Cellular immunometabolism and regulation of mitochondrial efficiency – healthy ageing across the life course

Abstract

As part of an ageing society understanding the science behind the ageing process is paramount in lightening the burden of age-related diseases such as cancer, diabetes and cardiovascular disease.
Extending the number of years lived disease-free is of great importance in alleviating the detrimental effect ageing populations have on the medical and social sectors. Mitochondria are referred to as the powerhouse of the cell, providing energy and controlling metabolism for normal cellular function. However, mitochondrial dysfunction throughout the ageing process has been highlighted as one of the hallmarks of ageing, alongside senescence of the immune system. The aim of this study was to analyse mitochondrial dysfunction and metabolic efficiency in the context of ageing using both murine and human models of ageing. The murine models used within the study have previously been observed to have shortened lifespan due to low-grade chronic inflammation and senescence. For the human models, naïve T cells and senescent terminal effector T cells as well as peripheral blood from individuals partaking in the Singapore Longitudinal Ageing Study were analysed. This study utilised several methods to analyse metabolism and mitochondrial structure of immune cells, including advanced microscopy techniques, flow cytometry, cell sorting and livecell metabolic analysis. This study established a variety of parameters contributing to mitochondrial dysfunction in each of the models tested. Mice with low-grade chronic inflammation showed reduced flexibility of mitochondrial structure in the bone marrow compared to wild-type mice alongside alterations in immune cell compartmentalisation in the spleen associated with a reduction in mitochondrial membrane potential of these cells, a marker of mitochondrial function.
Mice with increased levels of senescence showed a similar phenomenon of reduced mitochondrial membrane potential as well as reductions in mitochondrial mass. These changes affected both the innate and adaptive arms of the immune system in these mice. In humans, measuring mitochondrial parameters associated with the development of senescence in CD4+ T cell populations, increased mitochondrial membrane potential was identified with the formation of memory which was reduced in senescent cells. Despite conservation of some glucose transporter proteins, alterations in the control of mitochondrial network dynamics were observed resulting in decreased optic atrophy 1 (Opa1) expression following the formation of memory which was further reduced upon senescence. Finally, comparison of peripheral blood cell metabolism between young and old individuals revealed a reduction in maximal respiration rate with age in humans. This effect did not result in alterations in adenosine triphosphate production as increased glucose uptake was observed in peripheral blood cells with age. Subsequent analysis of resident immune cells populations revealed an age-associated increase in mitochondrial mass in both innate and adaptive immune cells. Taken together these results point towards mitochondrial dysfunction. In conclusion, mitochondrial dysfunction in ageing was attributed to alterations in mitochondrial mass and membrane potential as well as Opa1 expression within the models used for this study. Therefore, it is proposed that mitochondrial dysfunction is involved in the ageing process of mice and humans and excessive mitochondrial dysfunction is associated with shortened lifespan.

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Identifiers

ORCID for Sylvia Pender: orcid.org/0000-0001-6332-0333

ORCID for Peter Smith: orcid.org/0000-0003-4400-6853

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