The new age of a human

The new age of a human
By Santanu Chakraborty

How does the cell ‘know’ to make a precise copy of itself. Clearly some sort of a blueprint would be needed

Otissues change as we get older often becoming less functional and sometimes degenerating over time. Yet some of us fare better than others; there is the rare forty year old who is significantly healthier than an average thirty year old. Such instances are observed often enough that scientists have wondered if they could come up with a measure of age that was not entire chronological. In other words, could we possibly measure age as a function of the material state of something(s) inside our bodies? The intuitive answer, it would seem, is obviously yes. Since aging leaves a clear and present trace in the body there should be one or more sets of molecules that we are made of which should also change in abundance or state with the age of the body. To see the logic behind a recent development that is proving a capable molecular indicator of human age, we must first look at the nature of DNA, the information carrying molecule of life.

Organisms, unicellular and multicellular, all divide into nearly identical daughter cells using raw materials that are sourced from the immediate environment. How does the cell ‘know’ to make a precise copy of itself. Clearly some sort of a blueprint would be needed. The search for such a blueprint material bore fruit when the German Friedrich Miescher isolated long stringy molecule called DNA (deoxyribonucleic acid) from inside cells in 1869. It would be many years later, 1953 in fact, when Francis Crick and James Watson would decipher the molecular structure of DNA using data obtained by Rosalind Franklin, Raymond Gosling and Maurice Wilkins, all at the University of Cambridge. The importance of deciphering the structure had been important to many scientists around the world, with multiple groups racing to find the structure first amongst whom were some who were already famous at the time (Linus Pauling and Lawrence Bragg) and some who would go on to do important work later (Max Perutz). They had all realized that the mechanisms by which DNA molecules coded for information and replicated would open the doors to a significant advancement of knowledge. Many years hence, many layers of the ‘code’ are better understood. The immediate code is the making of protein molecules starting from DNA. These were understood early in the day. Much progress then happened in understanding the physico-chemical structures of the inner machineries of cells eventually leading to a more nuanced understanding of life processes.

The four constituent molecules of DNA are adenine (A), thymine (T), cytosine (C) and guanine (G). Imagine these as being alphabets put together into one or more millions of molecules long mega-molecule inside cells. The long molecule then folds up into a tiny dot inside a cell. This collection of ‘aphabets’ is the ‘book’ of life which will be read out in myriad ways throughout an animals life. The study of these molecules and their readouts is genetics and for a long time the focus was purely on the sequence of DNA in an organism. But how could organisms react to changing circumstances and learn, remembering in their code altered responses to environmental factors?

There are possibly many different ways. One relatively recent discovery is that our DNA is coated along pretty much its entire length with protein molecules which in turn can acquire marks – recognizable chemical modifications – in response to the environmental history of the organism. These we call epigenetic modifications. Large scale alterations of the epigenetic marks on our DNA can happen when we, for example, go through a prolonged period of starvation, inhale smoke or alter our diet. Another such factor is age.

In 2013, Steve Horvath, proposed (Genome Biology, 2013:14:R115) that the pattern of epigenetic marks could be used to predict the age of a human. The statistical methods used are not hard to get some intuition for. Say you have DNA marker identity and positions along the entire stretch of the human genome (the ideal case) for an infinite (or at least very large number) of individuals whose ages range from just born to as long as they lived. The human genome sequence is more than 3 billion base pairs long. So for each individual you would have a 3 billion long sequence of letters describing the DNA itself (...ATCGGGGTTA ...) and an equally long string of zeros and ones (...0111001101...), where zero stands for unmarked and one stands for marked for describing the epigenetic state of the DNA. This is the simplest possible case where we have assumed that there is only one kind of mark and it can be only off or on.

Mathematical methods were then used to analyse such data with age yielding a model that can predict the individuals age to within less than five percent of its total lifespan in both humans and mice. Such combinations - of genetics, data and mathematics – may well be used in early diagnostics to check for anything from accelerated aging to cancer sooner than we think.
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