Cadmium (Cd) accumulates with aging and is elevated in long-lived species. Metallothioneins (MTs), small cysteine-rich proteins involved in metal homeostasis and Cd detoxification, are known to be related to longevity. However, the relationship between Cd accumulation, the role of MTs, and aging is currently unclear. Specifically, we do not know if long-lived species evolved an efficient metal stress response by upregulating their MT levels to reduce the toxic effects of environmental pollutants, such as Cd, that accumulate over their longer life span. It is also unknown if the number of MT genes, their expression, or both protect the organisms from potentially damaging effects during aging. To address these questions, we reanalyzed several cross-species studies and obtained data on MT expression and Cd accumulation in long-lived mouse models. We confirmed a relationship between species maximum life span in captive mammals and their Cd content in liver and kidney. We found that although the number of MT genes does not affect longevity, gene expression and protein amount of specific MT paralogs are strongly related to life span in mammals. MT expression rather than gene number may influence the high Cd levels and longevity of some species. In support of this, we found that overexpression of MT-1 accelerated Cd accumulation in mice and that tissue Cd was higher in long-lived mouse strains with high MT expression. We conclude that long-lived species have evolved a more efficient stress response by upregulating the expression of MT genes in presence of Cd, which contributes to elevated tissue Cd levels.

镉 (Cd) 会随着年龄的增长而积累，并在长寿物种中升高。金属硫蛋白 (MTs) 是一种参与金属稳态和 Cd 解毒的富含半胱氨酸的小蛋白质，已知与长寿有关。然而，Cd 积累、MTs 的作用和衰老之间的关系目前尚不清楚。具体来说，我们不知道长寿物种是否通过上调其 MT 水平来减少环境污染物（如 Cd）的毒性作用，从而进化出有效的金属应激反应，这些污染物在其较长的寿命期间积累。也不知道 MT 基因的数量、它们的表达或两者是否保护生物体在衰老过程中免受潜在的破坏性影响。为了解决这些问题，我们重新分析了几项跨物种研究，并获得了长寿小鼠模型中 MT 表达和 Cd 积累的数据。我们证实了圈养哺乳动物的物种最长寿命与其肝脏和肾脏中的 Cd 含量之间的关系。我们发现，虽然 MT 基因的数量不影响寿命，但特定 MT 旁系同源物的基因表达和蛋白质数量与哺乳动物的寿命密切相关。MT 表达而不是基因数量可能会影响某些物种的高 Cd 水平和寿命。为了支持这一点，我们发现 MT-1 的过表达加速了小鼠中 Cd 的积累，并且在具有高 MT 表达的长寿小鼠品系中组织 Cd 更高。我们得出结论，长寿物种通过在 Cd 存在下上调 MT 基因的表达，进化出更有效的应激反应，这有助于提高组织 Cd 水平。