Introduction: Fatigue is a common issue among the elderly with chronic illnesses. This pilot study examined the effects of hemoglobin, age, Sirtuin1 (SIRT1), and rs7069102 on fatigue in older persons with chronic illness in Indonesia. Methods: A cross-sectional study of 129 elderly individuals with chronic illnesses was conducted using a moderated mediation analysis. A questionnaire was used to evaluate fatigue, SIRT1 levels were measured using ELISA, and the genotypes of rs7069102 were identified using PCR-CTPP. Hayes’ approach was used in both the mediation and moderated mediation studies. Results: Hemoglobin levels were negatively correlated with fatigue (r = -0.182, p = 0.038), but age was positively correlated with fatigue (r = 0.183, p = 0.039). The mediation analysis revealed that age had no significant effect on the relationship between hemoglobin level and fatigue. However, moderated mediation analysis indicated a significant indirect effect of the rs7069102 GG genotype on the relationship between hemoglobin, age, and fatigue at all SIRT1 levels (β(mean-1SD) = -0.100, p = 0.010; β(mean) = -0.112, p = 0.007; β(mean+1SD) = -0.122, p=0.006). Conclusion: This study shows that the rs7069102 GG genotype at all SIRT1 plasma levels acts as a mediator, reducing the effect of age-related hemoglobin on fatigue. These findings indicate the intricate interaction between genetic factors, physiological parameters, and fatigue perception in these individuals, suggesting further investigation.