The Sir2-p53-IGF link in mammalian life-span control

描述(由申请人提供)：为应对生命早期营养不良而进行的代谢重新编程会阻碍细胞分裂、器官生长和分化，并可能导致永久性生长缺陷，以及寿命缩短。节俭表型假说认为，胎儿营养不良会对胎儿的生长发育造成限制和改变，这可被认为是实现新陈代谢节俭。然而，在营养丰富的条件下，有益于在营养不良条件下生存的适应性变化可能是有害的，并导致健康和寿命降低。在我们资助的第二个周期中，我们将继续研究节俭表型背后的分子机制，以及后生动物的大小和寿命是如何耦合的。我们的假设是，它们一方面需要生长因子驱动的通路和另一方面代谢通路的协调活动，而将两者联系在一起的是肿瘤抑制因子P53的活性。具体地说，我们提出代谢灵活性是Delta40P53的功能，Delta40P53是P53的胚胎亚型，可以感知环境并调节全长P53对关键代谢靶基因的反应活性。我们从将在第二轮资助中进行的实验中收集的信息将在辅助生殖技术(ART)和健康老龄化方面有重要应用。在过去的几十年里，巨大的进步使婴儿有可能由之前被认为不育的夫妇怀孕并出生。然而，新的证据表明，使用抗逆转录病毒疗法出生的人容易出现与心血管和代谢功能障碍相关的中年健康下降，并可能面临预期寿命缩短的风险。ART孕育的人类与发育早期遭受营养压力的实验动物在表型上的重叠是惊人的，需要理解这一点，不仅是为了它本身，还因为不这样做意味着错失了设计更合理的策略来优化全人类健康和福祉的机会。我们新实验的重点是在干细胞首次出现的早期发育窗口期间发生的事件，这些事件可能永久地影响大小和寿命的轨迹。我们将使用我们独特的小鼠品系和一个、两个或三个拷贝的Delta40P53来发展这样一种概念，即(非常)早期发生的事件会使个人倾向于在以后的生活中发生变化，即使是在老年。这种截然不同的和 衰老生物学这一几乎未被探索的领域与包括人类在内的真兽类哺乳动物有着特别的关系。

DESCRIPTION (provided by applicant): Metabolic reprogramming in response to malnutrition early in life impedes cell division, organ growth, and differentiation, and can lead to permanent growth deficits, as well as decreased life span. The "thrifty phenotype" hypothesis proposes that poor fetal nutrition imposes growth and developmental constraints and changes upon the fetus, which may be considered as achieving metabolic thrift. However, adaptive changes that are beneficial to survival under conditions of poor nutrition may be detrimental under conditions of nutritional abundance and lead to reduced health--‐ and life span. In the second cycle of funding for our grant entitled, ¿The Sir2¿p53¿IGF link in mammalian life span control,¿ we will pursue studies to delineate the molecular mechanism underlying the thrifty phenotype and how metazoan size and life span are coupled. Our hypothesis is that they require the coordinated activity of growth factor driven pathways on the one hand and metabolic pathways on the other, and that what links the two is the activity of the tumor suppressor p53. Specifically, we propose that metabolic flexibility is the function of Delta40p53, an embryonic isoform of p53 that can ¿sense¿ the environment and modulate the activity of full-length p53 on key metabolic target genes in response. The information we glean from the experiments to be undertaken in a second cycle of funding will have important applications in assisted reproductive technology (ART) and in healthy aging. Enormous advances over the past several decades have made it possible for babies to be conceived by and born to couples previously deemed infertile. Emerging evidence indicates, however, that individuals born using ART are prone to decrements in mid-life health associated with cardiovascular and metabolic dysfunction and might be at risk for reduced life expectancy. The overlap in phenotype between humans conceived by ART and experimental animals subjected to nutrient stress early in development is striking and needs to be understood, not just for its own sake, but also because not doing so represents a missed opportunity for designing more rational strategies to optimize the health and well being of all humans. The focus of our new experiments is on events occurring during an early developmental window, when stem cells first arise, that could permanently affect the trajectories of size and life span. We will be using our unique mouse strains with one, two, or three copies of Delta40p53 to develop the notion that events that occur (very) early in life can predispose individuals to changes that occur much later in life, even in old age. This distinct and virtually unexplored field of aging biology has particular relevance to eutherian mammals, including humans.