Aging and Geroscience: Putting epigenetic biomarkers to the test for clinical trials

Reliable biomarkers are needed to test the effectiveness of interventions intended to improve health and extend lifespan.
  1. Jamie N Justice  Is a corresponding author
  2. Stephen B Kritchevsky
  1. Internal Medicine Section on Gerontology and Geriatrics, Wake Forest School of Medicine, United States
  2. Sticht Center for Healthy Aging and Alzheimer’s Prevention, Wake Forest School of Medicine, United States

Geroscience is a developing discipline based on the premise that health can be improved by targeting aging. This hypothesis is supported by evidence that interventions (such as changes in diet) can improve the health and extend the lifespan of various animal models (López-Otín et al., 2013). Clinical trials are underway to test the geroscience hypothesis in humans (Barzilai et al., 2016). Definitive tests of the hypothesis must demonstrate reduced rates of age-related diseases and death, but the length of time and size of trial needed to test the hypothesis are both substantial. Therefore, objective, quantifiable characteristics of the aging process – known as biomarkers – that can be tracked in clinical trials are needed for the field to progress.

Useful biomarkers should meet several criteria: i) their measurement should be reliable and feasible; ii) they should be relevant to aging; iii) they should robustly and consistently predict trial endpoints, such as functional ability, disease, or death; and iv) they should be responsive to interventions such as treatments targeting aging biology (Justice et al., 2018). Practically speaking, this means that a change in the level of a biomarker should parallel changes in the susceptibility to disease, age of death, or loss of function. Interventions that target aging and support the geroscience hypothesis should therefore also lead to changes in these biomarkers, which will be reflected in the incidence or severity of age-related diseases and functional decline.

Biomarkers based on DNA methylation levels look promising. Briefly, these biomarkers quantify the proportion of cells in which a gene locus is methylated. Small but consistent changes in the methylation of some loci occur in organisms with older ages, and early methods for estimating age using epigenetics took advantage of these chronologic changes (Hannum et al., 2013; Horvath, 2013). However, critics argue that while these ‘clocks’ may be associated with chronological age, it is uncertain whether they reflect meaningful change in the context of interventions affecting the underlying biology.

Estimators based on the levels of DNA methylation are now being developed to detect a myriad of disease states and predict mortality and adverse health events, and each is unique to its calibration method. A few of these estimators are calibrated to detect aging-related outcomes, which makes them attractive as possible biomarkers for clinical trials in geroscience. Now, in eLife, Daniel Belsky (Columbia University) and colleagues in the United States, the United Kingdom, Denmark and New Zealand report the development of a new epigenetic biomarker called Dunedin Pace of Aging methylation (DunedinPoAm) that is able to detect how aging phenotypes change over time (Belsky et al., 2020).

The new biomarker relies on a composite measure called the Pace of Aging that was developed by Belsky and colleagues several years ago (Belsky et al., 2015). The Pace of Aging is calculated based on a number of age-related phenotypic changes that occur over time. In the new work this measure was used to calibrate and validate a DNA-wide methylation clock in four independent cohorts. This is in contrast to previous approaches in which methylation biomarkers were calibrated using endpoints such as chronological age, death, environmental exposure or other biomarkers.

Is DunedinPoAm developed to the point where it could be relied upon as a biomarker for clinical trials targeting biological aging? Figure 1 shows four criteria that are used to evaluate DNA methylation as a biomarker. DunedinPoAm appears to satisfy the first three criteria. It remains to be seen if it can satisfy the fourth, which involves being responsive to interventions. One of the cohorts used to validate the new approach consisted of middle-aged, non-obese adults enrolled in the CALERIE trial. This trial tested the effects of caloric restriction – an intervention that has been successful in animal models – over a period of two years. DunedinPoAm was able to predict changes in the Pace of Aging measure in the control group, but not in the group that had been calorie restricted. However, it remains to be seen whether interventions which affect aging biology change DunedinPoAm in a way that is consistent with the phenotypic changes observed in the trial.

Assessing DNA methylation biomarkers for use in clinical trials in geroscience.

How do five DNA methylation-based biomarkers (listed in row 1) fare when assessed against four biomarker criteria for clinical trials targeting aging (listed in column 1)? All five biomarkers meet the first three criteria, but none as yet satisfy the fourth criterion. Row 2 lists how each biomarker was calibrated. Horvath and Hannum are both epigenetic age estimators (Horvath, 2013; Hannum et al., 2013); GrimAge is a mortality estimator (Lu et al., 2019); PhenoAge is a health and lifespan biomarker (Levine et al., 2018); and DunedinPoAm is an estimator of change in aging phenotype over time (Belsky et al., 2020).

