Sirtuins in Cognitive Ageing and Alzheimer's Disease
Sirtuins in Cognitive Ageing and Alzheimer's Disease
Purpose of review Sirtuins are a family of enzymes highly conserved in evolution and involved in mechanisms known to promote healthy ageing and longevity. This review aims to discuss recent advances in understanding the role of sirtuins, in particular mammalian SIRT1, in promoting longevity and its potential molecular basis for neuroprotection against cognitive ageing and Alzheimer's disease pathology.
Recent findings Accumulative increase in oxidative stress during ageing has been shown to decrease SIRT1 activity in catabolic tissue, possibly by direct inactivation by reactive oxygen. SIRT1 overexpression prevents oxidative stress-induced apoptosis and increases resistance to oxidative stress through regulation of the FOXO family of forkhead transcription factors. In addition, resveratrol strongly stimulates SIRT1 deacetylase activity in a dose-dependent manner by increasing its binding affinity to both the acetylated substrate and NAD. Recently, SIRT1 has been shown to affect amyloid production through its influence over the ADAM10 gene. Upregulation of SIRT1 can also induce the Notch pathway and inhibit mTOR signalling.
Summary Recent studies have revealed some of the mechanisms and pathways that are associated with the neuroprotective effects of SIRT1.
Ageing involves a progressive, time-dependent reduction in biochemical and physiological function that leads to an increased risk of transience and death. The accumulation of reactive oxygen species (ROS) over several years is thought to play a key role in substantially facilitating the ageing process. ROS, such as hydroxyl radicals (HO), superoxide anions (O2) and hydrogen peroxide (H2O2), are produced as unwanted by-products of normal cellular respiration. Although endogenous antioxidants such as superoxide dismutase (SOD), catalase, peroxidases and nonprotein molecules [e.g. vitamin C and E, uric acid and glutathione (GSH)] act as defence against these free radicals, a small percentage of ROS generated can escape the electron transport chain and cause havoc in the mitochondria, resulting in damage to important macromolecules, including the lipid membrane bilayer, intracellular protein, DNA and RNA, which become dysfunctional. The unsequestered build-up of ROS within the mitochondria can trigger numerous deleterious processes, such as the release of cytochrome c and the activation of caspases. These apoptotic proteins can activate additional degradative enzymes such as DNases, which cleave nuclear DNA.
The brain, which comprises 2–3% of the body weight but accounts for 20–25% of the body's O2 consumption, generates the highest levels of ROS of any body organ. It is therefore likely that age-related brain changes are greatly influenced by the build-up of ROS. Brain metabolism is reduced in physiological ageing, and this may also be associated with decreased metabolic regulation and increased ROS levels. All theories regarding the cause and pathogenesis of Alzheimer's disease also take into account ageing as the key risk factor of Alzheimer's disease, highlighting the importance of this mechanism in Alzheimer's disease. A better understanding of the modifiers of the oxidative stress mechanisms is therefore crucial in the fight against cognitive decline with ageing and the development of Alzheimer's disease.
Renewed evidence has shown that the neuroprotective effects of sirtuins may be closely associated with their catalytic ability to regulate numerous biological systems that can modulate the cellular response to enhanced ROS production. The beneficial effects of sirtuins as longevity assurance factors is related to their activity as mediators of several calorie restriction pathways aimed at slowing the rate of free radical generation.
Abstract and Introduction
Abstract
Purpose of review Sirtuins are a family of enzymes highly conserved in evolution and involved in mechanisms known to promote healthy ageing and longevity. This review aims to discuss recent advances in understanding the role of sirtuins, in particular mammalian SIRT1, in promoting longevity and its potential molecular basis for neuroprotection against cognitive ageing and Alzheimer's disease pathology.
Recent findings Accumulative increase in oxidative stress during ageing has been shown to decrease SIRT1 activity in catabolic tissue, possibly by direct inactivation by reactive oxygen. SIRT1 overexpression prevents oxidative stress-induced apoptosis and increases resistance to oxidative stress through regulation of the FOXO family of forkhead transcription factors. In addition, resveratrol strongly stimulates SIRT1 deacetylase activity in a dose-dependent manner by increasing its binding affinity to both the acetylated substrate and NAD. Recently, SIRT1 has been shown to affect amyloid production through its influence over the ADAM10 gene. Upregulation of SIRT1 can also induce the Notch pathway and inhibit mTOR signalling.
Summary Recent studies have revealed some of the mechanisms and pathways that are associated with the neuroprotective effects of SIRT1.
Introduction
Ageing involves a progressive, time-dependent reduction in biochemical and physiological function that leads to an increased risk of transience and death. The accumulation of reactive oxygen species (ROS) over several years is thought to play a key role in substantially facilitating the ageing process. ROS, such as hydroxyl radicals (HO), superoxide anions (O2) and hydrogen peroxide (H2O2), are produced as unwanted by-products of normal cellular respiration. Although endogenous antioxidants such as superoxide dismutase (SOD), catalase, peroxidases and nonprotein molecules [e.g. vitamin C and E, uric acid and glutathione (GSH)] act as defence against these free radicals, a small percentage of ROS generated can escape the electron transport chain and cause havoc in the mitochondria, resulting in damage to important macromolecules, including the lipid membrane bilayer, intracellular protein, DNA and RNA, which become dysfunctional. The unsequestered build-up of ROS within the mitochondria can trigger numerous deleterious processes, such as the release of cytochrome c and the activation of caspases. These apoptotic proteins can activate additional degradative enzymes such as DNases, which cleave nuclear DNA.
The brain, which comprises 2–3% of the body weight but accounts for 20–25% of the body's O2 consumption, generates the highest levels of ROS of any body organ. It is therefore likely that age-related brain changes are greatly influenced by the build-up of ROS. Brain metabolism is reduced in physiological ageing, and this may also be associated with decreased metabolic regulation and increased ROS levels. All theories regarding the cause and pathogenesis of Alzheimer's disease also take into account ageing as the key risk factor of Alzheimer's disease, highlighting the importance of this mechanism in Alzheimer's disease. A better understanding of the modifiers of the oxidative stress mechanisms is therefore crucial in the fight against cognitive decline with ageing and the development of Alzheimer's disease.
Renewed evidence has shown that the neuroprotective effects of sirtuins may be closely associated with their catalytic ability to regulate numerous biological systems that can modulate the cellular response to enhanced ROS production. The beneficial effects of sirtuins as longevity assurance factors is related to their activity as mediators of several calorie restriction pathways aimed at slowing the rate of free radical generation.
