Highlights d Accumulation of circRNAs with age is slowed down in longlived insulin mutant flies d A circRNA encoded by the sulfateless gene is induced in longlived insulin mutants d Overexpression of circSfl extends the lifespan of fruit flies d CircSfl is translated, and the resulting peptide is sufficient to extend lifespan

One of the most robust and reproducible methods to prolong lifespan in a variety of organisms is inhibition of the mTORC1 (mechanistic target of rapamycin complex 1) pathway. mTORC1 is a metabolic sensor that promotes anabolic growth when nutrients are abundant. Inhibition of mTORC1 extends lifespan, but also frequently has other effects such as stunted growth, slowed development, reduced fertility, and disrupted metabolism. It has long been assumed that suppression of anabolism and resulting phenotypes such as impaired growth and reproduction may be causal to mTORC1 longevity, but this hypothesis has not been directly tested. RAGA-1 is an upstream activator of TORC1. Previous work from our lab using a C. elegans model of mTORC1 longevity, the long-lived raga-1 null mutant, found that the presence of RAGA-1 only in the neurons suppresses longevity of the null mutant. Here, we use the auxin-inducible degradation (AID) system to test whether neuronal mTORC1 inhibition is sufficient for longevity, and whether any changes in lifespan are also linked to stunted growth or fertility. We find that life-long AID of RAGA-1 either in all somatic tissue or only in the neurons of C. elegans is sufficient to extend lifespan. We also find that AID of RAGA-1 or LET-363/mTOR beginning at day 1 of adulthood extends lifespan to a similar extent. Unlike somatic degradation of RAGA-1, neuronal degradation of RAGA-1 does not impair growth, slow development, or decrease the reproductive capacity of the worms. Lastly, while AID of LET-363/mTOR in all somatic cells shortens lifespan, neuronal AID of LET-363/mTOR promotes longevity. This work demonstrates that targeting mTORC1 specifically in the neurons uncouples longevity from growth and reproductive impairments, challenging previously held ideas about the mechanisms of mTORC1 longevity and elucidating the promise of tissue-specific aging therapeutics.

Aging is the primary risk factor for Parkinson’s disease (PD) and cognitive impairment from PD is a major and unmet biomedical challenge. Klotho, a pleiotropic protein, extends lifespan and enhances cognition. Whether longevity factors such as klotho can counteract PD-related mortality and deficits in mice or associate with resistance to PD in humans is unknown. Here we show that transgenic elevation of klotho increased lifespan, improved synaptic and cognitive, but not motor, functions in mice, and decreased steady state α-synuclein levels in the brains of mice that express wildtype human α-synuclein. In humans, a genetic variant of KLOTHO that increases circulating klotho levels associated with better executive cognition and less CSF abnormalities of α-synuclein in individuals with PD. Thus, klotho can counteract cognitive deficits related to PD, possibly modulating α-synuclein levels – and these findings may be relevant to new therapeutic pathways for human PD.

Geroscience aims to target the aging process to extend healthspan. However, even isogenic individuals show heterogeneity in natural aging rate and responsiveness to pro-longevity interventions, limiting translational potential. Using in vivo mini gene reporters in isogenic C. elegans, we show that alternative splicing of mRNAs related to lipid metabolism in young animals is coupled to subsequent life expectancy. Further, activity of RNA splicing factors REPO-1 and SFA-1 early in life modulates effectiveness of specific longevity interventions via POD-2/ACC1 and regulation of lipid utilization. In addition, early inhibition of REPO-1 renders animals refractory to late onset suppression of the TORC1 pathway. Together these data suggest that activity of RNA splicing factors and the metabolic landscape early in life can modulate responsiveness to longevity interventions and may explain variance in efficacy between individuals.One Sentence SummaryEfficacy of pro-longevity interventions in C. elegans is determined by the activity of splicing factors and the lipid metabolic landscape early in the life of the individual.