Longevity Papers

Honokiol (HKL), one of the major bioactive components of the traditional Chinese medicine Magnolia officinalis, has garnered significant attention because of its extensive pharmacological activities. Numerous studies have demonstrated that SIRT3 plays a crucial regulatory role in the disease intervention mechanisms mediated by HKL. HKL can bind to the SIRT3 protein, not only directly increasing its deacetylase activity but also forming a positive feedback loop by activating its transcription factors, thereby further promoting SIRT3 expression. This dual regulatory mechanism effectively restores the function of downstream proteins, activates intracellular protective mechanisms, and combats a variety of pathological processes, including aging, oxidative stress, inflammation, cell death, mitochondrial dysfunction, and metabolic disorders. It has shown broad prospects in the prevention and treatment of chronic diseases such as neurodegenerative diseases, cardiovascular diseases, degenerative bone and joint diseases, lung diseases, and metabolic disorders. Although HKL is a highly recognized SIRT3 activator, there is currently no comprehensive review systematically summarizing the research on HKL as a SIRT3 activator. This review comprehensively summarizes the research progress over the past decade since the discovery of HKL as a SIRT3 activator. Through in-depth analysis of the literature, we focused on elucidating the biological functions of HKL through SIRT3 activation in various disease models and the signaling pathways involved. These findings emphasize the therapeutic development value and significant application potential of HKL as a SIRT3 activator, providing a theoretical basis for the development of natural products that target SIRT3.

Longevity interventions in mammals are typically discovered on a case-by-case basis, hindering systematic geroprotector development. We developed a platform for the identification of longevity interventions integrating longevity gene expression biomarkers within and across species, in silico chemical screening, analyses of selected compounds in cell culture, short-term dietary interventions coupled with omics profiling, and ultimately lifespan studies in mice. This approach identified compounds (selumetinib, vorinostat, celastrol, AZD-8055, LY-294002) that extended lifespan and/or healthspan in aged C57BL/6JN male mice, with limited effects in females. In addition, selumetinib and vorinostat increased lifespan when administered to young, genetically heterogeneous UM-HET3 mice. Our biomarker-driven platform accelerates geroprotector discovery, offering a scalable approach to target conserved longevity pathways.

Cohesin is a DNA tethering complex essential for chromosome structure and function. In fission yeast, defects in the cohesin loader Mis4 result in chromosome segregation defects and dysregulated expression of genes near chromosome ends. A genetic screen for suppressors of the thermosensitive growth defect of mis4-G1487D identified several hypomorphic mutants of the Target of Rapamycin Complex 1 (TORC1), a conserved kinase that integrates cellular signals to regulate growth and metabolism through substrate-specific phosphorylation. Here, we demonstrate that the TORC1 pathway modulates cohesin functions in chromosome segregation and gene expression. In the context of compromised cohesin loading, the incidence of chromosome segregation defects was modulated by the growth medium in a TORC1-dependent manner. Pharmacological or genetic down-regulation of TORC1 activity restored cohesin binding to its chromosomal sites and improved mitotic chromosome segregation. Notably, reduced TORC1 activity also increased cohesin binding and chromosome transmission fidelity in wild-type cells. These results suggest that environmental cues influence chromosome stability via TORC1. Biochemically, TORC1 co-purified with cohesin and reduced TORC1 activity correlated with decreased phosphorylation of specific residues on Mis4 and cohesin. Mutations in cohesin that mimic the non-phosphorylated state mirrored the effects of TORC1 downregulation, showing that TORC1 is part of the network that controls cohesin phosphorylation to modulate its functions. Finally, we show that the functional interaction between TORC1 and Mis4 extends to the regulation of stress-responsive genes. Our findings reveal a TORC1-cohesin link that may facilitate cellular adaptation to environmental changes. Given that TORC1 inhibitors and calorie restriction extend lifespan in diverse species, this connection raises the intriguing possibility that cohesin-mediated changes in chromosome structure contribute to these effects.