PT  - JOURNAL ARTICLE
AU  - Martin I. Lind
AU  - Sanjana Ravindran
AU  - Zuzana Sekajova
AU  - Hanne Carlsson
AU  - Andrea Hinas
AU  - Alexei A. Maklakov
TI  - Experimentally reduced insulin/IGF-1 signalling in adulthood extends lifespan of parents and improves Darwinian fitness of their offspring
AID  - 10.1101/405019
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 405019
4099  - http://biorxiv.org/content/early/2019/01/29/405019.short
4100  - http://biorxiv.org/content/early/2019/01/29/405019.full
AB  - Classical theory maintains that ageing evolves via energy trade-offs between reproduction and survival leading to accumulation of unrepaired cellular damage with age. In contrast, the emerging new theory postulates that ageing evolves because of deleterious late-life hyper-function of reproduction-promoting genes leading to excessive biosynthesis in late-life. The hyper-function theory uniquely predicts that optimizing nutrient-sensing molecular signalling in adulthood can simultaneously postpone ageing and increase Darwinian fitness. Here we show that reducing evolutionarily conserved insulin/IGF-1 nutrient-sensing signalling via daf-2 RNA interference (RNAi) fulfils this prediction in Caenorhabditis elegans nematodes. Long-lived daf-2 RNAi parents showed normal fecundity as self-fertilizing hermaphrodites and improved late-life reproduction when mated to males. Remarkably, the offspring of daf-2 RNAi parents had higher Darwinian fitness across three different genotypes. Thus, reduced nutrient-sensing signalling in adulthood improves both parental longevity and offspring fitness supporting the emerging view that sub-optimal gene expression in late-life lies at the heart of ageing.Impact Statement Understanding mechanisms underpinning ageing is fundamental to improving quality of life in an increasingly long-lived society. Recent breakthroughs have challenged the long-standing paradigm that the energy trade-off between reproduction and somatic maintenance causes organismal senescence via slow accumulation of unrepaired cellular damage with age. The emerging new theory of ageing provides a conceptually novel framework by proposing that ageing is a direct consequence of physiological processes optimized for early-life function, such as growth and early-life reproduction, that are running ‘too high’ (i.e. at hyperfunction) in late adulthood. Contrary to the classic view based on damage accumulation, the hyperfunction theory proposes that suboptimal gene expression in late-life causes ageing via excessive biosynthesis. Thus, the hyperfunction theory uniquely predicts that longevity and Darwinian fitness can be simultaneously increased by reducing unnecessarily high levels of nutrient-sensing signalling in adulthood. Here we show that reducing evolutionarily conserved nutrient-sensing signalling pathway fulfils this prediction in Caenorhabditis elegans nematodes. We found that downregulation of the insulin/IGF-1 signalling in adult C. elegans nematodes not only improves longevity but, most intriguingly, increases fitness of the resulting offspring in the next generation. We found support for increase in offspring fitness across different genetic backgrounds. Our findings contradict the theoretical conjecture that energy trade-offs between growth, reproduction and longevity is the universal cause of senescence and provide strong experimental support for the emerging hyperfunction theory of ageing.