Luigi Ferruci

💬 Biography
Dr. Luigi Ferrucci is a geriatrician and an epidemiologist who conducts research on the causal pathways leading to progressive physical and cognitive decline in older persons. He has made major contributions in the design of many epidemiological studies conducted in the U.S. and in Europe. Dr. Ferrucci received a Medical Degree and Board Certification in 1980, Board Certification in Geriatrics in 1982 and Ph.D. in Biology and Pathophysiology of Aging in 1998 at the University of Florence, Italy. Between 1985 and 2002 he was Chief of Geriatric Rehabilitation at the Department of Geriatric Medicine and Director of the Laboratory of Clinical Epidemiology at the Italian National Institute of Aging. In September 2002, he became the Chief of the Longitudinal Studies Section at NIA. From 2002 to present he is the Director of the Baltimore Longitudinal Study of Aging. Dr. Ferrucci is currently the Scientific Director of NIA, since May 2011.

🎤 Presentation: When Oxygen Becomes Limiting: Hypoxia as a Central Mechanism of Biological Aging
Aging is commonly conceptualized as the cumulative accumulation of molecular damage; however, this view does not fully account for the dynamic and partially reversible nature of biological aging revealed by recent biomarkers. In this keynote, I propose that relative tissue hypoxia is a central, systems-level driver of biological aging, integrating molecular, physiological, and structural mechanisms across tissues.
At the epigenetic level, age-associated DNA methylation changes in circulating immune cells are enriched near binding sites of transcription factors involved in the hypoxic response, suggesting that oxygen availability shapes the aging epigenome. Physiological measurements demonstrate that skeletal muscle oxygen tension is lower in older than in younger animals and that aging blunts adaptive responses to intermittent hypoxia. Experimentally, intermittent hypoxia accelerates epigenetic aging across multiple tissues in old mice, a process that is largely reversible upon restoration of normoxia, indicating that epigenetic clocks reflect dynamic physiological stress rather than irreversible damage. Concordantly, exposure of humans to high altitude induces rapid epigenetic age acceleration.
These findings support a broader model in which aging progressively induces a state of chronic, mild hypoxia in many tissues. Age-related alterations in oxygen transport and delivery—combined with extracellular matrix remodeling, microvascular rarefaction, and endothelial dysfunction—reduce tissue perfusion and oxygen diffusion. Hypoxia-driven metabolic reprogramming suppresses mitochondrial oxidative phosphorylation, leading to energetic failure, impaired cellular maintenance, and induction of cellular senescence. Senescent cells, through the senescence-associated secretory phenotype, further stiffen the extracellular matrix and exacerbate vascular dysfunction, reinforcing hypoperfusion and closing a self-sustaining vicious cycle.
Together, this framework positions hypoxia not as a passive consequence of aging, but as a primary biological driver linking epigenetic aging, mitochondrial dysfunction, vascular decline, inflammation, and loss of resilience, with important implications for interventions targeting the aging process.