Putting epigenetic biomarkers to the test for clinical trials

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Abstract

Reliable biomarkers are needed to test the effectiveness of interventions intended to improve health and extend lifespan.

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An epigenetic biomarker of aging for lifespan and healthspan

Morgan E Levine, Ake T. Lu, Austin Quach … (2018)

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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Quantification of biological aging in young adults.

Daniel W Belsky, Avshalom Caspi, Renate Houts … (2015)

Antiaging therapies show promise in model organism research. Translation to humans is needed to address the challenges of an aging global population. Interventions to slow human aging will need to be applied to still-young individuals. However, most human aging research examines older adults, many with chronic disease. As a result, little is known about aging in young humans. We studied aging in 954 young humans, the Dunedin Study birth cohort, tracking multiple biomarkers across three time points spanning their third and fourth decades of life. We developed and validated two methods by which aging can be measured in young adults, one cross-sectional and one longitudinal. Our longitudinal measure allows quantification of the pace of coordinated physiological deterioration across multiple organ systems (e.g., pulmonary, periodontal, cardiovascular, renal, hepatic, and immune function). We applied these methods to assess biological aging in young humans who had not yet developed age-related diseases. Young individuals of the same chronological age varied in their "biological aging" (declining integrity of multiple organ systems). Already, before midlife, individuals who were aging more rapidly were less physically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biological aging in young adults can be used to identify causes of aging and evaluate rejuvenation therapies.

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Reversal of epigenetic aging and immunosenescent trends in humans

Gregory M Fahy, Robert Brooke, James Watson … (2019)

Abstract Epigenetic “clocks” can now surpass chronological age in accuracy for estimating biological age. Here, we use four such age estimators to show that epigenetic aging can be reversed in humans. Using a protocol intended to regenerate the thymus, we observed protective immunological changes, improved risk indices for many age‐related diseases, and a mean epigenetic age approximately 1.5 years less than baseline after 1 year of treatment (−2.5‐year change compared to no treatment at the end of the study). The rate of epigenetic aging reversal relative to chronological age accelerated from −1.6 year/year from 0–9 month to −6.5 year/year from 9–12 month. The GrimAge predictor of human morbidity and mortality showed a 2‐year decrease in epigenetic vs. chronological age that persisted six months after discontinuing treatment. This is to our knowledge the first report of an increase, based on an epigenetic age estimator, in predicted human lifespan by means of a currently accessible aging intervention.

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Author and article information

Contributors

Jamie N Justice:

ORCID: https://orcid.org/0000-0003-2953-4404

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 09 June 2020

Publication date Collection: 2020

Volume: 9

Electronic Location Identifier: e58592

Affiliations

[1 ]Internal Medicine Section on Gerontology and Geriatrics, Wake Forest School of Medicine Winston-SalemUnited States

[2 ]Sticht Center for Healthy Aging and Alzheimer’s Prevention, Wake Forest School of Medicine Winston-SalemUnited States

Author information

Jamie N Justice https://orcid.org/0000-0003-2953-4404

Stephen B Kritchevsky https://orcid.org/0000-0003-3336-6781

Article

Publisher ID: 58592

DOI: 10.7554/eLife.58592

PMC ID: 7282804

PubMed ID: 32515735

SO-VID: ece9092b-664a-423a-956b-031a06c41433

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This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

History

Date received : 03 June 2020

Date accepted : 03 June 2020

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Author impact statement Reliable biomarkers are needed to test the effectiveness of interventions intended to improve health and extend lifespan.

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ScienceOpen disciplines: Life sciences

Keywords: aging,biological aging,dna methylation,epigenetic,human,life-course

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ScienceOpen disciplines: Life sciences

Keywords: aging, biological aging, dna methylation, epigenetic, human, life-course

Putting epigenetic biomarkers to the test for clinical trials

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Most cited references 5

An epigenetic biomarker of aging for lifespan and healthspan

Quantification of biological aging in young adults.

Reversal of epigenetic aging and immunosenescent trends in humans

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