Affiliations 

  • 1 Department of Pharmacology, Chameli Devi Institute of Pharmacy, Khandwa Road, Village Umrikheda, Near Tollbooth, Indore, Madhya Pradesh, 452020, India
  • 2 Pharmacy Program, Department of Pharmaceutical Sciences, Batterjee Medical College, P.O. Box 6231, 21442, Jeddah, Saudi Arabia
  • 3 Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India
  • 4 Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
  • 5 Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
  • 6 Department of Microbiology, Graphic Era Deemed to be University, Dehradun, 248002, India
  • 7 Department of Biochemistry, Faculty of Medicine, Bioscience, and Nursing, MAHSA University, 42610, Jenjarom, Selangor, Malaysia
  • 8 Department of General Surgery, Consultant Head and Neck Surgical Oncology, Dr.D.Y.Patil Medical College, Hospital and Research Centre, Pimpri, Pune, India
  • 9 Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
  • 10 School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T Road, Phagwara, Punjab, India
  • 11 Department of Zoology, Kalindi College, University of Delhi, 110008, New Delhi, India
  • 12 Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India. Gaurav.gupta@chitkara.edu.in
Biogerontology, 2025 Feb 26;26(2):65.
PMID: 40011269 DOI: 10.1007/s10522-025-10207-0

Abstract

Aging and metabolic disorders share intricate molecular pathways, with the Forkhead box O (FOXO)- Sirtuin 1 (SIRT1) axis emerging as a pivotal regulator of cellular stress adaptation, metabolic homeostasis, and longevity. This axis integrates nutrient signaling with oxidative stress defence, modulating glucose and lipid metabolism, mitochondrial function, and autophagy to maintain cellular stability. FOXO transcription factors, regulated by SIRT1 deacetylation, enhance antioxidant defence mechanisms, activating genes such as superoxide dismutase (SOD) and catalase, thereby counteracting oxidative stress and metabolic dysregulation. Recent evidence highlights the dynamic role of reactive oxygen species (ROS) as secondary messengers in redox signaling, influencing FOXO-SIRT1 activity in metabolic adaptation. Additionally, key redox-sensitive regulators such as nuclear factor erythroid 2-related factor 2 (Nrf2) and Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) interact with this pathway, orchestrating mitochondrial biogenesis and adaptive stress responses. Pharmacological interventions, including alpha-lipoic acid (ALA), resveratrol, curcumin and NAD+ precursors, exhibit therapeutic potential by enhancing insulin sensitivity, reducing oxidative burden, and restoring metabolic balance. This review synthesizes current advancements in FOXO-SIRT1 regulation, its emerging role in redox homeostasis, and its therapeutic relevance, offering insights into future strategies for combating metabolic dysfunction and aging-related diseases.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.