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Abstract
Carbonic anhydrase inhibitors are used to treat glaucoma and cancers. Carbonic anhydrases perform a crucial role in the conversion of carbon dioxide and water into bicarbonate and protons. However, there is little information about carbonic anhydrase isoforms during the process of ageing. Mitochondrial dysfunction is implicit in ageing brain and muscle. We have interrogated isolated mitochondrial fractions from young adult and middle aged mouse brain and skeletal muscle. We find an increase of tissue specific carbonic anhydrases in mitochondria from middle-aged brain and skeletal muscle. Mitochondrial carbonic anhydrase II was measured in the Purkinje cell degeneration (pcd5J) mouse model. In pcd5J we find mitochondrial carbonic anhydrase II is also elevated in brain from young adults undergoing a process of neurodegeneration. We show C.elegans exposed to carbonic anhydrase II have a dose related shorter lifespan suggesting that high CAII levels are in themselves life limiting. We show for the first time that the mitochondrial content of brain and skeletal tissue are exposed to significantly higher levels of active carbonic anhydrases as early as in middle-age. Carbonic anhydrases associated with mitochondria could be targeted to specifically modulate age related impairments and disease.
Highlights
Brain ageing is associated with cognitive decline and neurodegeneration
Mitochondria accumulate perinuclearly and are regulators of calcium signalling providing more evidence that the upregulation in calsequestrin that we observe is protective in ageing skeletal muscle [18]
We suggest that the action of dorzolamide hydrochloride in glaucoma should be analysed for its likely effect on the raised CAII levels we find in ageing retinal mitochondria
Summary
Brain ageing is associated with cognitive decline and neurodegeneration. Normal ageing often leads to levels of decline in cognition, with estimates of a fifth of people over 71 affected by impairment that is not classed as dementia [1]. Loss of mitochondrial functionality is implicated as a key factor leading to age related decline and the development of many neurodegenerative diseases. Increasing our understanding of the changes that occur in the normal process of ageing is crucial to help distinguish between the biological features of disease and that of ageing itself. ROS are unlikely to be the only factors contributing to age-related mitochondrial dysfunction. An understanding of how mitowww.aging‐us.com chondrial composition changes with age can shed light on the mechanisms affecting these organelles throughout the lifetime of mammals. A complication, when looking at diseases of ageing, is the inability to separate the effect of normal ageing from diseaserelated changes in the mitochondrion, for example in Parkinson’s disease where mitochondrial changes are clearly important, yet not always distinguishable from the effects of ageing [5, 8]
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