Testing a novel hypothesis for a bioenergetic-endocrinological regulation of telomere dynamics

越来越明显的是，老年人的健康和功能在很大程度上取决于发育阶段所经历的条件。越来越多的证据表明，早期发育受损的足迹嵌入在端粒（TL）的长度中，端粒是DNA和蛋白质的复合物，在染色体末端形成保护杯，随着年龄的增长和氧化应激的暴露而变短。TL损耗模式的许多潜在机制以及对生物体的因果影响仍未得到解决。一个主要现象是糖皮质激素（GCs）在人类和动物的不同个体发育阶段对TLs的缩短作用。到目前为止，GCs对TL的作用被认为是负面的副作用，因为它们促进氧化应激和下调端粒酶活性（一种维持TL长度的酶）。然而，GCs是至关重要的激素，没有它，生物体会在数小时内死亡。因此，合乎逻辑的问题是：为什么gc会直接导致TL缩短？我提出了一个新的假设，即这些激素通过节省TL维持所需的资源，在能量需求增加时有助于调节TL长度。例如，GCs抑制TORC1酶（Rapamycin Complex 1的靶标，一种细胞生长调节剂），该酶参与控制TL长度。然而，从生物能量学的角度来看，GCs对tl的作用从未得到解决，尽管它符合它们在调节能量和生活史权衡中的基本作用。这一新视角将极大地增加我们对应激条件下TL损耗的理解，并有可能使我们找到方法来抵消缩短TL的不利后果。本研究的目的是调查TL动力学是否是一种机制，通过这种机制，至少有时是一种适应性的方式来解决能量权衡。在提议的研究中，我将操纵生活在野外的大山雀（Parus major）雏鸟的能量状态。我将使用鸟类模型，因为鸟类红细胞有功能性线粒体，这将允许我反复测量血液中的TL动力学。我将专注于个体发生阶段（生长阶段），在此阶段，TL消耗是广泛，快速的，并且可以产生持久的影响，以测试是否：通过比较添加核苷酸的雏鸟与对照组的TL长度，可以发现TL缩短是由高能量需求（生长和食物供应的变化）引起的。同样的问题将从激素的角度进行评估，通过使用GC激素来测试这一途径对TL的调节。2. 在一定范围内，通过量化实验雏鸟和对照雏鸟的生理状况（线粒体活性、amp激活的蛋白激酶和氧化应激）、形态特征（质量、体型）和行为反应（人格特征），可以发现TL缩短具有适应性。

It is becoming evident that being healthy and functional at old age largely depends on the conditions experienced during developmental phases. Accumulating evidence suggests that the footprint of impaired early development is embedded in the length of telomeres (TL) - complexes of DNA and proteins that form protective cups at the end of chromosome - which become shorter with progressing age and exposure to oxidative stress. Many mechanisms underlying patterns of TL attrition, as well as the causal consequences for organisms are still unresolved. One major phenomenon is the shortening effect that glucocorticoids (GCs) exert on TLs at different ontogenetic stages in both humans and animals. Thus far, the actions of GCs on TL have been viewed as negative side effects since these promote oxidative stress and down-regulate telomerase activity (an enzyme for maintaining TL length). However, GCs are vital hormones without which organisms would perish within hours. The logical question therefore is: why should GCs directly cause TL shortening? I am proposing the novel hypothesis that these hormones contribute to regulating TL length during times of increased energy need by saving resources needed for TL maintenance. For example, GCs inhibit the enzyme TORC1 (Target of Rapamycin Complex 1, a regulator of cell growth), which is involved in the control of TL length. However a bioenergetics perspective of the actions of GCs on TLs has never been addressed, even though it is in line with their fundamental role in mediating energy and life-history trade-offs. This new perspective would greatly increase our understanding of TL attrition under stressful conditions, and likely enable us to find ways to counteract the adverse consequences of shortened TL. The aim of the proposed study is to investigate whether TL dynamics are one mechanism by which energetic trade-offs are resolved in, at least sometimes, an adaptive way. In the proposed study I will manipulate the energetic state of great tit (Parus major) nestlings living in the wild. I will use an avian model because avian erythrocytes have functional mitochondria, which will allow me to repeatedly measure TL dynamics in blood. I will focus on an ontogenetic stage (growth) during which TL attrition is extensive, fast and can have long lasting repercussions to test whether:1. TL shortening is induced by high energy demands (growth and variation in food availability) by comparing TL length of nestlings supplemented with nucleotides with that of controls. The same question will be evaluated from a hormonal perspective by administering GC hormones, to test this pathway for TL regulation. 2. Within a certain range, TL shortening is adaptive by quantifying physiological condition (mitochondrial activity, AMP-activated protein kinase and oxidative stress), morphological traits (mass, body size) and behavioral responses (personality traits) in experimental and control nestlings.