Sure many of you already are aware of Josh Mittledorf studies on aging and his unbreakable faith on the programmed theory of ageing. This post on his blog gives us his well exposed and argued, imho, take on stochastic methylation clocks:
Stochastic methylation clocks?
Posted on August 14, 2024
Methylation clocks have found their way into the community of aging research as a way to test anti-aging interventions without having to wait for mortality statistics. But methylation clocks are only useful for this purpose if aging is an epigenetic program, and most aging researchers still resist this paradigm. Just this year, some researchers have noticed this tension, and they have proposed that the methylation changes measured by epigenetic clocks are random drift, not under the body’s control. Below, I show why they are wrong about this, and why it may not even be possible to build an epigenetic clock based on unprogrammed drift.
Beginning in 2013, I took an early interest in methylation clocks because of the intrinsic link to programmed aging. It had became clear that gene expression was a powerful way to understand growth, development, and metabolism. Every cell in the body has the same genes, and these do not change over a lifetime. It is switching genes on and off in particular places and particular times that is responsible for all the essential processes of life.
Thus the default assumption is that gene expression = epigenetics is a tightly-controlled process. Genes are turned on when and where they are needed, and turned off otherwise. It was natural to think that the timing of gene expression to implement growth and development continued to implement an aging program later in life.
So, when Steve Horvath taught us that genes are turned on and off over a lifetime with the regularity of clockwork, I was enthusiastic about potential of the technology to evaluate anti-aging interventions. Not only that, I interpreted the regularity of gene expression changes with age as evidence for an aging program, and I said so.
The Horvath clocks were useful, and have been adopted. Some people were aware that the technology itself was a contradiction to their theoretical belief that aging is not (“cannot be”) under the body’s control. This tension between theory and practice has been simmering for 10 years, and just this year a proposed reconciliation has emerged: Three papers on stochastic methylation changes have been published in 2024. Their thesis is that methylation clocks are measuring loss of focus in the methylation pattern, rather than a directed process. “Dysregulation”, “stochastic change”, and “epigenetic entropy” are other names for the same idea.
My view is that these articles are ideologically motivated, and unconvincing. Yes, some of the changes in methylation that occur with age seem to be random and undirected. But the Horvath clocks were built on methylation sites that change most reliably and consistently over a lifetime. Sites that change randomly are less useful, and are left out of the algorithms. We have every reason to believe that their directed change with age is under the body’s control.
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https://joshmitteldorf.scienceblog.com/2024/08/14/stochastic-methylation-clocks/