The cost of longevity: transgenerational consequences of parental lifespan extension for offspring fitness

世界人口正在经历前所未有的老龄化，根据联合国人口司1950-2050年的报告，在21世纪，这一全球现象将以越来越快的速度使现有的医疗保健系统负担过重。饮食限制（DR）被定义为减少食物消费而不营养不良，是改善健康和延长广泛模式生物寿命的最有效方法。此外，暂时禁食的DR改善了人类健康，而DR模拟药物二甲双胍降低了所有原因的死亡率。因此，通过暂时禁食和DR模拟药物的DR方法有望通过改善老年人的健康状况来改善人口老龄化问题。DR引起的健康和寿命的改善可能会被其他关键生活史特征的权衡所抵消，寿命的增加往往会导致生育力的降低。值得注意的是，据报道，几种基于DR的治疗方法大大增加了模式生物的寿命，从而避免了这种负面影响。由于这些治疗方法是从模式生物的实验室研究转化到人类身上的，因此了解其潜在机制并确保不会对后代产生意外的跨代影响至关重要。我们最近提出，为了充分理解寿命和生殖之间的权衡，我们需要改变我们的研究重点，将父母寿命延长对后代健康的影响纳入其中。有两个关键原因：第一，增加对维持亲本体细胞的资源分配可能导致对维持亲本生殖细胞的投资减少，从而导致生殖系突变率增加和发育中胚胎的供应减少。我们的试点研究，使用小杆线虫模型系统，支持这一想法，并表明，通过暂时禁食DR提高寿命，健康寿命和晚年繁殖的父母，在降低后代的健身成本。第二，父母寿命的延长也可能对后代产生负面影响，这是由于父母的预期效应。父母可以为后代在DR环境中的生存编程，这可能会导致伤害，因为后代将在其中发育和生活的预期（DR）和实际（正常喂养）环境之间的不匹配。尽管增加父母寿命会对后代的衰老和健康产生不利影响的假设有很强的理论基础，但我们目前缺乏经验数据来评估这一说法。在这个项目中，我们将使用一个经典的模式生物老化-即秀丽隐杆线虫解决这一知识差距。首先，我们将测试是否暂时禁食，DR模拟药物和基因表达沉默的饮食限制反应基因在C。秀丽隐杆线虫在精神上影响配子的遗传和表型质量，从而降低后代和祖代的健康和适应性。第二，我们将测试DR动物是否以牺牲正常环境中的适应性为代价来编程它们的后代在DR环境中的生存。第三，我们将实验性地操纵DR动物将它们的资源重新投资于生殖系维持，并测试这种投资是否会改善它们后代的适应性。这项工作很重要，因为1）它将通过关注父母衰老和后代健康之间被忽视的权衡，为我们理解衰老进化的原因提供重大进展; 2）因为它将直接使未来研究DR对人类生殖系突变和后代健康的影响。由于DR对营养传感分子信号通路的影响在进化上是保守的，从蠕虫到人类，这项工作与英国促进健康老龄化的研究重点直接相关。

The world population is experiencing unprecedented ageing, and, according to the UN Population Division report 1950-2050, in the 21st century this global phenomenon will overburden existing healthcare systems at an ever increasing rate. Dietary restriction (DR), defined as reduced food consumption without malnutrition, is the most robust way to improve health and increase lifespan in a wide range of model organisms. Moreover, DR by temporary fasting improves human health, and the DR-mimicking drug metformin reduces mortality from all causes. Therefore, the DR approach via temporary fasting and DR-mimicking pharmaceuticals is promising to ameliorate the problems of population ageing by improving health into old age. Improvements in health and longevity arising from DR may be offset by trade-offs with other key life-history traits, with increased lifespan often resulting in reduced fecundity. Remarkably, several DR-based treatments that substantially increase lifespan in model organisms are reported to circumvent such negative effects. Because these treatments are being translated from the laboratory studies on model organisms to humans, it is of paramount importance to understand the underlying mechanisms and to ensure that there are no unintended transgenerational effects on offspring.We recently proposed that to fully understand the trade-off between longevity and reproduction we need to change our research focus to incorporate the effects of parental lifespan extension on offspring fitness. There are two key reasons why:First, increased allocation of resources into the maintenance of the parental somatic cells can lead to reduced investment in the maintenance of parental germ cells leading to an increase in the germline mutation rate and reduced provisioning in the developing embryos. Our pilot studies, using the Caenorhabditis nematode worm model system, support this idea and show that DR by temporary fasting improves lifespan, healthspan and late-life reproduction of parents, at the cost of reduced offspring fitness. Second, parental lifespan extension can also result in negative consequences for the offspring, stemming from anticipatory parental effects. Parents can program offspring for survival in DR environment, which can result in harm because of the mismatch between the anticipated (DR) and the actual (normal feeding) environments in which offspring will develop and live. Despite a strong theoretical basis for the hypothesis that boosting parental longevity can deleteriously affect offspring ageing and fitness, we currently lack the empirical data to evaluate this claim. In this project, we will address this knowledge gap using a classic model organism for ageing - namely Caenorhabditis elegans nematodes. First, we will test whether temporary fasting, DR-mimicking pharmaceuticals and gene expression silencing of dietary restriction response genes in C. elegans detrimentally affect the genetic and phenotypic quality of the gametes - thereby reducing offspring and grand-offspring health and fitness. Second, we will test whether DR animals program their offspring for survival in DR environment at the cost to fitness in a normal environment. Third, we will experimentally manipulate DR animals to re-invest their resources to germline maintenance and test whether such investment will improve fitness of their offspring. This work is important because 1) it will provide a major advance in our understanding of why ageing evolves, by focusing on an overlooked trade-off between parental ageing and offspring fitness; and 2) because it will directly enable future research of DR effects on germline mutation and offspring health in humans. Because DR effects on nutrient-sensing molecular signalling pathways are evolutionarily conserved from worms to humans, this work is directly relevant to UK research priorities of promoting healthy ageing.