The Mechanism of Programmed Aging: The Way to Create a Real Remedy for Senescence.

BACKGROUND: Accumulation of various damages is considered the primary cause of aging throughout the history of gerontology. No progress has been made in extending animal lifespan under the guidance of this concept. This concept denies the existence of longevity genes, but it has been experimentally shown that manipulating genes that affect cell division rates can increase the maximum lifespan of animals. These methods of prolonging life are unsuitable for humans because of dangerous side effects, but they undoubtedly indicate the programmed nature of aging. OBJECTIVE: The objective was to understand the mechanism of programmed aging to determine how to solve the problem of longevity. METHODS: Fundamental research has already explored key details relating to the mechanism of programmed aging, but they are scattered across different fields of knowledge. The way was to recognize and combine them into a uniform mechanism. RESULTS: Only a decrease in bioenergetics is under direct genetic control. This causes many different harmful processes that serve as the execution mechanism of the aging program. The aging rate and, therefore, lifespan are determined by the rate of cell proliferation and the magnitude of the decrease in bioenergetics per cell division in critical tissues. CONCLUSION: The mechanism of programmed aging points the way to achieving an unlimited healthy life; it is necessary to develop a means for managing bioenergetics. It has already been substantially studied by molecular biologists and is now waiting for researchers from gerontology.

Evaluation of the Droplet-Microarray Platform for High-Throughput Screening of Suspension Cells.

Phenotypic cell-based high-throughput screenings play a central role in drug discovery and toxicology. The main tendency in cell screenings is the increase of the throughput and decrease of reaction volume in order to accelerate the experiments, reduce the costs, and enable screenings of rare cells. Conventionally, cell-based assays are performed in microtiter plates, which exist in 96- to 1536-wells formats and cannot be further miniaturized. In addition, performing screenings of suspension cells is associated with risk of losing cell content during the staining procedures and incompatibility with high-content microscopy. Here, we evaluate the Droplet-Microarray screening platform for culturing, screening, and imaging of suspension cells. We demonstrate pipetting-free cell seeding and proliferation of cells in individual droplets of 3-80 nL in volume. We developed a methodology to perform parallel treatment, staining, and fixation of suspension cells in individual droplets. Automated imaging of live suspension cells directly in the droplets combined with algorithms for pattern recognition for image analysis is demonstrated. We evaluated the developed methodology by performing a dose-response study with antineoplastic drugs. We believe that the DMA screening platform carries great potential to be adopted for broad spectrum of screenings of suspension cells.

Reprogramming of energy metabolism as a driver of aging.

Aging is characterized by progressive loss of cellular function and integrity. It has been thought to be driven by stochastic molecular damage. However, genetic and environmental maneuvers enhancing mitochondrial function or inhibiting glycolysis extend lifespan and promote healthy aging in many species. In post-fertile Caenorhabditis elegans, a progressive decline in phosphoenolpyruvate carboxykinase with age, and a reciprocal increase in pyruvate kinase shunt energy metabolism from oxidative metabolism to anaerobic glycolysis. This reduces the efficiency and total of energy generation. As a result, energy-dependent physical activity and other cellular functions decrease due to unmatched energy demand and supply. In return, decrease in physical activity accelerates this metabolic shift, forming a vicious cycle. This metabolic event is a determinant of aging, and is retarded by caloric restriction to counteract aging. In this review, we summarize these and other evidence supporting the idea that metabolic reprogramming is a driver of aging. We also suggest strategies to test this hypothesis.

The Lag of the Proliferative Aging Clock Underlies the Lifespan-Extending Effect of Calorie Restriction.

BACKGROUND: The nature of the life-extending effect of calorie restriction (CR) is an unsolved problem in biology since 30 years of the last century. Furthermore, many different factors that cause analogous life-extending effect, so called CR-mimetic factors, have been found. They increase the lifespan of different animal species (repeatedly in invertebrates) and therefore remain in the forefront of anti-aging researches. The aims of this paper is to find an overarching solution for the nature of CR and all CR-mimetic factors and to analyze the consequences following this phenomenon. METHODS: The analysis of empirical scientific data, which concern aging process and boundary areas from the point of view of the bioenergetics theory of aging. RESULTS: "Anything that affects a living system that slows (accelerates) the rate of cell division entails extending (reducing) life duration" is this overarching solution. CR is one of such factors that cause a retardation in the rate of cell divisions due to the shortage in 'construction materials' necessary for doubling cell mass during reduplication. This put a brake on realization of the aging program. To draw this conclusion, a new concept of the proliferative aging clock based on bioenergetics theory of aging was put forward. This clock governs the rate of the aging process via programmed, proliferative dependent and stepwise bioenergetics decline. CONCLUSION: The mechanism of the life-extending effect of CR and CR-mimetic factors is not related to that of natural aging, therefore this unable to be the basis for elaboration of radical remedy for senescence. However, both the CR and some of CR-mimetic factors can undoubtedly lead to human life extension: our organism differs from that of the other mammals only slightly. It is the wellbeing and vulnerability of such extended life that are under consideration. To achieve a healthy and unlimited life it is necessary to reprogram gene expression so that cell bioenergetics levels either remain at a previous level after cell division, which will stop aging, or else grow, which will result in organism rejuvenation.