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

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Alpha-1 Antitrypsin Deficiency and Accelerated Aging : A New Model for an Old Disease? / Crossley, Diana; Stockley, Robert; Sapey, Elizabeth.

In: Drugs and Aging, Vol. 36, No. 9, 01.09.2019, p. 823-840.

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@article{51ab3f7c48294630a8d104b3ab10d135,
title = "Alpha-1 Antitrypsin Deficiency and Accelerated Aging: A New Model for an Old Disease?",
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.",
author = "Diana Crossley and Robert Stockley and Elizabeth Sapey",
note = "Publisher Copyright: {\textcopyright} 2019, Springer Nature Switzerland AG. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",
year = "2019",
month = sep,
day = "1",
doi = "10.1007/s40266-019-00684-7",
language = "English",
volume = "36",
pages = "823--840",
journal = "Drugs and Aging",
issn = "1170-229X",
publisher = "Springer",
number = "9",

}

RIS

TY - JOUR

T1 - Alpha-1 Antitrypsin Deficiency and Accelerated Aging

T2 - A New Model for an Old Disease?

AU - Crossley, Diana

AU - Stockley, Robert

AU - Sapey, Elizabeth

N1 - Publisher Copyright: © 2019, Springer Nature Switzerland AG. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2019/9/1

Y1 - 2019/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85067294589&partnerID=8YFLogxK

U2 - 10.1007/s40266-019-00684-7

DO - 10.1007/s40266-019-00684-7

M3 - Review article

C2 - 31179525

AN - SCOPUS:85067294589

VL - 36

SP - 823

EP - 840

JO - Drugs and Aging

JF - Drugs and Aging

SN - 1170-229X

IS - 9

ER -