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When the data on epidemiology and pathophysiology are analyzed, aging is usually perceived as a process that results from the combined influence of constitutional or so-called « genetic » factors, life-style associated factors and external events.  Gerontobiology looks into all the specific medical and biological features of aging on the scale of the human body and develops concepts such as « harmonious » aging, « vulnerable » and « hypercatabolic » states, illustrating the highly heterogeneous characteristics of the aging process. The extreme heterogeneity of aging can be illustrated for a given age by a residual life-expectancy that varies considerably from one individual to another and by the onset, or not, of degenerative disorders, especially cardiovascular and neurological diseases, bone and joint disorders, diabetes and also neoplasms, pathologies in which constitutional determinants and other external factors play a role as they do in aging.

The concept of cell aging, or senescence, differs from the aging of an organism as a whole and its features can be observed in primary somatic cell cultures.  After a certain number of divisions the cell cycle permanently shuts down and a senescent phenotype is observed in which major changes have taken place both in the cells themselves and in their genetic expression program.  This is known as replicative senescence and is caused by the unrelenting shortening of the DNA that forms the end of the chromosomes (or telomeres) each time the cell divides.  The erosion of the telomeres is paced by the cell cycle and can be considered as a mechanism that acts as a “mitotic clock”; the cells count the number of divisions rather than chronological time.   If this counting mechanism is deregulated to compensate for the shortening of the telomeric DNA, due to the up-regulation of telomerase reverse transcriptase or other alternative mechanisms that lengthen the DNA (a mechanism known as ALT for example) the cells end up by becoming immortal, which is what usually happens in cancer.  A noteworthy comment here is that Elisabeth Blackburn, Carole Greider and Jack Scoztack, were awarded the Noble prize for Medicine in 2009 for their work in this area, showing the medical community’s awareness of the importance of these phenomena.

More generally, the destiny of a cell in a eukaryotic organism obeys precisely set rules of homeostasis when it is proliferating, differentiating or during apoptosis and senescence.  However, all the factors that are required to regulate each of these stages are coded by a set of identical genetic material in each cell, which is identically reproduced each time the cell divides.  This is why a special mechanism known as DDR (short for DNA damage response) is required to maintain the integrity of the genome and fine-tune the structure of the DNA. This structure, chromatin, ensures that specific gene expression programs are expressed at each stage of the cell cycle and each cell state. The mechanisms involved are often known as “epigenetic”, although they do not always involve inheritance of the chromatin state.  Studying the DNA damage response and chromatin is one of the most promising avenues of research in terms of the biology of aging, because time, together with constitutional and environmental factors, has a direct influence on the integrity of the DNA in the chromosomes (mutations) and their chromatin organization (epimutation).  The characteristic heterogeneity of the aging of the body is probably directly related to chromatin regulation mechanisms and many degenerative disorders are largely influenced, if not directly caused, by genetic or epigenetic dysfunctions.

Amongst these disorders, malignancy is also heterogeneous and is one of the best-known deregulations of cell proliferation, differentiation, apoptosis and senescence.  Surprisingly, senescence protects the cells against malignancy.  In agreement with the increase in the incidence of cancer with age, cell senescence can also facilitate the development of cancer, making the relationship between aging and cancer even more complex.

As in all the physiological mechanisms of homeostasis, the regulation and balance between ageing and cancer in superior eukaryotes and in humans in particular, is extremely complex.  On the scale of the cell, accumulated DNA damage seems to be a common cause of aging and the development of cancer, but the p53-dependent adaptive response illustrates the phenomenon of antagonistic pleiotropy, because increasing the anti-tumoral cell response leads to premature ageing.  On the scale of an organism, the inhibition of the IGF-1 and GH dependent channels induces a reduction in cell metabolism, whilst protecting against oxidative stress, aging and the development of malignancies.

From this work, it emerges that aging is a way for the body to attempt to escape from cancer, but the attempt remains vain because cell damage builds up as time goes on.  Cell senescence may thus prevent us from dying of cancer young, whilst ageing our body which, in return, increases the likelihood of malignancy as we get older.

Going into more detail of the understanding of these multiple interconnections requires synergy between many areas of molecular, cellular or biomedical experimental biology or biology more generally dedicated to the study of systems modeling ageing and cancer.

This is the goal that IRCAN (Institute of Research on Cancer and Aging in Nice) has set for itself.

The research carried out at IRCAN involves major areas of basic research in biology, public health (oncology, geriatrics, age-related disorders such as diabetes, renal failure, neurodegenerative and cardiovascular disease) and sustainable development to improve our understanding of the body’s response to environmental stress.


Nice, 2012