How Does Methylation Testing Compare to Other Ways of Measuring Biological Age?

How does Methylation testing compare to other ways of measuring biological age?

Quick overview of what you’ll learn from this blog post:

  • Learn about the key traits that make a clinically useful biomarker of biological age.
  • Examine the pros and cons of the four main types of biological age testing.
  • Dive into why DNA Methylation is widely regarded as the best biomarker of aging.

The need for valid, practical markers of biological age is important to applying recent lifespan and healthspan research breakthroughs. A biological age predictor that can reveal information on mortality and morbidity risk has profound clinical implications. Especially now that research is finding effective interventions to slow or reverse biological aging.

One challenge of testing applied age-reduction interventions is measuring the outcome in an accurate and clinically useful way.

The existence of such markers was previously questioned because the effects of many chronic diseases seem inseparable from normal aging. The rate of biological aging can also vary across different tissues, so it may not be feasible to assume a measurable overall rate of aging. Instead, it may be more prudent to focus on a variety of different systems, even different tissues to build a more comprehensive understanding of aging.

However, now we know that biomarkers do exist that can accurately detect the biological process of aging. We can also use that measurement to predict things like mortality, disease morbidity, and even phenotype outcomes and time-to-death.

How do we choose the best biomarker?

The American Federation for Aging Research (AFAR) formulated the criteria for aging biomarkers as follows:

  1. It must predict the rate of aging. In other words, it would tell exactly where a person is in their total life span. It must be a better predictor of life span than chronological age.
  2. It must monitor a basic process that underlies the aging process, not the effects of disease.
  3. It must be able to be tested repeatedly without harming the person. For example, a blood test or an imaging technique.
  4. It must be something that works in humans and in laboratory animals, such as mice. This is so that it can be tested in lab animals before being validated in humans.

So, let’s dive into the 4 main types of biological age measurements.

Telomere Length

Telomeres are repeating sequences of nucleoprotein caps located at the ends of chromosomes. Each time a cell undergoes mitosis, a section of these nucleotides is cleaved, and the telomere shortens incrementally. This is an overly simplistic description given that oxidative stress is also associated with telomere shortening, and multiple mechanisms exist for telomere lengthening as well. It was the most investigated aging biomarker, as of 2021.

A relationship between telomere length and several diseases has been found, and it has successfully predicted health outcomes such as physical function and morbidity. However, several studies have found no association between age or mortality and telomere length.

While Telomere length may be associated with various disease processes, its use as a predictor of biological age is so far contradictory. It has a low predictive power. Likewise, there has been very little clinical evidence of a patient’s ability to deliberately lengthen telomeres.

Telomere Length can be a powerful predictor of specific senescence-related conditions, and some diseases that are related to what happens to cells at the end of their life, but does not appear to be the best predictor of age.

Functional Age Estimators

Although not blood biomarkers, functional age estimators are included here due to their ease of use and relevance to aging research. The term functional age is now commonly found in the literature, but these tools were initially intended to be a method for estimating frailty and the likelihood of care entry, not biological age.

Historically, functional age was measured through functional tests that could be done in a clinical setting. It looked at markers like cognitive function and cardio-respiratory fitness.

More recently, some functional age estimators have been shown to estimate mortality-risk and therefore present as highly practical measures for lifestyle modification research. However, these markers often only work well as averaged indicators in very large samples, and vary significantly between individuals.

While it may be possible to overcome those limitations with artificial intelligence, this method is not currently a good choice for tracking an individual’s unique aging rate.

Composite Biomarkers / Allostatic Load Indices

Fava et al. describes allostatic load as reflecting the cumulative effects of stressful experiences in daily life that may lead to disease over time (Fava et al., 2019). Like telomere length, allostasis and allostatic load have been extensively researched.

The challenge of using it as a clinical tool is the general lack of consensus regarding the relative contribution of each marker or combination of markers. There are potential opportunities to develop even simpler, more accurate composite age biomarkers. As it stands, allostatic load appears to be significantly correlated with mortality risk, and may serve as valuable tools for aging research in the future.

Omics / Multi-Omics

In this method, we analyze the transcriptome, methylome, proteome, and metabolome to build a larger and more complex picture of the changes an organism is undergoing at different levels. This process is a useful way to approach the inherent complexity of the aging process.

With this approach, there is no single biological age, but rather a metabolic age, proteomic age, or methylome age. They all work together to create a broader picture, and a more nuanced understanding of aging. Within Omics is DNA Methylation, also called epigenetic clocks in reference to aging.

DNA Methylation and Epigenetic Clocks

Methylation can change the activity of a DNA segment without changing the sequence. The term epigenetic “clock” refers to tools that analyze DNA methylation levels within a set of Cytosine-PhosphateGuanine (CpG) sites and are generally acknowledged as accurate measures of biological age.

There are several DNA Methylation clocks that have been created, and more are in development. So far, DNA Methylation clocks are the current best predictors of mortality. In addition to measuring mortality risk, some markers have the added capability of predicting the risk of developing specific disease processes, like congestive heart failure, coronary heart disease, and type 2 diabetes.

“Epigenetic Clock” is a broad term for a host of different algorithms that use DNA methylation to detect aging and health statuses.

Individual clocks may be most effective only using a certain tissue, or it could perform similarly among various tissue types. Some algorithms are trained to detect methylation that flags epigenetic-influenced diseases, while others detect phenotypes. Some algorithms can even accurately predict time-to-death.

Why choose epigenetic clocks?

  • Methylation is the best clinical biomarker for aging and disease prediction
  • It’s an incredibly useful tool for tracking the effectiveness of anti-aging interventions in real-time.
  • Since we use a combination of different algorithms, you receive a broader and more complete picture of health, compared to other biomarkers.

DNA Methylation may be a fairly new biomarker compared to something like telomere length, but there’s already a host of research showing its unprecedented potential as a clinical tool for both aging and disease prediction.

Methylation affects every part of the body, and it can be both changed and reversed by direct personal action, unlike the genome. DNA Methylation offers a high predictive power for long-term disease risks, impacts of aging – and can offer real-time feedback on how interventions are affecting individual patients. It offers patients a feeling of control over their own health and future, where a genetic test’s results are set in stone.

Within the omics, analysis of DNA methylation is the most robust indicator of age-related changes, and has become a huge area of research. However, questions still remain: to what extent are epigenetic clocks caused by age, and to what extent do they cause symptoms of aging? How does the epigenome change with age? Since genetic ‘Nature’ and environmental ‘Nurture’ are so closely entwined and mutually influential in the field of epigenetics, finding a clear cause/effect relationship is difficult.

As research continues across the world, and in TruDiagnostic’s own laboratories, we hope to gain more insights into the science behind aging and clearer answers to these questions.


This blog was written in partnership with TruDiagnostic. TruDiagnostic is a Health Data company, specializing in epigenetic testing & research. They use a multi-omic approach to help scientists, physicians, and patients understand and benefit from the information found in the fluid epigenome.

The primary focus for TruDiagnostic is DNA Methylation – they offer a variety of algorithms and lab services for researchers, physicians, and consumers who want the most accurate and insightful longevity analysis from a CLIA-certified and HIPAA-compliant lab.

TruDiagnostic began with TruAge – a test that measures Biological Age by looking at Methylation. They now provide a full suite of aging related metrics. This includes telomere length measurements, intrinsic and extrinsic age calculations, immune cell subset deconvolution, current pace of aging, and more. It is available through AgelessRx here.

TruAge is trusted by clinical trials and academic research institutions across the world.

Note: The above statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.