GrimAge clock – it’s all a matter of time

Study finds that the DNA methylation GrimAge clock can predict an individual’s lifespan and healthspan with accuracy.

It is no secret that the precise number of years from birth of an individual, known as chronological age, doesn’t reflect an individual’s biological age. Biological age reflects a person’s physiology and health of their tissues.

Longevity.Technology: Nutrition, genetics, lifestyle and diseases all affect biological age; researchers have worked hard over the past few decades to pin-point biomarkers – measurable biological characteristics – that can reflect a person’s true chronological age. News broke yesterday that psychomarkers, psychological markers, can also measure aging. One of the most promising biomarkers identified lies in epigenetics, the study of heritable phenotypic changes to gene expression.

One epigenetic process called DNA methylation looks at the addition or removal of a methyl-group from Cytosine-phospho-Guanine (CpG) sites. Mathematical models analysing age acceleration through methylated CpG site analysis have been developed with the aim of measuring biological age – these are known as epigenetic clocks.

The first-generation clocks were developed by Drs Gregory Hannum and Steve Horvath. Hannum analysed 71 CpG sites from DNA obtained from blood [1], while Horvath considered 353 CpG site from multiple tissues [2]. Both managed to accurately predict a person’s chronological age.

While this may be useful in a forensic application, in terms of Longevity these clocks correlated weakly with biological age and clinical measures of aging diseases such as high blood pressure.

Second-generation clocks such as PhenoAge outcompeted the first generation clocks by using a 2-stage approach. Creatinine, c-reactive protein and 8 other marker levels were measured and weighted to develop a phenotypic age estimator. This factor then led to the identification of 513 CpG sites that “marked differences in disease and mortality among individuals of the same calendar age” [3].

The latest epigenetic clock, GrimAge, measured age acceleration through a different approach: after identifying DNA methylation of 12 plasma proteins and considering lifetime tobacco exposure (smoking pack years), the biomarkers were regressed to lifespan and all causes of death. This identified a whopping 1030 CpG sites [4].

Study finds that DNA methylation GrimAge clock can predict an individual’s lifespan and healthspan with accuracy.
Steve Horvath: Professor in Human Genetics and Biostatistics at UCLA and inventor of the Horvath Clock.

In Professor Horvath’s own words, what this epigenetic clock achieved is the ability to predict mortality risk from person to person.

Yet in the field there is a mutual concern that early studies tend to show publication bias, and a group of researchers, including Horvath, aimed to review all the developed epigenetic clocks in a paper now published in the Journal of Gerontology.

By analysing different cognitive and physiological outcomes from a 490 cohort of people over 50 years of age and considering sex, socio-economic and lifestyle factors, the authors obtained evidence supporting previously reported observations that Hannum and Horvath clocks lack sensitivity. They speculate that this could be due to failure to capture extrinsic life stressors.

Furthermore, this study provides evidence that both PhenoAge and GrimAge are more accurate predictors of “functional health and performance measures”. GrimAge however was found to be superior: when the variables analysed were adjusted to the full model GrimAge variation went beyond socio-economic and lifestyle factors despite having a stronger statistical association.

Genetics, psychosocial stress factors, nutritional deficiencies and toxin exposure are known trigger epigenetic modifications with negative implications for Longevity.

The researchers reflected on the factors that were not accounted for but that could affect age acceleration and ameliorate the GrimAge model. Genetics, psychosocial stress factors, nutritional deficiencies and toxin exposure are known trigger epigenetic modifications with negative implications for Longevity [5].

A GrimAge clock can aid research into Longevity and help prognosticate diseases. While Horvath cautions to take mortality risk GrimAge outcomes with caution, an approach like this could be both prophylactic and therapeutic. Rejuvenation therapies could be developed if specific factors increasing age acceleration can be identified and reversed.

Ultimately, the goal application would be in precision medicine which aims to account for a patient’s lifestyle, environment and genetics. The precision medicine market, worth $57 billion in 2019, is steadily growing, particularly in the US, UK and China [6].

Big pharma has also accentuated their focus on precision medicine, as it is common for certain groups to have varied responses to drugs. GrimAge could provide a platform to characterise population variation’s in order to develop more efficient medicine with fewer side effects for each group.

On top of this, we see an increased consumer attention to a healthy lifestyle, but what this looks like will be unique to each person. A consumer GrimAge clock could expand the market and push research into Longevity further.

As this field expands and epigenetic clocks become more accurate, therapeutics will become more personalised and efficient. In parallel, GrimAge will one day be able to identify, prevent and possibly reverse aging – the key to our Longevity.

Image credit: Pete Linforth / Pixabay