Interdisciplinary Topics in Gerontology

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Inactivation of the GH/insulin/IGF-1 signaling molecules corresponding genes as well as the inactivation of serine/threonine protein kinase mTOR increases life span in nematodes, fruit flies and mice. Evidence has emerged that antidiabetic biguanides and rapamycin are promising candidates for pharmacological interventions leading to both life span extension and prevention of cancer. The available data on the relationship of two fundamental processes--aging and carcinogenesis--have been suggested to be a basis for understanding these two-side effects of biguanides and rapamycin...

Aging is a systemic process which progressively manifests itself at multiple levels of structural and functional organization from molecular reactions and cell-cell interactions in tissues to the physiology of an entire organ. There is ever increasing data on biomedical relevant network interactions for the aging process at different scales of time and space. To connect the aging process at different structural, temporal and spatial scales, extensive systems biological approaches need to be deployed. Systems biological approaches can not only systematically handle the large-scale datasets (like high-throughput data) and the complexity of interactions (feedback loops, cross talk), but also can delve into nonlinear behaviors exhibited by several biological processes which are beyond intuitive reasoning...

With modern medicine and an awareness of healthy lifestyle practices, people are living longer and generally healthier lives than their ancestors. These successes of modern medicine have resulted in an increasing proportion of elderly in society. Research groups around the world have investigated the contribution of gut microbial communities to human health and well-being. It was established that the microbiota composition of the human gut is modulated by lifestyle factors, especially diet. The microbiota composition and function, acting in concert with direct and indirect effects of habitual diet, is of great importance in remaining healthy and active...

From the perspective of systems biology, melatonin is relevant to aging in multiple ways. As a highly pleiotropic agent, it acts as a modulator and protectant of mitochondrial electron flux, a potent antioxidant that supports the redox balance and prevents excessive free radical formation, a coregulator of metabolic sensing and antagonist of insulin resistance, an immune modulator, a physiological hypnotic and, importantly, an orchestrating chronobiotic. It entrains central and peripheral circadian clocks and is required for some high-amplitude rhythms...

The physiological responses to nutrient availability play a central role in aging and disease. Genetic and pharmacological studies have identified highly conserved cellular signaling pathways that influence aging by regulating the interface between nutrient and hormone cues and cellular growth and maintenance. Among these pathways, the mechanistic target of rapamycin (mTOR) has been most reproducibly shown to modulate aging in evolutionarily diverse organisms as reduction in mTOR activity extends life span from yeast to rodents...

Aging is associated with immunosenescence and accompanied by a chronic inflammatory state which contributes to metabolic syndrome, diabetes and their cardiovascular consequences. Risk factors for cardiovascular diseases (CVDs) and diabetes overlap, leading to the hypothesis that both share an inflammatory basis. Obesity is increased in the elderly population, and adipose tissue induces a state of systemic inflammation partially induced by adipokines. The liver plays a pivotal role in the metabolism of nutrients and exhibits alterations in the expression of genes associated with inflammation, cellular stress and fibrosis...

Individuals of the same age differ greatly with respect to their health status and life span. We have suggested that the health status of individuals can be represented by the number of health deficits that they accumulate during their life. We have suggested that this can be measured by a fitness-frailty index (or just a frailty index), which is the ratio of the deficits present in a person to the total number of deficits considered (e.g. available in a given database or experimental procedure). Further, we have proposed that the frailty index represents the biological age of the individual, and suggested an algorithm for its estimation...

Aging is a consequence of an organism's evolution, where specific traits that lead to the organism's development eventually promote aged phenotypes or could lead to age-related diseases. In this sense, one theory that broadly explored development and its association to aging is the developmental aging theory (DevAge), which also encompasses most known age-associated theories. Thus, we employed different systems biology tools to prospect developmental and aging-associated networks for human and murine models for evolutionary comparison...

