Frailty and Biological Age

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Abstract

A reliable model of biological age is instrumental in the field of geriatrics and gerontology. This model should account for the heterogeneity and plasticity of aging and also accurately predict aging-related adverse outcomes. Epigenetic age models are based on DNA methylation levels at selected genomic sites and can be significant predictors of mortality and healthy/unhealthy aging. However, the biological function of DNA methylation at selected sites is yet to be determined. Frailty is a syndrome resulting from decreased physiological reserves and resilience. The frailty index is a probability-based extension of the concept of frailty. Defined as the proportion of health deficits, the frailty index quantifies the progression of unhealthy aging. The frailty index is currently the best predictor of mortality. It is associated with various biological factors and provides insight into the biological processes of aging. Investigation of the multi-omics factors associated with the frailty index will provide further insight.

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The Hallmarks of Aging

Carlos López-Otín, Maria Blasco, Linda Partridge … (2013)

Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects. Copyright © 2013 Elsevier Inc. All rights reserved.

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DNA methylation age of human tissues and cell types

Steve Horvath, Ilias Lagkouvardos (2014)

Background It is not yet known whether DNA methylation levels can be used to accurately predict age across a broad spectrum of human tissues and cell types, nor whether the resulting age prediction is a biologically meaningful measure. Results I developed a multi-tissue predictor of age that allows one to estimate the DNA methylation age of most tissues and cell types. The predictor, which is freely available, was developed using 8,000 samples from 82 Illumina DNA methylation array datasets, encompassing 51 healthy tissues and cell types. I found that DNA methylation age has the following properties: first, it is close to zero for embryonic and induced pluripotent stem cells; second, it correlates with cell passage number; third, it gives rise to a highly heritable measure of age acceleration; and, fourth, it is applicable to chimpanzee tissues. Analysis of 6,000 cancer samples from 32 datasets showed that all of the considered 20 cancer types exhibit significant age acceleration, with an average of 36 years. Low age-acceleration of cancer tissue is associated with a high number of somatic mutations and TP53 mutations, while mutations in steroid receptors greatly accelerate DNA methylation age in breast cancer. Finally, I characterize the 353 CpG sites that together form an aging clock in terms of chromatin states and tissue variance. Conclusions I propose that DNA methylation age measures the cumulative effect of an epigenetic maintenance system. This novel epigenetic clock can be used to address a host of questions in developmental biology, cancer and aging research.

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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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Journal

Journal ID (nlm-ta): Ann Geriatr Med Res

Journal ID (iso-abbrev): Ann Geriatr Med Res

Journal ID (publisher-id): AGMR

Title: Annals of Geriatric Medicine and Research

Publisher: Korean Geriatrics Society

ISSN (Print): 2508-4798

ISSN (Electronic): 2508-4909

Publication date (Print): September 2021

Publication date (Electronic): 17 August 2021

Volume: 25

Issue: 3

Pages: 141-149

Affiliations

[1 ]Tulane University School of Medicine, New Orleans, LA, USA

[2 ]Tulane Center for Aging & Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA

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Corresponding Author: Sangkyu Kim, PhD Tulane Center for Aging & Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA E-mail: skim5@ 123456tulane.edu

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Sangkyu Kim http://orcid.org/0000-0001-6761-2579

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Publisher ID: agmr-21-0080

DOI: 10.4235/agmr.21.0080

PMC ID: 8497950

PubMed ID: 34399574

SO-VID: 7e55e7e9-7c9f-4623-b977-229354ec1bb0

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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Frailty and Biological Age

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Hearing Loss and Restoration

Most cited references 73

The Hallmarks of Aging

DNA methylation age of human tissues and cell types

An epigenetic biomarker of aging for lifespan and healthspan

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