dunedin Study (SI Appendix). When they were38 y old, we examined their physiologies to test whether this youngpopulation would show evidence of individual variation in agingdespite remaining free of age-related disease. We next tested thehypothesis that cohort members with “older” physiologies at age 38had actually been aging faster than their same chronologically agedpeers who retained “younger” physiologies; specifically, we testedwhether indicators of the integrity of their cardiovascular, meta-bolic, and immune systems, their kidneys, livers, gums, and lungs,and their DNA had deteriorated more rapidly according to mea-surements taken repeatedly since a baseline 12 y earlier at age 26.We further tested whether, by midlife, young adults who wereaging more rapidly already exhibited deficits in their physicalfunctioning, showed signs of early cognitive decline, and lookedolder to independent observers.
ResultsAre Young Adults Aging at Different Rates? Measuring the aging pro-cess is controversial. Candidate biomarkers of aging are numerous,
Significance
The global population is aging, driving up age-related diseasemorbidity. Antiaging interventions are needed to reduce theburden of disease and protect population productivity. Youngpeople are the most attractive targets for therapies to extendhealthspan (because it is still possible to prevent disease in theyoung). However, there is skepticism about whether agingprocesses can be detected in young adults who do not yet havechronic diseases. Our findings indicate that aging processes canbe quantified in people still young enough for prevention ofage-related disease, opening a new door for antiaging thera-pies. The science of healthspan extension may be focused onthe wrong end of the lifespan; rather than only studying oldhumans, geroscience should also study the young.
Author contributions: D.W.B., A.C., R.P., and T.E.M. designed research; D.W.B., A.C., R.H.,H.J.C., D.L.C., A.D., H.H., S.I., M.E.L., J.D.S., K.S., B.W., A.I.Y., R.P., and T.E.M. performedresearch; M.E.L. contributed new reagents/analytic tools; D.W.B., A.C., R.H., H.H., andT.E.M. analyzed data; and D.W.B., A.C., and T.E.M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Freely available online through the PNAS open access option.1To whom correspondence should be addressed. Email: [email protected].
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1506264112/-/DCSupplemental.
www.pnas.org/cgi/doi/10.1073/pnas.1506264112 PNAS Early Edition | 1 of 7
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Faster aging predicts subjective signs
Quantification of biological aging in young adultsDaniel W. Belskya,b,1, Avshalom Caspic,d,e,f, Renate Houtsc, Harvey J. Cohena, David L. Corcorane, Andrea Danesef,g,HonaLee Harringtonc, Salomon Israelh, Morgan E. Levinei, Jonathan D. Schaeferc, Karen Sugdenc, Ben Williamsc,Anatoli I. Yashinb, Richie Poultonj, and Terrie E. Moffittc,d,e,f
aDepartment of Medicine, Duke University School of Medicine, Durham, NC 27710; bSocial Science Research Institute, Duke University, Durham, NC 27708;cDepartment of Psychology & Neuroscience, Duke University, Durham, NC 27708; dDepartment of Psychiatry & Behavioral Sciences, Duke UniversitySchool of Medicine, Durham, NC 27708; eCenter for Genomic and Computational Biology, Duke University, Durham, NC 27708; fSocial, Genetic, &Developmental Psychiatry Research Centre, Institute of Psychiatry, Kings College London, London SE5 8AF, United Kingdom; gDepartment of Child &Adolescent Psychiatry, Institute of Psychiatry, King’s College London, London SE5 8AF, United Kingdom; hDepartment of Psychology, The HebrewUniversity of Jerusalem, Jerusalem 91905, Israel; iDepartment of Human Genetics, Gonda Research Center, David Geffen School of Medicine, University ofCalifornia, Los Angeles, CA 90095; and jDepartment of Psychology, University of Otago, Dunedin 9016, New Zealand
Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved June 1, 2015 (received for review March 30, 2015)
Antiaging therapies show promise in model organism research.Translation to humans is needed to address the challenges of anaging global population. Interventions to slow human aging willneed to be applied to still-young individuals. However, most humanaging research examines older adults, manywith chronic disease. Asa result, little is known about aging in young humans. We studiedaging in 954 young humans, the Dunedin Study birth cohort,tracking multiple biomarkers across three time points spanningtheir third and fourth decades of life. We developed and validatedtwo methods by which aging can be measured in young adults,one cross-sectional and one longitudinal. Our longitudinal mea-sure allows quantification of the pace of coordinated physiologicaldeterioration across multiple organ systems (e.g., pulmonary,periodontal, cardiovascular, renal, hepatic, and immune function).We applied these methods to assess biological aging in younghumans who had not yet developed age-related diseases. Youngindividuals of the same chronological age varied in their “biologicalaging” (declining integrity of multiple organ systems). Already,before midlife, individuals who were aging more rapidly were lessphysically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biologicalaging in young adults can be used to identify causes of agingand evaluate rejuvenation therapies.
