What Do Epigenetic Aging Clocks Actually Measure?

In math, time can be defined as an ongoing and continuous sequence of events that occur in succession, from past through present, and to the future.

Time is used to quantify, measure or compare the duration of events or the intervals between them, and even, sequence events.

Slippery time

How old are you? Chances are the number you came up with is based on the year you were born in. That, however, is just a number, as the cliché teaches us.

There are 50-year-olds who seem ready to roll into a grave, and there are 50-year-olds who are in such great shape that they put most 20-year-olds to shame. Chronologically, both 50-year-olds are the same age. Yet it feels weird to truly consider them equally old.

That’s because chronological age and biological age don't have to correspond perfectly. On average, they tend to linger close to each other, but some people buck that trend by being biologically significantly younger or older than their chronological age seems to suggest.

How do we know our biological age, though? Isn’t that purely subjective?

In part, yes. Subjective experience and psychology will play a role. At the same time, we can’t deny that there are plenty of physiological processes that play a role too. But that’s difficult to measure. A lot of tissues and molecules are involved and they don’t age at the same rate or in the exact same way.

Machine learning and data mining are particularly suited to deal with such issues. In a previous post, we looked at implementing machine learning in aging research. Not much later, a study in mice appeared where machine learning was used to develop two ‘aging clocks’. Another study used protein levels in the blood of human participants to attempt the development of an aging clock.

Recently, researchers have dived even deeper, into the epigenetic level. The dynamics of the epigenetic tags that can latch onto DNA and change gene activity are thought to reflect various aspects of aging. (Such epigenetic clocks have been used to, for example, study embryonal development or investigate why some animals seem age-resistant.)

Epigenetic ticking

While scientists keep improving those epigenetic clocks, the question of which aging processes they truly measure remains.

A recent study tried to answer that question.

The researchers used one of the most recent and most accurate multi-tissue epigenetic clocks, the Skin&blood clock, to track aging in cell cultures of different human cell types.

Because they were working in cell cultures, the researchers were able to keep close tabs on various processes known to be involved in aging and see how their progression was matched — or not — by the ticking of the epigenetic clock.

Long story short:

…epigenetic aging is distinct from cellular senescence, telomere attrition and genomic instability, it is associated with nutrient sensing, mitochondrial activity and stem cell composition.

The scientists also wondered when the epigenetic clock starts ticking. By having human embryonic stem cells differentiate into different cell types, they found that the clock starts pretty much at the moment of differentiation. Or:

As such, epigenetic aging is a part of the process of life that begins from the early moments of ESC differentiation.

(Interestingly, that clock might tick a little bit backward in the early days.)

Aging, the researchers (rightfully, I think) conclude, is complicated.

The absence of a connection between the other aging hallmarks and epigenetic aging suggests that aging is a consequence of multiparallel mechanisms, crudely divided into deterministic pathways: those associated with epigenetic aging and stochastic ones, which are independent of epigenetic aging and may result instead from wear and tear.