Contents
About HDAC inhibitors used in anti-aging treatments
HDAC inhibitors (histone deacetylase inhibitors)
Genes within cells are wrapped in substances called histones. This exists to protect acetyl groups, which are important gene switches, but as aging progresses, HDACs lose acetyl groups, turning off the switch and making it impossible to maintain youthful gene expression patterns. HDAC inhibitors prevent this acetyl group from being removed and maintain the following functions.
1. Activation of autophagy: Cleans waste products that cause aging
2. Suppression of oxidative stress: Reduces cell damage through antioxidant action
3. Mitochondrial protection: maintain energy production and keep cells active
HDAC inhibitors range from class I to IV. Among these, class I/II HDAC
inhibitors (histone deacetylase inhibitors) suppress the activation of the
SASP (senescence-associated secretory phenomenon) gene, which causes
aging cells to release factors that cause chronic inflammation, through
epigenetic regulation (senostatic effect). It mainly works to suppress the
expression of SASP factors (IL-6, IL-8, etc.). Many of the “HDAC inhibitors”
(vorinostat, etc.) used in the treatment of blood cancer target class I/II
HDACs and do not normally act on class III HDACs (SIRT1).
HDAC inhibitors include
Sodium valproate (antiepileptic drug), phenylbutyric acid (urea cycle
disorder treatment drug). These include natural polyphenols such as
beta-hydroxybutyrate (made by the body during fasting and ketogenic diets),
butyric acid, resveratrol, quercetin, curcumin, berberine, and sulforaphane.
On the other hand, class III HDAC (SIRT1) generally refers to a protein
family called sirtuin, and is a deacetylase that is the key to suppressing
“SASP (senescence-associated secretory phenomenon)” in which aging cells
secrete inflammatory factors. SIRT1 binds to the promoter region of the
SASP gene and deacetylates histones, thereby directly suppressing the
expression of these aging factors. When SIRT1 activity decreases with
cellular aging, the expression of SASP factors (IL-6, IL-8, MMPs, etc.)
increases, which spreads inflammation to surrounding tissues.
Class I/II HDACs require zinc ions (Zn2+), whereas class III uses NAD+
(nicotinamide adenine dinucleotide) as a cofactor.
Overview of class III HDAC (sirtuin)
• Composition: In humans, there are seven types, SIRT1 to SIRT7.
• Localization: The location within the cell varies depending on the type.
o Nucleus: SIRT1, SIRT2, SIRT6, SIRT7
o Mitochondria: SIRT3, SIRT4, SIRT5
o Cytoplasm: SIRT1, SIRT2
• Main function: Deacetylates not only histones but also non-histone proteins, and is involved in a wide range of biological phenomena such as:
o Longevity/Aging Control: Starting from research on yeast Sir2, its involvement in preventing aging and extending lifespan is attracting attention.
o Metabolic regulation: metabolic control and maintenance of mitochondrial function during energy shortages.
o DNA repair/genome stability: DNA damage repair and gene silencing by maintaining heterochromatin structure.
o Stress response: Control of cell survival and apoptosis (cell death).
Antitumor effects of HDAC inhibitors and precautions when using them
HDAC (histone deacetylase) inhibitors have been reported to have the effect
of increasing the expression of NKG2D ligands (MICA/B, ULBP, etc.) on the
surface of cancer cells and activating tumor immunity by NK cells.
Tusidinostat and vorinostat, which are used as anticancer drugs to treat
leukemia and myeloma, and sodium valproate, which is used as an
antiepileptic drug, are known. These class I/II HDAC inhibitors are expected
to reduce the proportion of regulatory T cells (hereinafter referred to as
Tregs) within tumors, thereby reducing immunosuppressive function
(activating cell-mediated immunity) and making NK cell attacks more effective. On the other hand, in cancer treatment, suppression of Tregs may lead to enhanced immune responses (for example, exacerbating autoimmune and inflammatory diseases), and it must be noted that the effects will vary depending on the type of inhibitor used and administration conditions.
