Group of Molecular Radiobiology and Gerontology, Institute of Biology, Komi Science Center of Russian Academy of Sciences.
Ageing Res Rev. 2012 Jan;11(1):51-66. doi: 10.1016/j.arr.2011.09.003. Epub 2011 Oct 5.
The Gadd45 proteins have been intensively studied, in view of their important role in key cellular processes. Indeed, the Gadd45 proteins stand at the crossroad of the cell fates by controlling the balance between cell (DNA) repair, eliminating (apoptosis) or preventing the expansion of potentially dangerous cells (cell cycle arrest, cellular senescence), and maintaining the stem cell pool. However, the biogerontological aspects have not thus far received sufficient attention. Here we analyzed the pathways and modes of action by which Gadd45 members are involved in aging, longevity and age-related diseases. Because of their pleiotropic action, a decreased inducibility of Gadd45 members may have far-reaching consequences including genome instability, accumulation of DNA damage, and disorders in cellular homeostasis - all of which may eventually contribute to the aging process and age-related disorders (promotion of tumorigenesis, immune disorders, insulin resistance and reduced responsiveness to stress). Most recently, the dGadd45 gene has been identified as a longevity regulator in Drosophila. Although further wide-scale research is warranted, it is becoming increasingly clear that Gadd45s are highly relevant to aging, age-related diseases (ARDs) and to the control of life span, suggesting them as potential therapeutic targets in ARDs and pro-longevity interventions.
Gadd45 蛋白因其在关键细胞过程中的重要作用而受到了深入研究。事实上，Gadd45 蛋白通过控制细胞（DNA）修复、消除（凋亡）或阻止潜在危险细胞的扩张（细胞周期阻滞、细胞衰老）以及维持干细胞库之间的平衡，处于细胞命运的十字路口。然而，生物老年学方面迄今为止尚未得到足够的重视。在这里，我们分析了 Gadd45 成员参与衰老、长寿和与年龄相关疾病的途径和作用模式。由于其多效性作用，Gadd45 成员的诱导能力降低可能会产生深远的后果，包括基因组不稳定、DNA 损伤的积累以及细胞内稳态的紊乱——所有这些都可能最终导致衰老过程和与年龄相关的疾病（促进肿瘤发生、免疫紊乱、胰岛素抵抗和对压力的反应性降低）。最近，dGadd45 基因已被确定为果蝇的长寿调节剂。尽管还需要进一步的广泛研究，但越来越明显的是，Gadd45 与衰老、与年龄相关的疾病（ARDs）以及寿命控制高度相关，这表明它们是 ARDs 和延长寿命干预的潜在治疗靶点。
