Gene Therapy Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice

This study used ultra-sensitive Duplex Sequencing to profile ~2.5 million mt-genomes in young and aged mice to investigate how mismatching between nuclear and mitochondrial ancestry impacts the somatic evolution of the mt-genome in different tissues throughout aging. Distinct mutational patterns, hotspots, and positive selection were observed, along with somatic reversion mutations realigning mito-nuclear ancestry. Findings highlight the dynamic and selection-driven nature of mitochondrial genomes throughout an organism's lifespan.

Using 33 million histological samples, age- and mortality-associated features were extracted from text narratives (The Human Pathome). Sexual dimorphism in aging was observed. Machine learning was used to identify predictive terms and themes that predict aging and mortality. Nintedanib emerged as a potential aging intervention, reducing senescence markers, pro-fibrotic genes, and extending fruit fly lifespan. Expanding population datasets holds promise for discovering novel aging interventions.

This study demonstrates that an agonist insulin INS-7 is drastically over-produced and causes shortened lifespan in lpd-3 mutants, a C. elegans model of human Alkuraya-Kučinskas syndrome.

Senescent cells evade immune clearance and accumulate in aging and chronic inflammation by upregulating programmed death-ligand 1 (PD-L1) via p16-mediated inhibition of CDK4/6. Macrophages expressing p16 create an immunosuppressive environment. Targeting PD-L1 with anti-PD-L1 antibody enhances cytotoxic T cell activity and eliminates p16, PD-L1-positive cells, providing a potential treatment for age-related diseases.