Epigenetics Clocks

Biologist Vadim Gladyshev on aging, DNA, and the biological age of organs

faq | June 25, 2024

When we see a person, we estimate their age quite accurately. However, sometimes people look either younger or older than their actual age. One possible reason is that a person’s skin might age at a different rate compared to other organs. Aging might vary among individuals, raising the question: what should be considered the universal age? 

Biological Age of the Organism

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If scientists could determine an organism’s biological age (its actual age) based on accumulated damage rather than chronological age, they could study the aging of different organs. This capability would allow them to test interventions affecting lifespan and their impact on biological age.

Until recently, there were no biomarkers to conduct such research. Scientists tried various options, but it became clear that oxidative damage, telomere length, or protein aggregates did not reflect an organism’s biological age.

Everything changed in 2011 when Steve Horvath, a scientist from Los Angeles, discovered that DNA methylation could be used to determine biological age. He focused on this method because one of the four DNA nucleotides, cytosine, can be methylated. This modification is relatively stable, and millions of such sites are in the genome. Analyzing all the methylation sites showed that certain cytosines’ methylation levels correlate with biological age. While a single site is inaccurate, a mathematical model incorporating several hundred such sites can reliably determine biological age.

Epigenetic Clocks

Biologist Vadim Gladyshev on UCP1, p16 proteins, the Brandt's bat and the naked mole rat phenomenon
In 2013, Steve Horvath published a seminal paper proposing the idea of epigenetic clocks based on DNA methylation, which reflects an organism’s biological age regardless of tissue type. Initially, this idea seemed incredible, and many were skeptical. Over time, it became clear that this model could be refined to more accurately describe the aging process. Various clocks emerged, such as those for blood, liver, other tissues, and general clocks. The term “Horvath’s clocks” has become well-known.

Other scientists studied and expanded upon Horvath’s ideas, finding that clocks could be constructed for chronological age and other characteristics. For instance, harmful phenotypic changes accumulate with age and can be used to build clocks. This led to the development of PhenoAge — phenotypic clocks.

There are also clocks focused on mortality, which consider the remaining years of life rather than the exact age of the organism. This concept resulted in GrimAge, which Horvath detailed in a paper published in 2019. These various clocks overlap but provide different insights into the biology of aging.

Tissue-Specific Clocks and Rejuvenation Effects

Harvard Prof. Vadim Gladyshev on oxidative species, origins of senescence, and cumulative damage
In our laboratory, we used the concept of such clocks on mice, which serve as a good model organism for testing various interventions and studying aging mechanisms. We created clocks that predict age regardless of mouse tissue.

Additionally, we developed blood clocks. If mice are calorie-restricted, their blood clocks indicate they are younger than their chronological age. It’s long known that calorie restriction extends lifespan, and according to these clocks, it also slows aging.

Another scenario involves “turning off” the growth hormone receptor. Mice with this gene turned off age more slowly. Alternatively, if adult cells are reprogrammed into embryonic cells through Yamanaka factors, their age resets according to our clocks. Other researchers have also published clocks, and there are currently about six different epigenetic clocks for mice, built primarily for chronological age.

The idea and development of epigenetic clocks have opened a new area in the biology of aging. Scientists are now addressing questions not even studied a few years ago. We can now investigate the aging rates of different organs, determine when aging begins and its dynamics across organs, explore how aging in one organ affects another, and integrate these processes to create a unified aging model. These are entirely new directions that we have only recently started to explore.

Steve Horvath has authored over a hundred papers. In 2015, he discovered that people with Down syndrome age faster and appear older than their chronological age. Similarly, obese individuals and those with HIV age faster. Horvath also noted that the cerebellum ages more slowly than other brain regions.

This research area has grown significantly, with entire conferences dedicated to these topics. Epigenetic research is crucial because these clocks can be used in clinical trials to test life-extending interventions. Epigenetic studies can explore rejuvenation and many other fundamental processes.

Professor, Department of Medicine, Division of Genetics, Harvard Medical School; Principle Investigator, Gladyshev Lab
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