Publications by authors named "Morgan E Levine"

44 Publications

A systematic review of biological, social and environmental factors associated with epigenetic clock acceleration.

Ageing Res Rev 2021 Apr 28;69:101348. Epub 2021 Apr 28.

Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.

Aging involves a diverse set of biological changes accumulating over time that leads to increased risk of morbidity and mortality. Epigenetic clocks are now widely used to quantify biological aging, in order to investigate determinants that modify the rate of aging and to predict age-related outcomes. Numerous biological, social and environmental factors have been investigated for their relationship to epigenetic clock acceleration and deceleration. The aim of this review was to synthesize general trends concerning the associations between human epigenetic clocks and these investigated factors. We conducted a systematic review of all available literature and included 156 publications across 4 resource databases. We compiled a list of all presently existing blood-based epigenetic clocks. Subsequently, we created an extensive dataset of over 1300 study findings in which epigenetic clocks were utilized in blood tissue of human subjects to assess the relationship between these clocks and numeral environmental exposures and human traits. Statistical analysis was possible on 57 such relationships, measured across 4 different epigenetic clocks (Hannum, Horvath, Levine and GrimAge). We found that the Horvath, Hannum, Levine and GrimAge epigenetic clocks tend to agree in direction of effects, but vary in size. Body mass index, HIV infection, and male sex were significantly associated with acceleration of one or more epigenetic clocks. Acceleration of epigenetic clocks was also significantly related to mortality, cardiovascular disease, cancer and diabetes. Our findings provide a graphical and numerical synopsis of the past decade of epigenetic age estimation research and indicate areas where further attention could be focused in the coming years.
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http://dx.doi.org/10.1016/j.arr.2021.101348DOI Listing
April 2021

Association of epigenetic age acceleration with risk factors, survival, and quality of life in patients with head and neck cancer.

Int J Radiat Oncol Biol Phys 2021 Apr 18. Epub 2021 Apr 18.

Emory University School of Nursing.

Purpose: Epigenetic age acceleration (EAA) is robustly linked with mortality and morbidity. This study examined risk factors of EAA and its association with overall survival (OS), progression-free survival (PFS), and quality of life (QOL) in patients with head and neck cancer (HNC) receiving radiotherapy.

Methods And Materials: Patients without distant metastasis were enrolled and followed before and end of radiotherapy, and 6-months and 12-months post-radiotherapy. EAA was calculated with DNAmPhenoAge at all four times. Risk factors included demographics, lifestyle, clinical characteristics, treatment-related symptoms, and blood biomarkers. Survival data were collected until August 2020; QOL was measured using Functional Assessment of Cancer Therapy-HNC.

Results: Increased comorbidity, HPV-unrelated, and severer treatment-related symptoms were associated with higher EAA (p=0.03 to <0.001). A non-linear association (quadratic) between body mass index (BMI) and EAA was observed: decreased BMI (when BMI<35,p=0.04) or increased BMI (when BMI≥35,p=0.01), was linked to higher EAA. Increased EAA (per year) was associated with worse OS (hazard ratio (HR)=1.11,95% CI=[1.03,1.18],p=0.004; HR=1.10,95% CI=[1.01,1.19], p=0.02, for EAA at 6-months and 12-months post-treatment, respectively), PFS (HR=1.10, 95% CI=[1.02,1.19], p=0.02; HR=1.14, 95% CI=[1.06,1.23], p<0.001; HR=1.08,95% CI=[1.02,1.14], p=0.01, for EAA before, end, and 6-months post-radiotherapy, respectively), and QOL over time (β=-0.61,p=0.001). An average of 3.25-3.33 years of age acceleration across time, which was responsible for 33% to 44% higher HRs of OS and PFS, was observed in those who died or developed recurrences compared to those who did not (all p<0.001).

Conclusion: Compared to demographic and lifestyle factors, clinical characteristics were more likely to contribute to faster biological aging in patients with HNC. Acceleration in epigenetic age resulted in more aggressive adverse events including OS and PFS. EAA could be considered as a marker for cancer outcomes, and decelerating aging could improve survival and QOL.
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http://dx.doi.org/10.1016/j.ijrobp.2021.04.002DOI Listing
April 2021

Biological Aging Predicts Vulnerability to COVID-19 Severity in UK Biobank Participants.

J Gerontol A Biol Sci Med Sci 2021 Mar 4. Epub 2021 Mar 4.

Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA.

Background: Age and disease prevalence are the two biggest risk factors for COVID-19 symptom severity and death. We therefore hypothesized that increased biological age, beyond chronological age, may be driving disease-related trends in COVID-19 severity.

Methods: Using the UK Biobank England data, we tested whether a biological age estimate (PhenoAge) measured more than a decade prior to the COVID-19 pandemic was predictive of two COVID-19 severity outcomes (inpatient test positivity and COVID-19 related mortality with inpatient test-confirmed COVID-19). Logistic regression models were used with adjustment for age at the pandemic, sex, ethnicity, baseline assessment centers, and pre-existing diseases/conditions.

Results: 613 participants tested positive at inpatient settings between March 16 and April 27, 2020, 154 of whom succumbed to COVID-19. PhenoAge was associated with increased risks of inpatient test positivity and COVID-19 related mortality (ORMortality=1.63 per 5 years, 95% CI: 1.43-1.86, p=4.7×10 -13) adjusting for demographics including age at the pandemic. Further adjustment for pre-existing disease s/conditions at baseline (ORM=1.50, 95% CI: 1.30-1.73 per 5 years, p=3.1×10 -8) and at the early pandemic (ORM=1.21, 95% CI: 1.04-1.40 per 5 years, p=0.011) decreased the association.

