Sci. Aging Knowl. Environ., 13 April 2005
Vol. 2005, Issue 15, p. pe10
[DOI: 10.1126/sageke.2005.15.pe10]

PERSPECTIVES

Time and Aging--Mechanisms and Meanings

Evi Wollscheid-Lengeling

The author is at the German Research Centre for Biotechnology, Mascheroder Weg 1, D-38124 Braunschweig, Germany. E-mail: Evi.Lengeling{at}gbf.de.

http://sageke.sciencemag.org/cgi/content/full/2005/15/pe10

Key Words: time • ethics • genetics of longevity • caloric restriction • hormesis • circadian rhythm

"Time and aging" was the theme of the 5th Annual Conference on Science and Society in Heidelberg, Germany, held on 5-6 November 2004. This series of meetings, organized by the European Molecular Biology Laboratory, brings together scientists with other members of society to discuss not only scientific views but also the potential social impact of scientific developments. The theme of aging and its various facets, such as the aging population, anti-aging drugs, and age-related diseases, could not have been better chosen for this purpose. An interesting mixture of scientific results and thoughts on ethics was presented and captivated even teenaged pupils from the international school of Stuttgart. During the first day, the stage was set primarily by discussions of scientific progress in the field of aging, whereas during the second day, speakers and discussion groups focused on ethical and religious issues associated with aging.

Tom Kirkwood from the University of Newcastle-upon-Tyne, the first speaker of the conference, started by asking several striking questions: Why do we age at all? What controls the length of life? During this exciting talk, he led logically through a number of hypotheses commonly cited as possible mechanisms that control longevity: Is life span controlled by a clock, by genes, by sex (an idea supported by findings that reproductive activity decreases life span; see Tatar Perspective and Mobbs Perspective), or by the accumulation of many forms of damage? He said that there is no indication of a clock controlling the length of life, although genes certainly seem to play a role in the variation of longevity seen within populations, including human populations. The accumulation of damage within cells and chromosomes and the efficiency with which it can be repaired is believed to play a major role in the aging process (see, for example, "Aging Research Grows Up", "The Two Faces of Oxygen", and Praticò Review). One finding that supports this idea is that centenarians exhibit higher than normal PARP-1 activity. This enzyme, a poly(ADP-ribose) polymerase, is involved in DNA repair. The possible influence of other factors, ranging from telomere shortening to socioeconomic circumstances, make it obvious that the aging process is a complex phenomenon. Thus, the length of life seems to be intrinsically malleable in the view outlined by Kirkwood.

The role of genetics in longevity in Iceland was discussed by Kári Stefánsson, deCODE Genetics, Reykjavik. Most Icelandic families have a preserved genealogy that reaches back at least five generations. Therefore, the Icelandic population represents a perfect setting to study genetic predispositions. In a study in which the phenotype and genotype of more than 50% of the adult Icelandic population has been investigated, scientists mapped two loci that influence longevity. One of the loci has a 0.9-Mb inversion that is significantly associated not only with longevity but also with an increased number of children in female carriers. The orientation of the inverted fragment influences the expression of several genes in the inverted region, such as the gene encoding the microtubule-associated protein tau, which has been implicated in Alzheimer's disease (AD; see "Detangling Alzheimer's Disease"). Thus, this finding might have consequences for mental performance, namely for the deterioration of cognitive function. The second longevity locus influences a gene cascade with variants that either predispose or protect for AD. Stefánsson concluded that living to old age has a strong genetic component.

It is well established that life span in many organisms can also be influenced by caloric restriction (CR). Wouldn't it be great if we could reduce our caloric intake (or potentially ingest CR mimetics; see "Dietary Drawbacks" and Kristal and Paolucci Perspective) and thereby prolong life, as seen for the mouse and other organisms? Lloyd Demetrius from Harvard University outlined why, from his point of view, CR should not influence longevity in humans. Different species developed different survival traits during evolution that influence life span. In his view, species with early sexual maturity, short reproductive periods, large litter sizes, and weak metabolic stability (that is, a weak capacity to maintain redox couples at steady-state values) will respond to CR because it postpones sexual maturity and increases metabolic stability by reducing the accumulation of macromolecular damage. In contrast, CR should have little or no effect on life span in species with late sexual maturity, long reproduction periods, and robust metabolic stability--all characteristics displayed by humans. Thus, he concludes that CR probably will not affect human life span.

