NAD+ and the Hallmarks of Aging Series – Part 3: Epigenetic Alteration – ALIVE BY SCIENCE – Bioavailable NAD+ Boosters

NAD+ and the Hallmarks of Aging Series – Part 3: Epigenetic Alteration

What is epigenetics?

It is well-known that the DNA sequence inside of the nucleus encodes all the information required for life. However, why do different cells/tissues work very differently even though they share the same genome? The answer is that they harbor different epigenetic marks that let them express different sets of genes, thus fulfilling different functions.

In general, epigenetics is a very broad term describing any functionally relevant changes to the genome that do not change in the nucleotide sequence. Specifically, they are small chemical modifications added to the DNA and histone which can alter their behavior and be recognized by other protein factors.

The most famous epigenetic marks include DNA methylation, histone methylation, and histone acetylation. The multiple enzymatic systems assuring the generation and maintenance of epigenetic patterns include DNA methyltransferases, histone acetylases, deacetylases, methylases, and demethylases, as well as protein complexes implicated in chromatin remodeling.

Epigenetic alterations during aging

A variety of epigenetic alterations affects all cells and tissues throughout life (Talens et al., 2012). Epigenetic changes involve alterations in DNA methylation patterns, modification of histones, and chromatin remodeling. Increased histone H4K16 acetylation, H4K20 trimethylation, or H3K4 trimethylation, as well as decreased H3K9 methylation or H3K27 trimethylation, constitute age-associated epigenetic marks (Fraga and Esteller, 2007; Han and Brunet, 2012).

histones

Age-related epigenetic changes (Sen et al., 2016)

Age-related epigenetic changes lead to dysregulation of gene expression

There are many other changes that happen at epigenetic levels, as shown in the figure above. As the epigenetic system is very complicated, it is important to understand its primary role. As mentioned at the beginning, it is to regulate gene expression and fulfill tissue-specific functions. Therefore, due to altered epigenetic regulation, the gene expression is dysregulated and the cell identity is gradually lost. For example, some muscle cells might start to express neuronal-specific genes and this would result in impaired tissue function, senescence, and cancer.

Epigenetic profile can be used to predict age and physiological status

Another interesting property of an epigenetic profile is that it can be used to accurately predict the biological age of individuals. Chronological age has a profound effect on genome-wide DNA methylation levels and the methylation states of millions of the 28 million CpG dinucleotides in the human genome change with age.

Epigenetic “€age estimators”€ are sets of CpGs (also known as “€clock CpGs”€) that are coupled with a mathematical algorithm to estimate the age of a DNA source, such as cells, tissues or organs. This estimated age, also referred to as epigenetic age or more precisely as DNAm age, is not only a reflection of chronological age but also of the biological age of the DNA source.

Owing to their accuracy, DNAm age estimators are often referred to as “€epigenetic clocks” (Horvath et al., 2018). Moreover, the epigenetic age acceleration (defined by the difference between the epigenetic age and chronological age) is associated with multiple physiological function and age-related diseases.

Epigenetic age is a measurement of the aging rate (Horvath et al., 2018)

Reverseablily of age-related epigenetic changes

Unlike DNA mutations, epigenetic alterations are reversible, hence offering opportunities for the design of novel anti-aging treatments. Restoration of physiological H4 acetylation through the administration of histone deacetylase inhibitors avoids the manifestation of age-associated memory impairment in mice (Peleg et al., 2010). Inhibitors of histone acetyltransferases also ameliorate the premature aging phenotypes of progeroid mice and extend their lifespan (Krishnan et al., 2011).

Epigenetic age acceleration (Topart et al., 2020)

Partial reprogramming reverses the epigenetic age

One recent study from Sinclair’s lab shows that induced expression of OSK, three of the Yamanaka factors which are primarily expressed in embryonic stem cells, can initiate epigenetic reprogramming and reverse the age-related epigenetic changes (Lu et al., 2020). Partial reprogramming also reversed the biological age measured by the methylation clock and rejuvenate the cell. It also promotes axon regeneration after optic nerve crush injury and restores vision in a mouse model of glaucoma and in normal old mice.

NAD+ and epigenetic alteration

Similar to other hallmarks of aging, epigenetic alteration is also intertwined with NAD+ metabolism. The Sirtuins, which are known as longevity proteins, belong to class III histone deacetylases (HDAC). A distinguishing feature of this class is that the catalytic activity of the enzymes depends on NAD+ and is regulated by dynamic changes in NAD+ levels and the NAD+/NADH ratio. In other words, Sirtuins remove the acetyl-modifications on the histone by consuming NAD+.

During aging, Sirtuin activity decreases due to a lack of NAD+ and histone acetylation levels increase, resulting in disregulation of gene expression and many age-related phenotypes. As the histone acetyl-transferase inhibitors can promote longevity, histone deacetylase activators may conceivably promote healthy aging. Restoration of NAD+ by NAD+ precursors can therefore provide an opportunity to boost Sirtuin activity and restore a more youthful epigenome.