Conclusions: PhenoAge measured in 2006-2010 was associated with COVID-19 severity outcomes more than 10 years later. These associations were partly accounted for by prevalent chronic diseases proximate to COVID-19 infection. Overall, our results suggest that aging biomarkers, like PhenoAge may capture long-term vulnerability to diseases like COVID-19, even before the accumulation of age-related comorbid conditions.
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http://dx.doi.org/10.1093/gerona/glab060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989601PMC
March 2021

Aging biomarkers and the brain.

Semin Cell Dev Biol 2021 Jan 25. Epub 2021 Jan 25.

Department of Pathology, Yale University School of Medicine, 310 Cedar Street, Suite LH 315A, New Haven, CT 06520, USA. Electronic address:

Quantifying biological aging is critical for understanding why aging is the primary driver of morbidity and mortality and for assessing novel therapies to counter pathological aging. In the past decade, many biomarkers relevant to brain aging have been developed using various data types and modeling techniques. Aging involves numerous interconnected processes, and thus many complementary biomarkers are needed, each capturing a different slice of aging biology. Here we present a hierarchical framework highlighting how these biomarkers are related to each other and the underlying biological processes. We review those measures most studied in the context of brain aging: epigenetic clocks, proteomic clocks, and neuroimaging age predictors. Many studies have linked these biomarkers to cognition, mental health, brain structure, and pathology during aging. We also delve into the challenges and complexities in interpreting these biomarkers and suggest areas for further innovation. Ultimately, a robust mechanistic understanding of these biomarkers will be needed to effectively intervene in the aging process to prevent and treat age-related disease.
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http://dx.doi.org/10.1016/j.semcdb.2021.01.003DOI Listing
January 2021

Associations of Age, Sex, Race/Ethnicity and Education with 13 Epigenetic Clocks in a Nationally Representative US Sample: The Health and Retirement Study.

J Gerontol A Biol Sci Med Sci 2021 Jan 16. Epub 2021 Jan 16.

Institute for Social Research, Survey Research Center, University of Michigan.

Background: Many DNA methylation based indicators have been developed as summary measures of epigenetic aging. We examine the associations between 13 epigenetic clocks, including 4 second generation clocks, as well as the links of the clocks to social, demographic and behavioral factors known to be related to health outcomes: sex, race/ethnicity, socioeconomic status, obesity and lifetime smoking pack years.

Methods: The Health and Retirement Study is the data source which is a nationally representative sample of Americans over age 50. Assessment of DNA methylation was based on the EPIC chip and epigenetic clocks were developed based on existing literature.

Results: The clocks vary in the strength of their relationships with age, with each other and with independent variables. Second generation clocks trained on health related characteristics tend to relate more strongly to the sociodemographic and health behaviors known to be associated with health outcomes in this age group.

Conclusions: Users of this publicly available data set should be aware that epigenetic clocks vary in their relationships to age and to variables known to be related to the process of health change with age.
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http://dx.doi.org/10.1093/gerona/glab016DOI Listing
January 2021

Reprogramming to recover youthful epigenetic information and restore vision.

Nature 2020 12 2;588(7836):124-129. Epub 2020 Dec 2.

Department of Genetics, Blavatnik Institute, Paul F. Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, MA, USA.

Ageing is a degenerative process that leads to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity. Changes to DNA methylation patterns over time form the basis of ageing clocks, but whether older individuals retain the information needed to restore these patterns-and, if so, whether this could improve tissue function-is not known. Over time, the central nervous system (CNS) loses function and regenerative capacity. Using the eye as a model CNS tissue, here we show that ectopic expression of Oct4 (also known as Pou5f1), Sox2 and Klf4 genes (OSK) in mouse retinal ganglion cells restores youthful DNA methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice. The beneficial effects of OSK-induced reprogramming in axon regeneration and vision require the DNA demethylases TET1 and TET2. These data indicate that mammalian tissues retain a record of youthful epigenetic information-encoded in part by DNA methylation-that can be accessed to improve tissue function and promote regeneration in vivo.
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http://dx.doi.org/10.1038/s41586-020-2975-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752134PMC
December 2020

Underlying features of epigenetic aging clocks in vivo and in vitro.

Aging Cell 2020 10 15;19(10):e13229. Epub 2020 Sep 15.

Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.

Epigenetic clocks, developed using DNA methylation data, have been widely used to quantify biological aging in multiple tissues/cells. However, many existing epigenetic clocks are weakly correlated with each other, suggesting they may capture different biological processes. We utilize multi-omics data from diverse human tissue/cells to identify shared features across eleven existing epigenetic clocks. Despite the striking lack of overlap in CpGs, multi-omics analysis suggested five clocks (Horvath1, Horvath2, Levine, Hannum, and Lin) share transcriptional associations conserved across purified CD14+ monocytes and dorsolateral prefrontal cortex. The pathways enriched in the shared transcriptional association suggested links between epigenetic aging and metabolism, immunity, and autophagy. Results from in vitro experiments showed that two clocks (Levine and Lin) were accelerated in accordance with two hallmarks of aging-cellular senescence and mitochondrial dysfunction. Finally, using multi-tissue data to deconstruct the epigenetic clock signals, we developed a meta-clock that demonstrated improved prediction for mortality and robustly related to hallmarks of aging in vitro than single clocks.
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http://dx.doi.org/10.1111/acel.13229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576259PMC
October 2020

Mouse brain transcriptome responses to inhaled nanoparticulate matter differed by sex and in interactions.

