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GrimAge and GrimAge2 explained: what they predict, what goes into them and how to read the gap

GrimAge and GrimAge2 explained: what they predict, what goes into them and how to read the gap

Specialty Testing Guide › TruAge Biological Age Testing

GrimAge is an epigenetic clock built to predict lifespan and healthspan rather than to match your birthday. It combines methylation-based estimates of several blood proteins and of smoking history into an age in years. The gap between your GrimAge and your actual age is the part that matters.

A positive gap means your methylation profile looks like that of people with higher mortality risk at your age. In large studies, GrimAge has been one of the strongest clock predictors of death, heart disease and cancer. For one person, it is a risk signal to read alongside your standard labs, not a diagnosis.

Key takeaways

  • GrimAge was trained to predict time to death, so a higher reading points to higher average risk, not a known disease.
  • Its building blocks are methylation stand-ins for seven plasma proteins and for pack-years of smoking, plus age and sex.
  • GrimAge2 added methylation estimates of C-reactive protein and HbA1c and predicted mortality better than the first version.
  • A two-year calorie restriction trial did not shift GrimAge significantly, so expect it to move slowly if at all.

How GrimAge is built

GrimAge was developed in two stages. First, researchers built methylation-based estimates, or surrogates, for blood proteins linked to health and for smoking. Then they combined the surrogates that best predicted time to death.

The final model uses chronological age, sex, a methylation estimate of smoking pack-years and methylation estimates of seven plasma proteins: adrenomedullin, beta-2 microglobulin, cystatin C, growth differentiation factor 15, leptin, plasminogen activator inhibitor 1 and tissue inhibitor of metalloproteinases 1.1

These are not measured protein levels. They are predictions from your DNA methylation of what those levels tend to be, which is why GrimAge should not be read as a blood protein test.

What GrimAge and GrimAge2 predict

In its original validation, GrimAge stood out among existing epigenetic clocks in predicting time to death, time to coronary heart disease and time to cancer.1 Its age-adjusted version was also strongly associated with the number of age-related conditions a person had.

An independent study in 490 older adults in Ireland compared four clocks. GrimAge acceleration was linked with 8 of 9 health outcomes in basic models and remained a significant predictor of walking speed, number of medications, frailty and death after full adjustment, while the two first-generation clocks were not predictive.2

The updated version, GrimAge2, published in 2022, adds methylation-based estimates of C-reactive protein, an inflammation marker, and HbA1c, a long-term blood sugar marker. Tested in 13,399 blood samples across nine cohorts, it predicted mortality better than the original version across several racial and ethnic groups.3

FeatureGrimAge (2019)GrimAge2 (2022)
InputsAge, sex, smoking estimate, 7 protein estimatesAdds inflammation (CRP) and blood sugar (HbA1c) estimates
Trained to predictTime to deathTime to death, in people aged 40 to 92
Main strengthStrong mortality and heart disease predictionBetter mortality prediction; tracks metabolic markers

How to read the gap

Most reports show GrimAge next to your chronological age, or as an acceleration value in years. If you are 55 and your GrimAge is 58, your acceleration is about plus 3 years. A negative value means your profile resembles lower-risk people your age.

Keep three points in mind. First, GrimAge includes your chronological age in its calculation, so part of the number is fixed. Second, the original clocks carried technical noise that could shift results between replicate measurements by years, and newer computational methods were developed to reduce that.4 Third, it reflects accumulated history as well as the present, so it may not drop quickly after a change in habits.

Can GrimAge change?

In the CALERIE trial, two years of calorie restriction slowed DunedinPACE slightly but did not significantly change GrimAge.5 That fits with GrimAge's design: it summarizes long-built risk, so it is not a quick feedback tool.

The useful question is not how to lower GrimAge. It is whether the risk it points to, often smoking, metabolic health, kidney function or inflammation, is already being checked and treated with standard tests.

Is GrimAge on a TruAge report?

The clinic's TruAge page lists GrimAge among the report's measures. TruDiagnostic's current published material, however, names OMICmAge, SymphonyAge and DunedinPACE as the three core TruAge clocks, with GrimAge-based components feeding into the heart score.6 Ask our team which scores your report will include and for current pricing.

Next step

To see how a result becomes a plan, read what to do with your TruAge results. For all guides on biological age testing through our Conshohocken clinic, visit the TruAge guide hub.

Frequently asked questions

Does a high GrimAge mean I will die early?

No. It means your methylation profile resembles that of people with higher average risk. It is a group-level signal, and it cannot predict what will happen to you as an individual.

Is GrimAge better than DunedinPACE?

They answer different questions. GrimAge estimates accumulated risk as an age; DunedinPACE estimates current speed of aging. In the DunedinPACE development study, DunedinPACE added prediction beyond GrimAge, so the two are complementary rather than interchangeable.

Why does GrimAge include smoking if I never smoked?

The smoking piece is a methylation estimate calculated for everyone, not a question about your habits. If your reading seems high for a never-smoker, discuss it with your clinician rather than over-reading it.

Related reading

This article is for general education and is not medical advice. Decisions about testing and treatment should be made with your clinician. If you have severe symptoms, call 911. For a suspected poisoning, call Poison Control at 1-800-222-1222.

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References

  1. Lu AT, et al. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (Albany NY) 2019. PMID 30669119 · doi:10.18632/aging.101684↩
  2. McCrory C, et al. GrimAge Outperforms Other Epigenetic Clocks in the Prediction of Age-Related Clinical Phenotypes and All-Cause Mortality. J Gerontol A Biol Sci Med Sci 2021. PMID 33211845 · doi:10.1093/gerona/glaa286↩
  3. Lu AT, et al. DNA methylation GrimAge version 2. Aging (Albany NY) 2022. PMID 36516495 · doi:10.18632/aging.204434↩
  4. Higgins-Chen AT, et al. A computational solution for bolstering reliability of epigenetic clocks: Implications for clinical trials and longitudinal tracking. Nat Aging 2022. PMID 36277076 · doi:10.1038/s43587-022-00248-2↩
  5. Waziry R, et al. Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial. Nat Aging 2023. PMID 37118425 · doi:10.1038/s43587-022-00357-y↩
  6. TruDiagnostic. About TruAge. TruDiagnostic 2026. Source↩
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