Fibroblast Growth Factor 21 (FGF21), Growth Differentiation Factor 15 (GDF15), and Humanin (HN) are mitochondrial stress-related mitokines, whose role in health and disease is still debated. In this study, we confirmed that their plasma levels are positively correlated with age in healthy subjects. However, when looking at patients with type 2 diabetes (T2D) or Alzheimer’s disease (AD), two age-related diseases sharing a mitochondrial impairment, we found that GDF15 is elevated in T2D but not in AD and represents a risk factor for T2D complications, while FGF21 and HN are lower in AD but not in T2D. Moreover, FGF21 reaches the highest levels in centenarian’ offspring, a model of successful aging. As a whole, these data indicate that (i) the adaptive mitokine response observed in healthy aging is lost in age-related diseases, (ii) a common expression pattern of mitokines does not emerge in T2D and AD, suggesting an unpredicted complexity and disease-specificity, and (iii) FGF21 emerges as a candidate marker of healthy aging.

成纤维细胞生长因子 21 (FGF21)、生长分化因子 15 (GDF15) 和护脑素 (HN) 是线粒体应激相关的线粒体因子，其在健康和疾病中的作用仍存在争议。在这项研究中，我们证实它们的血浆水平与健康受试者的年龄呈正相关。然而，当观察患有 2 型糖尿病 (T2D) 或阿尔茨海默氏病 (AD)（这两种与年龄相关的疾病都有线粒体损伤）的患者时，我们发现 GDF15 在 T2D 中升高，但在 AD 中则没有升高，并且是 T2D 并发症的危险因素，而 FGF21 和 HN 在 AD 中较低，但在 T2D 中则不然。此外，FGF21 在百岁老人的后代中达到最高水平，这是成功衰老的典范。总体而言，这些数据表明（i）在健康衰老中观察到的适应性丝分裂因子反应在与年龄相关的疾病中消失，（ii）丝分裂因子的常见表达模式在 T2D 和 AD 中没有出现，这表明不可预测的复杂性和疾病-特异性，以及 (iii) FGF21 成为健康衰老的候选标志物。