Elife 2020 06 24;9. Epub 2020 Jun 24.

Leonard Davis School of Gerontology, University of Southern California, Los Angeles, United States.

The neurotoxicity of air pollution is undefined for sex and alleles. These major risk factors of Alzheimer's disease (AD) were examined in mice given chronic exposure to nPM, a nano-sized subfraction of urban air pollution. In the cerebral cortex, female mice had two-fold more genes responding to nPM than males. Transcriptomic responses to nPM had sex- interactions in AD-relevant pathways. Only 3 mice responded to nPM in genes related to Abeta deposition and clearance (, , ). Other responding genes included axonal guidance, inflammation (AMPK, NFKB, APK/JNK signaling), and antioxidant signaling (NRF2, HIF1A). Genes downstream of NFKB and NRF2 responded in opposite directions to nPM. knockdown in microglia augmented NFKB responses to nPM, suggesting a critical role of NRF2 in air pollution neurotoxicity. These findings give a rationale for epidemiologic studies of air pollution to consider sex interactions with alleles and other AD-risk genes.
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http://dx.doi.org/10.7554/eLife.54822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314548PMC
June 2020

Schizophrenia and Epigenetic Aging Biomarkers: Increased Mortality, Reduced Cancer Risk, and Unique Clozapine Effects.

Biol Psychiatry 2020 08 8;88(3):224-235. Epub 2020 Feb 8.

Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.

Background: Schizophrenia (SZ) is associated with increased all-cause mortality, smoking, and age-associated proteins, yet multiple previous studies found no association between SZ and biological age using Horvath's epigenetic clock, a well-established aging biomarker based on DNA methylation. However, numerous epigenetic clocks that may capture distinct aspects of aging have been developed. This study tested the hypothesis that altered aging in SZ manifests in these other clocks.

Methods: We performed a comprehensive analysis of 14 epigenetic clocks categorized according to what they were trained to predict: chronological age, mortality, mitotic divisions, or telomere length. To understand the etiology of biological age differences, we also examined DNA methylation predictors of smoking, alcohol, body mass index, serum proteins, and cell proportions. We independently analyzed 3 publicly available multiethnic DNA methylation data sets from whole blood, a total of 567 SZ cases and 594 nonpsychiatric controls.

Results: All data sets showed accelerations in SZ for the 3 mortality clocks up to 5 years, driven by smoking and elevated levels of 6 age-associated proteins. The 2 mitotic clocks were decelerated in SZ related to antitumor natural killer and CD8T cells, which may help explain conflicting reports about low cancer rates in epidemiological studies of SZ. One cohort with available medication data showed that clozapine is associated with male-specific decelerations up to 7 years in multiple chronological age clocks.

Conclusions: Our study demonstrates the utility of studying the various epigenetic clocks in tandem and highlights potential mechanisms by which mental illness influences long-term outcomes, including cancer and early mortality.
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http://dx.doi.org/10.1016/j.biopsych.2020.01.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368835PMC
August 2020

Assessment of Epigenetic Clocks as Biomarkers of Aging in Basic and Population Research.

Authors:
Morgan E Levine

J Gerontol A Biol Sci Med Sci 2020 02;75(3):463-465

Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.

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http://dx.doi.org/10.1093/gerona/glaa021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328198PMC
February 2020

Midlife Study of the Louisville Twins: Connecting Cognitive Development to Biological and Cognitive Aging.

Behav Genet 2020 03 9;50(2):73-83. Epub 2019 Dec 9.

Department of Pediatrics, University of Louisville, Louisville, KY, USA.

The Louisville Twin Study (LTS) began in 1958 and became a premier longitudinal twin study of cognitive development. The LTS continuously collected data from twins through 2000 after which the study closed indefinitely due to lack of funding. Now that the majority of the sample is age 40 or older (61.36%, N = 1770), the LTS childhood data can be linked to midlife cognitive functioning, among other physical, biological, social, and psychiatric outcomes. We report results from two pilot studies in anticipation of beginning the midlife phase of the LTS. The first pilot study was a participant tracking study, in which we showed that approximately 90% of the Louisville families randomly sampled (N = 203) for the study could be found. The second pilot study consisted of 40 in-person interviews in which twins completed cognitive, memory, biometric, and functional ability measures. The main purpose of the second study was to correlate midlife measures of cognitive functioning to a measure of biological age, which is an alternative index to chronological age that quantifies age as a function of the breakdown of structural and functional physiological systems, and then to relate both of these measures to twins' cognitive developmental trajectories. Midlife IQ was uncorrelated with biological age (- .01) while better scores on episodic memory more strongly correlated with lower biological age (- .19 to - .31). As expected, midlife IQ positively correlated with IQ measures collected throughout childhood and adolescence. Additionally, positive linear rates of change in FSIQ scores in childhood significantly correlated with biological age (- .68), physical functioning (.71), and functional ability (- .55), suggesting that cognitive development predicts lower biological age, better physical functioning, and better functional ability. In sum, the Louisville twins can be relocated to investigate whether and how early and midlife cognitive and physical health factors contribute to cognitive aging.
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http://dx.doi.org/10.1007/s10519-019-09983-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033012PMC
March 2020

Changing Disease Prevalence, Incidence, and Mortality Among Older Cohorts: The Health and Retirement Study.

