Chapter 169
Changing Aging — 6
Epigenetics is all about our DNA 3D packaging, which can be broken down to three principal components: methylation, histones, and chromatin, collectively giving this packaging immense power to turn our genes on or off. As we age, our DNA gets methylated. In other words, a methyl group is added to specific cytosine nucleotides of DNA, known as CpG methylation, which can change gene expression. Our DNA also experiences other changes: our histones get acetylated, and our chromatin undergoes unfavorable remodeling. Typically, DNA methylation leads to a gene’s silencing, while histone acetylation leads to its activation. The epigenome’s relationship with aging seems bidirectional: it plays a major role in both regulating it and being modulated by it. With all our twenty thousand genes potentially impacted by DNA methylation and changes of histone or chromatin, along with noncoding RNAs, one would expect the epigenome to have some interaction with most, if not all, of the twelve hallmarks of aging—and it does.
Of the epigenetic components, DNA methylation is the easiest to measure. Researchers have developed tools, known as epigenetic clocks, to predict biological age. These clocks measure the accumulation and pattern of DNA methylation to determine the biological age of a cell or tissue, such as the blood, which provides a comparison of biologic versus chronologic age. If the blood cells are biologically older than chronologic age, that is an indicator of accelerated aging. The functionality of these clocks was validated in 2011 and has continued to be more precisely defined so we can more accurately estimate biological age. We can say more about these clocks and biomarkers of aging, but for now, the fact that methylation has been relied upon as a key way to track the aging process reinforces the pivotal role of epigenetics. The maximal lifespan across 348 mammalian species (partly represented in fig. 12.2), including humans, is predicted by epigenetic clocks. A clever analysis using the technique of Mendelian randomization of DNA methylation data was used to support its cause-and-effect relationship with health span and longevity.
That was brought home by my friend Juan Carlos Izpisua Belmonte, previously at the Salk Institute and more recently moved to Altos Labs, who made a chain of remarkable discoveries about epigenetic alteration, how it rejuvenated cells and whole animals, culminating in a seminal paper published in 2016. We gave him our Scripps Research Award in 2018 for the Future of Genomic Medicine, but it took years before the impact of this extraordinary work of rewinding time at the whole organism level was fully appreciated. Belmonte and his team used the four Yamanaka gene transcription factors (Oct3/4, Klf4, Sox2, c-Myc, abbreviated OKSM) named after Shinya Yamanaka, the stem cell scientist who won the Nobel Prize in 2012 for discovery of reprogramming an adult cell back to a pluripotent stem cell (known as induced pluripotent stem cells, iPSCs). When reprogramming is achieved, all the epigenetic marks are erased.
But with partial reprogramming, as pioneered by Belmonte’s team at the Salk Institute, instead of forming pluripotent stem cells, just the aging epigenetic signatures are removed and the cell’s identity is preserved. In this way, for example, old heart muscle cells would become young ones, but still were heart muscle cells. The partial reprogramming was then used to extend healthy aging and lifespan of prematurely aging mice. But achieving partial rather than complete reprogramming is the major challenge. One strategy is to use a brief OKSM exposure time. Fine-tuning this transient perturbation of the transcription factors can be thought of as adjusting a “volume control knob” to get the optimal setting. Otherwise, loss of identity of cells would ensue with potential transformation to cancer.