Open research questions in Genetics, Aging, and Longevity in Model Organisms

What the literature leaves open

• future studies of beyond-the-canon sperm will uncover an expanding repertoire of surprising behaviors, - studies of the sperm's behavior in other species, - investigation of the relationship between sperm activity and reproductive success

  The physical consequences of sperm gigantism · 2026 · DOI

• The physical consequences of sperm gigantism are not well understood. The collective dynamics of sperm in the seminal vesicles are not well studied. The mechanisms underlying the sperm's fast and smooth laning and slow collective material flows are not well understood.

  The physical consequences of sperm gigantism · 2026 · DOI

• The lack of strong clinical evidence for the effectiveness of anti-aging treatments. The need for validated measures of biological aging. The controversy surrounding peptides and their potential risks.

  Anti-aging interventions need less hype and more clinical evidence · 2026 · DOI

• While several transcriptional targets modify synapses, little is known about targets regulating excitability.

  MEF-2 repression of GEM-4/Copine expression decreases muscle excitability by increasing gap junction coupling · 2026 · DOI

• While the mitochondrial unfolded protein response (UPRmt) and AMP-activated protein kinase (AMPK) are both established regulators of this process, whether distinct mitochondrial lesions converge on a single, unified survival mechanism remains unclear.

  Divergent Retrograde Signaling Pathways Coordinate Longevity and Metformin Responses in Complex I and Complex IV Deficient C. elegans · 2026 · DOI

• Secondary bacterial metabolites can regulate animal physiology, but the specific bacterial genes and molecules responsible for regulating, synthesizing, and transporting these molecules and the mechanisms by which they impact animal physiology often remain unclear.

  Bacterial-derived cyclic lipopeptides suppress dauer arrest in C. elegans · 2026 · DOI

• Rice bran, a nutrient-dense byproduct rich in bioactive compounds, offers potential to modulate these systems, yet its in vivo effects on aging remain underexplored.

  Rice Bran as a Novel Dietary Supplement Improves Lifespan, Antioxidant Defense, and Locomotor Performance in Drosophila melanogaster Meigen (Diptera: Drosophilidae) · 2026 · DOI

• The regulation and physiological relevance of the contractions and many of these flows remain incompletely understood.

  RhoGAP54D promotes cell size asymmetry and inhibits pulsatile myosin activity in Drosophila neural stem cells · 2026 · DOI

• While their hazards could be mediated through biotransformation pathways of detoxification and/or bioactivation and associated metabolites, the biotransformation of these tire-derived contaminants in soil organisms, key environmental compartments directly exposed to tire wear, remains unexplored.

  Biotransformation of Tire-Derived 6PPD and 6PPD-Q in Soil Nematode Caenorhabditis elegans : Unraveling Novel Phosphorylation Products and Distinct Kinetic Profiles · 2025 · DOI

• 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 However, the mechanisms by which neurotransmission from sleep-active neurons induces sleep and determines the duration of sleep remain poorly understood.

  The neuropeptide FLP-11 induces and self-inhibits sleep through the receptor DMSR-1 in Caenorhabditis elegans · 2025 · DOI

• 8 , 11 However, how RIS and FLP-11 control sleep is not well understood, as the receptor through which FLP-11 acts has yet to be identified.

  The neuropeptide FLP-11 induces and self-inhibits sleep through the receptor DMSR-1 in Caenorhabditis elegans · 2025 · DOI

• Background Caenorhabditis elegans fed a high-glucose Escherichia coli OP50 diet exhibit reduced fecundity, but the underlying mechanisms remain unclear.

  High-glucose diets differentially modulate phosphatidylcholine metabolism and fecundity in Caenorhabditis elegans · 2025 · DOI

• How nutrient signaling controls cell fate decisions to drive regional changes in cell-type composition remains unclear.

  Stem cell mTOR signaling directs region-specific cell fate decisions during intestinal nutrient adaptation · 2024 · DOI

• Aspects of intestine biology are not well understood, including the export of the nutrients it imports and the molecules it synthesizes, as well as the complete functions and protein content of the gut granules.

  Single-tissue proteomics in Caenorhabditis elegans reveals proteins resident in intestinal lysosome-related organelles · 2024 · DOI

• However, the nutritional basis and the underlying nutrient sensing mechanism essential for animal regrowth after developmental arrest remain to be explored.

  Bacterial vitamin B6 is required for post-embryonic development in C. elegans · 2024 · DOI

• The molecular mechanisms that govern the metabolic commitment to reproduction, which often occurs at the expense of somatic reserves, remain poorly understood.

  The F-box protein FBXL-5 governs vitellogenesis and lipid homeostasis in C. elegans · 2024 · DOI

• “Leader cells” remodel ECM, sense guidance cues, reorganize their cytoskeleton, and coordinate follower cells, but the molecular programs enabling these functions remain unclear.

  Stage-specific transcriptomics of a leader cell reveals cell machineries driving collective invasion · 2026 · DOI

• The current nutritional and longevity strategies lack individualization in response to metabolic stressors. The proposed framework aims to address this limitation.

  Precision Longevity: a Systems Biology framework for dynamic metabolic modulation and Healthspan optimization · 2026 · DOI

• The separation between soma and germline in animals. The need to investigate the intergenerational effects of dietary restriction. The complexity of the mechanisms underlying the intergenerational transfer of ribosome abundance.

