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Loss of epigenetic information is a major driver of aging
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Loss of epigenetic information is a major driver of aging.
Cell: After 13 Years of Research, Controversy Resolved: Epigenetic Information Loss, Not Genetic Mutations, Identified as Primary Driver of Aging.
All living organisms experience an increase in entropy, manifested as the loss of genetic and epigenetic information. In yeast, as time progresses, the relocation of chromatin-modifying proteins leads to the loss of cellular identity, a hallmark of yeast aging.
On January 12, 2023, the team led by David A. Sinclair at Harvard Medical School published a research paper titled “Loss of epigenetic information as a cause of mammalian aging” in Cell.
The study employed a system known as “ICE” (inducible changes to the epigenome) and found that disruptions in epigenetic information result in mouse aging, and restoring epigenomic integrity can reverse signs of aging.
In essence, this data aligns with the information theory of aging, which posits that the loss of epigenetic information is a reversible cause of aging.
Life relies on the intricate interplay between cellular mechanisms and the information stored in the genome and epigenome, often referred to as biological “hardware” and “software.”
It remains unclear whether aging is driven by “hardware” failures, “software” malfunctions, or a combination of both.
In the 1950s, Szilard and Medawar independently proposed that aging stems from mutations caused by DNA damage, resulting in the loss of genetic information.
One of the most relevant forms of DNA damage linked to aging is double-strand DNA breaks (DSBs), occurring at rates of 10-50 instances per cell per day.
However, the question of whether genetic mutations are the primary driving force of aging has been challenged recently.
Many types of aged cells lack mutations, and strains of mice or humans with higher mutation rates show little evidence of premature aging. Mammals can clone new individuals from somatic cells of old ones with normal lifespans.
Cellular identity during development is determined by transcriptional networks and chromatin structures. Cells must maintain their identity by preserving epigenetic information and low entropy for optimal function.
The notion that epigenetic information loss, rather than genetic mutations, could be a potential cause of aging emerged in yeast studies in the 1990s.
The relocation of the silent information regulator complex (Sir2/3/4) from stable mating loci to unstable rDNA was linked to infertility, a hallmark of yeast aging.
This correlated with changes in histone occupancy, histone modifications (like H3K56ac and H4K16ac), and gene transcription.
Overexpression of SIR2, histones, or deletion of the histone methyltransferase gene SET2 extended yeast lifespan, suggesting that epigenetic changes are not only biomarkers but also causal factors in yeast aging.
Epigenetic changes associated with aging, including alterations in DNA methylation (DNAme) patterns, H3K4me3, H3K9me3, and H3K27me3 modifications, are also observed in multicellular organisms.
Examples include worm strains lacking H3K4 trimethylation complex, which live longer, and flies overexpressing the Sir2 gene, as well as long-lived naked mole rats with relatively stable epigenomes. Many epigenetic changes follow specific patterns, including methylation of specific CpGs in the epigenetic clock.
The reasons behind changes in the mammalian epigenome over time remain unclear.
Clues still come from yeast. A primary driver in yeast is DSBs, repair of which requires epigenetic regulatory factors like Sir2, Hst1, Rpd3, Gcn5, and Esa1.
The “relocation of chromatin modifiers” (RCM) hypothesis and subsequent “information theory of aging” propose that eukaryotic aging is driven by the loss of transcriptional networks and epigenetic information over time, governed by a conserved mechanism evolved to collectively regulate responses to cellular damage, like DSBs or compression injuries.
To test whether epigenetic changes are a cause of mammalian aging, the study developed a system to degrade and reset cellular and murine epigenetic information.
The study’s data suggest that mammalian aging is a “software” issue, resulting from epigenetic information damage, which can be restored from existing backup copies.
“This 13-year study, we believe, is the first to show that epigenetic changes are a primary driver of mammalian aging,” said David Sinclair, the corresponding author of the paper from Harvard Medical School. The team’s wide array of experiments confirms a long-anticipated truth: DNA alterations are not the sole or even primary cause of aging. Instead, the results suggest that chromatin’s chemical and structural changes accelerate aging without altering the genetic code itself.
Loss of epigenetic information is a major driver of aging
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