Sirtuins are a conserved family of proteins found in all domains of life. The first known sirtuin, Sir2 (silent information regulator 2) of Saccharomyces cerevisiae, from which the family derives its name, regulates ribosomal DNA recombination, gene silencing, DNA repair, chromosomal stability and longevity. Sir2 homologues also modulate lifespan in worms and flies, and may underlie the beneficial effects of caloric restriction, the only regimen that slows aging and extends lifespan of most classes of organism, including mammals. Sirtuins have gained considerable attention for their impact on mammalian physiology, since they may provide novel targets for treating diseases associated with aging and perhaps extend human lifespan. In this review we describe our current understanding of the biological function of the seven mammalian sirtuins, SIRT1-7, and we will also discuss their potential as mediators of caloric restriction and as pharmacological targets to delay and treat human age-related diseases.

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Sirtuins in mammals: insights into their biological function

Neurodegenerative diseases of the central nervous system are often associated with impaired learning and memory, eventually leading to dementia An important aspect in pre-clinical research is the exploration of strategies to re-establish learning ability and access to long-term memories By using a mouse model that allows temporally and spatially restricted induction of neuronal loss, we show here that environmental enrichment reinstated learning behaviour and re-established access to long-term memories after significant brain atrophy and neuronal loss had already occurred Environmental enrichment correlated with chromatin modifications (increased histone-tail acetylation) Moreover, increased histone acetylation by inhibitors of histone deacetylases induced sprouting of dendrites, an increased number of synapses, and reinstated learning behaviour and access to long-term memories These data suggest that inhibition of histone deacetylases might be a suitable therapeutic avenue for neurodegenerative diseases associated with learning and memory impairment, and raises the possibility of recovery of long-term memories in patients with dementia

Recovery of learning and memory is associated with chromatin remodelling

A progressive loss of neurons with age underlies a variety of debilitating neurological disorders, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), yet few effective treatments are currently available. The SIR2 gene promotes longevity in a variety of organisms and may underlie the health benefits of caloric restriction, a diet that delays aging and neurodegeneration in mammals. Here, we report that a human homologue of SIR2, SIRT1, is upregulated in mouse models for AD, ALS and in primary neurons challenged with neurotoxic insults. In cell-based models for AD/tauopathies and ALS, SIRT1 and resveratrol, a SIRT1-activating molecule, both promote neuronal survival. In the inducible p25 transgenic mouse, a model of AD and tauopathies, resveratrol reduced neurodegeneration in the hippocampus, prevented learning impairment, and decreased the acetylation of the known SIRT1 substrates PGC-1alpha and p53. Furthermore, injection of SIRT1 lentivirus in the hippocampus of p25 transgenic mice conferred significant protection against neurodegeneration. Thus, SIRT1 constitutes a unique molecular link between aging and human neurodegenerative disorders and provides a promising avenue for therapeutic intervention.

/pdf/sirt1-deacetylase-protects-against-neurodegeneration-in-4gvo25vxzt.pdf

SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis.

Tau pathology in Alzheimer disease and other tauopathies

Excitotoxicity and stroke: identifying novel targets for neuroprotection.

https://www.cell.com/neuron/pdf/S0896-6273(03)00627-5.pdf

Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles

Disclosed are improved methods of treating individuals with Alzheimer's disease (AD) as well as methods to diagnose AD in an individual. Also included are compounds and methods of identifying compounds to treat AD. The present invention also discloses methods for decreasing the phosphorylation of amyloid precursor protein (APP), including inhibiting phosphorylation of amino acid residue tyrosine 668 of APP and for reducing cleavage of APP. The present invention further discloses transgenic (Tg), non-human animals and cells expressing a p25 transgene that are models of neurodegenerative diseases. Embodiments of the present invention are directed to methods wherein the Tg animals and Tg cells of the invention are used to screen for modulators of neurodegenerative disorders. The Tg animals and cells of the present invention are useful for elucidating the mechanisms of neurodegenerative disorders.

Compounds and methods for treating neurodegenerative disorders

The limited onboard energy of autonomous mobile robots poses a tremendous challenge for practical deployment. Hence, efficient computing solutions are imperative. A crucial shortcoming of state-of-the-art computing solutions is that they ignore the robot’s operating environment heterogeneity and make static, worst-case assumptions. As this heterogeneity impacts the system’s computing payload, an optimal system must dynamically capture these changes in the environment and adjust its computational resources accordingly. This paper introduces RoboRun, a mobile-robot runtime that dynamically exploits the compute-environment synergy to improve performance and energy. We implement RoboRun in the Robot Operating System (ROS) and evaluate it on autonomous drones. We compare RoboRun against a state-of-the-art static design and show 4.5X and 4X improvements in mission time and energy, respectively, as well as a 36% reduction in CPU utilization.

RoboRun: A Robot Runtime to Exploit Spatial Heterogeneity

Transgenic mice expressing inducible human p25

The limited onboard energy of autonomous mobile robots poses a tremendous challenge for practical deployment. Hence, efficient computing solutions are imperative. A crucial shortcoming of state-of-the-art computing solutions is that they ignore the robot's operating environment heterogeneity and make static, worst-case assumptions. As this heterogeneity impacts the system's computing payload, an optimal system must dynamically capture these changes in the environment and adjust its computational resources accordingly. This paper introduces RoboRun, a mobile-robot runtime that dynamically exploits the compute-environment synergy to improve performance and energy. We implement RoboRun in the Robot Operating System (ROS) and evaluate it on autonomous drones. We compare RoboRun against a state-of-the-art static design and show 4.5X and 4X improvements in mission time and energy, respectively, as well as a 36% reduction in CPU utilization.

Jonathan Cruz

Papers

Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles

Compounds and methods for treating neurodegenerative disorders

RoboRun: A Robot Runtime to Exploit Spatial Heterogeneity

Transgenic mice expressing inducible human p25

RoboRun: A Robot Runtime to Exploit Spatial Heterogeneity