  Dietary restriction shapes intergenerational ribosome abundance and early growth of Caenorhabditis elegans offspring · 2026 · DOI

• Further investigation of the mechanisms underlying the intergenerational transfer of ribosome abundance. Examination of the effects of other environmental conditions on the development and growth of organisms. Study of the applications of the research in fields such as agriculture and biotechnology.

  Dietary restriction shapes intergenerational ribosome abundance and early growth of Caenorhabditis elegans offspring · 2026 · DOI

• The complexity of the regulatory networks governing sperm development and function. The limited understanding of the downstream effectors of the SPE-8/SPE-6 pathway. The difficulty of studying sperm activation in vivo.

  The intrinsically disordered protein SPE-56 is required for acrosomal-like exocytosis and fertility in Caenorhabditis elegans · 2026 · DOI

• Further characterization of the molecular mechanisms of SPE-56 function. Investigation of the conservation of SPE-56 function in other species. Exploration of the potential applications of SPE-56 in fertility treatments.

  The intrinsically disordered protein SPE-56 is required for acrosomal-like exocytosis and fertility in Caenorhabditis elegans · 2026 · DOI

• The discovery and decipherment of neural circuits remain challenging due to the necessity of comprehending the functions of signaling molecules and neuronal cells. The regulatory mechanisms of biogenic amine-mediated modulation of neural circuits are not fully understood.

  Deciphering the regulatory mechanism of neural behavioral decisions through biogenic amine-mediated modulation of neural circuits in Caenorhabditis elegans · 2026 · DOI

• The pumping behavior has long attracted significant research interest. As previously described, ADF neurons promote 5-HT production in response to bacterial food. In the downstream of ADF neurons, 5-HT inhibits RIC neurons by a chloride channel receptor MOD-1 in well-fed. OA from RIC neurons acts on two dierence receptors: SER-3/SER-6 in SIA neurons and SER- 6 in AWB neurons in starvation. A feedforward neural circuit is composed of three neurons: ADF, RIC and SIA with a simple mechanism, disinhibition, which lead to pumping increase (Liu et al., 2019). And an ADF → RIC → AWB → ADF neural feedback Although only four biogenic amines have been identified in C. elegans, these signaling molecules are capable of modulating a wide range of behavioral responses by diverse regulatory mechanisms. The complex spatial instructions of behavior originate from the interaction of dierent neurons in neural circuits mediated by multiple neurotransmitters and receptors, and are implemented through excitation, inhibition, feedforward, and feedback. These behavioral and metabolic regulations involve multi-level neurophysiological mechanisms of neural signaling.

  Deciphering the regulatory mechanism of neural behavioral decisions through biogenic amine-mediated modulation of neural circuits in Caenorhabditis elegans · 2026 · DOI

• C. elegans lacks a circulatory (cardiovascular) system, a blood-brain barrier, a stomach, bones, and acquired immune responses. Genes or proteins may be limited (fewer isomers) or differ from those in mammals. A direct method to convert the dose/concentration used in C. elegans to mammals is not available.

  Utilizing Caenorhabditis elegans as an In Vivo Model for Identifying Small Molecules Modulating Lipid Metabolism: A Guideline · 2026 · DOI

Most-cited papers in Genetics, Aging, and Longevity in Model Organisms

• Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans · Nature · 1998 · 12,454 citations
• Alzheimer's Disease: The Amyloid Cascade Hypothesis · Science · 1992 · 6,354 citations
• The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans · Nature · 2000 · 3,930 citations
• Rapamycin fed late in life extends lifespan in genetically heterogeneous mice · Nature · 2009 · 3,296 citations
• Systematic functional analysis of the Caenorhabditis elegans genome using RNAi · Nature · 2003 · 3,213 citations
• A C. elegans mutant that lives twice as long as wild type · Nature · 1993 · 3,003 citations
• A Cellular Function for the RNA-Interference Enzyme Dicer in the Maturation of the let-7 Small Temporal RNA · Science · 2001 · 2,189 citations
• Statistical guidelines for contributors to medical journals. · BMJ · 1983 · 476 citations
• From geroscience to precision geromedicine: Understanding and managing aging · Cell · 2025 · 383 citations
• Biological Aging Is No Longer an Unsolved Problem · Annals of the New York Academy of Sciences · 2007 · 325 citations

Most recent work

• Heritability of intrinsic human life span is about 50% when confounding factors are addressed · Science · 2026
• Chronic low-dose exposure to chlorpyrifos reduces life span in a wild fish by accelerating aging · Science · 2026
• Multimodal clocks of human aging · Cell · 2026
• Bridging the gap between the connectome and whole-brain activity in C. elegans · bioRxiv · 2026
• Perception of Temperature Even in the Absence of Actual Change is Sufficient to Drive Transgenerational Epigenetic Inheritance · bioRxiv · 2026
• Nutrition and longevity – diet in centenarians · Journal of Translational Medicine · 2026
• ztf-16 is a novel heterochronic modulator that opposes adult cell fate in dauer and continuous life histories in Caenorhabditis elegans · bioRxiv · 2026
• Oligomerization and positive feedback on membrane binding stabilize PAR-3 asymmetries in the C. elegans zygote · Current Biology · 2026
• Intraspecific variation in the duration of epigenetic inheritance in wild isolates of C. elegans · Current Biology · 2026
• Thermosensory neuron dysfunction alters transposable element regulation · bioRxiv · 2026

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