J Gerontol A Biol Sci Med Sci 2019 11;74(Suppl_1):S21-S26

Department of Pathology, School of Medicine, Yale University, New Haven, Connecticut.

Background: This article investigates changes in disease prevalence, incidence, and mortality among four cohorts of older persons in the Health and Retirement Study.

Methods: We examine two cohorts initially aged 51 to 61, whom we call younger cohorts, and two older cohorts aged 70 to 80 at the start of observation. Each of the paired cohorts was born about 10 years apart. We follow the cohorts for approximately 10 years.

Results: The prevalence of cancer, stroke, and diabetes increased in later-born cohorts; while the prevalence of myocardial infarction decreased markedly in both later-born cohorts. The incidence of heart disease, myocardial infarction, and stroke decreased among those in the later-born older cohort; while only the incidence of myocardial infarction decreased in the later-born younger cohort. On the other hand, diabetes incidence increased among those in both later-born cohorts. Death rates among those with heart disease, cancer, and diabetes decreased in the later-born cohorts. The declining incidence of three cardiovascular conditions among those who are over age 70 reflects improving population health and has resulted in stemming the increase in prevalence of people with heart disease and stroke.

Discussion: While these results provide some important signs of improving population health, especially among those over 70; trends for those less than 70 in the United States are not as positive.
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http://dx.doi.org/10.1093/gerona/glz075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853787PMC
November 2019

Associations of genetics, behaviors, and life course circumstances with a novel aging and healthspan measure: Evidence from the Health and Retirement Study.

PLoS Med 2019 06 18;16(6):e1002827. Epub 2019 Jun 18.

Department of Pathology, Yale School of Medicine, New Haven, Connecticut, United States of America.

Background: An individual's rate of aging directly influences his/her susceptibility to morbidity and mortality. Thus, quantifying aging and disentangling how various factors coalesce to produce between-person differences in the rate of aging, have important implications for potential interventions. We recently developed and validated a novel multi-system-based aging measure, Phenotypic Age (PhenoAge), which has been shown to capture mortality and morbidity risk in the full US population and diverse subpopulations. The aim of this study was to evaluate associations between PhenoAge and a comprehensive set of factors, including genetic scores, childhood and adulthood circumstances, and health behaviors, to determine the relative contributions of these factors to variance in this aging measure.

Methods And Findings: Based on data from 2,339 adults (aged 51+ years, mean age 69.4 years, 56% female, and 93.9% non-Hispanic white) from the US Health and Retirement Study, we calculated PhenoAge and evaluated the multivariable associations for a comprehensive set of factors using 2 innovative approaches-Shapley value decomposition (the Shapley approach hereafter) and hierarchical clustering. The Shapley approach revealed that together all 11 study domains (4 childhood and adulthood circumstances domains, 5 polygenic score [PGS] domains, and 1 behavior domain, and 1 demographic domain) accounted for 29.2% (bootstrap standard error = 0.003) of variance in PhenoAge after adjustment for chronological age. Behaviors exhibited the greatest contribution to PhenoAge (9.2%), closely followed by adulthood adversity, which was suggested to contribute 9.0% of the variance in PhenoAge. Collectively, the PGSs contributed 3.8% of the variance in PhenoAge (after accounting for chronological age). Next, using hierarchical clustering, we identified 6 distinct subpopulations based on the 4 childhood and adulthood circumstances domains. Two of these subpopulations stood out as disadvantaged, exhibiting significantly higher PhenoAges on average. Finally, we observed a significant gene-by-environment interaction between a previously validated PGS for coronary artery disease and the seemingly most disadvantaged subpopulation, suggesting a multiplicative effect of adverse life course circumstances coupled with genetic risk on phenotypic aging. The main limitations of this study were the retrospective nature of self-reported circumstances, leading to possible recall biases, and the unrepresentative racial/ethnic makeup of the population.

Conclusions: In a sample of US older adults, genetic, behavioral, and socioenvironmental circumstances during childhood and adulthood account for about 30% of differences in phenotypic aging. Our results also suggest that the detrimental effects of disadvantaged life course circumstances for health and aging may be further exacerbated among persons with genetic predisposition to coronary artery disease. Finally, our finding that behaviors had the largest contribution to PhenoAge highlights a potential policy target. Nevertheless, further validation of these findings and identification of causal links are greatly needed.
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http://dx.doi.org/10.1371/journal.pmed.1002827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581243PMC
June 2019

The role of epigenetic aging in education and racial/ethnic mortality disparities among older U.S. Women.

Psychoneuroendocrinology 2019 06 6;104:18-24. Epub 2019 Feb 6.

Department of Pathology, Yale School of Medicine, New Haven, CT 06511, USA; Department of Epidemiology, Yale School of Public Health, New Haven, CT 06511, USA. Electronic address:

Background: Higher mortality experienced by socially disadvantaged groups and/or racial/ethnic minorities is hypothesized to be, at least in part, due to an acceleration of the aging process. Using a new epigenetic aging measure, Levine DNAmAge, this study aimed to investigate whether epigenetic aging accounts for mortality disparities by race/ethnicity and education in a sample of U.S. postmenopausal women.

