Longevity Papers

The emerging field of senolytics is centered on eliminating senescent cells to block their contribution to the progression of age-related diseases, including cancer, and to facilitate healthy aging. Enhancing the selectivity of senolytic treatments toward senescent cells stands to reduce the adverse effects associated with existing senolytic interventions. Taking advantage of lipofuscin accumulation in senescent cells, we describe here the development of a highly efficient senolytic platform consisting of a lipofuscin-binding domain scaffold, which can be conjugated with a senolytic drug via an ester bond. As a proof of concept, we present the generation of GL392, a senolytic compound that carries a dasatinib senolytic moiety. Encapsulation of the GL392 compound in a micelle nanocarrier (termed mGL392) allows for both in vitro and in vivo (in mice) selective elimination of senescent cells via targeted release of the senolytic agent with minimal systemic toxicity. Our findings suggest that this platform could be used to enhance targeting of senotherapeutics toward senescent cells.

Cellular senescence, which entails cellular dysfunction and inflammatory factor release-the senescence-associated secretory phenotype (SASP)-is a key contributor to multiple disorders, diseases, and the geriatric syndromes. Targeting senescent cells using senolytics has emerged as a promising therapeutic strategy for these conditions. Among senolytics, the combination of dasatinib and quercetin (D + Q) was the earliest and one of the most successful so far. D + Q delays, prevents, alleviates, or treats multiple senescence-associated diseases and disorders with improvements in healthspan across various preclinical models. While early senolytic therapies have demonstrated promise, ongoing research is crucial to refine them and address such challenges as off-target effects. Recent advances in senolytics include new drugs and therapies that target senescent cells more effectively. The identification of senescence-associated antigens-cell surface molecules on senescent cells-pointed to another promising means for developing novel therapies and identifying biomarkers of senescent cell abundance.

Introduction: FAM162A is a mitochondrial protein evolutionarily conserved across taxa and ubiquitously expressed in various tissues. It is known for its role in hypoxia-induced apoptosis. However, paradoxically, FAM162A is overexpressed in cancer, where its pro-apoptotic function seems overridden, suggesting an alternative role associated with mitochondrial function and cell survival. Additionally, its precise localization and topology remain controversial. Objectives: To assess the role of FAM162A in mitochondrial structure, dynamics, and bioenergetics and its impact on cell viability, while establishing its precise localization, orientation, and topology. Additionally, to generate a transgenic Drosophila model overexpressing human FAM162A to evaluate its effects on organismal survival under normal and stress conditions. Methods: Localization, orientation, and topology were determined by protease protection assays in COS7 cells. Loss- and gain-of-function experiments were performed to assess mitochondrial function and turnover by confocal microscopy, immunoblots and Seahorse technology. A transgenic Drosophila model overexpressing human FAM162A was generated to evaluate organismal survival under normal and stress conditions. Results: FAM162A is essential for maintaining mitochondrial ultrastructure and bioenergetics, thereby influencing cell viability and stress resistance. Localization studies revealed that FAM162A resides predominantly in the inner mitochondrial membrane, particularly within the cristae, where it modulates the fusion protein OPA1. Transgenic Drosophila overexpressing human FAM162A exhibited increased lifespan and locomotor activity under both normal and heat stress conditions. Conclusion: FAM162A emerges as a crucial player in maintaining mitochondrial integrity and bioenergetics. Its functional role, potentially mediated through interaction with OPA1, impacts mitochondrial health, stress resistance, cellular viability, and organismal longevity.

The shelterin complex protects chromosome ends from the DNA damage repair machinery and regulates telomerase access to telomeres. Shelterin is composed of six proteins (TRF1, TRF2, TIN2, TPP1, POT1 and RAP1) that can assemble into various subcomplexes in vitro. However, the stoichiometry of the shelterin complex and its dynamic association with telomeres in cells is poorly defined. To quantitatively analyze the shelterin function in living cells we generated a panel of cancer cell lines expressing HaloTagged shelterin proteins from their endogenous loci. We systematically determined the total cellular abundance and telomeric copy number of each shelterin subunit, demonstrating that the shelterin proteins are present at telomeres in equal numbers. In addition, we used single-molecule live-cell imaging to analyze the dynamics of shelterin protein association with telomeres. Our results demonstrate that TRF1-TIN2-TPP1-POT1 and TRF2-RAP1 form distinct subcomplexes that occupy non-overlapping binding sites on telomeric chromatin. TRF1-TIN2-TPP1-POT1 tightly associates with chromatin, while TRF2-RAP1 binding to telomeres is more dynamic, allowing it to recruit a variety of co-factors to chromatin to protect chromosome ends from DNA repair factors. In total, our work provides critical mechanistic insight into how the shelterin proteins carry out multiple essential functions in telomere maintenance and significantly advances our understanding of macromolecular structure of telomeric chromatin.