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NAD+, SIRT3, and Why Your Genes Matter

NAD+ is a central molecule in every cell that helps turn food into usable energy, supports DNA repair, and coordinates cellular responses to stress. NAD+ also activates sirtuins, a family of proteins linked to cellular health and longevity. SIRT3 is an important sirtuin located in mitochondria. It helps mitochondria produce energy efficiently, reduce oxidative stress, and maintain healthy fat metabolism.

Variants in the SIRT3 gene can change how well SIRT3 works. When SIRT3 activity is lower, mitochondria may make energy less efficiently and produce more oxidative stress. This can contribute to metabolic disturbances and raise risk for conditions such as fatty liver disease and coronary artery disease. The SIRT3 variant rs28365927 is one example with different effects depending on your genotype.

How to Think About This Information

  • This report is educational and is not medical advice. PlexusDx does not provide medical advice. Always discuss genetic findings and health strategies with your healthcare provider before starting new treatments, supplements, or major lifestyle changes.
  • Genetics is one part of risk. Lifestyle, environment, medications, and other health conditions also strongly influence outcomes.

Practical Ways to Support NAD+ and SIRT3 Function

Whether your SIRT3 genotype suggests reduced activity or typical function, the following evidence-informed lifestyle, diet, and monitoring strategies can help support mitochondrial and metabolic health.

Diet and Nutrition

  • Focus on whole foods: a variety of vegetables, fruits, lean proteins, healthy fats, and whole grains to support overall metabolism and liver health.
  • Support NAD+ production with B vitamin rich foods: niacin containing foods such as poultry, fish, nuts, legumes, and whole grains; riboflavin and B6 sources like eggs, dairy, and leafy greens; and adequate dietary protein for tryptophan, a precursor for NAD+ synthesis.
  • Include antioxidants and polyphenols: berries, dark leafy greens, green tea, and colorful vegetables help reduce oxidative stress that challenges mitochondria.
  • Limit added sugars and refined carbohydrates to reduce fat accumulation in the liver and improve metabolic balance.
  • Moderate alcohol intake or avoid alcohol if you have liver concerns.

Exercise and Activity

  • Aim for a mix of aerobic exercise and resistance training. Regular physical activity promotes mitochondrial biogenesis and improves insulin sensitivity.
  • High intensity interval training, when appropriate, can boost mitochondrial function. Start gradually and consult your provider if you have cardiovascular or other health issues.

Sleep and Stress

  • Prioritize quality sleep. Poor sleep disrupts metabolic regulation and NAD+ homeostasis.
  • Use stress reduction techniques such as mindfulness, breathing exercises, or gentle movement to lower chronic inflammation and oxidative burden.

Fasting and Meal Timing

  • Intermittent fasting or time restricted eating may boost NAD+ and sirtuin activity in some people and improve metabolic markers. Discuss with your clinician before beginning, especially if you have diabetes, low blood pressure, or are pregnant or breastfeeding.

Supplements to Discuss with Your Healthcare Provider

  • NAD+ precursors such as nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN) may increase NAD+ levels. Safety and long term effects are still under study. Work with your clinician on dosing and monitoring.
  • B vitamins, particularly niacin, B3, B6, B2, and B12, support NAD+ synthesis and general metabolic health. A clinician can assess whether a B complex supplement is appropriate.
  • Resveratrol is a polyphenol that can activate sirtuins in laboratory studies. Effects in humans vary and doses should be reviewed with a clinician.
  • Coenzyme Q10 can support mitochondrial electron transport and may be helpful if mitochondrial stress is suspected.
  • Antioxidants such as vitamin C, vitamin E, and plant polyphenols can help manage oxidative stress. Discuss interactions with medications before starting supplements.

Clinical Monitoring and Tests to Consider

  • Liver enzymes: ALT and AST to screen for liver inflammation or fatty liver disease.
  • Lipid panel and fasting glucose or HbA1c to assess cardiometabolic risk.
  • Inflammatory markers such as hs-CRP if cardiovascular risk is a concern.
  • Weight, waist circumference, and blood pressure monitoring as practical measures of metabolic health.

Genetic Interpretation for SIRT3 Variant rs28365927

The section below explains common genotypes for rs28365927 and what they may mean for SIRT3 function and health. Use the accordion to open the genotype that matches your result. Remember to review results with your healthcare provider for personalized recommendations.

Two effect alleles (AA)

If your genotype is AA you carry two copies of the effect allele. This variant is associated with reduced SIRT3 activity. Lower SIRT3 function can impair mitochondrial energy production and weaken defenses against oxidative stress. Consequences may include less efficient fat metabolism and increased cellular inflammation. Research links this genotype with an increased risk of fatty liver disease and coronary artery disease. To help offset genetic risk, focus on a nutrient dense diet rich in B vitamins and antioxidants, regular aerobic and resistance exercise, quality sleep, and stress management. Consider discussing NAD+ precursor supplements, resveratrol, and CoQ10 with your healthcare provider. Regular monitoring of liver enzymes, lipid panel, and glucose metabolism is reasonable when indicated by your clinician.

One effect allele (AG)

If your genotype is AG you carry one copy of the effect allele. This may modestly influence SIRT3 function and mitochondrial efficiency. People with this genotype may have a likely increased risk of fatty liver disease and coronary artery disease compared with those without the effect allele, although individual risk depends on lifestyle and other health factors. Strategies to support NAD+ and SIRT3 include a balanced diet high in B vitamins and polyphenol rich foods, consistent exercise, prioritizing sleep, and managing stress. Discuss with your healthcare provider whether NAD+ precursors or other supplements are appropriate. Periodic clinical monitoring such as liver enzymes, lipid profile, and glucose testing can help track metabolic health over time.

No effect alleles (GG)

If your genotype is GG you carry two copies of the non-effect allele. This genotype is associated with typical SIRT3 function, suggesting your SIRT3 protein likely operates at standard efficiency in mitochondria. With normal SIRT3 activity your cells can effectively use NAD+ to support energy production, DNA repair, and antioxidant defenses. Maintain a healthy lifestyle to preserve mitochondrial function: balanced nutrition, regular exercise, sleep, and stress reduction. Continue routine health screenings as recommended by your clinician.

Next Steps

  • Share these results with your primary care clinician or a genetics-informed provider to interpret them in the context of your personal and family health history.
  • Consider lifestyle adjustments and clinical tests discussed above with your provider.
  • If considering supplements or significant dietary changes, consult a healthcare professional to review safety, dosing, and interactions with medications.

PlexusDx provides educational genetic information and does not offer medical advice. Always consult your healthcare provider for medical care and before making any changes to your treatment, medications, or health regimen.