Sergiy Libert

SIRT1 activates MAO-A in the brain to mediate anxiety and exploratory drive.

SIRT1 is a NAD(+)-dependent deacetylase that governs a number of genetic programs to cope with changes in the nutritional status of cells and organisms. Behavioral responses to food abundance are important for the survival of higher animals. Here we used mice with increased or decreased brain SIRT1 to show that this sirtuin regulates anxiety and exploratory drive by activating transcription of the gene encoding the monoamine oxidase A (MAO-A) to reduce serotonin levels in the brain. Indeed, treating animals with MAO-A inhibitors or selective serotonin reuptake inhibitors (SSRIs) normalized anxiety differences between wild-type and mutant animals. SIRT1 deacetylates the brain-specific helix-loop-helix transcription factor NHLH2 on lysine 49 to increase its activation of the MAO-A promoter. Both common and rare variations in the SIRT1 gene were shown to be associated with risk of anxiety in human population samples. Together these data indicate that SIRT1 mediates levels of anxiety, and this regulation may be adaptive in a changing environment of food availability.

Metabolic and neuropsychiatric effects of calorie restriction and sirtuins.

Most living organisms, including humans, age. Over time the ability to do physical and intellectual work deteriorates, and susceptibility to infectious, metabolic, and neurodegenerative diseases increases, which leads to general fitness decline and ultimately to death. Work in model organisms has demonstrated that genetic and environmental manipulations can prevent numerous age-associated diseases, improve health at advanced age, and increase life span. Calorie restriction (CR) (consumption of a diet with fewer calories but containing all the essential nutrients) is the most robust manipulation, genetic or environmental, to extend longevity and improve health parameters in laboratory animals. However, outside of the protected laboratory environment, the effects of CR are much less certain. Understanding the molecular mechanisms of CR may lead to the development of novel therapies to combat diseases of aging and to improve the quality of life. Sirtuins, a family of NAD(+)-dependent enzymes, mediate a number of metabolic and behavioral responses to CR and are intriguing targets for pharmaceutical interventions. We review the molecular understanding of CR; the role of sirtuins in CR; and the effects of sirtuins on physiology, mood, and behavior.

Neurogenesis directed by Sirt1

Differentiation of neuronal stem cells into astrocytes or neurons is important in maintaining brain function. Oxidative stress and inflammation are now shown to bias differentiation toward astrocytes by modulating activity of the anti-ageing gene Sirt1. These findings link a longevity gene to the activity of neuronal stem cells and their response to stress.

Deviation of innate circadian period from 24 h reduces longevity in mice

The variation of individual life spans, even in highly inbred cohorts of animals and under strictly controlled environmental conditions, is substantial and not well understood. This variation in part could be due to epigenetic variation, which later affects the animal’s physiology and ultimately longevity. Identification of the physiological properties that impact health and life span is crucial for longevity research and the development of anti‐aging therapies. Here, we measured individual circadian and metabolic characteristics in a cohort of inbred F1 hybrid mice and correlated these parameters to their life spans. We found that mice with innate circadian periods close to 24 h (revealed during 30 days of housing in total darkness) enjoyed nearly 20% longer life spans than their littermates, which had shorter or longer innate circadian periods. These findings show that maintenance of a 24‐h intrinsic circadian period is a positive predictor of longevity. Our data suggest that circadian period may be used to predict individual longevity and that processes that control innate circadian period affect aging.

Lattice percolation approach to numerical modelling of tissue aging

We describe a percolation-type approach to modelling of the processes of aging and certain other properties of tissues analysed as systems consisting of interacting cells. Tissues are considered as structures made of regular healthy, senescent, dead (apoptotic) cells, and studied dynamically with the ongoing processes including regular cell division to fill vacant sites left by dead cells, healthy cells becoming senescent or dying, and other processes. Statistical-mechanics description can provide patterns of time dependence and snapshots of morphological system properties. An illustrative application of the developed theoretical modelling approach is reported, confirming recent experimental findings that inhibition of senescence can lead to extended lifespan.

Insights into Physiology of Aging and Novel Ways to Increase Lifespan

The vital instinct of self preservation governs the very existence of organisms including Homo sapiens species. The desire to exist elucidates itself in the innate wish of humanity to delay or eliminate aging, age associated deterioration and subsequent death. The searches for some form of the “fountain of youth” are plentifully presented in all the cultures of the world. In the modern world of biotechnology the search continues, now for a “gene”, which would provide us with the answer to aging. Drosophila melanogaster is an excellent model organism to study aging. Fruit flies have high degree of conservation of molecular mechanism with those of mammals, powerful genetics and a short lifespan. 48th Annual Drosophila Research Conference in Philadelphia, Pennsylvania had a separate session devoted to the physiology of aging, which consisted of eight platform talks and over 40 poster presentations. This report provides critical analysis of the work presented. Briefly, the idea that adipose tissue plays a central role in longevity determination becomes more accepted and the pathways that control adiposity are being investigated. The mechanisms by which suppression of insulin/TOR signaling are able to extend longevity continues to be the most abundant direction. Dilp3 (Drosophila insulin like peptide 3) might be the longevity determining insulin. The proposed role of immune and sensory systems in longevity determination is being supported. Neuronal degeneration is suggested to be the cause of death of old flies.

MTCH2 is a conserved regulator of lipid homeostasis.

More than one‐third of U.S. adults have obesity, causing an alarming increase in obesity‐related comorbidities such as type 2 diabetes. The functional role of mitochondrial carrier homolog 2 (MTCH2), a human obesity‐associated gene, in lipid homeostasis was investigated in Caenorhabditis elegans, cell culture, and mice.

SIRT6 knockout cells resist apoptosis initiation but not progression: a computational method to evaluate the progression of apoptosis

Apoptosis is essential for numerous processes, such as development, resistance to infections, and suppression of tumorigenesis. Here, we investigate the influence of the nutrient sensing and longevity-assuring enzyme SIRT6 on the dynamics of apoptosis triggered by serum starvation. Specifically, we characterize the progression of apoptosis in wild type and SIRT6 deficient mouse embryonic fibroblasts using time-lapse flow cytometry and computational modelling based on rate-equations and cell distribution analysis. We find that SIRT6 deficient cells resist apoptosis by delaying its initiation. Interestingly, once apoptosis is initiated, the rate of its progression is higher in SIRT6 null cells compared to identically cultured wild type cells. However, SIRT6 null cells succumb to apoptosis more slowly, not only in response to nutrient deprivation but also in response to other stresses. Our data suggest that SIRT6 plays a role in several distinct steps of apoptosis. Overall, we demonstrate the utility of our computational model to describe stages of apoptosis progression and the integrity of the cellular membrane. Such measurements will be useful in a broad range of biological applications.