Sunday, December 15, 2013

Some New Aspects Of Cellular Aging

The more theories there are to explain a set of facts, the less we understand it. There is no better example of this than the theories of cellular aging. A short list of the theories of the cause of the aging process include: the telomere length theory, the reproductive cell cycle theory, the DNA damage theory, the autoimmune theory, the free-radical theory, the cross-linkage theory, the error accumulation theory, the somatic mutation theory, the reliability theory, the wear and tear theory and so on. It resembles more the story of the blind men who feel a different part of the elephant. Researchers are describing some genetic and biochemical findings associated with aging, not the cause.

A recent study in Nature (1) makes the task even more difficult. Until now, most researches thought that aging is inevitable in most if not all species and starts occurring after the peak reproductive age. Researchers at the Max Planck Institute, however, found an extraordinary diversity in the processes of aging among the 46 species they studied, ranging from the lifespan of the fruit fly (a few days) to humans (roughly 100 years) to hydra (centuries, practically immortal). They studied 11 mammal species, 12 other vertebrates, 10 invertebrates, 12 plants and one algae. What they found was that most of our ideas on aging are false since they are based mostly on mammals and birds, which are not representative of all species on the planet. Some species become weaker with age (e.g. humans, other mammals and birds) others become stronger with age (e.g. tortoises and some trees) while other remain the same (e.g. Hydra and the hermit crab).

One theory of aging has been that evolution preserves the organism only as long as it is necessary for reproduction after which there is no evolutionary force or reason for the organism to continue to survive. In humans, where the period of fertility is short compared to life span after the peak fertility period, there is the added evolutionary benefit of grandparents, which allowed the parents to travel long distances to look for better hunting grounds while the grandparents stayed with the grandchildren. One of our closest relatives, the chimpanzee, travels only short distances from its usual habitat and has a shorter lifespan after peak reproductive age. But other species, like the alpine swift and the yellow baboon, continue to be fertile throughout their lives. In certain plant species, like the agave, hypericum, and borderea species, fertility increases with age. There is also no correlation between mortality rates and aging throughout many species, as there is with humans where age-related diseases accumulate with age. The conclusion of the study is that theories of aging have to be rethought when species other than mammals are considered.

One species, the Hydra, is a very peculiar organism in that it shows no signs of aging and is essentially immortal. The Hydra reproduces by budding rather than mating. A study in the Proceedings of the National Academy of Sciences (2,3) shows that the Hydra’s immortality is due to the continuous self-renewal of its stem cells which, in turn, is associated with the transcription factor FoxO. The FoxO gene exists in all animals and humans, which means that it is very important since it has been preserved over the ages of evolution. The study found a direct link between the FoxO gene and stem cell aging, as well as an increase in the immune system of the Hydra.

In the Caenorhabditis elegans, (4) the absence of the protein LET-418/Mi2, which is known to be involved in transcriptional repression, embryonic patterning, germ line development and DNA repair, has been shown to increase longevity and enhance stress resistance.

In another study, scientists at the University of Liverpool (5) have looked at the genomes of more than 30 mammalian species to identify those proteins that have evolved to increase the longevity of species. Among the proteins they found one that responds to DNA damage and which evolves and mutates in a non-random way to increase the life-span of species. Proteins associated with the degradation of damaged proteins were also found in mammals that have evolved to have longer lives.

But aging is not purely determined by one’s genetic makeup. A new study in the International Journal of Epidemiology (6) has found 22 metabolites in blood linked to aging; they were higher in older people than in young people. One of these, C-glyTrp, linked to lung function, bone mineral density, cholesterol and blood pressure, is also associated with birth weight. This metabolite can be detected in the womb and is affected by the nutrition of the baby. It has been known for a long time that a person’s birth weight affects health in middle and old age. In this study looking at identical twins, they found that manipulating the gene controlling the level of the metabolite of one twin by epigenetic means (whereby the gene is switched on or off by environmental factors), could affect the twin’s birth weight and later aging process compared to its twin brother. Finding the pathways that affect all of the metabolites associated with aging and age-related disease early on in development might also prove a fruitful path to affect later aging.

This has been just a taste of some of the new developments in the aging arena. It’s clear that lifespan limits are genetically determined, since each species has its own median lifespan. We are only beginning to discover some of the genes associated with longevity, many of which have been preserved over the eons of evolution. It is also clear that studies of species other than mammals need to be undertaken before we can formulate a comprehensive theory of aging.

1.     Owen R. Jones, Alexander Scheuerlein, Roberto Salguero-Gómez, Carlo Giovanni Camarda, Ralf Schaible, Brenda B. Casper, Johan P. Dahlgren, Johan Ehrlén, María B. García, Eric S. Menges, Pedro F. Quintana-Ascencio, Hal Caswell, Annette Baudisch, James W. Vaupel. Diversity of ageing across the tree of life. Nature, 2013; DOI: 10.1038/nature12789
2.     Christian-Albrechts-Universitaet zu Kiel (2012, November 13). Solving the mystery of aging: Longevity gene makes Hydra immortal and humans grow older. ScienceDaily. Retrieved December 15, 2013, from http://www.sciencedaily.com­ /releases/2012/11/121113091953.htm
3.     Boehm, A., et al., PNAS November 12, 2012; DOI: 10.1073/pnas.1209714109
4.     De Vaux, V., Pfefferli, C., Passannante, M., Belhaj, K., von Essen, A., Sprecher, S. G., Müller, F. and Wicky, C. (2013), The Caenorhabditis elegans LET-418/Mi2 plays a conserved role in lifespan regulation. Aging Cell, 12: 1012–1020. DOI: 10.1111/acel.12129
5.     University of Liverpool (2012, March 29). Why some animals live longer than others. ScienceDaily. Retrieved December 15, 2013, from http://www.sciencedaily.com/releases/2012/03/120329112105.htm
6.     Menni, C., et al. Metabolomic markers reveal novel pathways of ageing and early development in human populations. Int. J. Epidemiol., July 8, 2013 DOI: 10.1093/ije/dyt094