Recently, Tsinghua University published research results in "Cell" and found that NMN can improve protein acetyl groups in the liver of aged mice.

Studies have shown that protein acetylation plays a key role in balancing redox homeostasis and energy metabolism during aging. NMN can treat aging-associated acetylation to reduce aging-associated dysfunction. In brief, there was a global increase in aging-associated protein acetylation in aged livers, which was prevented by NMN for 4 weeks.

1). What is protein acetylation?

Protein acetylation is a common protein modification process in which acetyl groups (-COCH3) are added to amino acid residues in proteins. Such modifications can alter a protein's activity, stability, and function. Acetylation of proteins plays a crucial role in regulating the aging process and age-related diseases.

The process of protein acetylation is accomplished by protein acetylases, which transfer the acetyl group from acetyladenosine to the target protein. Longevity protein Sirtuins is a class of sirtuins, in which SIRT1 and SIRT3 play a major role in this regard. Since the expression of sirtuins is dependent on NAD+, many studies have confirmed that supplementing the NAD+ precursor NMN can increase the level of NAD+ and improve age-related physiological decline.

Protein acetylation plays an important role in many diseases, such as cancer, diabetes, neurodegenerative and immune diseases. Therefore, it is an important research direction to study the role and regulation mechanism of protein acetylation in diseases.

The research of Tsinghua University explored the anti-aging effect of NMN from the perspective of protein acetylation. The protein acetylation levels in the livers of 8-week-old mice and 96-week-old mice were compared, and the situation of aged mice after intraperitoneal injection of NMN was observed.

The results showed that NMN supplementation not only suppressed the aging-associated increase in protein acetylation, but also regulated fatty acid β-oxidation, tricarboxylic acid (TCA) cycle, and valine degradation.

Protein acetylation was significantly enhanced in aged liver compared with young liver, and NMN decreased age-associated protein acetylation.
In particular, NAD(P)transhydrogenase (NNT) was significantly hyperacetylated at K70 in the liver of aged mice, and NMN supplementation not only reduced the acetylation intensity, but also did not affect the protein level. Acetylation of cytochrome 3a25 (Cyp3a25) was also significantly increased in aging liver, which was completely abolished by NMN supplementation.

The tricarboxylic acid cycle (TCA) is a metabolic pathway common in aerobic organisms, the final metabolic pathway of the three major nutrients (sugars, lipids, amino acids), and the hub of the metabolic connection of sugars, lipids, and amino acids. Enzymes involved in the Krebs cycle were also hyperacetylated in aging livers, and NMN supplementation prevented age-related hyperacetylation, the study found.

2). Effect of NMN treatment on hepatic acetamide

Research suggests that NMN may have the potential to treat hepatic acetamide. Acetamide is a lipid that is increased in alcoholic liver disease.

Studies have found that NMN can inhibit the accumulation of fat in the liver by activating the protein acetylase SIRT1, thereby reducing liver acetamide levels. In addition, NMN can also reduce the accumulation of fat in the liver by inhibiting the lipid transport protein CD36.

In animal studies, administration of NMN can reduce the pathological changes of alcoholic liver disease and reduce the level of hepatic acetamide.

The latest research data prove that as the human body ages, it will lead to more hyperacetylated peptides, and NMN treatment prevents acetylation. In addition, NMN also reduced the acetylation of most of the 2647 peptides (class II) that exhibited age-related acetylation in the liver.

Overall, 553 proteins were associated with 1171 class II peptides, and acetylation levels were significantly reduced by NMN supplementation. 266 proteins were distributed among 356 class I peptides, and the degree of acetylation increased after NMN treatment.

Most of the proteins exhibiting aging-associated increased acetylation were involved in fatty acid β-oxidation, probiotic metabolism, valine degradation, and the TCA cycle. Enzymes involved in the TCA cycle were also hyperacetylated in aged livers, and NMN treatment prevented age-related hyperacetylation without altering protein expression levels.

3). NMN reduces acetylation in aged liver

Hepatic acetylation in the elderly is a common aging-related disorder associated with decreased liver function and increased disease risk.

The study found that NMN can inhibit liver acetylation by activating the protein acetylase SIRT1 to increase intracellular energy levels. NMN can also inhibit cellular oxidative stress by inhibiting the protein acetylase KAT5, thereby delaying liver aging.

To investigate the function and mechanism of NMN, the experimental group was injected intraperitoneally with NMN (500 mg/kg body weight) or equivalent PBS every other day for 4 weeks. Protein acetylation, NAD+ and NADH levels, or NAD+/NADH ratio were significantly enhanced in aged liver compared with young liver, but NMN decreased age-related protein acetylation.

This study demonstrates that protein acetylation plays a key role in balancing redox homeostasis and energy metabolism during aging. NMN can improve aging-related acetylation to reduce aging-related dysfunction. These junctions demonstrate the great potential of NMNs in combating aging and aging-related functional decline.

Source: Luo, Chengting et al. “Nicotinamide Mononucleotide Administration Amends Protein Acetylome of Aged Mouse Liver.” Cells vol. 11,10 1654. 16 May. 2022, doi:10.3390/cells11101654