Academy

NAD+ and Cellular Energy

Nicotinamide adenine dinucleotide (NAD+) is a coenzyme present in every living cell that plays a central role in energy metabolism and cellular repair. It functions as an essential electron carrier, assisting in redox reactions that generate adenosine triphosphate (ATP), the primary energy currency of cells. As we age, NAD+ levels naturally decline due to increased demands on repair processes and cumulative cellular damage. Low NAD+ availability can impair mitochondrial function, reduce energy production, and slow down critical pathways such as sirtuin activation, which is linked to DNA repair and longevity.

Supplementation with NAD+ precursors like nicotinamide mononucleotide (NMN) offers a practical route to restore intracellular NAD+ pools. NMN is converted into NAD+ within cells, boosting energy metabolism and supporting vital processes such as oxidative phosphorylation. By maintaining robust NAD+ levels, cells can more effectively manage stress responses, promote efficient energy generation, and activate longevity-associated proteins.

• Sources of NAD+ precursors: NMN, NR (nicotinamide riboside), and niacinamide.
• Key benefits: Enhanced mitochondrial function, improved DNA repair, and increased cellular resilience.
• Considerations: Studies indicate optimal dosing and formulation are crucial for bioavailability and effectiveness.

Senescent Cells and Senolytic Strategies

Cellular senescence is a state in which cells lose the ability to divide and adopt a pro-inflammatory secretory profile, known as the senescence-associated secretory phenotype (SASP). While senescence initially acts as a protective mechanism against damaged or pre-cancerous cells, accumulation of senescent cells over time can drive chronic inflammation, tissue dysfunction, and age-related diseases.

Senolytics are a class of compounds designed to selectively induce apoptosis in senescent cells. Common natural senolytics include quercetin, fisetin, and spermidine. These molecules target survival pathways unique to senescent cells, facilitating their clearance by the immune system. Removing senescent cells has been shown in preclinical models to reduce inflammatory signaling, improve tissue function, and delay the onset of age-associated disorders.

• Mechanisms of action: Inhibition of anti-apoptotic proteins like BCL-2 and BCL-xL.
• Research highlights: Fisetin supplementation reduced senescent cell burden and improved physical function in animal models.
• Safety and dosing: Intermittent dosing strategies are often employed to minimize potential side effects.

Urolithin A and Mitochondrial Health

Urolithin A is a metabolite produced by gut microbiota from dietary ellagitannins found in pomegranates, walnuts, and berries. It has gained attention for its ability to induce mitophagy, the selective turnover of damaged mitochondria. Efficient mitophagy is essential for maintaining a healthy population of mitochondria, reducing oxidative stress, and preserving energy output.

By promoting the clearance of dysfunctional mitochondria and stimulating biogenesis of new organelles, Urolithin A supports metabolic health and cellular vitality. Clinical studies have demonstrated improvements in muscle endurance and mitochondrial biomarkers in older adults following Urolithin A supplementation. This makes Urolithin A a valuable component of targeted formulations aimed at enhancing mitochondrial function and overall healthspan.

• Key actions: Stimulates mitophagy and enhances mitochondrial biogenesis.
• Applications: Supports muscle function, reduces age-related decline, and boosts endurance.
• Sources: Pomegranate extract and direct supplementation.