In this deep dive, Matt examines the growing trend of direct-to-consumer biological (epigenetic) age testing kits, exploring their purpose, popularity, and limitations. He outlines his experimental design to evaluate the accuracy and precision of these tests, addressing important questions about what they truly measure and how reliable they are. Matt unpacks the difference between biological and chronological age, discusses the co-marketing strategies employed by these companies, and reflects on his own results to provide a critical perspective on the value of these kits.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Measuring biological aging in humans: A quest - PMC

The increase in the aging population has grown into one of the largest public health issues as the rising incidence of age-related diseases in elderly demographics represents the greatest driver of rising healthcare costs, as well as declining function, independence, and quality of life.

Underlying biological mechanisms of aging are central to the increased susceptibility to disease and disability that occur with age. The goal of the geroscience field is to elucidate the mechanisms driving the aging process and target them with gerotherapeutics to prevent or delay the progression of multi-morbidity. This review describes the rate of biological aging process as being determined by the balance between the rate of damage accumulation and resolution. The authors emphasize the fundamental role of biomarkers that serve as reference metrics for the rate of biological aging in order to validate gerotherapeutics in humans. Further, they highlight the role of different hallmarks of aging (HoA) in the aging process as well as how they are measured within preclinical studies. One of these HoA is epigenetic dysregulation, the most popular ‘-omics’ measure used to develop biological aging clocks that predict the risk of morbidity and mortality.

DNA methylation aging clocks: challenges and recommendations | Genome Biology | Full Text

This paper reviews the history of epigenetic clock were development and highlights both the utility and challenges of applying them within the clinic to accurately track biological aging. Some of the challenges include:

1)     Variability of epigenetic signatures across tissues

2)     Multi-dimensionality of epigenetic sites make it easy to find correlations, many of which may not be indicative of biological aging

3)     Training datasets that may not accurately reflect aging signatures of present-day populations/individuals

4)     Stability of clocks over time and their sensitivity to non-age-related processes

The development of next-generation epigenetic clocks that adequately address these challenges and are associated with positive clinical changes in prospective clinical trials holds promise for effective application` in the clinic.

GrimAge Outperforms Other Epigenetic Clocks in the Prediction of Age-Related Clinical Phenotypes and All-Cause Mortality - PMC

There are several commercially available epigenetic clocks designed to predict biological age and the risk for age-related morbidity and mortality. Few studies compare the different epigenetic clocks in parallel for their ability to predict age-related adverse outcomes. This study evaluated four of the most popular research-grade epigenetic clocks (Horvath, Hannum, PhenoAge, GrimAge) for their associations with a wide range of clinical phenotypes, including walking speed, grip strength, frailty, polypharmacy, cognitive assessments, and mortality in 490 elderly participants in the Irish Longitudinal Study on Aging. GrimAge was the only clock reliably correlated with any clinical metric, including walking speed, polypharmacy, frailty and mortality. The authors highlight the variability and specificity that must be considered when utilizing epigenetic clocks for evaluating health and aging.

Contextualizing aging clocks and properly describing biological age - Johnson - Aging Cell - Wiley Online Library

There are many conflicting perspectives on the utility of biological age clocks and how to define  biological age, even amongst experts within the geroscience field. This paper defines biological age as an abstract concept that is used to describe the internal, external, and functional decline that occurs during the aging process. The authors propose that due to the tissue-specific heterogeneity and multifaceted nature of biological aging, it cannot be quantified by a single metric. Just as metrics like VO2 max and ApoB only reflect aspects of aging and risk for adverse age-related outcomes, the same is likely true for current-generation biological age clocks. As such, the output of biological age clocks should not be conflated with systemic aging. In order to increase the specificity of data from biological age clocks, the authors suggest describing the output of an aging clock based on the type of input data used (e.g epigenetic or transcriptomic) or the biospecimen/functional assessment used to evaluate biological age.

Biomarkers of aging and epigenetic clocks | Peter Attia, M.D. & Matt Kaeberlein, Ph.D.

In this 10 minute clip from The Drive podcast, Peter Attia and Matt unpack the science behind epigenetic clocks, how they are developed, and their concerns about the limitations of present-day clocks and their ability to predict positive/negative health trends. Matt suggests that epigenetic clocks most likely capture a signal that correlates with health change, but it is not clear how applicable it may be for evaluating changes relevant to the biological aging process. Prospective studies are needed to demonstrate that changes in epigenetic clocks predict hard age-related outcomes like morbidity and mortality. This ha yet to be demonstrated even in preclinical studies.