Thread by @JoinLifespan

A major new paper reframes aging as a systems failure of epigenetic information. Not wear and tear but a software problem. This is what the Information Theory of Aging predicts and, if correct, means aging is reversible.

Let's dive in... 🧵

This image of the Waddington landscape shows cell identity, where the top is no identity and the valleys are specific cell identities. An fertilized egg goes from of the mountain and the cells spread out. Cells move from one valley to another during aging...

Some new scientific words have been invented or co-opted for the new field of Age Reprogramming:
Epigenetic memory
Epigenetic drift
Positional Memory
Shannon entropy (cf. Claude).
Not included in review:
Rejuvenation
Epigenetic noise
Exdifferentiation
Redifferentiation

Dr. Vadim Gladyshev @harvardmed, co-author, a leader in the study of aging at the epigenetic level (and the scientist who showed embryos undergo a reset of age at day 7). Dr. Doğa Yücel, a postdoc is first author

This review is one of the most important syntheses in years. It doesn’t just catalog things. It proposes a unifying framework. ie. aging is a breakdown of epigenetic fidelity, the ability of cells to maintain correct gene expression over time...

They define four interacting pillars of epigenetic aging:
1. Loss of nuclear architecture
2. Breakdown of epigenetic memory
3. Nucleosome / histone drift
4. Transcriptional reprogramming
These aren’t isolated. They interact to accelerate aging

What’s striking is the systems view. Aging is not one pathway failing but is a network collapse of gene regulation. Cells lose the ability to maintain identity as gene expression becomes noisy, then tissues lose function. Says this is why we get diseases...

This aligns directly with Information Theory (ITOA):
Aging is not primarily DNA damage because animals can be cloned

It’s loss of epigenetic information that tells cells how to read DNA correctly. The instructions, or biological software, are corrupted...

One key insight is that epigenetic drift is structured, not random. It follows predictable patterns across tissues, meaning aging is programmable and therefore malleable (Lu, Tian & Sinclair, Nature Aging, 2023)

Aging cells don’t just become noisy. They are actively reprogrammed into stress-response states (AP-1 driven). This fits with findings in the Sinclair, Ksander and He labs.... that acute cell stress, e.g. DNA breaks or nerve injury, accelerates biological aging

PRC2 is a protein complex that facilitates embryogenesis but also seems to be necessary for age reversal by OSK. PRC2 sites overlap with OSK changes to DNA methylation, for example (Lu et al., Nature 2020)

Their message is not to target single pathways anymore. Start restoring system-level control of the (epi)genome, like epigenetic reprogramming with OSK, chromatin modifiers, and gene-binding (TF) factor-based therapies

Perhaps the most important takeaway is that aging is a loss of the ability to maintain cellular identity. And if identity can be restored, aging can be reversed. Such statements were heretical just a few years ago

We’re seeing a shift in the field: from damage control to information restoration. From slowing aging to resetting it. This review marks that transition

Link to the paper @NatureGenet nature.com/articles/s4158…