Anemia in Centenarians Is Associated with Elevated Serum 2−Methylcitric Acid but Not Other Measures of Cobalamin Deficiency or Renal Status.

Anemia in seniors is associated with increased mortality and frailty. It is important to determine the cause of anemia in order to initiate specific therapies. We studied cobalamin (Cbl) and folate status with other clinical and laboratory parameters associated with anemia in 234 centenarians from north Georgia aged 98–108 years, 197 female, 46 African-American. The Cbl and folate dependant metabolites included methylmalonic acid (MMA), total homocysteine (Hcys) and 2-methylcitric acid (MC). MMA, MC and Hcys are elevated in clinical Cbl deficiency. MC is also elevated with even mild renal insufficiency. Metabolites were assayed by capillary gas chromatography/mass spectrometry. The median hemoglobin (Hgb) and hematocrit (Hct) were 12.0 g/dL and 35.2 %. Severe anemia (Hgb < 8 g/dL) occurred in only 1 white female with serum ferritin of 10 ng/mL. The 10^th percentile for hemoglobin was 10.0 g/dL, and in this group, serum MC was increased (p = 0.021), albumin trended lower (p = 0.056) but serum folate, Cbl, Hcys, MMA, and creatinine were not significantly different. Univariate analysis between variables for the whole cohort showed that Hgb was inversely correlated with Hcys (p = 0.028), MC (p = 0.003), creatinine (p = 0.030) and directly with albumin (p = 0.001). In multivariate analysis, albumin was the strongest positive predictor of Hgb and MC was significantly inversely related, whereas creatinine and Hcys were no longer independent determinants. Elevated MMA with low Cbl was common in this cohort but not associated with anemia. Even those above the 90^th percentile for MMA (844–8080 nmol/L) actually had higher Hgb as compared to the rest of the cohort, 12.3 vs. 12.0 mg/dL (p = 0.096). Folate status was high in this cohort (50^th percentile (12.9 ng/mL) and those taking a multivitamin (33%) had 1.5 fold higher serum folate (p < 0.001), 17 % lower Hcy (p = 0.001) and 24 % lower MMA (p = 0.045) but no difference in Hgb. The only racial difference was that MMA was lower in African-Americans (p <0.001) and the only sex difference was that creatinine was higher in males (p = 0.025). Those with MC above the 90^th percentile (> 415 nmol/L) had lower Hgb (p = 0.038), higher creatinine (p = 0.003), Hcy (p = 0.003) and MMA (p = 0.060). Ferritin was less than 50 ng/mL in 10/22 subjects with the lowest 10^th percentile Hgb value (< 10.0 g/dL). One subject had apparent folate deficiency and 7/22 had serum creatinine > 1.3 mg/dL. Two subjects with MCV > 100 fl had renal insufficiency. In conclusion, 1. High serum 2-methylcitric acid and low serum albumin predict anemia in centenarians. 2. Serum 2-methylcitric acid may be a sensitive indicator of renal failure- associated anemia. 3. Cbl deficiency was not associated with anemia in this cohort with high folate status.