Mild heat shock is another manipulation that can increase life span in certain model organisms (see "Stress for Success"). Suresh Rattan, University of Aarhus, explained the phenomenon--called hormesis--of beneficial and health-promoting effects arising from challenging cells and organisms with mild stress. In cultured human skin fibroblasts, for example, mild heat shock promotes the maintenance of a normal protein profile as the cells age. Such a moderate heat shock stress stimulus also improves cellular resistance to oxidative and glycoxidative stress. Whether these observations on fibroblast cells will hold true in other mammalian cells or even organisms like humans still has to be investigated. "Is a visit to the sauna a beneficial stress that will prolong life?" asked someone in the audience. The answer: Maybe, but it also depends on whether you believe it will.

Several other speakers also dealt with aging-related issues at the cellular level. Each day we experience death, although not consciously, as millions of cells in our body undergo apoptosis (see "More Than a Sum of Our Cells"). Thus, in an organism, life and death of cells have to be at equilibrium to ensure health. If the balance is distorted, malfunction and, ultimately, disease will follow. Peter Krammer, German Cancer Research Center, Heidelberg, described the mechanisms of apoptosis involving the CD95 receptor pathway. CD95 is a member of the tumor necrosis factor receptor superfamily. Apoptosis of cells through this receptor pathway is necessary, for example, for the down-regulation of an immune response after a pathogen is defeated. Too little apoptosis leads to autoimmune diseases and cancer (see Campisi Perspective). On the other hand, too much apoptosis might also be dangerous, leading to tissue lesions (see Andersen Review). Krammer proposed that manipulation of the CD95 pathway could be used to control apoptosis and thereby disease.

Ueli Schibler, from the University of Geneva, discussed another aspect of aging: internal clocks and the measurement of time. Almost all processes in nature are, in one way or another, built on cycles with a period of defined length, such as circadian rhythms. These cycles influence gene expression in cells and tissue. The associated clocks are required for the proper coordination of the molecular life in a cell through the cyclic accumulation and/or activity of downstream regulators. Knock-out strains of mice with mutations in three genes (DBP, HLF, and TEF) that encode members of a family of transcription factors, all of which are under circadian clock control, have shorter life spans than do wild-type mice.

Aubrey de Grey, University of Cambridge, urged that biogerontologists studying these many different aspects of aging work together and unify their force to influence politicians and decision makers in society and science funding agencies to increase funding of aging-related research. He also made a plea for more research on anti-aging medicine (see de Grey Viewpoint) that might increase life span dramatically.

The popular view of a steady increase of human life expectancy was contradicted by Jay Olshansky, University of Illinois (see Tuljapurkar Perspective). He asked, "Will human life expectancy decline in the 21st century?" and suggested that it would. He outlined this somewhat provocative view quite convincingly. Life expectancy has increased in the past century because modern medicine has reduced the death rate in infants considerably and protected the elderly from infections. Olshansky sees no major developments coming up in the near future to further increase life span. On the contrary, he argued that, because of the upcoming obesity pandemic in children and adults, and because of an increase in communicable infectious diseases like influenza, tuberculosis, and newly arising infections, life expectancy will decrease in the 21st century.

During the panel discussion, chaired by Andreas Kruse, University of Heidelberg, numerous points were raised that emphasized the complexity of the aging phenomenon. The questions asked by the audience tended to address the social and cultural aspects of aging. One such facet that was discussed was how an individual's perception of time can be very different from reality. It is not unusual that when looking in the mirror, the young old and even the oldest old are astonished to see an old face looking back. The influence of psychological effects on the aging process will be hard to prove, although everyone would confirm them intuitively. The environment in which people age is also of great interest; the point was raised that laboratory mice that have demanding surroundings such as a playground (that is, an environment with features found in a natural habitat, such as "tunnels," or equipment for gymnastics) exhibit longer life spans than do control mice. As we learn more about how to "age well," it is hoped that society will place greater value on the strengths and capacities of old people, such as their wisdom and experience. We should take advantage of these capacities more fully than we do now, particularly as many countries are confronted with an aging society.

As a final note, Frances R. Balkwill was awarded the 2004 European Molecular Biology Organization's Award for Communication in the Life Sciences at the meeting. This honor was given to her because of her authorship of a number of excellent science books for children, including an educational book on human immunodeficiency virus and acquired immunodeficiency syndrome, as well as for her work as director of the Centre of the Cell project (a new science center for children) in London. Her impressive work in educating the next generation in an affectionate way, without hiding the sometimes sad side of life, is a hopeful sign for our future.


April 13, 2005 Citation: E. Wollscheid-Lengeling, Time and Aging--Mechanisms and Meanings. Sci. Aging Knowl. Environ. 2005 (15), pe10 (2005).








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