Kloeden P E, Rössler R, Rössler O E
Department of Mathematics and Computer Science, Deakin University, Geelong, Victoria, Australia.
Ann N Y Acad Sci. 1994 May 31;719:474-82. doi: 10.1111/j.1749-6632.1994.tb56852.x.
An epigenetic approach starts out from the direct (rather than the underlying genetic) causes. An epigenetic approach to aging has little chance of succeeding before a minimum amount of knowledge has been accumulated on the "genetic programming" that is currently believed to underlie aging. Two recent advances, one empirical and one theoretical, jointly brighten the prospect. The empirical one is the discovery that melatonin functions as an aging-controlling hormone in mammals. In 1979, Dilman and co-workers isolated a biologically active pineal extract (epithalamin) in rats which, as they later showed, stimulates melatonin production. Pierpaoli and co-workers in 1987 directly administered melatonin to mice. Both groups observed a surprising 25-percent increase of life span in conjunction with a postponed senescence. A similar effect was also achieved with an engraftment of young pineal tissue into the thymus of old mice by Pierpaoli's group. Beneficial effects of epithalamin in humans were reported by Dilman's group. The second advance is a deductive evolution-theoretical approach to aging discovered in 1988. In populations living in a niche with a fixed carrying capacity, any individual is in the long run replaced by a single successor. It follows that, as the expected cumulative number of adult progeny of the same sex approaches unity as a function of life time of the progenitor, the latter's survivability must approach zero if the sum is to remain unity. A physiological prediction follows: a centralized physicochemical clock--like a sedimentation process--must exist somewhere in the organism controlling a secreted substance that reaches all cells. In this way, the pineal coacervates and the pineal's hormonal product melatonin were arrived at on an independent route again. While melatonin as a drug has been used on human volunteers for decades, its anti-aging effect has yet to be proved. Detailed hormone profiles in different age groups and under different life styles have to be performed. A modified Hayflick in vitro experiment is also needed to elucidate the mechanism by which melatonin works in cells.
一种表观遗传学方法从直接(而非潜在的基因)原因入手。在尚未积累足够关于目前被认为是衰老基础的“基因编程”的知识之前,采用表观遗传学方法研究衰老几乎没有成功的机会。最近有两项进展,一项是实证性的,一项是理论性的,共同照亮了前景。实证性进展是发现褪黑素在哺乳动物中作为一种控制衰老的激素发挥作用。1979年,迪尔曼及其同事在大鼠中分离出一种生物活性松果体提取物(epithalamin),他们后来发现这种提取物能刺激褪黑素的产生。1987年,皮尔帕奥利及其同事直接给小鼠注射褪黑素。两组都观察到寿命惊人地延长了25%,同时衰老也被推迟。皮尔帕奥利团队将年轻的松果体组织植入老年小鼠的胸腺中也取得了类似效果。迪尔曼团队报告了epithalamin对人类的有益作用。第二项进展是1988年发现的一种演绎进化 - 理论性的衰老研究方法。在生活在具有固定承载能力生态位中的种群中,从长远来看,任何个体都会被一个单一的后继者所取代。由此可见,随着同性成年后代的预期累积数量作为祖先寿命的函数接近1时,如果总和要保持为1,那么祖先的生存能力必然接近零。由此得出一个生理学预测:一个集中的物理化学时钟——就像一个沉淀过程——必然存在于生物体的某个地方,控制着一种能到达所有细胞的分泌物质。通过这种方式,又通过一条独立的途径得出了松果体凝聚物和松果体的激素产物褪黑素。虽然褪黑素作为一种药物已在人类志愿者身上使用了几十年,但其抗衰老作用尚未得到证实。必须对不同年龄组和不同生活方式下的详细激素谱进行研究。还需要进行改进的海弗利克体外实验,以阐明褪黑素在细胞中发挥作用的机制。