The role of physiological complexity in aging and evolution

生理复杂性在衰老和进化中的作用

• 批准号: RGPIN-2018-06096
• 负责人: Cohen, Alan
• 金额: $ 2.91万
• 依托单位: Université de Sherbrooke
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=688119
• 关键词: role; physiological; complexity; aging; evolution

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.

衰老是生物学中最不为人所知的现象之一。在生理层面上，实际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跨物种寿命的多样性，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衰老的生理学和进化中的作用。我从以下原则开始：体内平衡是由调节网络结构决定的一种新兴特性，因此自然选择必须在整个网络上运作，以在不扰乱体内平衡能力的情况下调整生理机能。反过来，体内平衡的逐渐丧失（失调）可能是衰老过程中不可或缺的一部分。因此，理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。******我在过去几年中的主要贡献是表明，可以使用通过适当的统计方法集成的现成血液生物标志物来量化大部分衰老过程。特别是，我在几个物种中证明，统计距离方法可用于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差距，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，证实了复杂的系统解释，并且可以全局测量或针对单独的生理系统进行测量。跨系统的失调率只有微弱的相关性。********在接下来的五年里，我将根据四个长期目标开展一系列有针对性的项目：***1) 使用实验方法和生物信息学方法来获取高通量数据，描述衰老过程中各个系统的生理失调***2) 测量生理的多元方法的统计、数学和理论发展 状态***3) 开发一个在生理生态学中使用生物标志物的实践和理论框架***4) 持续开发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******产生的结果将有助于了解衰老机制和进化的基础知识，并有助于推进关于如何维持和调整体内平衡及其如何进化的理论模型。在实践层面上，它们将有助于指导生态生理学研究中身体状况的测量。我的项目的跨学科性质将继续为一些下一代最有才华的总部人员提供良好的培训环境。