biological aging | cognitive aging | aging | healthspan | geroscience
By 2050, the world population aged 80 y and above will morethan triple, approaching 400 million individuals (1, 2). As the
population ages, the global burden of disease and disability isrising (3). From the fifth decade of life, advancing age is asso-ciated with an exponential increase in burden from many differentchronic conditions (Fig. 1). The most effective means to reducedisease burden and control costs is to delay this progression byextending healthspan, years of life lived free of disease and dis-ability (4). A key to extending healthspan is addressing the prob-lem of aging itself (5–8).At present, much research on aging is being carried out with
animals and older humans. Paradoxically, these seemingly sen-sible strategies pose translational difficulties. The difficulty withstudying aging in old humans is that many of them already haveage-related diseases (9–11). Age-related changes to physiologyaccumulate from early life, affecting organ systems years beforedisease diagnosis (12–15). Thus, intervention to reverse or delaythe march toward age-related diseases must be scheduled whilepeople are still young (16). Early interventions to slow aging canbe tested in model organisms (17, 18). The difficulty with thesenonhuman models is that they do not typically capture thecomplex multifactorial risks and exposures that shape humanaging. Moreover, whereas animals’ brief lives make it feasible tostudy animal aging in the laboratory, humans’ lives span manyyears. A solution is to study human aging in the first half of thelife course, when individuals are starting to diverge in their aging
trajectories, before most diseases (and regimens to managethem) become established. The main obstacle to studying agingbefore old age—and before the onset of age-related diseases—is the absence of methods to quantify the Pace of Aging inyoung humans.We studied aging in a population-representative 1972–1973 birth
cohort of 1,037 young adults followed from birth to age 38 y with95% retention: the Dunedin Study (SI Appendix). When they were38 y old, we examined their physiologies to test whether this youngpopulation would show evidence of individual variation in agingdespite remaining free of age-related disease. We next tested thehypothesis that cohort members with “older” physiologies at age 38had actually been aging faster than their same chronologically agedpeers who retained “younger” physiologies; specifically, we testedwhether indicators of the integrity of their cardiovascular, meta-bolic, and immune systems, their kidneys, livers, gums, and lungs,and their DNA had deteriorated more rapidly according to mea-surements taken repeatedly since a baseline 12 y earlier at age 26.We further tested whether, by midlife, young adults who wereaging more rapidly already exhibited deficits in their physicalfunctioning, showed signs of early cognitive decline, and lookedolder to independent observers.
ResultsAre Young Adults Aging at Different Rates? Measuring the aging pro-cess is controversial. Candidate biomarkers of aging are numerous,
Significance
The global population is aging, driving up age-related diseasemorbidity. Antiaging interventions are needed to reduce theburden of disease and protect population productivity. Youngpeople are the most attractive targets for therapies to extendhealthspan (because it is still possible to prevent disease in theyoung). However, there is skepticism about whether agingprocesses can be detected in young adults who do not yet havechronic diseases. Our findings indicate that aging processes canbe quantified in people still young enough for prevention ofage-related disease, opening a new door for antiaging thera-pies. The science of healthspan extension may be focused onthe wrong end of the lifespan; rather than only studying oldhumans, geroscience should also study the young.
