Hiskias Gerrit Keizer, R Brands, Ronald Sake Oosting, Willem Seinen
{"title":"A comprehensive model for the biochemistry of ageing, senescence and longevity.","authors":"Hiskias Gerrit Keizer, R Brands, Ronald Sake Oosting, Willem Seinen","doi":"10.1007/s10522-024-10097-8","DOIUrl":null,"url":null,"abstract":"<p><p>Various models for ageing, each focussing on different biochemical and/or cellular pathways have been proposed. This has resulted in a complex and non-coherent portrayal of ageing. Here, we describe a concise and comprehensive model for the biochemistry of ageing consisting of three interacting signalling hubs. These are the nuclear factor kappa B complex (NFκB), controlling the innate immune system, the mammalian target for rapamycin complex, controlling cell growth, and the integrated stress responses, controlling homeostasis. This model provides a framework for most other, more detailed, biochemical pathways involved in ageing, and explains why ageing involves chronic inflammation, cellular senescence, and vulnerability to environmental stress, while starting with the spontaneous formation of advanced glycation end products. The totality of data underlying this model suggest that the gradual inhibition of the AMPK-ISR probably determines the maximal lifespan. Based on this model, anti-ageing drugs in general, are expected to show hormetic dose response curves. This complicates the process of dose-optimization. Due to its specific mechanism of action, the anti-aging drug alkaline phosphatase is an exception to this rule, because it probably exhibits saturation kinetics.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":" ","pages":"615-626"},"PeriodicalIF":4.4000,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biogerontology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s10522-024-10097-8","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/3/5 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"GERIATRICS & GERONTOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Various models for ageing, each focussing on different biochemical and/or cellular pathways have been proposed. This has resulted in a complex and non-coherent portrayal of ageing. Here, we describe a concise and comprehensive model for the biochemistry of ageing consisting of three interacting signalling hubs. These are the nuclear factor kappa B complex (NFκB), controlling the innate immune system, the mammalian target for rapamycin complex, controlling cell growth, and the integrated stress responses, controlling homeostasis. This model provides a framework for most other, more detailed, biochemical pathways involved in ageing, and explains why ageing involves chronic inflammation, cellular senescence, and vulnerability to environmental stress, while starting with the spontaneous formation of advanced glycation end products. The totality of data underlying this model suggest that the gradual inhibition of the AMPK-ISR probably determines the maximal lifespan. Based on this model, anti-ageing drugs in general, are expected to show hormetic dose response curves. This complicates the process of dose-optimization. Due to its specific mechanism of action, the anti-aging drug alkaline phosphatase is an exception to this rule, because it probably exhibits saturation kinetics.
人们提出了各种老化模式,每种模式都侧重于不同的生化和/或细胞途径。这导致对老化的描述复杂而不连贯。在这里,我们描述了一个由三个相互作用的信号枢纽组成的简明而全面的老化生化模型。它们分别是控制先天性免疫系统的核因子卡巴 B 复合物(NFκB)、控制细胞生长的雷帕霉素哺乳动物靶复合物以及控制体内平衡的综合应激反应。这一模型为其他大多数涉及老化的更详细的生化途径提供了一个框架,并解释了为什么老化涉及慢性炎症、细胞衰老和易受环境压力影响,同时以高级糖化终产物的自发形成为起点。这一模型所依据的全部数据表明,AMPK-ISR 的逐渐抑制可能决定了人的最长寿命。根据这一模型,抗衰老药物一般会呈现激素剂量反应曲线。这使得剂量优化过程变得更加复杂。由于其特殊的作用机制,抗衰老药物碱性磷酸酶是一个例外,因为它可能表现出饱和动力学。
期刊介绍:
The journal Biogerontology offers a platform for research which aims primarily at achieving healthy old age accompanied by improved longevity. The focus is on efforts to understand, prevent, cure or minimize age-related impairments.
Biogerontology provides a peer-reviewed forum for publishing original research data, new ideas and discussions on modulating the aging process by physical, chemical and biological means, including transgenic and knockout organisms; cell culture systems to develop new approaches and health care products for maintaining or recovering the lost biochemical functions; immunology, autoimmunity and infection in aging; vertebrates, invertebrates, micro-organisms and plants for experimental studies on genetic determinants of aging and longevity; biodemography and theoretical models linking aging and survival kinetics.