Spermidine & Epigenetic Alterations

The third hallmark of aging is epigenetic alterations, or changes to the epigenome.

What is the epigenome?

The epigenome corresponds to a set of chemical modifications to your genome that can tell the genome what to do (what genes are expressed). The term epigenome is derived from the Greek word epi which literally means "above" the genome. The human genome is the complete set of DNA (about 3 billion base pairs) that makes each individual unique. DNA holds the instructions for building the proteins that carry out a variety of functions in a cell. The epigenome consists of markers, which are small chemicals and proteins that attach to DNA and regulate gene activity, essentially turning genes ON or OFF, thus controlling the production of certain proteins in particular cells. Although your DNA remains the same in every cell, the chemical "add-ons" vary, distinguishing one cell type from another.  For example, specialized cells in the eye turn on genes that make proteins that can detect light, while specialized cells in red blood cells make proteins that carry oxygen from the air to the rest of the body. Epigenetic modifications naturally occur during development and tissue differentiation but can also be influenced by environmental factors like smoking, diet, and disease. These influences trigger chemical responses that alter the epigenome, sometimes causing harm. While adaptability in the epigenome is essential for health, malfunctions in the proteins that regulate these markers can lead to disease. Over time, lifestyle choices and cellular stressors can disrupt gene regulation, contributing to aging-related decline.

The main epigenetic markers include:

1. DNA methylation: addition of methyl groups (-CH₃) to cytosine (one of the four bases that make up DNA – the C, in the ATGC bases), typically silencing gene expression. Over time, DNA methylation patterns become dysregulated, leading to either excessive silencing or activation of genes that should be tightly controlled.
2. Histone modifications: acetylation (addition of an acetyl group -COCH₃, which activates genes), methylation (addition of a methyl group, that can activate or repress), and other modifications altering chromatin structure (which is the packaging of the DNA). Histone deacetylation (removal of acetyl groups) often increases with age, resulting in reduced gene activity that supports cell repair and function, contributing to aging and age-related diseases.
3. Chromatin remodeling: structural changes in chromatin affecting DNA accessibility and gene transcription. Aging can lead to a decrease in chromatin remodeling efficiency, making it harder for cells to activate or deactivate genes as needed.
4. Non-coding RNA regulation: special RNAs that don’t code for protein (miRNAs and lncRNAs) and modulate gene expression post-transcriptionally. Aging can affect the expression of these non-coding RNAs, disrupting their role in gene regulation.

Epigenetic alterations contribute to aging by causing a loss of cellular identity (e.g., stem cells losing their differentiation potential), increasing the expression of pro-inflammatory and pro-aging genes, impairing DNA repair and mitochondrial function, and leading to a decline in tissue regeneration and resilience.

Spermidine has been shown to play a role in preventing epigenetic alterations that contribute to aging through several key mechanisms:

1. Enhances autophagy: Spermidine triggers autophagy, the process where cells clean up damaged proteins and organelles. By encouraging autophagy, it helps clear out damaged histones and other regulators of gene expression, ensuring the chromatin structure stays in good shape. This helps prevent the buildup of dysfunctional epigenetic markers that can accelerate aging.
2. Modulates histone acetylation: A paper published in the journal Nature Cell Biology showed that spermidine induces hypoacetylation of histone H3 (one of the 5 main histone proteins involved in the structure of chromatin). ​This process involves the inhibition of histone acetyltransferases (HATs), leading to the deacetylation of specific lysyl residues on histone H3. The hypoacetylation of histone H3 is associated with the suppression of oxidative stress and necrosis, and it correlates with the upregulation of autophagy-related genes. This epigenetic modification is crucial for the extension of lifespan in various organisms, including yeast, flies, worms, and human cells. Spermidine can also activate histone deacetylases (HDACs), such as SIRT1, which remove acetyl groups from histones. By keeping histone acetylation in balance, spermidine helps ensure that genes aren’t mistakenly turned on or off, a common issue with aging.
3. Reduces oxidative stress: Spermidine has antioxidant properties that reduce oxidative stress, a major driver of epigenetic alterations. Oxidative stress can damage DNA and mess with DNA methylation patterns. By reducing oxidative stress, spermidine helps protect the integrity of the epigenome, preventing the drift that happens as we age.
4. Supports DNA methylation patterns: Spermidine may influence DNA methyltransferases (DNMTs), enzymes responsible for adding methyl groups to DNA, which regulate gene expression. By maintaining proper DNA methylation patterns, spermidine helps prevent the silencing of tumor suppressor genes or the activation of oncogenes, which are common epigenetic changes in aging.
5. Activates SIRT1 and other longevity pathways: By activating SIRT1, spermidine helps counteract age-related epigenetic changes, such as the loss of heterochromatin (tightly packed DNA) and the accumulation of repressive epigenetic marks.
6. Promotes cellular homeostasis: Spermidine supports overall cellular homeostasis by improving mitochondrial function, reducing inflammation, and enhancing stress resistance. A stable cellular environment reduces the likelihood of epigenetic dysregulation, preserving youthful gene expression patterns. 

TLDR!

Spermidine prevents epigenetic alterations by enhancing autophagy, modulating histone acetylation, reducing oxidative stress, supporting DNA methylation patterns, and activating longevity pathways like SIRT1. These actions help maintain proper gene expression and chromatin structure, counteracting the epigenetic changes that drive aging and age-related diseases. By preserving the epigenome, spermidine contributes to healthier aging and longevity.