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

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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.