De Loof Arnold
Functional Genomics and Proteomics Group, Department of Biology, KU Leuven-University of Leuven, Leuven, Belgium.
Commun Integr Biol. 2017 Jul 14;10(4):e1341024. doi: 10.1080/19420889.2017.1341024. eCollection 2017.
Cells are powerful miniature electrophoresis chambers, at least during part of their life cycle. They die at the moment the voltage gradient over their plasma membrane, and their ability to drive a self-generated electric current carried by inorganic ions through themselves irreversibly collapses. Senescence is likely due to the progressive, multifactorial damage to the cell's electrical system. This is the essence of the "Fading electricity theory of aging" (De Loof et al., Aging Res. Rev. 2013;12:58-66). "Biologic electric current" is not carried by electrons, but by inorganic ions. The major ones are H, Na, K, Ca, Mg, Cl and HCO. Ca and H in particular are toxic to cells. At rising concentrations, they can alter the 3D-conformation of chromatin and some (e.g. cytoskeletal) proteins: Calcitox and Protontox. This paper only focuses on Calcitox and endogenous sesquiterpenoids. pH-control and Ca-homeostasis have been shaped to near perfection during billions of years of evolution. The role of Ca in some aspects of aging, e.g., as causal to neurodegenerative diseases is still debated. The main anti-Calcitox mechanism is to keep free cytoplasmic Ca as low as possible. This can be achieved by restricting the passive influx of Ca through channels in the plasma membrane, and by maximizing the active extrusion of excess Ca e.g., by means of different types of Ca-ATPases. Like there are mechanisms that antagonize the toxic effects of Reactive Oxygen Species (ROS), there must also exist endogenous tools to counteract Calcitox. During a re-evaluation of which mechanism(s) exactly initiates the fast aging that accompanies induction of metamorphosis in insects, a causal relationship between absence of an endogenous sesquiterpenoid, namely the farnesol ester named "juvenile hormone," and disturbed Ca-homeostasis was suggested. In this paper, this line of thinking is further explored and extended to vertebrate physiology. A novel concept emerges: horseshoe-shaped sesquiterpenoids seem to act as "inbrome" agonists with the function of a "chemical valve" or "spring" in some types of multi-helix transmembrane proteins (intramolecular prenylation), from bacterial rhodopsins to some types of GPCRs and ion pumps, in particular the SERCA-Ca-pump. This further underpins the Fading Electricity Theory of Aging.
细胞是强大的微型电泳室，至少在其生命周期的一部分时间内是这样。当它们质膜上的电压梯度以及驱动无机离子携带的自发电电流通过自身的能力不可逆地崩溃时，细胞就会死亡。衰老可能是由于细胞电系统受到渐进性、多因素的损害。这就是“衰老的渐逝电理论”的本质（De Loof等人，《衰老研究评论》，2013年；12:58 - 66）。“生物电流”不是由电子携带，而是由无机离子携带。主要的无机离子有H、Na、K、Ca、Mg、Cl和HCO。特别是Ca和H对细胞有毒。随着浓度升高，它们会改变染色质和一些（如细胞骨架）蛋白质的三维构象：钙毒素和质子毒素。本文仅关注钙毒素和内源性倍半萜。在数十亿年的进化过程中，pH控制和钙稳态已形成得近乎完美。Ca在衰老的某些方面的作用，例如作为神经退行性疾病的病因，仍存在争议。主要的抗钙毒素机制是尽可能使细胞质中的游离Ca保持在低水平。这可以通过限制Ca通过质膜通道的被动内流，并通过最大限度地主动排出过量的Ca来实现，例如借助不同类型的Ca - ATP酶。就像存在对抗活性氧（ROS）毒性作用的机制一样，也必定存在内源性工具来对抗钙毒素。在重新评估究竟是哪种机制确切引发昆虫变态诱导时伴随的快速衰老过程中，有人提出内源性倍半萜（即名为“保幼激素”的法尼醇酯）的缺失与钙稳态紊乱之间存在因果关系。在本文中，这一思路得到进一步探索并扩展到脊椎动物生理学。一个新的概念出现了：马蹄形倍半萜似乎作为“inbrome”激动剂，在某些类型的多螺旋跨膜蛋白（分子内异戊二烯化）中起“化学阀”或“弹簧”的作用，从细菌视紫红质到某些类型的GPCR和离子泵，特别是SERCA钙泵。这进一步支持了衰老的渐逝电理论。
