Cardiovascular disease, which is the leading cause of death from noncommunicable diseases, is largely an aging-related disease [1]. As we age, the heart as a pumping organ will age, its ability to stretch and contract decrease, and it will gradually be unable to pump blood throughout the body, eventually leading to heart failure in patients, which will seriously affect people's healthy life [2].
As a result, scientists are increasingly concerned about how to reverse heart aging and maintain heart function, and the mitochondria as a cell power station are closely related to heart function, which makes mitochondrial targeting anti-aging substances on the stage. Shinichiro Imai' team, a top expert in the field of anti-aging star substance NMN, published a study in geroScience, the official journal of the American Association on Aging, on April 13, and demonstrated the anti-cardiac aging effects of the mitochondrial targeting substances NMN and elamipretide (SS-31) from the metabolic level [3].
What about the anti-cardiac aging effects of NMN and SS-31?
Cardiac aging, manifested by a decrease in the capacity of the heart to contract (heart function), is accompanied by changes in protein abundance and post-translational modifications of proteins [3].
The nicotinamide mononucleotides NMN and SS-31 are two mitochondrially targeted anti-aging substances that have previously been shown to be effective in restoring cardiac function in older mice[3].
The former is a biosynthetic precursor of NAD+, an essential molecule for mitochondrial energy metabolism, which mainly enhances the systolic function of the heart, and the latter is a synthetic tetrapeptide that binds to the intrachondria membrane of the mitochondria, which can improve mitochondrial function, reduce reactive oxygen species ROS production, reduce the level of pro-inflammatory factors, and mainly enhance the diastolic function of the heart [4-5].
Previously, scholars have speculated that mitochondrial-targeted anti-aging substances may repair age-related dysfunction by reversing changes in proteins that occur with aging [3]. Therefore, observing the changes in protein abundance and post-translational modification after treatment may be able to successfully find the anti-cardiac aging targets of NMN and SS-31.
Effects of NMN and SS-31 on heart protein abundance
The researchers divided the mice into four groups: the young group, the elderly control group, the NMN-treated elderly group, and the SS-31-treated elderly group [3].
In individual mice, they found no significant effects of NMN and SS-31 on protein abundance[3].
However, when they summarized the data, they found that the heart protein abundance of the young and old groups was very different, and the protein abundance of the treated elderly mice changed closer to that of the younger mice, which meant that NMN and SS-31 treatments did promote heart rejuvenation [3].
The difference between the red group is the young group and the green is the elderly group, which is very different; the blue old +SS-31 group and the black old +NMN group are closer to the young group
They further analyzed the proteins that exhibited differences in abundance.
First, comparing young mice with old mice, they found that the mitochondrial protein abundance was particularly significantly affected by aging, including mitochondrial signal transduction pathways, related proteins in the energy-producing oxidative phosphorylation pathway, and SIRT signal transduction pathway-related proteins in the mitochondria related to energy metabolism. In addition, troponin and protomyosin, essential proteins that directly mediate myocardial contraction, are also significantly affected by aging. These are closely related to cardiac function [3].
Second, when the researchers considered the effects of NMN and SS-31 treatments, they found that the protein abundance of the treated elderly mice did not seem to be consistent with the young group, but they all showed the recovery of inactivation pathways with aging, such as the protein abundance of the citric acid cycle, the main pathway of energy production in the body, which did recover to a large extent, making the elderly mice younger [3].
This means that NMN and SS-31 are particularly effective against changes in energy metabolism caused by heart aging [3].
So how do they do it?
Probably because they combat mitochondrial dysfunction caused by aging, thus preventing them from releasing reactive oxygen species that cause oxidative stress in cells and damage proteins, DNA, etc. [3].
NMN can be converted to NAD+, increasing NAD+ levels in vivo, activating THE DNA repair enzyme PARP, which requires NAD+, and processing for the accumulation of DNA mutations to avoid mitochondrial dysfunction [4]. SS-31 also stabilizes cardiolipins on the membranes within mitochondria, improves the activity of complexes in the oxidative respiratory chain (energy-producing processes) of the mitochondria, and reduces the production of reactive oxygen species ROS that causes damage, thereby improving the state of the mitochondria [5].
