Interdisciplinary topics in gerontology最新文献

In this chapter, we describe in detail the age-dependent modifications of connective tissues, separately for their cellular and extracellular compartments. Cell aging was studied by the in vitro method established by Hayflick as well as by ex vivo explant cultures, and results with both methods are discussed. Follows then the description of age changes of macromolecular components of extracellular matrix as well as the decline with age of receptor-mediated cell-matrix interactions. These interactions mediated by several types of receptors, as integrins, the elastin receptor and others, play a crucial role for the definition and regulation of the differentiated cell phenotype. Age-related modifications of both matrix components and receptors are discussed in order to explain the mechanisms of the age-dependent modulations of cell-matrix interactions. Finally, we discuss the relations between age changes of matrix components and the onset of age-related diseases, especially cardiovascular pathologies mostly involved in age-dependence of functions and limitation of longevity.

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. A more recent discovery was the demonstration that several receptor-mediated functions decline with age because either of the loss of receptors or their uncoupling from their specific signalling pathways. The mechanisms and biological as well as pathological consequences of this age-dependent receptor loss and signal transduction changes are described in this chapter.

Fifty years ago, it was demonstrated by Leonard Hayflick that human diploid fibroblasts grown in culture have a finite lifespan. Since that time, innumerable experiments have been published to discover the mechanism(s) that are responsible for this 'Hayflick limit' to continuous growth. Much new information has been gained, but there are certain features of this experimental system which have not been fully understood. One is the fact that different populations of the foetal lung strains WI-38 and MRC-5 have a range in division potential of at least a millionfold. The commitment theory of cellular aging, published more than 30 years ago, is able to explain this, but it has been consistently ignored. The theory predicts that bottlenecks, which are transient reductions in population size, can significantly reduce lifespan, or increase variability of lifespans. Computer simulations specify the effects of bottlenecks on longevity, and these were confirmed in two series of experiments. Commitment to senescence may be the loss of telomerase, which leads to the erosion of telomeres and the inability to grow indefinitely. Many experiments have been done with skin fibroblasts from human donors of different age, and it was originally thought that in vitro lifespan was inversely correlated with donor age. In these experiments, a single skin biopsy produces a population of cells that are grown to senescence. However, there is no reason to believe that skin fibroblasts are less variable in their in vitro lifespan than foetal lung strains, in which case the data points with skin cells are so variable that they may completely obscure any inverse correlation between culture lifespans and donor age.

Evolutionary theories of aging explain why we age. These theories take into account the fact that, in the wild, mean lifespan of many species is usually shorter than it could be in protected environments. In such conditions, because most of animals die before reaching old age, there is no selection in favor or against alleles with effects at old age. Alleles with negative effects at this age can thus accumulate in successive generations, particularly if they also have positive effects at young age and are thus retained by selection. This chapter describes the evolutionary theories of aging and their consequences for the understanding of the biology of aging as well as the challenges to these theories. It is argued that these theories offer a reasonable explanation to the existence of the aging process even if they can surely be refined.

Cell senescence is one of the major paradigms of aging research. It started with the demonstration by L. Hayflick of the limited number of divisions by normal, nontransformed cells, not shown by transformed malignant cells, this processes being largely regulated by the telomere-telomerase system. A complete renewal of this discipline came from the demonstration that cells can enter senescence at any time by an anti-oncogene-triggered pathway, enabling them to escape malignancy. The senescent cell became a major actor of the aging process, among others, by the acquisition of the senescence-associated secretory phenotype. This chapter is devoted to the regulatory process involved in the acquisition of the senescent cell phenotype and its role in organismal aging.

As older patients present with an average of three comorbidities beside their cancer, geriatric oncology can provide unique clues to translational research in aging and cancer. We illustrate this approach with the example of the metabolic syndrome and cancer. Epidemiologic and clinical cohorts highlighted an association between the metabolic syndrome and a higher risk and worse prognosis of various cancers. In a bedside-to-bench transition, this led to an interest in analyzing the potential mechanisms underlying this association. At least ten potential mechanisms could be implicated, with the challenge of understanding which are the dominant ones in human patients. Bench-to-bedside studies are beginning to shed some light on that aspect, and some therapeutic trials are beginning to exploit the lessons learned.

The prognosis of acute myeloid leukemia (AML) in the elderly is poor with overall less than 5% of the patients expected to be alive after 5 years. In many studies, age was an independent poor prognostic factor. In the elderly, the frequency of secondary forms of AML, of unfavorable cytogenetics, expression of multidrug resistance genes in part explains the poor outcome. However, based on genetic and molecular studies, there is no evidence for specific biological features of the disease in the elderly. Host-related factors including comorbidity and reduced functional reserves also account for the severity of the disease. Finally, population-based studies show that approximately 30% of patients older than 65 years are offered intensive chemotherapy. This chapter summarizes the recent advances in the biology of AML, in particular the impact of new molecular markers. An overview of the studies that have evaluated comorbidities and results of geriatric assessments in these patients are also presented.

Recent developments in oncogeriatric surgery focus on several items - preoperative risk estimation and identification of frail patients and optimalization of perioperative care. New screening tools are being evaluated and show promising results. There is increasing evidence that preoperative training of frail patients might decrease the rate of postoperative complications and increase survival. The recent trend towards individualized treatment schemes will certainly be of benefit for the elderly population. More tools are becoming available to answer the most difficult question of all, namely whether surgery is the optimal treatment in this individual frail elderly oncogeriatric patient.