Kern, Carina et al. (2021) International Worm Meeting "C. elegans provide milk for their young"

Gems , David, Townsend, StJohn, Kern, Carina, Salzmann, Antoine, Comisel , Ruxandra

[International Worm Meeting, 2021]

Aging in C. elegans is unusual in terms of the severity and early onset of senescent pathology, particularly affecting organs involved in reproduction (1-3). For example, in post-reproductive hermaphrodites, intestinal biomass is converted into yolk leading to intestinal atrophy and yolk steatosis (3). While such post-reproductive yolk production has long been viewed as futile (1,4), we wondered if it could somehow promotes fitness. We report that sperm-depleted hermaphrodites vent copious amounts of yolk through the vulva. This yolk can be consumed by larvae and promote their growth. This implies that post-reproductive mothers can continue to contibute to reproductive fitness by converting their biomass into a substance that serves a similar function to milk. This suggests that gut atrophy is a cost of a form of primitive lactation (also seen in certain insects). Moreover, unfertilized oocytes function as vectors carrying yolk to larvae. This type of massive reproductive effort involving biomass repurposing that causes organ degeneration is characteristic of semelparous organisms (i.e. that exhibit only a single reproductive episode) ranging from monocarpic plants to Pacific salmon, where it frequently leads to rapid death (reproductive death). We also observed yolk venting in hermaphrodites of other Caenorhabditis species and in Pristionchus pacificus hermaphrodites, but not in females of either genus. Moreover, females do not exhibit gut atrophy or steatosis and are longer lived, suggesting absence of reproductive death. Furthermore, across species germline ablation strongly increases lifespan in nematode hermaphrodites but not females; similarly, in diverse animal and plant species blocking sexual maturation e.g. by gonadectomy frequently causes large increases in lifespan in organisms that undergo reproductive death, but not in those that don't. Insulin/IGF-1 signaling, which accelerates C. elegans aging, also promotes yolk production and gut atrophy (1,3). These results suggest that C. elegans hermaphrodites exhibit reproductive death, suppression of which increases lifespan. If correct, this has significant implications in terms of what one can learn about human aging from C. elegans. (1) Nature 2002 419: 808. (2) Genetics 2002 161: 1101. (3) Curr. Biol. 2018 28: 2544. (4) BMC Physiol. 2011 11: 11.

Gems, David et al. (2021) International Worm Meeting "Three programmatic mechanisms of aging in C. elegans"

Galimov, Evgeniy, Kern, Carina, Gems, David

[International Worm Meeting, 2021]

One of the main objectives of research on aging in C. elegans is to develop an understanding of the fundamental principles that govern the process of senescence (aging) including the development of diseases of aging. Attaining this understanding has proven to be difficult, despite major advances in terms of knowledge of genes and pathways which affect lifespan. Work in the Gems lab has investigated two different ideas about aging in C. elegans. First, and initially, that it results mainly from the accumulation of stochastic molecular damage. Second, and more recently, that it results mainly from non-stochastic programmatic mechanisms driven by wild-type gene action. Tests of the damage theory yielded largely negative effects [1-6]. By contrast, tests of programmatic theories have both supported such theories [7-11] and led to elaborations of them [12-16]. Our recent work suggests a new picture of C. elegans aging as driven by three distinct forms of programmatic mechanism. First, programs optimized for fitness in early life that later run on in futile fashion, causing pathology. This is exemplified by uterine tumor formation which results from run-on of embryogenetic programs [10, 11], consistent with recent programmatic theories [17-19]. Second, costly programs that promote aging as part of a suicidal reproductive effort (semelparous reproductive death, c.f. Pacific salmon). For example, consumption of intestinal biomass to support production of yolk that is vented to support larval growth leads to gut atrophy (see presentation by C.C. Kern)[8, 16, 20]. Third, programmed adaptive death, that can evolve in organisms that exist in clonal, high-density populations and, particularly, where reproductive death occurs [12-14]. We suggest that the unusually high degree of plasticity in aging in C. elegans reflects suppression of genetically determined reproductive death and adaptive death. [1] Free Radic Biol Med (2003) 34, 277. [2] Free Radic Biol Med (2004) 37, 239. [3] Free Radic Biol Med (2011) 51, 1575. [4] Genes Dev (2008) 22, 3236. [5] Cell Cycle (2009) 8, 1681. [6] Mech Ageing Dev (2012) 133, 282. [7]. Oncotarget (2016) 7, 39082. [8] Curr Biol (2018) 28, 2544. [9] Antioxid Redox Signal (2013) 19, 321. [10] Aging (2018) 10, 1188. [11] NPJ Aging Mech Disease (2018) 4, 6. [12] Philos Trans R Soc B (2021) 376, 20190730. [13] Ageing Res Rev (2019) 50, 58. [14] Biochem (Moscow) (2019) 84, 1433. [15] Preprints (2020) 2020110019. [16] BioRxiv (2020) doi.org/10.1101/2020.1111.1115.380253. [17] Physiol (2005) 20, 252. [18] Cell Cycle (2006) 5, 2087. [19] Proc Biol Sci (2019) 286, 20191604. [20] J Gerontol A (2019) 74, 1180.

Hsiung, Kuei Ching et al. (2021) International Worm Meeting "Are levels of autophagy increased or decreased in daf-2 insulin/IGF-1 mutants?"

Gems, David, Chapman, Hannah, Hsiung, Kuei Ching

[International Worm Meeting, 2021]

According to one theory, molecular damage is the principal cause of ageing, while somatic maintenance mechanisms act against damage accumulation and ageing. One such maintenance mechanism is autophagy, which can remove damaged cellular constituents. Autophagy is considered a likely mechanism protecting against ageing. Various findings support the view that autophagy levels are elevated in daf-2 insulin/IGF-1 receptor mutants in C. elegans, and that autophagy contributes to their extended lifespan. We have been investigating the causes of intestinal atrophy, a major senescent pathology in C. elegans. Our evidence supports the view that gut atrophy is the result of the intestine consuming its own biomass to support yolk synthesis in sperm-depleted hermaphrodites [1], an example of a programmatic mechanism of ageing [2]. This yolk is vented via the vulva after reproduction and can support larval growth [3] (see presentation by C.C. Kern). Such intestinal biomass repurposing is facilitated by autophagy, and greatly reduced in daf-2 mutants [1,4]. This suggests that autophagy is decreased in daf-2 mutants. Consistent with this, it has been reported that protein turnover is also reduced in daf-2 mutants. To try to resolve the conflicting conclusions about the relationship between IIS, autophagy and ageing in C. elegans we are re-examining effects of knockdown of genes encoding the machinery of autophagy on pathology and ageing, taking into consideration issues of timing and severity of knockdown, daf-2 allele class, temperature, bacterial status and other issues. Our interim data will be described. [1] M. Ezcurra, et al (2018) Curr. Biol. 28: 2544. [2] A.A Maklakov, T. Chapman (2019) Proc. Biol. Sci. 286: 20191604. [3] C.C. Kern et al (2020) BioRxiv doi.org/10.1101/ 2020.11.15.380253. [4] A. Benedetto, D. Gems (2019) Autophagy 15: 731.