The role of physiological complexity in aging and evolution

衰老是生物学中最不为人所知的现象之一。在生理学层面上，有数以百计的机械理论，在进化层面上，我们仍然没有令人信服的方法来解释物种寿命的多样性，或者为什么许多物种似乎根本不会衰老。我的研究项目的核心是努力了解复杂系统动力学在生理学和衰老进化中的作用。我从这样一个原理开始：内稳态是由调节网络的结构决定的一种突现性质，因此自然选择必须在整个网络上运作，以调整生理学而不干扰内稳态能力。反过来，体内平衡的逐渐丧失（失调）可能是衰老过程的一个组成部分。因此，了解和测量复杂网络中的稳态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。在过去的几年里，我的主要贡献是表明，大部分衰老过程可以通过适当的统计方法使用现成的血液生物标志物进行量化。特别是，我已经在几个物种中表明，统计距离方法可以用来量化个体的生理状态与一系列血液生物标志物的群体平均值的距离，并且这种测量对应于失调，失调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，确认了复杂的系统解释，并且可以在全球范围内或针对单独的生理系统进行测量。在未来五年，我将根据四个长期目标，通过一系列有针对性的项目来跟进这一点：1）使用高通量数据的实验方法和生物信息学方法表征衰老期间的逐系统生理失调2）统计学，数学，和理论发展的多变量方法来衡量生理状态3）发展一个实用和理论框架，用于生物标志物在生理生态学4）继续发展一个比较和理论框架，以了解整个生命树的寿命和衰老的演变所产生的结果将有助于对衰老的机制和演变的基本知识，并提出如何维持和调整体内平衡及其如何演变的理论模型。在实践层面上，它们将用于指导生理生态学研究中的身体状况测量。我的项目的跨学科性质将继续为下一代最有才华的HQP提供一个良好的培训环境。

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 state3) Developing a practical and theoretical framework for use of biomarkers in physiological ecology4) Continuing development of a comparative and theoretical framework to understand the evolution of lifespan and aging across the tree of lifeThe 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.