Author contributions: D.W.B., A.C., R.P., and T.E.M. designed research; D.W.B., A.C., R.H.,H.J.C., D.L.C., A.D., H.H., S.I., M.E.L., J.D.S., K.S., B.W., A.I.Y., R.P., and T.E.M. performedresearch; M.E.L. contributed new reagents/analytic tools; D.W.B., A.C., R.H., H.H., andT.E.M. analyzed data; and D.W.B., A.C., and T.E.M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Freely available online through the PNAS open access option.1To whom correspondence should be addressed. Email: [email protected].
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1506264112/-/DCSupplemental.
www.pnas.org/cgi/doi/10.1073/pnas.1506264112 PNAS Early Edition | 1 of 7
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Part 2 Interim Summary
• The rate of aging can be measured in healthy young adults
Repeated-measures clinical-exam and blood-test data can track aging-related changes decades in advance of disease onset
• The aging rate in healthy young adults is already variable
• A faster rate of aging correlates with deficits in physical and cognitive function and subjective signs of aging
44
Do early-life risks accelerate the page of aging?
Belsky etal.2017AgingCell
Age Year Number Percent*
Birth 1972-733 1975-76 1037 100%5 1977-78 991 967 1979-80 954 929 1981-82 955 9211 1983-84 925 9013 1985-86 850 8215 1987-88 976 9518 1990-91 993 9721 1993-94 992 9726 1998-99 980 9632 2004-05 972 96
38 2010-12 961 95%45 2017-18 ?? ??
45
Life-Course Design
Belsky etal.2017AgingCell
Age Year Number Percent*
Birth 1972-733 1975-76 1037 100%5 1977-78 991 967 1979-80 954 929 1981-82 955 9211 1983-84 925 9013 1985-86 850 8215 1987-88 976 9518 1990-91 993 9721 1993-94 992 9726 1998-99 980 9632 2004-05 972 96
38 2010-12 961 95%45 2017-18 ?? ??
46
Life-Course Design
Belsky etal.2017AgingCell
0
5
10
15
Perc
ent
-6 -4 -2 0 2Childhood Self Control
Childhood Self-Control
0
5
10
15
Perc
ent
60 80 100 120 140Childhood IQ
Childhood IQ
0
5
10
15
Perc
ent
-3 -2 -1 0 1 2Childhood Health
Childhood Health
0
10
20
30
40
Perc
ent
-1 0 1 2 3 4Adverse Childhood Experiences
Adverse Childhood Experiences
0
5
10
15
Perc
ent
50 60 70 80 90 100Age of Longest Lived Grandparent
Age of Longest-Lived Grandparent
0
5
10
15
20
Perc
ent
1 2 3 4 5 6Childhood Social Class
Childhood SES
47
Observationalratings,parent,teacher,&self-reportsofhyperactivity,lackofpersistence,inattention,impulsiveaggression,impulsivity
Ages3-11years
WechslerIntelligenceScalesforChildren(WISC)Ages7,9,11,13
LungfunctionBloodpressureAnthropometryBalance&MotorClinicalinterview
Ages3,5,7,9,11
5typesofchildharmPhysicalabuseEmotionalabuseSexualabusePhysicalneglectEmotionalneglect
5typesofhouseholddysfunctionSubstanceabuseMentalillnessIncarcerationPartnerviolenceParentallossAges3-15
BasedonparentaloccupationBirth-age15
FamilialLongevity
Ageoflongest-livedgrandparent
ChildhoodSES ACEs ChildhoodHealth ChildhoodIQ ChildhoodSelf-Control
Belsky etal.2017AgingCell
48
Midlife pace of aging has origins in childhood
Belsky etal.2017AgingCell
49
<15minbattery5-pointscale
Belsky etal.2017AgingCell
Construct Measurement
FamilialLongevity Grandparent >80y(lifeexpectancy)
ChildhoodSocialClass Low (e.g.low-skilloccupation)
ACEs CDCACEInventory
ChildhoodIQ Loweducation
ChildhoodSelf-Control 5-item Nurserating
Retrospective Personal-History Risk Assessment for Screening Geroprotector Trial Participants
50
5332
15
54
1927
4322
35
4733
20
45
32
23
4031
29
31 28 41 30 26 43 28 14 58
0%
20%
40%
60%
80%
100%
NoRisks 1Risk
2+Risks
NoRisks 1Risk
2+Risks
NoRisks 1Risk
2+Risks
CohortPrescriptionRegister
(N=686)HospitalAdmission
(N=183)
Fast
Normal
