The effect of Plasmodium infection on cellular aging in humans

Abstract

Telomeres play an essential role in maintaining chromosomal integrity and stability. Telomere shortening is part of the natural aging process, nevertheless, accelerated telomere shortening has been linked to chronic diseases and premature aging. Recently, malaria infections have been found to affect cellular aging and lifespan in birds, and telomere shortening was detected in travellers treated for malaria. The aim of this thesis was to study the effect of single and repeated malaria infections on cellular aging in humans, and to explore potential mechanisms underlying telomere attrition during infection.

Within a closely monitored controlled human malaria infection (CHMI) study, we detected that Plasmodium falciparum parasiteamia resulted in accelerated TL in peripheral blood, which was fully reversed after treatment and parasite clearance. Moreover, we found a correlation between TL and CDKN2A, a marker of cellular senescence, and identified increased cytokine production and low expression levels of antioxidant enzymes as potential drivers of accelerated telomere shortening during infection.

We further evaluated whether infection driven telomere attrition is synchronized across immune cell-subtypes, or if it is rather cell-type specific. By assessing TL dynamics in peripheral blood mononuclear cells (PBMC) of travellers with acute malaria, we found that TL is largely synchronized across cell types, nevertheless, we identified cell-type specific differences during the course of malaria infection that are likely to reflect the host immune reaction.

Next, we investigated the impact of repeated clinical episodes of malaria and asymptomatic carriage of parasites on telomere dynamics in naturally exposed individuals, living in malaria endemic areas. Studying children with different malaria exposure in Kenya, we did not find evidence of that repeated Plasmodium infections in children impact cellar aging by accelerating telomere shortening, however, asymptomatic Plasmodium infection seem to have a slightly positive effect on TL, which requires further studies to provide a comprehensive explanation, in particular the study of TL during immune reactions.

Finally, we explored telomere dynamics in all aged individuals in a longitudinal followed population cohort in Tanzania over a period of three decades. The study provides detailed information on age and sex specific changes in telomere length, revealing that the sex-difference with females having longer TL than males emerges during adolescence and remains throughout life.

Together, this thesis adds fundamental knowledge to the relationship of malaria infection and cellular aging in humans. The work contributes to the expanding field of aging biology by showing a transient effect of acute infection on TL, while identifying inflammation and oxidative stress as contributing mechanisms, and further provides age and sex-specific characteristics of telomere dynamics during different life stages. Future studies are needed in endemic areas to further investigate potential long-term consequences of infectious diseases on aging.