I. Mitochondria and Aging: A NUPEPS Scientific Perspective
Mitochondria—often described as the cell’s powerhouse—generate most of the cell’s ATP and participate in essential metabolic and signaling pathways. With age, mitochondrial performance naturally declines, contributing significantly to the aging process. This decline includes:
- Accumulation of mitochondrial DNA (mtDNA) mutations
- Decreased activity of mitochondrial respiratory chain complexes, reducing ATP output
- Increased mitochondrial reactive oxygen species (ROS), which damage proteins, lipids, and nucleic acids
- Disturbed calcium homeostasis, impairing normal cellular function
These age-related changes create a feedback loop of energy loss, oxidative damage, and cellular dysfunction—ultimately accelerating biological aging.
II. Mechanisms of Action of SS-31 (Elamipretide)
1. Enhancing Mitochondrial Energy Metabolism
Improved ADP Sensitivity
Aging reduces mitochondrial responsiveness to ADP, compromising ATP production. Research shows that SS-31 interacts directly with the mitochondrial ADP/ATP carrier ANT, increasing ADP uptake and improving mitochondrial respiration. In aging muscle tissue, this leads to:
- Higher ADP-stimulated respiration
- Increased ATP generation
- Improved mitochondrial energetic efficiency
Support of Respiratory Chain Complexes
SS-31 may stabilize the structure of respiratory chain complexes or modulate proteins that affect their function. Studies demonstrate restored complex activity in aging models following SS-31 treatment, highlighting its beneficial impact on mitochondrial bioenergetics.
2. Reducing Oxidative Stress
Lowering Mitochondrial ROS Production
SS-31 reduces mitochondrial ROS through:
- Improved electron transport efficiency, minimizing electron leakage
- Direct interaction with mitochondrial membranes, decreasing oxidative damage sites
In aged cardiac cells, SS-31 significantly lowers mitochondrial ROS, demonstrating strong antioxidant potential.
Reinforcing Antioxidant Defenses
SS-31 may support endogenous antioxidant systems, such as:
- Superoxide dismutase (SOD)
- Catalase (CAT)
- Glutathione peroxidase (GSH-Px)
In cellular models, SS-31 increases the activity of these enzymes, improving cellular resilience against oxidative stress.
3. Stabilizing Mitochondrial Membranes
Selective Binding to Mitochondrial Phospholipids
SS-31 has a chemical structure that enables high affinity for phosphatidylserine-rich regions of the mitochondrial membrane. This interaction:
- Protects membrane phospholipids from oxidation
- Helps maintain membrane potential
- Prevents opening of the mitochondrial permeability transition pore (mPTP)
Regulation of Membrane-Associated Proteins
SS-31 may also influence key mitochondrial membrane proteins such as VDAC, supporting healthy metabolite transport and signaling.
III. Anti-Aging Effects of SS-31 Across Systems
1. Cardiovascular System
Improved Cardiac Function in Aging
In aged mouse models, 8 weeks of SS-31 treatment led to:
- Enhanced diastolic function
- Reduced mitochondrial proton leak
- Decreased cardiac ROS and protein oxidation
- Restoration of redox balance
- Increased phosphorylation of cMyBP-C Ser282, supporting improved cardiac relaxation
Vascular Protection
In hypertension-induced cerebral microbleed models, SS-31:
- Reduced mitochondrial ROS in vascular tissue
- Mitigated oxidative damage
- Delayed onset and reduced incidence of microbleeds
This underscores SS-31’s potential to support vascular integrity with age.
2. Nervous System
Protection Against Cognitive Decline
In aged mice exposed to isoflurane, SS-31:
- Reversed mitochondrial dysfunction
- Restored synaptic plasticity proteins (synaptophysin, PSD-95, p-CREB)
- Enhanced BDNF signaling
- Upregulated NMDA receptor subunits (NR2A, NR2B) and CaMKII isoforms
These effects collectively improved learning and memory.
Mitigating Effects of Sleep Deprivation
Short-term SS-31 treatment in aged mice prevented sleep-deprivation-induced:
- Cognitive impairment
- ROS elevation
- Mitochondrial ATP loss
- Neuroinflammation
SS-31 also normalized synaptic plasticity markers, demonstrating strong neuroprotective properties.
3. Renal System
In 26-month-old mice, 8 weeks of SS-31 treatment:
- Improved mitochondrial morphology
- Reduced glomerulosclerosis
- Lowered cellular aging markers (p16, SA-β-Gal)
- Enhanced epithelial and endothelial cell density
- Decreased indicators of podocyte injury
These findings support SS-31’s ability to restore kidney structure and mitochondrial health in aged organisms.
4. Cellular-Level Effects
Delaying Cellular Senescence
In HEK293T cells under oxidative stress, SS-31:
- Reduced SA-β-gal staining
- Lowered ROS
- Improved mitochondrial membrane potential
- Increased ATP
- Downregulated aging-related proteins (p53, p21, Ac-p53)
- Upregulated Sirt1
These results demonstrate SS-31’s capacity to counteract cellular aging pathways.
Protection Against Oxidative Damage
In ARPE-19 cells, SS-31 treatment:
- Improved cell survival
- Reduced ROS
- Preserved mitochondrial membrane potential
- Lowered cell death markers
- Suppressed RIP3 upregulation
This highlights potent cytoprotective effects relevant to aging-associated tissue damage.
Conclusion
At NUPEPS Peptides, we recognize SS-31 (Elamipretide) as a promising peptide-based strategy for supporting mitochondrial health and combating age-related decline. Through its multifaceted influence on energy metabolism, oxidative stress reduction, and structural maintenance of mitochondria, SS-31 demonstrates significant potential across cardiovascular, neurological, renal, and cellular aging models.