There is not one systems biology of aging, but two. Though aging can evolve in either sexual or asexual species when there is asymmetric reproduction, the evolutionary genetics of aging in species with frequent sexual recombination are quite different from those arising when sex is rare or absent. When recombination is rare, selection is expected to act chiefly on rare large-effect mutations, which purge genetic variation due to genome-wide hitchhiking. In such species, the systems biology of aging can focus on the effects of large-effect mutants, transgenics, and combinations of such genetic manipulations...

Animals and plants have biological clocks that help to regulate circadian cycles, seasonal rhythms, growth, development and sexual maturity. If aging is not a stochastic process of attrition but is centrally orchestrated, it is reasonable to suspect that the timing of senescence is also influenced by one or more biological clocks. Evolutionary reasoning first articulated by G. Williams suggests that multiple, redundant clocks might influence organismal aging. Some aging clocks that have been proposed include the suprachiasmatic nucleus, the hypothalamus, involution of the thymus, and cellular senescence...

Computational modelling is a key component of systems biology and integrates with the other techniques discussed thus far in this book by utilizing a myriad of data that are being generated to quantitatively represent and simulate biological systems. This chapter will describe what computational modelling involves; the rationale for using it, and the appropriateness of modelling for investigating the aging process. How a model is assembled and the different theoretical frameworks that can be used to build a model are also discussed...

This chapter will introduce a few additional network concepts, and then it will focus on the application of the material in the previous chapter to the study of systems biology of aging. In particular, we will examine how the material can be used to study aging networks in two sample species: Caenorhabditis elegans and Saccharomyces cerevisiae.

This chapter will briefly address the history of systems biology and complexity theory and its use in understanding the dynamics of aging at the 'omic' level of biological organization. Using the idea of treating a biological organism like a network, we will examine how network mathematics, particularly graph theory, can provide deeper insight and can even predict potential genes and proteins that are related to the control of organismal life span. We will begin with a review of the history of network analysis at the cellular level and follow that by an introduction to the various commonly used network analysis variables...

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Regulation of longevity depends on genetic and environmental factors. According to Svanborg, a Swedish geriatrician, over the last decades human life expectancy increased as well as the age at onset of fatal diseases. Nevertheless, autopsies of centenarians revealed the presence of several severe pathologies which could have killed them much earlier. Therefore, the emphasis is on regulation of resistance dependent on the expression of genes such as Sirtuins, mTOR pathway and others controlling body resistance...

Aging is a normative biological process, and not simply a physical one. It is not accurate to define it by the fact that life has an entropic cost, and to characterize it as a pure imbalance between exergonic and endergonic reaction in metabolism (the free radical theory of aging) or finally as an imbalance between the excessive formation of reactive oxygen species and limited antioxidant defenses. In connective tissues, aging is alteration. And alteration is more than destruction or degradation. It deals with self-destruction and with the so-called molecular vicious circles of aging...

Neurodegenerative diseases, including Alzheimer's, Parkinson's and prion diseases are a major and growing public health issue for aging populations as aging is the greatest risk factor for neurodegeneration. Protein misfolding and spreading are common to these neurodegenerative diseases. There are many high-quality reviews concerning these diseases; also in this brief chapter, I have tried to give a summary of the principal points involved in the pathogenesis of these three clinical entities.

Aging is a complex phenomenon the cause of which is not fully understood, despite the plethora of theories proposed to explain it. As we age, changes in essentially all physiological functions, including immunity, are apparent. Immune responses decrease with aging, contributing to the increased incidence of different chronic diseases with an inflammatory component (sometimes referred to as 'inflamm-aging'). It is clear from many studies that human longevity may be influenced by these changes in the immune system, but how they proceed is not clearly determined...

Communication between cells is the most important evolutionarily conserved mechanism which enabled the bioconstruction of multicellular organisms. These mechanisms all comprise some general properties such as specific receptors recognized by agonists, molecules capable of activating them as well as the intracellular signalling pathways which activate the effector functions. A large number of such receptors and transmission pathways have been described, and both agonists and antagonists have been identified and are used in medicine...