The role of physiological complexity in aging and evolution

衰老是生物学中最鲜为人知的现象之一。在生理层面上，有数百种机械理论，而在进化层面上，我们仍然没有令人信服的方法来解释不同物种的寿命差异，或者为什么许多物种似乎根本不会衰老。我的研究计划的核心是努力了解复杂系统动力学在衰老的生理学和进化中的作用。我首先提出的原则是，动态平衡是由调控网络的结构决定的一种紧急属性，因此自然选择必须在整个网络上进行操作，以在不干扰动态平衡能力的情况下调整生理。反过来，动态平衡的逐渐丧失(失调)很可能是衰老过程中不可或缺的一部分。因此，了解和测量复杂网络中的动态平衡和失调的方法可以揭示生理进化、衰老的进化和衰老的机制。我在过去几年的主要贡献是表明，通过适当的统计方法，可以使用现成的血液生物标记物来量化大部分衰老过程。特别是，我已经在几个物种中展示了统计距离方法可以用来通过一系列血液生物标志物来量化个人的生理状态与群体平均水平的距离，并且这种测量对应于失调，后者随着年龄的增长而增加，并预测死亡率。该指标对生物标志物的精确选择不敏感，证实了复杂系统的解释，可以全局测量，也可以针对单独的生理系统进行测量。不同系统之间的失调率只有弱相关性。*在接下来的五年里，我将在四个长期目标下进行一系列有针对性的项目：*1)使用高通量数据的实验方法和生物信息学方法来表征老化过程中逐个系统的生理失调率*2)统计、数学、3)在生理生态学中使用生物标志物的实用和理论框架*4)继续发展比较和理论框架，以了解生命之树上寿命和衰老的演变*所产生的结果将有助于了解衰老的机制和进化的基本知识，并促进关于如何维持和调节内稳态以及它如何进化的理论模型。在实践层面上，它们将用于指导生态生理研究中身体状况的测量。我的项目的跨学科性质将继续为下一代最有才华的HQP提供良好的培训环境。

Aging is one of the least understood phenomena in biology. At a physiological level, there are literally hundreds of mechanistic theories, and at an evolutionary level we still have no convincing way to explain the diversity of lifespans across species, or why many species appear not to age at all. The core of my research program is an effort to understand the role of complex systems dynamics in both the physiology and evolution of aging. I start with the principle that homeostasis is an emergent property determined by the structure of regulatory networks, and that natural selection must thus operate on whole networks to adjust physiology without perturbing homeostatic capacity. In turn, gradual loss of homeostasis (dysregulation) is likely to be an integral part of the aging process. Ways to understand and measure homeostasis and dysregulation in complex networks could thus shed light on physiological evolution, the evolution of aging, and the mechanisms of aging.******My key contribution over the last several years has been to show that much of the aging process can be quantified using readily available blood biomarkers integrated through appropriate statistical methods. In particular, I have shown in several species that a statistical distance method can be used to quantify how far an individual's physiological state is from the population average across a series of blood biomarkers, and that this measure corresponds to dysregulation, which increases with age and predicts mortality. The metric is not sensitive to the precise choice of biomarkers, confirming a complex systems interpretation, and can be measured either globally or for separate physiological systems. Dysregulation rates across systems are only weakly correlated.******Over the next five years, I will follow up on this with a series of targeted projects under four long-term objectives:***1) Characterizing system-by-system physiological dysregulation during aging using experimental approaches and bioinformatics approaches to high-throughput data ***2) Statistical, mathematical, and theoretical development of multivariate approaches to measure physiological state***3) Developing a practical and theoretical framework for use of biomarkers in physiological ecology***4) Continuing development of a comparative and theoretical framework to understand the evolution of lifespan and aging across the tree of life******The results generated will contribute to basic knowledge on the mechanisms and evolution of aging, and to advancing theoretical models of how homeostasis is maintained and adjusted and how it evolves. At a practical level, they will serve to guide the measurement of body condition in ecophysiological research. The interdisciplinary nature of my program will continue to provide an excellent training environment for some of the next generation's most talented HQP.