Slow
PaceofAging
Belsky etal.2017AgingCell
Personal-history risk assessment identifies fast-aging group
51
Part 2 Summary
• The rate of aging can be measured in healthy young adults
Repeated-measures clinical-exam and blood-test data can track aging-related changes decades in advance of disease onset
• The aging rate in healthy young adults is already variable
• A faster rate of aging correlates with deficits in physical and cognitive function and subjective signs of aging
• Midlife aging rate has origins in childhood
Possible to screen participants to balance enrollment in geroprotector trials
Outline
IntroductionBiological aging is a treatment target for healthspan extension
Part 1. Human trials of geroprotectorsChallenges & opportunities
Part 2. Quantification of biological aging in young adults
Part 3. Testing biological aging in a geroprotector trial
Conclusion
53
Alternative Geroprotector Trial Design
Biologica
lAge
Y1 Y2 Y3
Control
Treatment
Rx
Control
SlowerPaceofAging
NormalPaceofAging
Years
54
https://calerie.duke.edu/
Weindruch &Walford 1982ScienceColmanetal.2009ScienceMattison etal.2014NatureColmanetal.2014NatComm
55
N=145Randomizedto25%CR(12%achieved)N=75RandomizedtoAL(2%CRonaverage)
Ravussin etal.2015JGMS
56
Belsky etal.2017JGBS
T1 T2 T3
Baseline 12mo 24mo
Biologica
lAge
Y1 Y2 Y3
Control
Treatment
Hypothesis
CR
AdLibitum
57
Belsky etal.2017JGBS
T1 T2 T3
Baseline 12mo 24mo
Biologica
lAge
Y1 Y2 Y3
Control
TreatmentCR
AdLibitumAlbuminAlkalinePhosphataseBUNCreatinineCRPHbA1c(glucose)SBPTotalcholesterolUricAcidWBC
Klemera &Doubal 2006Mech AgDevLevine2013JGBSCohenetal.2013Mech AgDevLietal.2015AgingCell
Repeatedmeasuresofbiologicalage• Klemera-Doubal methodBiologicalAge• HomeostaticDysregulation
58
Belsky etal.2017JGBS
T1 T2 T3
Baseline 12mo 24mo
Klemera-Doubal methodBiologicalAgeatbaseline
59
Belsky etal.2017JGBS
T1 T2 T3
Baseline 12mo 24mo
-1
0
1
2
3
Cha
nge
in K
DM
Bio
logi
cal A
ge (y
ears
)
Baseline 12-months 24-months CALERIE Assessment
60
Belsky etal.2017JGBS
T1 T2 T3
Baseline 12mo 24mo
-1
0
1
2
3
Cha
nge
in K
DM
Bio
logi
cal A
ge (y
ears
)
Baseline 12-months 24-months CALERIE Assessment
Ad LibitumCaloric Restriction
Randomized to
61
Part 3 Summary
• Moderate (~10%) CR slows the rate of biological aging as measured from physiology
• Implementation of biological aging measures within already-collected data from RCTs can advance validation efforts
• Long-term follow-up will be needed (and should be planned for)
Outline
IntroductionBiological aging is a treatment target for healthspan extension
Part 1. Human trials of geroprotectorsChallenges & opportunities
Part 2. Quantification of biological aging in young adults
Part 3. Testing biological aging in a geroprotector trial
Conclusion
63
Conclusions
• Aging is a lifelong process with effects already manifest by midlife
• The midlife rate of aging is variable in apparently healthy adults
Interventions to slow aging should begin early
• The midlife rate of aging can be measured
• The midlife rate of aging can be modified (e.g. by CR)
Geroprotector trials should consider the rate of change in biological age as a surrogate endpoint for healthspan extension
64
Not all measures of aging measure the same thing
Belsky et al. AJE 2017
65
Not all measures of aging measure the same thing
Belsky et al. AJE 2017
66
Next Steps
• Refine measures to quantify biological aging
Critical validation is that rate of change predicts healthspan
• Expand scope of intervention testing
Exercise trials and other lifestyle interventions are low hanging fruit
But Rx is the frontier
67
ThankYou!