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不堪重负。饮食限制（DR）被定义为减少食物消费而不出现营养不良，是改善多种模式生物健康和延长寿命的最有力方法。此外，通过暂时禁食来预防耐药可改善人体健康，而类似耐药的药物二甲双胍可降低各种原因造成的死亡率。因此，通过暂时禁食和仿制耐药药物的耐药方法有望通过改善老年健康状况来改善人口老龄化问题。DR带来的健康和寿命的改善可能被其他关键生活史特征的权衡所抵消，寿命的延长往往导致繁殖力的降低。值得注意的是，据报道，几种基于dr的治疗方法可以显著延长模式生物的寿命，从而避免这种负面影响。由于这些治疗方法正在从模式生物的实验室研究转化到人类，因此了解潜在机制并确保对后代没有意外的跨代影响至关重要。我们最近提出，为了充分理解长寿和繁殖之间的权衡，我们需要改变我们的研究重点，纳入父母寿命延长对后代健康的影响。这主要有两个原因：首先，用于维持亲本体细胞的资源分配增加，可能导致用于维持亲本生殖细胞的投资减少，从而导致种系突变率增加，并减少发育中的胚胎的供给。我们使用隐杆线虫模型系统进行的初步研究支持了这一观点，并表明暂时禁食的DR改善了父母的寿命、健康寿命和晚年繁殖，但代价是降低了后代的适应性。其次，由于预期的亲代效应，父母寿命的延长也会给后代带来负面影响。父母可以对后代进行编程，使其在DR环境中生存，由于预期（DR）与后代发育和生活的实际（正常喂养）环境之间的不匹配，这可能会造成伤害。尽管提高父母寿命会对后代的衰老和健康产生有害影响这一假设有很强的理论基础，但我们目前缺乏实证数据来评估这一说法。在这个项目中，我们将利用一种经典的衰老模式生物——秀丽隐杆线虫来解决这一知识缺口。首先，我们将测试秀丽隐杆线虫饮食限制反应基因的暂时禁食、模仿耐药药物和基因表达沉默是否会对配子的遗传和表型质量产生不利影响，从而降低后代和后代的健康和适应能力。其次，我们将测试DR动物是否会以牺牲正常环境的适应性为代价来编程其后代在DR环境中的生存。第三，我们将通过实验操纵DR动物将其资源重新投入到生殖系维护中，并测试这种投资是否会提高其后代的适合度。这项工作很重要，因为1)通过关注父母衰老和后代健康之间被忽视的权衡，它将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对人类种系突变和后代健康的影响成为可能。由于DR对营养传感分子信号通路的影响在进化上从蠕虫到人类都是保守的，因此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.