Dissertation

Metformin Decreases Aging and Diabetes Associated Chronic Inflammation and has an Immunomodulatory Role

Tizazu, Anteneh Mehari

2019

Overview

Aging is unlikely programmed but the result of a series of damages. Reducing the damages and/or improving the resilience to stressors may extend lifespan and healthspan. Advances in drug and vaccine development played an important role in extending lifespan in the world population by preventing and curing many infectious diseases which were fatal to humans in early days. The number of individuals over the age of 60 was 900 million in 2015 and this number is expected to rise to 2 billion by the year 2050. This demographic change is a current and future challenge of nations across the globe.Diabetes is one of the common diseases associated with aging and its risk increases with age. The number of individuals having diabetes has increased from 180 million in 1980 to 422 million in 2014 and its prevalence has almost doubled from 4.7% in 1980 to 8.5% in 2014 among the adult population. Low-grade chronic inflammation termed as “Inflammaging” is one feature of elderly individuals and it has been associated with different age-related disease. Pro-inflammatory cytokines like IL-6, TNF, and CRP have been associated with pathological conditions like diabetes, Alzheimer’s disease, and cardiovascular disease.Many aging studies directly compare young and old individuals to identify different changes associated with age including changes in the immune system. But few studies have shown that both young and old individuals are diverse and have a different aging trajectory. Here in this project, we tried to approach the aging process in two perspectives one is by chronological age and the other is by pathological age and looked for changes associated with chronic inflammation, immunosenescence, and functionality of the immune cell.With clinical data and structured questionnaires we stratified our groups in the elderly category: diabetic, pre-diabetic, non-diabetic but with other comorbidities, and healthy while we used young individuals as a control. We showed that even healthy aging is accompanied by low-grade inflammation. The situation worsens in individuals with diabetes and prediabetes. One important finding is the impact of treatments as individuals under metformin monotherapy have a lower level of inflammatory molecules like TNF, sTNFRI, and sTNRII. Five-year mortality data showed that diabetic individuals under metformin monotherapy had a lower mortality rate compared to diabetic patients under other nonmetformin therapy.The classical signs of aging and immunosenescence were present in the cohort we have studied (i) decrease of naïve CD4 and CD8 T cells (ii) increase in CD16-expressing monocytes (iii) increase in frequency of mature NK cells. On the other hand, diabetic and pre-diabetic individuals displayed further reduced naïve/memory ratio (define with CD27 and CD45RO). Similarly to the observation on inflammation diabetic individuals taking metformin have closer immune cell signature of healthy old individuals. To have insight into the pro/anti-inflammatory capacity of immune cells, their activation revealed that healthy old individuals had a higher level of both pro-inflammatory molecules like TNF, IL-6 and antiinflammatory molecule like IL-10 compared to young individuals. Lastly we asses the effect of metformin on chronic inflammation and its potential immunomodulatory role in vitro using PBMCs and in vivo in mice.

• Publisher: ProQuest Dissertations & Theses
• Subject: Aging / Biochemistry / Chemistry / DNA methylation / Gerontology / Mortality / Older people / Tumor necrosis factor-TNF
• ISBN: 9798352683859