{"id":1240,"date":"2024-08-14T15:08:04","date_gmt":"2024-08-14T15:08:04","guid":{"rendered":"https:\/\/joshmitteldorf.peachpuff-wolverine-566518.hostingersite.com\/?p=1240"},"modified":"2024-08-14T15:08:04","modified_gmt":"2024-08-14T15:08:04","slug":"stochastic-methylation-clocks","status":"publish","type":"post","link":"https:\/\/scienceblog.com\/joshmitteldorf\/2024\/08\/14\/stochastic-methylation-clocks\/","title":{"rendered":"Stochastic methylation clocks?"},"content":{"rendered":"

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\u2019s 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.<\/span><\/em><\/p>\n

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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.<\/span><\/p>\n

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.<\/span><\/p>\n

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.<\/span><\/p>\n

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 (\u201ccannot be\u201d) under the body\u2019s 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. \u201cDysregulation\u201d, \u201cstochastic change\u201d, and \u201cepigenetic entropy\u201d are other names for the same idea.<\/span><\/p>\n

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\u2019s control.\u00a0<\/span><\/p>\n

I have <\/span>written previously<\/span><\/a> that there are two possibilities for the purpose of directed methylation changes over time. Type 1 changes are destroying the body, tending gradually toward programmed death. Inflammation, autoimmunity, and apoptosis are dialed up, while repair and quenching of ROS are dialed down. Type 2 changes are the opposite: the body perceives that it is in trouble and turns on repair programs. Type 2 changes are part of an ancient defense program, not explicitly timed to age, but reliably timed to the extent that the accumulation of damage (to which they respond) is reliably timed.\u00a0<\/span><\/p>\n

Distinguishing Type 1 from Type 2 methylation changes remains a major challenge. Both are occurring simultaneously, and they are difficult to disentangle. But if we wish to use methylation clocks to measure the anti-aging benefits of an intervention, Type 1 and Type 2 should be counted in opposite directions. \u201cYounger\u201d according to Type 1 means less self-destruction, and this is good. \u201cYounger\u201d according to Type 2 means less repair, and this is bad. There is the danger that an intervention might interfere with the body\u2019s repair, probably shortening life expectancy, but if our methylation clock includes Type 2 sites, the intervention might be scored as beneficial.<\/span><\/p>\n

 <\/p>\n

Stochastic clocks<\/strong><\/h1>\n

Three research articles have been published this year promoting the idea that epigenetic clocks are based on methylation changes with age that are primarily stochastic. In other words, they are dysregulation, loss of information. My purpose in this column is to expose the fallacies in their methods. I believe that the way sites are selected for the clocks strongly selects for directed, non-random changes.<\/span><\/p>\n

Entropic theories of aging have been discredited since the 19th century<\/strong><\/h2>\n

Len Hayflick was a reigning sage of the aging biology community, and the most prominent proponent today of the theory that aging reflects an inevitable accumulation of entropy. Entropic theories of aging have never been coherent, but they are nevertheless experiencing a resurgence in recent years, primarily because neo-Darwinist theories of aging are all failing. I find this ironic, because the neo-Darwinist theories arose precisely because scientists realized that the Second Law of Thermodynamics does not apply to living systems.\u00a0<\/span><\/p>\n

There is no necessity for entropy of living things to increase, because living things are constantly taking in low-entropy food and dumping high-entropy waste products into the environment. In fact, living things accumulate information as they grow. All of life is an end run around the Second Law of Thermodynamics. Therefore, aging needs an explanation from evolution, not from physics.<\/span><\/p>\n

The first neo-Darwinst theory to be proposed (<\/span>Medawar, 1952<\/span><\/a>) was the idea of a \u201cselection shadow\u201d. The natural world is highly competitive, and no animals in the wild live long enough for their fitness to decline from age. This was a plausible idea when it was proposed, but field studies in the 1990s demonstrated that it is incorrect; indeed, many animals in the wild live long enough to die of old age. Half a century after Medawar, <\/span>Ricklefs<\/span><\/a>, <\/span>Promislow<\/span><\/a>, <\/span>Bonduriansky<\/span><\/a>, and <\/span>Jones et al<\/span><\/a> independently compiled evidence that, in the natural world, there is no selection shadow.\u00a0<\/span><\/p>\n

The second neo-Darwinst theory (<\/span>Williams, 1957<\/span><\/a>) was that aging is a side-effect of genes for fertility. Fertility is so important to natural selection that fertility genes are selected even at the expense of deterioration and early death. There are many observed contradictions to this theory<\/span><\/p>\n