C. elegans Eats Its Own Intestine to Make Yolk Leading to Multiple Senescent Pathologies

Abstract

SummaryAging (senescence) is characterized by the development of numerous pathologies, some of which limit lifespan. Key to understanding aging is discovery of the mechanisms (etiologies) that cause senescent pathology. In C. elegans, a major senescent pathology of unknown etiology is atrophy of its principal metabolic organ, the intestine. Here we identify a cause of not only this pathology but also of yolky lipid accumulation and redistribution (a form of senescent obesity): autophagy-mediated conversion of intestinal biomass into yolk. Inhibiting intestinal autophagy or vitellogenesis rescues both visceral pathologies and can also extend lifespan. This defines a disease syndrome leading to multimorbidity and contributing to late-life mortality. Activation of gut-to-yolk biomass conversion by insulin/IGF-1 signaling (IIS) promotes reproduction and senescence. This illustrates how major, IIS-promoted senescent pathologies in C. elegans can originate not from damage accumulation but from direct effects of futile, continued action of a wild-type biological program (vitellogenesis).

Experimentally reduced insulin/IGF-1 signaling in adulthood extends lifespan of parents and improves Darwinian fitness of their offspring

“…More recently, it has been suggested that nutrient sensing IIS/TOR molecular signalling pathways that govern growth and development result in excessive biosynthesis in late‐life leading to different pathologies and increased mortality (Blagosklonny ; ; Gems and Partridge ; Ezcurra et al. ). These proximate explanations rest on the fundamental assumption that the strength of natural selection declines with age because of environmental mortality from a range of biotic and abiotic hazards (e.g., predation, pathogens, competition, starvation) (Williams ).…”

“…Thus, progressively weakening selection in adulthood may result in suboptimal levels of IIS/TOR signaling leading to pathology and senescence (Ezcurra et al. ). However, unlike the classic energy trade‐off theory, the functional trade‐off hypothesis predicts that it should be possible to modify adult physiology to improve both longevity and fitness.…”

“…Instead, several authors proposed that ageing can result from molecular signalling networks being optimized for development, growth, and early‐life reproduction rather than for late‐life reproduction and longevity (Blagosklonny ; Kenyon ; Antebi ; Gems and Partridge ; Ezcurra et al. ). For example, the hyperfunction theory maintains that ageing is driven by excessive nutrient‐sensing molecular signaling in adulthood, which results in cellular hypertrophy leading to age‐related pathologies (Blagosklonny , ; Ezcurra et al.…”

“…For example, the hyperfunction theory maintains that ageing is driven by excessive nutrient‐sensing molecular signaling in adulthood, which results in cellular hypertrophy leading to age‐related pathologies (Blagosklonny , ; Ezcurra et al. ). These ideas can be traced back to the original AP theory by George Williams, who suggested that the same physiological processes that are beneficial for fitness early in life can become detrimental for organismal fitness with age because of the reduced strength of natural selection on late‐life function (Williams ).…”

“…However, this hypothesis suffered several setbacks in recent years, with many empirical studies challenging the importance of energy trade-offs in organismal senescence (reviewed in Flatt 2011;Kenyon 2011;Antebi 2013;Gems and Partridge 2013;Maklakov and Immler 2016;Flatt and Partridge 2018). Instead, several authors proposed that ageing can result from molecular signalling networks being optimized for development, growth, and early-life reproduction rather than for late-life reproduction and longevity (Blagosklonny 2010;Kenyon 2010;Antebi 2013;Gems and Partridge 2013;Ezcurra et al 2018). For example, the hyperfunction theory maintains that ageing is driven by excessive nutrient-sensing molecular signaling in adulthood, which results in cellular hypertrophy leading to age-related pathologies (Blagosklonny 2006(Blagosklonny , 2010Ezcurra et al 2018).…”