Abstract

Late in life, the body is at war with itself. There is a program of self-destruction (phenoptosis) implemented via epigenetic and other changes. I refer to these as type (1) epigenetic changes. But the body retains a deep instinct for survival, and other epigenetic changes unfold in response to a perception of accumulated damage (type (2)). In the past decade, epigenetic clocks have promised to accelerate the search for anti-aging interventions by permitting prompt, reliable, and convenient measurement of their effects on lifespan without having to wait for trial results on mortality and morbidity. However, extant clocks do not distinguish between type (1) and type (2). Reversing type (1) changes extends lifespan, but reversing type (2) shortens lifespan. This is why all extant epigenetic clocks may be misleading. Separation of type (1) and type (2) epigenetic changes will lead to more reliable clock algorithms, but this cannot be done with statistics alone. New experiments are proposed. Epigenetic changes are the means by which the body implements phenoptosis, but they do not embody a clock mechanism, so they cannot be the body’s primary timekeeper. The timekeeping mechanism is not yet understood, though there are hints that it may be (partially) located in the hypothalamus. For the future, we expect that the most fundamental measurement of biological age will observe this clock directly, and the most profound anti-aging interventions will manipulate it.

中文翻译：

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生物钟：为什么我们需要它们，为什么我们不能信任它们，如何改进它们

摘要

在生命的晚年，身体正在与自己交战。有一个通过表观遗传和其他变化实现的自我毁灭（表观凋亡）程序。我将这些称为（1）型表观遗传变化。但身体保留了一种深层的生存本能，并且其他表观遗传变化是为了响应累积损伤的感知而展开的（类型（2））。在过去的十年中，表观遗传时钟有望加速抗衰老干预措施的探索，因为它可以快速、可靠、方便地测量抗衰老干预措施对寿命的影响，而无需等待死亡率和发病率的试验结果。然而，现存的时钟并不区分类型（1）和类型（2）。反转式（1）变化可延长寿命，但反转式（2）会缩短寿命。这就是为什么所有现存的表观遗传时钟可能会产生误导。类型（1）和类型（2）表观遗传变化的分离将导致更可靠的时钟算法，但这不能仅通过统计来完成。提出了新的实验。表观遗传变化是机体实现表亡的手段，但它们不体现时钟机制，因此不能成为机体的主要计时器。尽管有迹象表明它可能（部分）位于下丘脑，但计时机制尚不清楚。对于未来，我们期望对生物年龄最基本的测量将直接观察这个时钟，而最深刻的抗衰老干预措施将操纵它。