Methods: 1834 participants from an ancillary study (BA23) in the Women's Health Initiative, a national study that recruited postmenopausal women (50-79 years) were included. Over the 22 years of follow-up, 551 women died, and 31,946 person-years were observed. Levine DNAmAge (unit in years) was calculated based on an equation that we previously developed in an independent sample, which incorporates methylation levels at 513 CpG sites.

Results: As previously reported, non-Hispanic blacks and Hispanics were epigenetically older than non-Hispanic whites of the same chronological age. Similarly, those with less education had older epigenetic ages than expected in the full sample, as well as among non-Hispanic whites and Hispanics, but not among non-Hispanic blacks. Non-Hispanic blacks and those with low education exhibited the greatest risk of mortality. However, this association was partially attenuated when accounting for differences in DNAmAge. Furthermore, formal mediation analysis suggested that DNAmAge partially mediated the mortality increase among non-Hispanic blacks, compared to non-Hispanic whites (proportion mediated, 15.8%, P = 0.002), as well as the mortality increase for those with less than high school education, compared to college educated (proportion mediated, 11.6%, P < 2E-16).

Conclusions: Among a group of postmenopausal women, non-Hispanic blacks and those with less education exhibit higher epigenetic aging, which partially accounts for their shorter life expectancies.
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http://dx.doi.org/10.1016/j.psyneuen.2019.01.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555423PMC
June 2019

Time and the Metrics of Aging.

Circ Res 2018 09;123(7):740-744

From the Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD (L.F., P.-L.K., E.M.S.).

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http://dx.doi.org/10.1161/CIRCRESAHA.118.312816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205734PMC
September 2018

Humanin Prevents Age-Related Cognitive Decline in Mice and is Associated with Improved Cognitive Age in Humans.

Sci Rep 2018 09 21;8(1):14212. Epub 2018 Sep 21.

Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.

Advanced age is associated with a decline in cognitive function, likely caused by a combination of modifiable and non-modifiable factors such as genetics and lifestyle choices. Mounting evidence suggests that humanin and other mitochondrial derived peptides play a role in several age-related conditions including neurodegenerative disease. Here we demonstrate that humanin administration has neuroprotective effects in vitro in human cell culture models and is sufficient to improve cognition in vivo in aged mice. Furthermore, in a human cohort, using mitochondrial GWAS, we identified a specific SNP (rs2854128) in the humanin-coding region of the mitochondrial genome that is associated with a decrease in circulating humanin levels. In a large, independent cohort, consisting of a nationally-representative sample of older adults, we find that this SNP is associated with accelerated cognitive aging, supporting the concept that humanin is an important factor in cognitive aging.
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http://dx.doi.org/10.1038/s41598-018-32616-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6154958PMC
September 2018

An epigenetic biomarker of aging for lifespan and healthspan.

Aging (Albany NY) 2018 04;10(4):573-591

Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.

Identifying reliable biomarkers of aging is a major goal in geroscience. While the first generation of epigenetic biomarkers of aging were developed using chronological age as a surrogate for biological age, we hypothesized that incorporation of composite clinical measures of phenotypic age that capture differences in lifespan and healthspan may identify novel CpGs and facilitate the development of a more powerful epigenetic biomarker of aging. Using an innovative two-step process, we develop a new epigenetic biomarker of aging, DNAm PhenoAge, that strongly outperforms previous measures in regards to predictions for a variety of aging outcomes, including all-cause mortality, cancers, healthspan, physical functioning, and Alzheimer's disease. While this biomarker was developed using data from whole blood, it correlates strongly with age in every tissue and cell tested. Based on an in-depth transcriptional analysis in sorted cells, we find that increased epigenetic, relative to chronological age, is associated with increased activation of pro-inflammatory and interferon pathways, and decreased activation of transcriptional/translational machinery, DNA damage response, and mitochondrial signatures. Overall, this single epigenetic biomarker of aging is able to capture risks for an array of diverse outcomes across multiple tissues and cells, and provide insight into important pathways in aging.
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http://dx.doi.org/10.18632/aging.101414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940111PMC
April 2018

Is 60 the New 50? Examining Changes in Biological Age Over the Past Two Decades.

Demography 2018 04;55(2):387-402

Davis School of Gerontology, University of Southern California, Los Angeles, CA, 90089, USA.

Increasing life expectancy has been interpreted as improving health of a population. However, mortality is not always a reliable proxy for the pace of aging and could instead reflect achievement in keeping ailing people alive. Using data from NHANES III (1988-1994) and NHANES IV (2007-2010), we examined how biological age, relative to chronological age, changed in the United States between 1988 and 2010, while estimating the contribution of changes in modifiable health behaviors. Results suggest that biological age is lower for more recent periods; however, the degree of improvement varied across age and sex groups. Overall, older adults experienced the greatest improvement or decreases in biological age. Males, especially those in the youngest and oldest groups, experienced greater declines in biological age than females. These differences were partially explained by age- and sex-specific changes in behaviors, such as smoking, obesity, and medication use. Slowing the pace of aging, along with increasing life expectancy, has important social and economic implications; thus, identifying modifiable risk factors that contribute to cohort differences in health and aging is essential.
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http://dx.doi.org/10.1007/s13524-017-0644-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897168PMC
April 2018

GWAS of epigenetic aging rates in blood reveals a critical role for TERT.

Nat Commun 2018 01 26;9(1):387. Epub 2018 Jan 26.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, 27599, USA.

DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9907 individuals, we find gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in three loci associated with extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggests causal influences of menarche and menopause on IEAA and lipoproteins on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) paradoxically confer higher IEAA (P < 2.7 × 10). Causal modeling indicates TERT-specific and independent effects on LTL and IEAA. Experimental hTERT-expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the epigenetic clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.
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http://dx.doi.org/10.1038/s41467-017-02697-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786029PMC
January 2018

Predictors and Implications of Accelerated Cognitive Aging.

Biodemography Soc Biol 2018 20;64(2):83-101. Epub 2018 Dec 20.

Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA.

Aging is a major risk factor for both normal and pathological cognitive decline. However, individuals vary in their rate of age-related decline. We developed an easily interpretable composite measure of cognitive age, and related both the level of cognitive age and cognitive slope to sociodemographic, genetic, and disease indicators and examine its prediction of dementia transition. Using a sample of 19,594 participants from the Health and Retirement Study, cognitive age was derived from a set of performance tests administered at each wave. Our findings reveal different conclusions as they relate to levels versus slopes of cognitive age, with more pronounced differences by sex and race/ethnicity for absolute levels of cognitive decline rather than for rates of declines. We also find that both level and slope of cognitive age are inversely related to education, as well as increased for persons with APOE ε4 and/or diabetes. Finally, results show that the slope in cognitive age predicts subsequent dementia among non-demented older adults. Overall, our study suggests that this measure is applicable to cross-sectional and longitudinal studies on cognitive aging, decline, and dementia with the goal of better understanding individual differences in cognitive decline.
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http://dx.doi.org/10.1080/19485565.2018.1552513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469682PMC
November 2019

Eleven Telomere, Epigenetic Clock, and Biomarker-Composite Quantifications of Biological Aging: Do They Measure the Same Thing?

Am J Epidemiol 2018 06;187(6):1220-1230

Department of Psychology and Neuroscience, Duke University, Durham, North Carolina.

The geroscience hypothesis posits that therapies to slow biological processes of aging can prevent disease and extend healthy years of life. To test such "geroprotective" therapies in humans, outcome measures are needed that can assess extension of disease-free life span. This need has spurred development of different methods to quantify biological aging. But different methods have not been systematically compared in the same humans. We implemented 7 methods to quantify biological aging using repeated-measures physiological and genomic data in 964 middle-aged humans in the Dunedin Study (New Zealand; persons born 1972-1973). We studied 11 measures in total: telomere-length and erosion, 3 epigenetic-clocks and their ticking rates, and 3 biomarker-composites. Contrary to expectation, we found low agreement between different measures of biological aging. We next compared associations between biological aging measures and outcomes that geroprotective therapies seek to modify: physical functioning, cognitive decline, and subjective signs of aging, including aged facial appearance. The 71-cytosine-phosphate-guanine epigenetic clock and biomarker composites were consistently related to these aging-related outcomes. However, effect sizes were modest. Results suggested that various proposed approaches to quantifying biological aging may not measure the same aspects of the aging process. Further systematic evaluation and refinement of measures of biological aging is needed to furnish outcomes for geroprotector trials.
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http://dx.doi.org/10.1093/aje/kwx346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248475PMC
June 2018

Biological Age, Not Chronological Age, Is Associated with Late-Life Depression.

J Gerontol A Biol Sci Med Sci 2018 09;73(10):1370-1376

Department of Biostatistics, Mailman School of Public Health, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute.

Background: The pathophysiology of late-life depression (LLD) is complex and heterogeneous, with age-related processes implicated in its pathogenesis. This study examined the cross-sectional and longitudinal association between depressive symptoms and a baseline multibiomarker algorithm of biological age (BA) that aggregates indicators of inflammatory, metabolic, cardiovascular, lung, liver, and kidney functioning.

Method: Data were analyzed from 2,776 men and women from the prospective observational Health Aging and Body Composition Study, who had both evaluable chronological age (CA) and BA. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) scale.

Results: A covariate-adjusted regression model showed that BA (B = 0.03, p = .0471) but not CA (B = -0.01, p = .7185) is associated with baseline CES-D scores. The mean baseline BA for individuals with a CES-D ≥ 10 was 1.28 years greater than in those with a CES-D < 10. Comparatively, there is only a 0.05-year difference in mean CA between the two depression groups. A covariate-adjusted longitudinal model found that baseline BA predicts CES-D score at follow-up (B = 0.04, p = .0058), whereas CA does not (B = 0.03, p = .4125). Additionally, an older BA significantly predicted a CES-D ≥ 10 (B = 0.02, p = .032) over a 10-year period.

Conclusions: A multibiomarker index of an older adult's BA outperformed their CA in predicting subsequent increased and clinically significant depressive symptoms. This result supports the evolving view of LLD as a brain disorder resulting from deleterious age-associated changes across numerous physiological systems.
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http://dx.doi.org/10.1093/gerona/glx162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132120PMC
September 2018

Contemporaneous Social Environment and the Architecture of Late-Life Gene Expression Profiles.

Am J Epidemiol 2017 09;186(5):503-509

Department of Human Genetics, Gonda Research Center, David Geffen School of Medicine, University of California, Los Angeles, USA.

