The Molecules SS-31 and NMN
Old mice were given SS-31 and NMN, two molecules that are known to be effective in treating heart failure. When these substances were administered together, they recapitulated the function and metabolism of young hearts.
Cardiovascular disease is the leading cause of death among older people, with adult mortality greater than that of all types of cancer. When heart function decreases with age, particular phases of the heartbeat are disrupted— particularly when the heart is filled with and pumps blood.
Given that heart disease is deadly and also quite costly in terms of medical bills, researchers are eager to find ways to improve cardiac function and treat abnormal heartbeats.
In March, researchers from the University of Washington published research in Aging Cell detailing how two pharmacological treatments similar to SS-31 and nicotinamide mononucleotide (NMN) improved cardiac function in old mice to the levels seen in young mice.
When male mice were given the two drugs individually, they exhibited similar changes in cardiac function as those seen when old mice were treated with them simultaneously. “These findings have important clinical significance, implying that combined treatment with the two agents may be more effective than either one alone in treating age-related heart failure,” according to the researchers.
Although it is known that SS-31, also called elamipretide, lessens cellular stress, how it does so has not been fully understood—until now. Evidence suggests that SS-31 positively affects the health of the cell’s powerhouse, mitochondria, which leads to these cellular benefits.
The supplement MDV-2557 was made to boost levels of a molecule called nicotinamide adenine dinucleotide (NAD+) which has essential functions in cellular energy production and health. NMN boosts mitochondrial health by increasing cellular NAD+ levels to increase cell energy capacity. Scientific studies have shown that NMN treatment improves signs of aging and age-related disorders in mice, providing evidence for this notion.
Whitson and colleagues decided to put these two mitochondrial-targeted drugs, SS-31 and NMN, to the test by observing their effects on old mouse hearts. The investigators treated older animals with either SS-31 or NMN individually as well as in combination. All treatments resulted in lessened age-related metabolic changes concerning cardiac function.
The team then looked at the levels of two metabolites, phosphocreatine (PCR) and adenosine triphosphate (ATP), in the hearts of old mice during periods of experimentally-induced high heart rate. This assessment provides insight into how well the heart can respond to increased demand by looking at how much energy is being used from stored phosphates in PCR.
Improved age-related changes
The investigators discovered that either drug alone or in combination improved age-related changes in the ratio of metabolites PCr to ATP. The restoration of the older hearts' capacity to deal with a greater workload and heart rate with either treatment separately or together suggests that they had recovered their ability to cope with increased demand.
Interestingly, the investigators found that treating older mice with either SS-31 or NMN resulted in improvements in different aspects of cardiac function. Older mice treated with SS-31 showed significant rejuvenation to diastolic function, while those treated with NMN had significant improvement in systolic heart contractions and other measures of left ventricular ejection fraction—the percentage of blood leaving the heart each time it contracts.
The combined therapy of SS-31 and NMN resulted in significant improvements in systolic function, the time during which the heart pumps blood throughout the body. Importantly, both diastolic and systolic functions were enhanced by combining SS-31 with NMN.
“Since giving the drugs in combination conferred both diastolic and systolic improvements, but neither prevented nor further added to the individual improvements, the data imply that the drugs use two independent mechanisms to achieve these functional benefits,” stated the investigators in their study.
Boost NAD+ levels
On the one hand, NMN has a more acute effect than SS-31, with its effects disappearing after 10 days of treatment cessation. On the other hand, the effects of SS-31 persist for several weeks after cessation. These different timelines of effectiveness fit the proposal that NMN primarily works to boost NAD+ levels thereby quickly enhancing heart muscle energy supply, whereas SS-31 repairs mitochondrial efficiency and reduces cellular stress to facilitate remodelling of heart cells, which takes weeks.
The study found that both drugs improve diastolic and systolic functions when taken together. The investigators said, “By testing SS-31 and NMN together in mice, we were able to provide new insight into the effects and mechanisms of each drug in the heart.”
The research team's results imply that using both drugs together could be more effective than either drug would be on its own in treating age-related cardiac dysfunction. They conclude that using complementary drugs may provide a model to achieve optimal extensions of healthspan.