Testing the geroscience hypothesis in clinical trials is still in its early days, so it is not surprising that DunedinPoAm does not yet meet the primary criterion for an aging biomarker. However, emerging evidence suggests that methylation state may change with intervention. Data from two small clinical studies, with fewer than 15 people in the control and intervention groups, suggest that methylation-based biomarkers just might meet the minimum burden of proof (Chen et al., 2019; Fahy et al., 2019). However, the acid test for any biomarker will be whether changes in its levels predict differences in the rate of chronic disease accumulation or progression, death or other clinical trial endpoints. This will require a large study like the planned Targeted Aging with MEtformin (TAME) trial, which will last for over four years and include 3000 test subjects. This trial will test the effects of metformin, a drug currently used to treat type 2 diabetes, on FDA-informed clinical disease endpoints and functional ability. Trials like this will provide a platform for discovery, data sharing, and widescale biomarker validation to accelerate the pace of progress in geroscience.

References

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Author details

  1. Jamie N Justice

    Jamie N Justice is in the Internal Medicine Section on Gerontology and Geriatrics and the Sticht Center for Healthy Aging and Alzheimer’s Prevention, Wake Forest School of Medicine, Winston-Salem, United States

    For correspondence
    jnjustic@wakehealth.edu
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2953-4404
  2. Stephen B Kritchevsky

    Stephen B Kritchevsky is in the Internal Medicine Section on Gerontology and Geriatrics and the Sticht Center for Healthy Aging and Alzheimer’s Prevention, Wake Forest School of Medicine, Winston-Salem, United States

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3336-6781

Publication history

  1. Version of Record published: June 9, 2020 (version 1)

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© 2020, Justice and Kritchevsky

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.

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  1. Jamie N Justice
  2. Stephen B Kritchevsky
(2020)
Aging and Geroscience: Putting epigenetic biomarkers to the test for clinical trials
eLife 9:e58592.
https://doi.org/10.7554/eLife.58592

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    Background:

    The association between cardiovascular disease (CVD) and selected psychiatric disorders has frequently been suggested while the potential role of familial factors and comorbidities in such association has rarely been investigated.

    Methods:

    We identified 869,056 patients newly diagnosed with CVD from 1987 to 2016 in Sweden with no history of psychiatric disorders, and 910,178 full siblings of these patients as well as 10 individually age- and sex-matched unrelated population controls (N = 8,690,560). Adjusting for multiple comorbid conditions, we used flexible parametric models and Cox models to estimate the association of CVD with risk of all subsequent psychiatric disorders, comparing rates of first incident psychiatric disorder among CVD patients with rates among unaffected full siblings and population controls.

    Results:

    The median age at diagnosis was 60 years for patients with CVD and 59.2% were male. During up to 30 years of follow-up, the crude incidence rates of psychiatric disorder were 7.1, 4.6, and 4.0 per 1000 person-years for patients with CVD, their siblings and population controls. In the sibling comparison, we observed an increased risk of psychiatric disorder during the first year after CVD diagnosis (hazard ratio [HR], 2.74; 95% confidence interval [CI], 2.62–2.87) and thereafter (1.45; 95% CI, 1.42–1.48). Increased risks were observed for all types of psychiatric disorders and among all diagnoses of CVD. We observed similar associations in the population comparison. CVD patients who developed a comorbid psychiatric disorder during the first year after diagnosis were at elevated risk of subsequent CVD death compared to patients without such comorbidity (HR, 1.55; 95% CI, 1.44–1.67).

    Conclusions:

    Patients diagnosed with CVD are at an elevated risk for subsequent psychiatric disorders independent of shared familial factors and comorbid conditions. Comorbid psychiatric disorders in patients with CVD are associated with higher risk of cardiovascular mortality suggesting that surveillance and treatment of psychiatric comorbidities should be considered as an integral part of clinical management of newly diagnosed CVD patients.

    Funding:

    This work was supported by the EU Horizon 2020 Research and Innovation Action Grant (CoMorMent, grant no. 847776 to UV, PFS, and FF), Grant of Excellence, Icelandic Research Fund (grant no. 163362-051 to UV), ERC Consolidator Grant (StressGene, grant no. 726413 to UV), Swedish Research Council (grant no. D0886501 to PFS), and US NIMH R01 MH123724 (to PFS).

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    Results: We demonstrated a long-term periodicity (about 24 years) in individual antibody responses. The reported cycles were robust to analytic and sampling approaches. Simulations suggested that individual-level cross-reaction between antigenically similar strains likely explain the reported cycle. We showed that the reported cycles are predictable at both individual and birth-cohort level and that cohorts show a diversity of phases of these cycles. Phase of cycle was associated with the risk of seroconversion to circulating strains, after accounting for age and pre-existing titers of the circulating strains.

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