Neutrophil senescence, comorbidities and clinical outcomes in sepsis

• Grant number: 25/02074-9
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: March 01, 2025
• End date: January 31, 2028
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Alessandra Gambero
• Grantee: Maria Carolina Ximenes de Godoy
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 24/01637-7 - Multiple long-term conditions and immunosenescence: cellular senescence and clinical outcomes in sepsis., AP.R

Abstract

In the last millennia, life expectancy has increased drastically, from just 25 years during the Bronze and Iron Ages to over 80 years today in developed countries. However, the increase in life expectancy and aging represent the most important non-modifiable risk factors for various diseases. The expansion of immunosuppressive CD16bright/D62Ldim neutrophils circulating with aging has been reported and is associated with reduced phagocytic and migratory activity, which impairs the host's response to infections but simultaneously increases the potential for host damage due to inflammation, production of reactive oxygen species (ROS), and protease activity. The aging of the immune system, known as immunosenescence, results from chronological aging (or telomere-dependent aging), but it can also be associated with environmental factors such as nutrition and physical inactivity, metabolic comorbidities like obesity and diabetes, antigenic exposure over a lifetime, stress-induced damage such as increased levels of reactive oxygen species (ROS) and mitochondrial dysfunction, and epigenetic changes, in which case it is referred to as early senescence.Sepsis remains a public health challenge, being the leading cause of death in intensive care units (ICUs). According to the World Health Organization, sepsis kills 11 million people each year and disables millions more. In Brazil, an estimated 240,000 deaths occur annually due to sepsis. Sepsis is a complex syndrome that develops as a dysregulated host response to infection, associated with severe acute organ dysfunction. Neutrophils are crucial components of the innate immune response during sepsis, and neutrophil immunosenescence has not yet been evaluated in this context. Therefore, our main objective is to assess whether patients with comorbidities associated with immunosenescence have worse outcomes in sepsis and whether these outcomes correlate with the presence of neutrophil senescence.