Fucoidans are senotherapeutics that enhance SIRT6-dependent DNA repair

Area of Science:

• Cellular senescence
• Aging research
• Natural product therapeutics

Background:

• Aging is characterized by senescent cells (SnCs) accumulation, leading to tissue dysfunction and age-related diseases.
• Senotherapeutics, including senolytics and senomorphics, are emerging as potential interventions to combat aging.
• Identifying novel compounds with senotherapeutic properties is crucial for extending healthspan.

Purpose of the Study:

• To identify novel senotherapeutics from natural sources.
• To investigate the senomorphic potential of fucoidans, particularly fucoidan from Fucus vesiculosus (Fucoidan-FV).
• To elucidate the molecular mechanisms underlying Fucoidan-FV's effects on senescence and DNA repair.

Main Methods:

• Phenotypic-based senescent cell screening assay to identify senotherapeutics.
• In vitro testing of Fucoidan-FV on different types of senescent cells (SnCs).
• In vivo studies in aged mice and a mouse model of accelerated aging to assess healthspan and senescence.
• Analysis of SIRT6 activity, DNA repair pathways, and gene expression profiles (inflammation, Wnt signaling, ECM remodeling).

Main Results:

• Fucoidan-FV demonstrated potent senomorphic activity in various SnCs.
• Treatment with Fucoidan-FV reduced senescence in multiple tissues of aged mice and extended healthspan in an accelerated aging model.
• Fucoidan-FV enhanced SIRT6 activity, leading to improved DNA repair and reduced senescence via SIRT6-dependent pathways.
• Fucoidan-FV modulated gene expression in SnCs, downregulating inflammatory and Wnt signaling pathways while upregulating DNA repair genes.

Conclusions:

• Fucoidans, particularly Fucoidan-FV, are identified as novel senotherapeutics with significant senomorphic effects.
• Fucoidan-FV extends healthspan and mitigates aging phenotypes in mice, partly through enhancing SIRT6-mediated DNA repair.
• These findings highlight the translational potential of fucoidans for treating age-related diseases and promoting healthy aging.