Project: Functional Increase

The aim of the A3 Action group "Functional Increase" is main

We are constructing the most comprehensive database on genetic variants associated with longevity in humans. This project is a collaborative crowdsourced endeavour which will create a resource that is very valuable for deciphering the genetics of human Aging. This database will allow for a greater understanding of aging so we can solve the problems of aging.

All things are ageing. – All things? Not everything! Although ageing is quite widespread, it is not a universal phenomenon. Ageing is actually an incr

It is well known that aging in multicellular organisms is a process, regulated by a great amount of different factors, and which is not mediated just

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Aging drives cancer and cancer is the result of aging.

Ectopic expression of defined pluripotence-associated Factors reprograms adult somatic cells back to an Embryonic Stem Cell-like state. During this process the phenoytpic characteristics of Aging are also reverted. Cells can even be directly reprogrammed from one cell type into another. The challenge is to reprogram old cells into young cells without the need of inducing the pluripotent state or changing the differentiation state.

The growth-cessation subroutine mediates the shut-down of cellular proliferation already in young/middle age and continues so with increasing age.

Gene silencing via RNA interference is mediated by microRNAs which are major controller of developmental processes and its plasticity conferred by diet. The function of specific miRNAs is going beyond the developmental period and extends in the control of lifespan via regulating the onset and the rate of aging.

This communication will critically evaluate whether the p53/p63/p73 family are potential functional homologs of the Ndt80 rejuvenation factor.

Aging is arguably the major biomedical challenge of the 21st century, and elucidating causal mechanisms of aging is one of the outstanding scientific challenges of our time. Longevity pathways, discovered in the past two decades, have yet fully to explain how lifespan is determined and which molecular processes drive aging. In the nematode worm C. elegans, feedback-loop circuits were found to regulate insulin-like signaling, inflammation and nutrient-sensing, and jointly to modulate lifespan over a 10-fold range. We propose to create the first unified model of lifespan-control circuits in worms, to robustly predict responses to perturbations. The initial model, treating lifespan as a function of transcript data, will be refined iteratively to incorporate effects of environment and genotype. By defining molecular circuits that control the rate and state of aging, we can predict means to slow or perhaps even reverse aging. Three highly collaborative and interdisciplinary aims are proposed:

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Several germ line genes become ectopically expressed in somatic tissues of long-lived C. elegans mutants. Somati

Dietary restriction without malnutrition delays ageing and extends lifespan, but the molecular mechanism is still unknown. Ageing gene expression changes originate from development and growth cessation, are modulated by diet, and manipulate circadian rhythmicity. A significant proportion of the genes differentially expressed under dietary restriction, during ageing and the juvenile growth period are under circadian control. Circadian clock genes are among the most significant interaction partners of dietary restriction differentially expressed genes in mouse and human interactome, while clock modulators interact highly significant with genes controlling nuclear lumen, ribosomal biogenesis and cell cycle. Canonical clock genes and clock modifiers itself exhibit differential expression upon DR, as well as during ageing and already during the juvenile period. Notable, for instance circadian mRNA expression of NAMPT was identified to increase during juvenile, while to decrease during ageing and is induced upon dietary restriction. Changing cycles in redox state and epigenetic marks could be possible mechanism to measure time over age.

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Cells are rejuvenated during gametogenesis. The induction of gametogenesis-related genes is the common response to dietary restriction across a variety of regimens and genotypes. Long-lived genetic DR-mimetics upregulate Ndt80. Constitutively upregulation of Ndt80 renders cells immortal. Ime1 and Ndt80 regulate ageing genes. Using an integrated approach the potential target genes of Ndt80 crucial for lifespan resetting were identified among them is the homolog of human BARKOR and telomerase TERT.

Dietary restriction (DR), limiting certain factors in diet without causing malnutrition, delays the ageing process and extends lifespan in multiple organisms. The conserved life-extending effect of DR suggests a fundamental mechanism, though it remains a subject of debate. We established a web-accessible database (GenDR) of DR-essential genes, which if genetically altered interfere with the effect of DR to extend the lifespan in model organisms (yeast, worm, fly and mice), and then explored the mechanistic links among DR-essential genes. Gene-regulatory circuits reveal that nutrient-sensitive, stress-response and meiotic transcription factors govern the DR induced transcriptional signature in yeast. Our comparative study shows that DR-essential genes are more conserved on the molecular level and interact with each other more than expected by chance. We suggest that DR commonly suppresses translation, while stimulates chromatin reorganization, reproductive processes (meiosis) and stress responses in species separated billions of years in evolution.