Seems to have come to a conclusion at this point?
But the scientists didn't stop there, they also wanted to determine which proteins were being abundant enough to affect heart function.
So they continued to identify specific proteins with differences in abundance, and found that there were 28 proteins related to cardiac diastolic function, which were basically positive correlations. Only hypoxanthine phosphate ribose transferase 1 (HPRT, which plays a role in the basic unit of synthesis of DNA and RNA, purine nucleotides), is strongly and negatively correlated with cardiac diastolic capacity [6].
Surprisingly, the researchers did not find any of the proteins with differences in abundance associated with cardiac contractile function [3].
Aging and drug treatment affect the acetylated state of the heart
The exploration of protein abundance came to an end, and the researchers then set their sights on the changes that occur in protein post-translational modifications during aging, and targeted the most common and most heart-related protein post-translational modifications, acetylation modifications[3].
There may be two variations in acetylation modification, one is that the acetylation of mitochondrial proteins increases with age, resulting in mitochondrial dysfunction, and the mitochondrial content of the heart is very high, so while the cardiac function declines, the entire heart may have a high accumulation of acetylation; second, there will be a loss of normal acetylation of specific residues during aging, resulting in the inability to perform normal functions [3].
The researchers enriched the acetylated polypeptides in the heart (which can be simply understood as small units used to make up the protein), and the acetylation status of the heart protein in the young and elderly groups still differs, but it is not as pronounced as the protein abundance. At the same time, the acetylation state of older mice treated with NMN was more "young", while the older mice treated with SS-31 were more different from young mice [3].
Note: There was a difference between the red young group and the green old group, but the difference in protein abundance was smaller than the difference in protein abundance, and the old +SS-31 group moved away from the young group
They then further explored which proteins this change in acetylation state could be.
They analyzed 501 acetylation sites that had significant modification differences in aging and found that SS-31 did not significantly change the acetylation status of the elderly mice. In elderly mice treated with NMN, many of the important protein acetylations related to mitochondrial energy metabolism increased significantly, which obviously did not conform to the expected route: NMN increased NAD+ levels in the body, activated SIRT proteins (especially SIRT3 and SIRT5 activity), and reduced hyperacetylation caused by aging to combat mitochondrial senescence [3].
Unfortunately, in this experiment, even in the hearts of MICE with SIRT3 knocked out, no change in total SIRT protein activity was detected, and the acetylation of mitochondrial energy metabolism-related proteins in elderly mice after NMN treatment was significantly increased [3].
This may be due to the fact that SIRT3 accounts for too little of the total SIRT protein activity, and there may be mechanisms that have not been discovered before, such as NMN may restore the acetylating deletion produced by these proteins during aging, which needs to be further explored by scientists [3].
Finally, the researchers once again linked the cardiac contractility and found 14 acetylation sites related to the diastolic capacity, and basically all of them showed a negative correlation. Two sites related to the ability of the heart to contract were also found [3].
This means that changes in the ability to contract during aging may be regulated by the acetylated state of heart proteins [3].
Rejuvenation of the heart still needs to be done
In short, in this study, scientists have shown us the anti-cardiac aging effect of NMN and SS-31 in an intuitive way, providing more in-depth theoretical support for their combination of two drugs (after all, one enhances the ability of the heart to contract, the other enhances the ability to relax, and it is very suitable), and identifies more protein targets for us to reverse cardiac aging, making the direction of research more broad and clear.
But from the experiment to the clinic, there is still a long way to go. For example, the undetectable change in THE ACTIVITY of the SIRT protein, or the use of NMN in the experiment at a dose of about 50 times that of NMN dietary supplements [3]! What a surprising number...
The author cheers for them, and also hopes that reversing cardiac aging can benefit thousands of families in the future!
—— TIMEPIE ——
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