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Angiotensin-converting enzyme gene variants are associated with both cortisol secretion and late-life depression.

ABSTRACT: Angiotensin-converting enzyme (ACE) is assumed to influence the activity of the hypothalamic-pituitary-adrenocortical (HPA) axis, which shows hyperactivity in depressed patients. ACE could thus be a promising candidate gene for late-life depression but this has not been examined previously. Depression was assessed in 1005 persons aged at least 65 years, at baseline and over the 10-year follow-up. A clinical level of depression (DEP) was defined as having a score of > or =16 on the Centre for Epidemiology Studies-Depression scale or a diagnosis of current major depression based on the Mini International Neuropsychiatric Interview and according to DSM-IV criteria. Seven single-nucleotide polymorphisms (SNPs) in the ACE gene were genotyped and diurnal cortisol secretion, as an index of HPA axis activity, was measured. Multivariable analyses were adjusted for socio-demographic and vascular factors, cognitive impairment, and apolipoprotein E. Strong significant associations were found between all seven SNPs and DEP and, in particular, first-onset DEP in persons without a past history of depression (P-values ranging from 0.005 to 0.0004). These associations remained significant after correction for multiple testing. The genotypes that were associated with an increased risk of DEP were also significantly associated with an increase in cortisol secretion under stress conditions. Variants of the ACE gene influence cortisol secretion and appear as susceptibility factors for late-life depression in the elderly population. Whether this could represent a common pathophysiological mechanism linking HPA axis and late-life depression remains to be explored.

SUBMITTER: Ancelin ML

PROVIDER: S-EPMC3849962 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Angiotensin-converting enzyme gene variants are associated with both cortisol secretion and late-life depression.

Ancelin M L ML Carrière I I Scali J J Ritchie K K Chaudieu I I Ryan J J

Translational psychiatry 20131105

Angiotensin-converting enzyme (ACE) is assumed to influence the activity of the hypothalamic-pituitary-adrenocortical (HPA) axis, which shows hyperactivity in depressed patients. ACE could thus be a promising candidate gene for late-life depression but this has not been examined previously. Depression was assessed in 1005 persons aged at least 65 years, at baseline and over the 10-year follow-up. A clinical level of depression (DEP) was defined as having a score of > or =16 on the Centre for Epi ...[more]

PMID: 24193727

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Project description:Animal aging is characterized by progressive, degenerative changes in many organ systems. Because age-related degeneration is a major contributor to disability and death in humans, treatments that delay age-related degeneration are desirable. However, no drugs that delay normal human aging are currently available. To identify drugs that delay age-related degeneration, we used the powerful Caenorhabditis elegans model system to screen for FDA-approved drugs that can extend the adult lifespan of worms. Here we show that captopril extended mean lifespan. Captopril is an angiotensin-converting enzyme (ACE) inhibitor used to treat high blood pressure in humans. To explore the mechanism of captopril, we analyzed the acn-1 gene that encodes the C. elegans homolog of ACE. Reducing the activity of acn-1 extended the mean life span. Furthermore, reducing the activity of acn-1 delayed age-related degenerative changes and increased stress resistance, indicating that acn-1 influences aging. Captopril could not further extend the lifespan of animals with reduced acn-1, suggesting they function in the same pathway; we propose that captopril inhibits acn-1 to extend lifespan. To define the relationship with previously characterized longevity pathways, we analyzed mutant animals. The lifespan extension caused by reducing the activity of acn-1 was additive with caloric restriction and mitochondrial insufficiency, and did not require sir-2.1, hsf-1 or rict-1, suggesting that acn-1 functions by a distinct mechanism. The interactions with the insulin/IGF-1 pathway were complex, since the lifespan extensions caused by captopril and reducing acn-1 activity were additive with daf-2 and age-1 but required daf-16. Captopril treatment and reducing acn-1 activity caused similar effects in a wide range of genetic backgrounds, consistent with the model that they act by the same mechanism. These results identify a new drug and a new gene that can extend the lifespan of worms and suggest new therapeutic strategies for addressing age-related degenerative changes.

Dataset Information

Angiotensin-converting enzyme gene variants are associated with both cortisol secretion and late-life depression.

Publications

Angiotensin-converting enzyme gene variants are associated with both cortisol secretion and late-life depression.

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