SS-31 and NMN: Two paths to improve metabolism and function in aged hearts

Introduction:

• Cardiovascular disease is a leading cause of death in older adults.
• Age-related decline in heart function is associated with frailty.
• The health of mitochondria, the powerhouses of cells, plays a key role in maintaining heart health.
• Two drugs, SS-31 and NMN, have been proposed to treat age-related heart dysfunction by targeting mitochondria.
• SS-31 reduces oxidative stress and protects against ischemia-reperfusion injury.
• NMN increases cellular NAD+ availability, improving mitochondrial health.
• Both drugs have the potential to rejuvenate aged hearts.

Methods:

• A study was conducted using aged mice (24 months old) as a model to test the effects of SS-31 and NMN on heart health.
• In vivo magnetic resonance spectroscopy, echocardiography, liquid chromatography tandem mass spectrometry, and other techniques were used to measure changes in heart function and metabolism.

Results:

1. Functional improvements:
   • SS-31 improved diastolic function (measured by the Ea/Aa ratio), while NMN fully restored systolic function at a higher workload.
   • The combination of the two drugs showed similar improvements to SS-31 alone.
2. Long-lasting effects:
   • SS-31 had a more lasting effect on cardiac functional improvements compared to NMN, which had a more transient effect.
3. Reduction in cardiac hypertrophy:
   • Both NMN and the combination of SS-31 and NMN reduced cardiac hypertrophy, partially restoring heart weight to a younger state.
   • SS-31 alone did not have a significant effect.
4. Mitochondrial function:
   • SS-31 normalized age-related increases in mitochondrial respiration and proton leak, while NMN did not have a significant effect.
5. Metabolic changes:
   • Both NMN and the combination treatment increased NAD(H) levels, while only the combination treatment resulted in significantly greater steady-state NAD(H) levels.
   • NMN restored decreased nicotinamide levels observed in aged hearts.
6. Energetic response to workload:
   • Old hearts showed a decreased ability to handle higher work demand, but both SS-31 and NMN treatments normalized the dynamics of PCr/ATP, a measure of energetic capacity.
7. NAD+ and mitochondrial NAD(P)H dynamics:
   • SS-31 and the combination treatment reversed age-related changes in NAD+ levels, while NMN treatment did not.
   • NMN increased mitochondrial NAD(P)H levels in response to higher workload, while SS-31 and the combination treatment had varying effects.

Discussion:

• SS-31 and NMN treatments have different effects on heart health, with SS-31 improving diastolic function and NMN improving systolic function.
• The combination of SS-31 and NMN may provide synergistic benefits by targeting different aspects of heart health.
• SS-31 primarily improves mitochondrial efficiency and reduces oxidative stress, while NMN increases NAD+ availability.
• The metabolic changes observed may play a role in diastolic dysfunction, but further research is needed to understand the exact mechanisms.
• Overall, combining SS-31 and NMN may be more effective in treating age-related heart dysfunction than using either drug alone.

Conclusion:

• Mitochondrial-targeted drugs SS-31 and NMN show promise in rejuvenating old hearts.
• SS-31 improves diastolic function and has long-lasting effects on cardiac function, while NMN improves systolic function and reduces cardiac hypertrophy.
• The combination of SS-31 and NMN provides synergistic benefits by targeting different aspects of heart health.
• Further research is needed to fully understand the mechanisms and potential of these drugs in treating age-related heart dysfunction.

Title of paper: SS-31 and NMN: Two paths to improve metabolism and function in aged hearts

Author(s): Whitson JA, Bitto A, Zhang H, Sweetwyne MT, Coig R, Bhayana S, Shankland EG, Wang L, Bammler TK, Mills KF, Imai SI, Conley KE, Marcinek DJ, Rabinovitch PS.

Year published: 2020

Published in: Aging Cell

Original article can be found here.