Bertoni-Freddari Carlo, Fattoretti Patrizia, Casoli Tiziana, Di Stefano Giuseppina, Giorgetti Belinda, Balietti Marta
Neurobiology of Aging Laboratory, INRCA Research Department, Via Birarelli, 60121 Ancona, Italy.
Exp Gerontol. 2008 May;43(5):389-93. doi: 10.1016/j.exger.2007.11.001. Epub 2007 Nov 13.
At variance with other organs, where the functional and structural units are repeated, the brain is a composite assembly of groups of cells with different metabolic features and functional units. Deterioration of brain function occurs when the number of neurons or their connections decrease below a critical reserve level and coping with environmental stimulation is seriously hampered. Physiopathological alterations of the synaptic junctional areas are reported to play a central role in the process of brain aging. Current research is documenting an age-related numeric loss of synapses which is paired by a significant enlargement of the persisting contact zones: the final outcome of these balanced changes is a significant reduction of the overall synaptic junctional area per unit volume of neuropil. The progressive decline of the mitochondrial metabolic competence, i.e. the capacity of select pools of organelles to provide adequate amounts of adenosine triphosphate is supposed to represent a key determinant in synaptic aging. Cytochemical estimations of the activity of cytochrome oxidase confirm that mitochondrial dysfunctions play an early role in synaptic deterioration. Zinc ions act as physiological neuromodulators at glutamatergic synapses, however, in order to avoid neurotoxic damage, the intracellular free Zn(++) concentration (Zn(++)) must be tightly controlled by: (i) extrusion (Zn(++) transporters); (ii) buffering (metallothioneins) and (iii) sequestration (mitochondria) systems. In physiological aging, if any of these systems is impaired and/or not adequately coordinated with the other two, the resulting significant rise of (Zn(++)) may inhibit the cellular energy providing systems and affect mitochondria as primary target.
与其他器官不同，其功能和结构单位是重复的，而大脑是由具有不同代谢特征的细胞群和功能单位组成的复合集合体。当神经元数量或其连接减少到临界储备水平以下，并且应对环境刺激的能力受到严重阻碍时，脑功能就会恶化。据报道，突触连接区域的生理病理改变在脑老化过程中起核心作用。目前的研究记录了与年龄相关的突触数量减少，同时伴随着持续接触区域的显著扩大：这些平衡变化的最终结果是每单位体积神经毡的总突触连接面积显著减少。线粒体代谢能力的逐渐下降，即细胞器特定池提供足够量三磷酸腺苷的能力，被认为是突触老化的关键决定因素。细胞色素氧化酶活性的细胞化学估计证实，线粒体功能障碍在突触退化中起早期作用。锌离子在谷氨酸能突触处作为生理性神经调节剂起作用，然而，为了避免神经毒性损伤，细胞内游离锌离子浓度（[Zn++]i）必须通过以下方式严格控制：（i） 排出（锌离子转运体）；（ii） 缓冲（金属硫蛋白）和（iii） 螯合（线粒体）系统。在生理性衰老过程中，如果这些系统中的任何一个受损和/或与其他两个系统协调不足，由此导致的（[Zn++]i）显著升高可能会抑制细胞能量供应系统，并将线粒体作为主要靶点进行影响。
