Interdisciplinary topics in gerontology最新文献

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.

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. In investigations by many groups, the frailty index has shown reproducible properties such as: age-specific, nonlinear increase, higher values in women, strong association with mortality and other adverse outcomes, and universal limit to its increase. At the level of individual, the frailty index shows complex stochastic dynamics, reflecting both stochasticity of the environment and the ability to recover from various illnesses. Most recently, we have proposed that the origin of deficit accumulation lies in the interaction between the environment, the organism and its ability to recover. We apply a stochastic dynamics framework to illustrate that the average recovery time increases with age, mimicking the age-associated increase in deficit accumulation.

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. mTOR has been shown to play a role in a broad range of diseases, and is of particular interest to human health and aging due to the availability of clinically approved pharmacological agents targeting the mTOR complexes and other components of the mTOR signaling network. Characterizing the role of mTOR in aging and health promises to provide new avenues for intervention in human aging and disease through modulation of this signaling pathway.

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 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. In this chapter, we will review the age-related changes in the immune response and assess the validity of the immune theory of aging (i.e. that these changes in immune response are the primary cause of aging). Many data in humans support the notion that age-associated immune dysfunction may at least in part explain the aging process. Explanatory power may be enhanced by combination with other theories such as the free radical theory. More longitudinal studies are needed to corroborate the immune theory of aging.

This chapter is intended to outline the main results of a research trend realized by the author during the last 45 years, focused on the main role played by the cell membrane in the aging process. It is a very wide field; therefore, the reader cannot expect in this limited space a detailed description, but will be given a wide, interdisciplinary insight into the main facts and theories regarding cellular aging. The central idea described here is the concept called the membrane hypothesis of aging (MHA). The history, the chemical roots, physicochemical facts, biophysical processes, as well as the obligatory biochemical consequences are all touched in by indicating the most important sources of detailed knowledge for those who are more interested in the basic biology of the aging process. This chapter covers also the available anti-aging interventions on the cell membrane by means of the centrophenoxine treatment based on the MHA. It also briefly interprets the possibilities of a just developing anti-aging method by using the recombinant human growth hormone, essential basis of which is the species specificity, and the general presence of receptors of this hormone in the plasma membrane of all types of cells.

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. Only a small fraction (<1%) of centenarians live to become supercentenarians (110 years), indicating a limit of performance and resistance of the body. This limit can be interpreted as 'tinkering' of nature instead of producing masterpieces as suggested by F. Jacob. These facts and theories are described in this chapter.

Aging is characterized by a progressive decline in cellular function, organismal fitness and increased risk of age-associated diseases and death. One potential cause of aging is the progressive accumulation of dysfunctional mitochondria and oxidative damage with age. Considerable efforts have been made in our understanding of the role of mitochondrial dysfunction and oxidative stress in aging and age-associated diseases. This chapter outlines the interplay between oxidative stress and mitochondrial dysfunction, and discusses their impact on senescence, cell death, stem cell function, age-associated diseases and longevity.

The observation that human fibroblasts have a limited number of cell population doublings in vitro led to the proposal that it is the expression of cellular aging. In vitro, the proliferation of human fibroblasts terminates with a postmitotic cell which was called senescent cell. Due to misinterpreted experiments, the latter was considered the hallmark of cellular aging, although obviously we do not age because our cells stop dividing. The so-called senescent cell has been the core of the investigation on cellular aging and of the theories proposed on the subject. The search for mechanisms responsible for the postmitotic state led to contradictory results, which accumulated when the term cell senescence was used to define the growth arrest due to a variety of causes. The mechanisms believed to be causing these multiple forms of cell senescence multiplied accordingly. This was disregarded claiming that there are multiple pathways to cell senescence. Since it was thought that aging favors malignant transformation, speculations were made to find a relationship between 'cell senescence' and cancers, which led to several paradoxes. The contradictions and paradoxes should be cleared to reestablish logic and order in the field and understand its relevance for human aging.

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. In worms, in yeast, and in other organisms, aging is also opposed to longevity that counteracts this self-destruction process, as if longevity was something like a developmental constraint (delay) opposed to an evolutionary one (alteration).