5-Amino-1MQ
5-Amino-1MQ is a potent and selective small-molecule inhibitor of nicotinamide N-methyltransferase (NNMT). By blocking NNMT, it aims to enhance cellular energy metabolism, increase NAD+ availability, and counteract age-related metabolic decline.
Structure
Synthetic, quinoline-based small molecule
Designed for selective inhibition of NNMT
Small-molecule pharmacological agent, not a peptide
Mechanism of Action
- NNMT Inhibition: Blocks the methylation of nicotinamide (NAM), reducing NAM consumption.
- NAD+ Boost: Increases substrate availability for the NAD+ salvage pathway, elevating cellular NAD+ levels, which support energy production and sirtuin-mediated longevity pathways.
- Methylation Pool Enhancement: Frees methyl groups (SAMe), potentially improving overall cellular methylation processes.
- Metabolic Enhancement: Higher NAD+ levels improve mitochondrial function, support energy metabolism, and reduce fat accumulation, reversing aspects of the aged metabolic phenotype.
Indications
(Preclinical and investigational uses):
Obesity & Metabolic Syndrome: Potential to improve metabolic health and reduce adiposity.
Age-Related Mitochondrial Decline: Supports mitochondrial function and energy metabolism in aging tissues.
Non-Alcoholic Fatty Liver Disease (NAFLD): Preclinical studies suggest potential for reducing hepatic fat accumulation.
Low NAD+ Conditions: Investigated for disorders associated with impaired NAD+ metabolism.
FoxO4
FoxO4 (Forkhead box protein O4) is a transcription factor within the FoxO family that regulates apoptosis, oxidative stress resistance, and cellular metabolism. Its inhibition has emerged as a potential senolytic strategy to eliminate senescent cells and restore tissue homeostasis.
Structure
Protein transcription factor containing a conserved forkhead (winged-helix) DNA-binding domain
Endogenous regulator of gene expression in stress response and cell cycle pathways
Pharmacological targeting is usually achieved via the designed inhibitory peptide FOXO4-DRI, which disrupts protein–protein interactions
Mechanism of Action
- Senescence Interference: In senescent cells, FoxO4 binds and sequesters p53 in the nucleus, preventing it from initiating apoptosis.
- FOXO4-DRI Inhibitor: The peptide disrupts the FoxO4–p53 interaction, freeing p53 to induce apoptosis selectively in senescent cells while sparing healthy ones.
- Gene Regulation: Under normal conditions, FoxO4 modulates transcription of genes involved in oxidative stress response, DNA repair, and cell cycle arrest, contributing to cellular survival and longevity.
Indications
(Preclinical and experimental; not approved for clinical use):
Senolytic Therapies: Targeted clearance of senescent cells in aging and age-related diseases
Frailty and Tissue Degeneration
Fibrotic Disorders (e.g., pulmonary, hepatic, or renal fibrosis)
Cancer Research: Due to FoxO4’s involvement in cell survival under stress conditions
MOTS-C
MOTS-c is a mitochondrial-derived peptide (MDP) encoded by the mitochondrial 12S rRNA gene. It functions as a hormone-like signal that communicates mitochondrial status to the nucleus and peripheral tissues, coordinating metabolism, stress adaptation, and energy homeostasis.
Structure
A 16–amino acid peptide: Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg
Encoded within mitochondrial DNA (mtDNA), distinguishing it from most regulatory peptides which are nuclear-encoded
Stable enough to act in both cytoplasmic and extracellular environments.
Mechanism of Action
- AMPK Activation: Translocates to the cytoplasm and nucleus, where it activates AMP-activated protein kinase (AMPK), the master regulator of cellular energy balance.
- Glucose Metabolism: Enhances glucose uptake and utilization in skeletal muscle, improving insulin sensitivity and protecting against metabolic dysfunction.
- Folate–Methionine Cycle Regulation: Links mitochondrial activity to one-carbon metabolism and purine biosynthesis, integrating energy status with biosynthetic pathways.
- Stress Resistance: Induces a protective adaptive stress response, increasing resilience to oxidative and metabolic stressors.
- Exercise Mimetic Effects: Promotes pathways similar to endurance exercise training, improving muscle metabolic flexibility.
Indications
(Preclinical and early-stage studies; not clinically approved):
Obesity and Insulin Resistance (including Type 2 Diabetes)
Age-Related Metabolic Decline and frailty
Exercise Performance and Muscle Metabolism optimization
Metabolic Stress Resilience in chronic disease and aging
SS-31
SS-31 (Elamipretide) is a synthetic, cell-permeable tetrapeptide engineered to selectively target and protect the inner mitochondrial membrane. It is one of the most advanced therapeutic candidates for diseases driven by mitochondrial dysfunction.
Structure
Tetrapeptide: D-Arg–2′,6′-DimethylTyr–Lys–Phe
Incorporates a unique aromatic residue allowing interaction with mitochondrial lipids
Small, positively charged, and cell-permeable, enabling rapid mitochondrial uptake
Mechanism of Action
- Cardiolipin Stabilization: Binds cardiolipin in the inner mitochondrial membrane, preserving its structure and role in the electron transport chain (ETC).
- Enhanced ATP Production: Optimizes ETC efficiency, increasing oxidative phosphorylation and cellular energy output.
- Reduced Oxidative Stress: Minimizes electron leak and decreases formation of reactive oxygen species (ROS).
- Inhibition of mPTP Opening: Prevents mitochondrial permeability transition pore activation, protecting against apoptotic and necrotic cell death.
Indications
(Preclinical and clinical, not yet FDA-approved):
Primary Mitochondrial Myopathies (PMM)
Barth Syndrome (genetic disorder of cardiolipin metabolism)
Neurodegenerative Disorders (Alzheimer’s disease, Parkinson’s disease, ALS – under study)
Cardiovascular Disease: Heart failure, ischemia-reperfusion injury, age-related cardiac decline
Other Investigational Uses: Retinal degeneration, kidney disease, skeletal muscle aging
