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Alpha-1 Antitrypsin Deficiency and Accelerated Aging: A New Model for an Old Disease?

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Abstract

Alpha-1 antitrypsin (AAT) protects the lung by inhibiting neutrophil proteinases, but AAT has many other non-proteolytic functions that are anti-inflammatory, antiviral and homeostatic. Approximately 1 in 1600 to 1 in 5000 people have the homozygous Z mutation, which causes AAT misfolding, accumulation in (predominantly) liver cells and low circulating levels of AAT, leading to AAT deficiency (AATD). AATD is classically a disease of neutrophilic inflammation, with an aggressive and damaging innate immune response contributing to emphysema and other pathologies. AATD is one of the most common genetic disorders but considerably under-recognised. Most patients are diagnosed later in life, by which time they may have accumulated significant lung, liver and multisystem damage. Disease presentation is heterogeneous and not fully explained by deficiency levels alone or exposure to cigarette smoking. This suggests other factors influence AATD-associated pathological processes. Aging itself is associated with organ dysfunction, including emphysema and airflow obstruction, inflammation, altered immune cell responses (termed immunosenescence) and a loss of proteostasis. Many of these processes are present in AATD but at an earlier age and more advanced stage compared with chronological aging alone. Augmentation therapy does not completely abrogate the manifold disease processes present in AATD. New approaches are needed. There is emerging evidence that both age- and AATD-related disease processes are amenable to correction by targeting proteostasis, autophagy, immunosenescence and epigenetic factors. This review explores the impact of the aging process on AATD presentation and discusses novel therapeutic strategies to mitigate low levels of AAT or misfolded AAT in an aging host.

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  1. Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Edgbaston, Birmingham, B15 2GW, UK

    Diana Crossley, Robert Stockley & Elizabeth Sapey

  2. Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, Queen Elizabeth Hospital, Mindelsohn Way, Edgbaston, Birmingham, B15 2GW, UK

    Elizabeth Sapey

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Crossley, D., Stockley, R. & Sapey, E. Alpha-1 Antitrypsin Deficiency and Accelerated Aging: A New Model for an Old Disease?. Drugs Aging 36, 823–840 (2019). https://doi.org/10.1007/s40266-019-00684-7

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