Researchers at leading biotech firms apply CRISPR-Cas9, base editing, and prime editing to modify genes tied to cellular aging, such as SIRT1 and FOXO3. They leverage both ex vivo stem cell approaches and lipid nanoparticle delivery in vivo to develop potential one-time therapies against cardiovascular and neurodegenerative conditions.
Key points
Ex vivo CRISPR-Cas9 editing of HSCs targets longevity genes (SIRT1, FOXO3) with HDR precision.
Base and prime editing platforms reduce off-target effects compared to standard Cas9, enhancing specificity.
Lipid nanoparticle delivery achieves >80% in vivo gene disruption of PCSK9 and ANGPTL3 in mouse liver.
Why it matters:
This breakthrough signifies a paradigm shift in anti-aging therapeutics, enabling precise genetic interventions to enhance healthspan over traditional drug approaches.
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Academy
CRISPR-Cas9: Mechanism and Applications
CRISPR-Cas9 originates from bacterial immune systems. It uses a Cas9 nuclease and a guide RNA (gRNA) to locate and cleave specific DNA sequences. The gRNA forms a complex with Cas9, guiding it to a precise genomic target adjacent to a protospacer adjacent motif (PAM). Upon binding, Cas9 introduces a double-strand break.
Following cleavage, the cell activates DNA repair pathways. Non-Homologous End Joining (NHEJ) often introduces small insertions or deletions at the break site, disrupting gene function. Homology-Directed Repair (HDR) uses a repair template to insert or correct sequences precisely. Researchers exploit these pathways to knock out genes or install new genetic information.
Advancements such as base editing and prime editing avoid double-strand breaks altogether. Base editors fuse a Cas9 nickase with a deaminase enzyme, enabling direct conversion of one DNA base into another. Prime editors combine a Cas9 nickase with reverse transcriptase and a specialized pegRNA, allowing precise insertions, deletions, and all base-to-base conversions with minimal off-target activity.
Effective delivery is critical. Viral vectors like AAV deliver CRISPR components efficiently but face size and immunogenicity constraints. Lipid nanoparticles (LNPs) offer non-viral delivery of Cas9 mRNA and gRNA, providing transient expression and reduced immune activation. Optimization of carrier composition and targeting ligands enables tissue-specific gene editing.
CRISPR in Longevity Science
In longevity research, CRISPR tools target genes that regulate aging processes. Key targets include SIRT1 and FOXO3, which influence stress responses and metabolic regulation. Editing the TERT promoter can reactivate telomerase, potentially delaying telomere shortening and cellular senescence.
Senescent cells accumulate with age and secrete inflammatory signals. CRISPR enables selective removal by targeting markers like p16INK4a. This senolytic strategy has shown improvements in tissue function in animal models.
Mitochondrial dysfunction contributes to aging. Emerging CRISPR-based approaches aim to correct mutations in mitochondrial DNA, enhancing cellular energy production and reducing oxidative stress.
Beyond individual genes, multiplex editing can modify entire pathways. Combining CRISPR interventions with senolytics, epigenetic reprogramming, and metabolic therapies offers a multifaceted approach to extend healthspan. Continued innovation in specificity, delivery, and safety is paving the way for clinical translation of gene-editing-based anti-aging therapies.