Lathe Richard, St Clair David
Division of Infection Medicine, Chancellor's Building, University of Edinburgh Medical School, Little France, Edinburgh, EH16 4SB, UK.
Institute of Medical Sciences, School of Medicine, University of Aberdeen, Aberdeen, AB25 2ZD, UK.
Biol Rev Camb Philos Soc. 2023 Aug;98(4):1424-1458. doi: 10.1111/brv.12959. Epub 2023 Apr 17.
The characteristic maximum lifespan varies enormously across animal species from a few hours to hundreds of years. This argues that maximum lifespan, and the ageing process that itself dictates lifespan, are to a large extent genetically determined. Although controversial, this is supported by firm evidence that semelparous species display evolutionarily programmed ageing in response to reproductive and environmental cues. Parabiosis experiments reveal that ageing is orchestrated systemically through the circulation, accompanied by programmed changes in hormone levels across a lifetime. This implies that, like the circadian and circannual clocks, there is a master 'clock of age' (circavital clock) located in the limbic brain of mammals that modulates systemic changes in growth factor and hormone secretion over the lifespan, as well as systemic alterations in gene expression as revealed by genomic methylation analysis. Studies on accelerated ageing in mice, as well as human longevity genes, converge on evolutionarily conserved fibroblast growth factors (FGFs) and their receptors, including KLOTHO, as well as insulin-like growth factors (IGFs) and steroid hormones, as key players mediating the systemic effects of ageing. Age-related changes in these and multiple other factors are inferred to cause a progressive decline in tissue maintenance through failure of stem cell replenishment. This most severely affects the immune system, which requires constant renewal from bone marrow stem cells. Age-related immune decline increases risk of infection whereas lifespan can be extended in germfree animals. This and other evidence suggests that infection is the major cause of death in higher organisms. Immune decline is also associated with age-related diseases. Taking the example of Alzheimer's disease (AD), we assess the evidence that AD is caused by immunosenescence and infection. The signature protein of AD brain, Aβ, is now known to be an antimicrobial peptide, and Aβ deposits in AD brain may be a response to infection rather than a cause of disease. Because some cognitively normal elderly individuals show extensive neuropathology, we argue that the location of the pathology is crucial - specifically, lesions to limbic brain are likely to accentuate immunosenescence, and could thus underlie a vicious cycle of accelerated immune decline and microbial proliferation that culminates in AD. This general model may extend to other age-related diseases, and we propose a general paradigm of organismal senescence in which declining stem cell proliferation leads to programmed immunosenescence and mortality.
不同动物物种的特征性最大寿命差异极大，从几小时到数百年不等。这表明最大寿命以及决定寿命的衰老过程在很大程度上是由基因决定的。尽管存在争议，但确凿的证据支持这一观点，即一次性繁殖物种会根据生殖和环境线索表现出进化编程的衰老。联体共生实验表明，衰老通过循环系统在全身进行协调，伴随着一生中激素水平的程序性变化。这意味着，与昼夜节律和年节律时钟一样，哺乳动物边缘脑中有一个主“年龄时钟”（生命时钟），它在整个生命周期中调节生长因子和激素分泌的全身变化，以及基因组甲基化分析所揭示的基因表达的全身改变。对小鼠加速衰老以及人类长寿基因的研究表明，进化上保守的成纤维细胞生长因子（FGFs）及其受体，包括klotho，以及胰岛素样生长因子（IGFs）和类固醇激素，是介导衰老全身效应的关键因素。这些以及其他多种因素中与年龄相关的变化被推断会通过干细胞补充失败导致组织维持能力逐渐下降。这对免疫系统影响最为严重，因为免疫系统需要骨髓干细胞不断更新。与年龄相关的免疫衰退会增加感染风险，而无菌动物的寿命可以延长。这以及其他证据表明，感染是高等生物死亡的主要原因。免疫衰退也与年龄相关疾病有关。以阿尔茨海默病（AD）为例，我们评估了AD由免疫衰老和感染引起的证据。现在已知AD脑的标志性蛋白Aβ是一种抗菌肽，AD脑中的Aβ沉积可能是对感染的反应而非疾病的原因。由于一些认知正常的老年人表现出广泛的神经病理学特征，我们认为病理学的位置至关重要——具体而言，边缘脑的病变可能会加剧免疫衰老，从而可能构成加速免疫衰退和微生物增殖的恶性循环的基础，最终导致AD。这个一般模型可能适用于其他年龄相关疾病，我们提出了一个生物体衰老的一般范式，即干细胞增殖下降导致程序性免疫衰老和死亡。