Ageing is a widespread phenomenon limiting the lifespan of almost all species. Virtually all organisms age, besides a few interesting exceptions. However what controls this process remains a great, but not insurmountable, challenge. Biological information is increasing with a exponential pace. Similar information technology is also advancing with an fast-pacing speed. The marriage of these two will certainly enable to re-engineer biological processes such as ageing. In this thesis, functional genomics approaches are applied on ageing. Particular attention is given to dietary restriction (DR), the most powerful non-genetic intervention now known to counteract the basic ageing process. Other therapeutics and methods are under development. Preliminary in an introduction the potential causes of ageing and its slow down by dietary restriction are discussed from an evolutionary perspective as well as methodologies to decipher it. Subsequently, first of all a class of genes which mediates the lifespan extension effect of a restricted diet was defined and those DR-essential genes were investigated on the level of molecular evolution, interactions and expressions. This lead to the discovery that DR evokes a light form of rejuvenation by potentially employing recycling machineries such as autophagy. Then all the ageing genes were classified into gerontogenes and ageing-suppressors, which promote and counteract the ageing process, respectively. Those classes are compared on the network and functional level and found to be associated totally different processes and clusters, although they also share certain functionalities. Then tissue-specific gene expression profiles were employed to investigate the activities of these defined classes in individual tissues upon DR. Following this, transcriptional regulation given rise to observed gene expression changes were reconstructed and specifically exemplified by predicting the potential target genes of a rejuvenating transcription factor found to be invoked by DR. Among the identified targets were telomerase and autophagy-related genes. Subsequently autophagy was investigated in more detail which revealed evidence that autophagic process oscillate on in ultradian-scale. Moreover, transcriptional signatures of defined processes, namely juvenile growth, ageing, and DR were found to be commonly connected via circadian cycles. Finally, an integrated unified explanation of ageing is presented.

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The lifespan extension phenomena by dietary restriction remains a mystery. Using a systems biology approach employing GenDR, interaction networks and gene expression data we investigated the obscure role of autophagy in mediating the longevity effect of dietary restriction. We found evidence for a crucial role of ultradian oscillation in lifespan prolongation.

Many genes regulate the ageing process in a positive or negative manner. Gerontogenes can speed up ageing by their normal activity, therefore decrease lifespan if hyperactivated and increase it if inactivated, while ageing-suppressor genes slow down ageing normally, hence decrease lifespan by lack of activity and their over-activation increases lifespan. In C. elegans these two classes of ageing-associated genes, share functional terms of enzyme/domain-specific binding, cell cortex and secretion and have their own specific terms as well as opposite molecular interaction network connectivity properties and only if grouped together having a significant higher specificity to interact to each other. In these networks of ageing-associated genes, clusters of either gerontogenes or ageing-suppressor genes appear to regulate distinct activities separately as well as similar processes together. Gerontogenes are acting on transcriptional and translational control, development and DNA metabolism, while ageing-suppressor genes are primary regulators of diverse activities for cell homeostasis like cytoskeleton structure, intracellular and nuclear organization, localization and transport, as well as proteasome system. Both gerontogenes and ageing-suppressor are participating in development and growth, phosphorylation mediated signalling, transmembrane transport, and regulation of cell death.

The fundamental process underlying organismal aging is one of the biggest chief mysteries of biology. We set our goal to solve this with the usage of increasingly computational power in an innovative way. The aging process is very plastic, it can be speeded up, slowed down, stopped, or even reversed. We aim to demonstrate the reversal of organismal aging by manipulating the expression of defined factors. Hundreds of genes and many more processes have been associated with lifespan control, yet the mechanisms of aging and anti-aging remain poorly understood. In order to cope with the enormous data in a systematic fashion we will create the first prototype of an in silico simulation of a multicellular organism (C. elegans) which integrates information from the molecular level to whole physiology. With both the exponential growing number of data and also rapidly increasing computational power such an undertaking is not impossible anymore. Moreover, in spite of the upcoming overwhelming data in the post-genomics era, there is a need to establish such a framework in order to guide experimental investigations aiming to solve the complex nature of aging and thereby advancing our integrated understanding of organismal life.

Decades of research on the oldest question of mankind, the scientific community was divided by two central dogmas. Once says that ageing is programmed, the other claims ageing is just damage accumulation. However, the truth might be very trivial. Ageing is caused by both by a program and by damage. Hence, in order to reverse ageing, we have to stop this program and to repair the damage. Therefore, we need basic research to illuminate this program and we need SENS, the Strategies for Engineered Negligible Senescence.

How to integrate the vast amount of interaction information out there in order to reveal biological processes.

Wonders of extraordinary long-lived species - will they ever end? Species adapted to their environments with a specific lifespan. Most species developed aging to speed up their evolution. Non-aging species normally would be out-competed by the aging species. However, in some biological niches longevity were acquired. It appears that numerous animal species evolved a remarkable feature of escaping the natural force of developing aging. The maximum lifespan of many of these long-lived species appear to be limited by our inability to record their life-history in capacity and the extrinsic force of mortality which is inverse to the intrinsic aging process. What can we learn from these long-lived species about human aging?

The ability to span 122 years of age [Young et al. 2010] marks humans as a long-lived species. While the modal lifespan in wealthy first-world countries is approximately 75-85 years of age, there exist unique statistical outliers that surpass this life expectancy by 15-25 (centenarians) and 25-35 years (supercentenarians). These individuals are hence attractive models for delayed aging and their longevity is presumed to arise from a wide array of environmental and genetic factors [Finch 2009].

As we are young everything regenerates perfectly. In fact, our body harbors the plan to reconstruct itself from scratch which is localized in the nucleus of each of our body cells. However, as we grow up our regenerative capacities decreases. Aging can in fact be viewed as the progressive downregulation of regenerative activities. Reactivating and manipulating these endogenous regenerative capacities will postpone aging and death in an unforeseen manner.

All things are ageing. – All things? Not everything! Although ageing is quite widespread, it is not a universal phenomenon. Ageing is actually an incredible plastic process which can be speeded up, slowed down, totally stopped or even reversed. Understanding what determines to age or not to age, the pace of ageing, and how modify its rate or even reverse it, would unlock the capacity to fight all the age-related reduction of functions and the negative changes which afflicts us as we get old.