Environmental or social challenges can stimulate a cascade of coordinated physiological changes in stress response systems. Unfortunately, chronic activation of these adaptations under conditions such as low socioeconomic status (SES) can have negative consequences for long-term health. While there is substantial evidence tying low SES to increased disease risk and reduced life expectancy, the underlying biology remains poorly understood. Using pilot data on 120 older adults from the Health and Retirement Study (United States, 2002-2010), we examined the associations between SES and gene expression levels in adulthood, with particular focus on a gene expression program known as the conserved transcriptional response to adversity. We also used a bioinformatics-based approach to assess the activity of specific gene regulation pathways involved in inflammation, antiviral responses, and stress-related neuroendocrine signaling. We found that low SES was related to increased expression of conserved transcriptional response to adversity genes and distinct patterns of proinflammatory, antiviral, and stress signaling (e.g., sympathetic nervous system and hypothalamic-pituitary-adrenal axis) transcription factor activation.
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http://dx.doi.org/10.1093/aje/kwx147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860329PMC
September 2017

A Weighted SNP Correlation Network Method for Estimating Polygenic Risk Scores.

Methods Mol Biol 2017 ;1613:277-290

Department of Human Genetics, University of California, Box 708822, 695 Charles E. Young Drive South, Los Angeles, CA, 90095, USA.

Polygenic scores are useful for examining the joint associations of genetic markers. However, because traditional methods involve summing weighted allele counts, they may fail to capture the complex nature of biology. Here we describe a network-based method, which we call weighted SNP correlation network analysis (WSCNA), and demonstrate how it could be used to generate meaningful polygenic scores. Using data on human height in a US population of non-Hispanic whites, we illustrate how this method can be used to identify SNP networks from GWAS data, create network-specific polygenic scores, examine network topology to identify hub SNPs, and gain biological insights into complex traits. In our example, we show that this method explains a larger proportion of the variance in human height than traditional polygenic score methods. We also identify hub genes and pathways that have previously been identified as influencing human height. In moving forward, this method may be useful for generating genetic susceptibility measures for other health related traits, examining genetic pleiotropy, identifying at-risk individuals, examining gene score by environmental effects, and gaining a deeper understanding of the underlying biology of complex traits.
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http://dx.doi.org/10.1007/978-1-4939-7027-8_10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998804PMC
May 2018

Genetic architecture of epigenetic and neuronal ageing rates in human brain regions.

Nat Commun 2017 05 18;8:15353. Epub 2017 May 18.

Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.

Identifying genes regulating the pace of epigenetic ageing represents a new frontier in genome-wide association studies (GWASs). Here using 1,796 brain samples from 1,163 individuals, we carry out a GWAS of two DNA methylation-based biomarkers of brain age: the epigenetic ageing rate and estimated proportion of neurons. Locus 17q11.2 is significantly associated (P=4.5 × 10) with the ageing rate across five brain regions and harbours a cis-expression quantitative trait locus for EFCAB5 (P=3.4 × 10). Locus 1p36.12 is significantly associated (P=2.2 × 10) with epigenetic ageing of the prefrontal cortex, independent of the proportion of neurons. Our GWAS of the proportion of neurons identified two genome-wide significant loci (10q26 and 12p13.31) and resulted in a gene set that overlaps significantly with sets found by GWAS of age-related macular degeneration (P=1.4 × 10), ulcerative colitis (P<1.0 × 10), type 2 diabetes (P=2.8 × 10), hip/waist circumference in men (P=1.1 × 10), schizophrenia (P=1.6 × 10), cognitive decline (P=5.3 × 10) and Parkinson's disease (P=8.6 × 10).
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http://dx.doi.org/10.1038/ncomms15353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454371PMC
May 2017

Epigenetic clock analysis of diet, exercise, education, and lifestyle factors.

Aging (Albany NY) 2017 02;9(2):419-446

Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.

Behavioral and lifestyle factors have been shown to relate to a number of health-related outcomes, yet there is a need for studies that examine their relationship to molecular aging rates. Toward this end, we use recent epigenetic biomarkers of age that have previously been shown to predict all-cause mortality, chronic conditions, and age-related functional decline. We analyze cross-sectional data from 4,173 postmenopausal female participants from the Women's Health Initiative, as well as 402 male and female participants from the Italian cohort study, Invecchiare nel Chianti.Extrinsic epigenetic age acceleration (EEAA) exhibits significant associations with fish intake (p=0.02), moderate alcohol consumption (p=0.01), education (p=3x10), BMI (p=0.01), and blood carotenoid levels (p=1x10)-an indicator of fruit and vegetable consumption, whereas intrinsic epigenetic age acceleration (IEAA) is associated with poultry intake (p=0.03) and BMI (p=0.05). Both EEAA and IEAA were also found to relate to indicators of metabolic syndrome, which appear to mediate their associations with BMI. Metformin-the first-line medication for the treatment of type 2 diabetes-does not delay epigenetic aging in this observational study. Finally, longitudinal data suggests that an increase in BMI is associated with increase in both EEAA and IEAA.Overall, the epigenetic age analysis of blood confirms the conventional wisdom regarding the benefits of eating a high plant diet with lean meats, moderate alcohol consumption, physical activity, and education, as well as the health risks of obesity and metabolic syndrome.
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http://dx.doi.org/10.18632/aging.101168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361673PMC
February 2017

DNA methylation-based measures of biological age: meta-analysis predicting time to death.

Aging (Albany NY) 2016 09;8(9):1844-1865

Institute of Epidemiology II, Helmholtz Zentrum München, 85764 Neuherberg, Germany.

Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p≤8.2x10, independent of chronological age, even after adjusting for additional risk factors (p<5.4x10, and within the racial/ethnic groups that we examined (non-Hispanic whites, Hispanics, African Americans). Epigenetic age estimates that incorporated information on blood cell composition led to the smallest p-values for time to death (p=7.5x10). Overall, this study a) strengthens the evidence that epigenetic age predicts all-cause mortality above and beyond chronological age and traditional risk factors, and b) demonstrates that epigenetic age estimates that incorporate information on blood cell counts lead to highly significant associations with all-cause mortality.
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http://dx.doi.org/10.18632/aging.101020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5076441PMC
September 2016

An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease.

Genome Biol 2016 08 11;17(1):171. Epub 2016 Aug 11.

Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.

Background: Epigenetic biomarkers of aging (the "epigenetic clock") have the potential to address puzzling findings surrounding mortality rates and incidence of cardio-metabolic disease such as: (1) women consistently exhibiting lower mortality than men despite having higher levels of morbidity; (2) racial/ethnic groups having different mortality rates even after adjusting for socioeconomic differences; (3) the black/white mortality cross-over effect in late adulthood; and (4) Hispanics in the United States having a longer life expectancy than Caucasians despite having a higher burden of traditional cardio-metabolic risk factors.

Results: We analyzed blood, saliva, and brain samples from seven different racial/ethnic groups. We assessed the intrinsic epigenetic age acceleration of blood (independent of blood cell counts) and the extrinsic epigenetic aging rates of blood (dependent on blood cell counts and tracks the age of the immune system). In blood, Hispanics and Tsimane Amerindians have lower intrinsic but higher extrinsic epigenetic aging rates than Caucasians. African-Americans have lower extrinsic epigenetic aging rates than Caucasians and Hispanics but no differences were found for the intrinsic measure. Men have higher epigenetic aging rates than women in blood, saliva, and brain tissue.

Conclusions: Epigenetic aging rates are significantly associated with sex, race/ethnicity, and to a lesser extent with CHD risk factors, but not with incident CHD outcomes. These results may help elucidate lower than expected mortality rates observed in Hispanics, older African-Americans, and women.
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http://dx.doi.org/10.1186/s13059-016-1030-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980791PMC
August 2016

Menopause accelerates biological aging.

Proc Natl Acad Sci U S A 2016 08 25;113(33):9327-32. Epub 2016 Jul 25.

Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, CA 90095

Although epigenetic processes have been linked to aging and disease in other systems, it is not yet known whether they relate to reproductive aging. Recently, we developed a highly accurate epigenetic biomarker of age (known as the "epigenetic clock"), which is based on DNA methylation levels. Here we carry out an epigenetic clock analysis of blood, saliva, and buccal epithelium using data from four large studies: the Women's Health Initiative (n = 1,864); Invecchiare nel Chianti (n = 200); Parkinson's disease, Environment, and Genes (n = 256); and the United Kingdom Medical Research Council National Survey of Health and Development (n = 790). We find that increased epigenetic age acceleration in blood is significantly associated with earlier menopause (P = 0.00091), bilateral oophorectomy (P = 0.0018), and a longer time since menopause (P = 0.017). Conversely, epigenetic age acceleration in buccal epithelium and saliva do not relate to age at menopause; however, a higher epigenetic age in saliva is exhibited in women who undergo bilateral oophorectomy (P = 0.0079), while a lower epigenetic age in buccal epithelium was found for women who underwent menopausal hormone therapy (P = 0.00078). Using genetic data, we find evidence of coheritability between age at menopause and epigenetic age acceleration in blood. Using Mendelian randomization analysis, we find that two SNPs that are highly associated with age at menopause exhibit a significant association with epigenetic age acceleration. Overall, our Mendelian randomization approach and other lines of evidence suggest that menopause accelerates epigenetic aging of blood, but mechanistic studies will be needed to dissect cause-and-effect relationships further.
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http://dx.doi.org/10.1073/pnas.1604558113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995944PMC
August 2016

Education and Psychosocial Functioning Among Older Adults: 4-Year Change in Sense of Control and Hopelessness.

J Gerontol B Psychol Sci Soc Sci 2018 06;73(5):849-859

USC Leonard Davis School of Gerontology, USC/UCLA Center on Biodemography and Population Health, University of Southern California, Los Angeles.

Objectives: This study investigates education differences in levels and change in sense of control and hopelessness among older adults.

Method: We used data from the Health and Retirement Study, an ongoing biennial survey of a nationally representative sample of older Americans, to examine education differences in sense of control (e.g., mastery and perceived constraints) and hopelessness. Our sample included 8,495 adults aged 52 and older who were interviewed in 2006/2008 and 2010/2012. We assessed separate models for change in sense of control and hopelessness, accounting for recent changes in social circumstances and health status.

Results: Low mastery, perceived constraints, and hopelessness were highest among individuals with less than a high school education. Over a 4-year period, this group experienced the greatest declines in psychosocial functioning, as indicated by greater increases in low mastery, perceived constraints, and hopelessness. Education differences existed net of recent negative experiences, specifically the loss of intimate social relationships and social support and increases in disease and disability.

Discussion: These findings highlight the importance of education for sense of control and hopelessness in older adulthood and demonstrate the cumulative advantage of higher levels of education for psychosocial functioning.
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http://dx.doi.org/10.1093/geronb/gbw031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283311PMC
June 2018