When that day comes, Promega hopes to have played a supporting role.

The Need

Why does a fruit fly have an average lifespan of 30 days while some tortoises live for 150 years? And why do all organisms seem to detoriate as they age? For instance, at age 65 a person is 100 times more like to have a tumor than at age 35, and cardiovascular disease and neurodegenerative disorders increase exponentially as a person ages (1,2). Life expectancy has increased dramatically in the last half of the 20th century—from 71.1 years for a female born in 1950 to 80.1 years for a female born in 2003 (3). As lifespan increases, there is a need to understand what controls aging in order to improve quality of later life.

Even before written history, human oral tradition described unusually aged patriarchs who, despite extreme age, could still lead productive lives and produce offspring. This interest in longevity and successful aging has persisted throughout history: alchemists in the Middle Ages and explorers of the New World searched for the elixir that would delay aging and extend life. Humans have long sought to extend life and age successfully through myth, magic, and medicine.

The Commitment to Understand the Biological Control of Aging and Longevity

Today, instead of looking to the stars for the key to longevity, we look to yeast, worms, flies and mice. Research on longevity using these model systems has taught us that age-related decline is not an inevitable consequence of passing time, but that lifespan and aging are highly regulated processes that are linked at the molecular level (1,4). By understanding the molecular regulation of aging and lifespan, researchers may be able to develop specific therapeutics to prevent age-related diseases such as atherosclerosis, neurodegeneration, arthritis, some cancers and possibly even slow the rate of aging in humans.

Recent Discoveries

As early as 1934, researchers noted that caloric restriction (CR) without malnutrition significantly increases lifespan and reduces age-related disorders in rats (4,5). The molecular pathways that are affected by CR are still not completely understood. Research reports have linked CR to the insulin signaling pathway, the TOR signaling pathway, and metabolic rate (1,4,5). Additionally research on longevity has identified an “aging-suppressor gene”, Klotho. When Klotho is over expressed in mice it increases lifespan, but when defective it results in premature aging and age-related defects (6,7). Telomeres, the parts of chromosomes that appear to regulate aging in cells in culture by “counting” cell divisions, may also have an important role to play in human aging (1).

Much of the research into the mechanisms that regulate lifespan and aging seems to be converging on a family of transcription factors, FOXO, which are inhibited by insulin/IGF-1 or TOR signaling. FOXO transcription factors are also activated by the Klotho protein (8). FOXO proteins regulate the transcription of a number of interesting genes including genes involved in metabolism, protection from oxidative stress, and protein folding (5). In C. elegans, a mutation in a gene for a specific isoform of the translation initiation factor eIF4E influences lifespan. Mutations of this isoform, which functions in the soma, protect from oxidative stress and increase worm lifespan. The pathway affected by the eIF4E mutation appears to be separate from the insulin/IGF-1, TOR, Klotho and FOXO pathways (9).

This Web site highlights a small selection of recent papers investigating various aspects of aging and longevity, each illuminating its piece of the puzzle. Use the links under "Longevity Research Today" on the right to view summaries highlighting some of the current research on the major genetic players in aging and longevity. Click on "More Longevity Citations" to browse through a larger selection of recent papers.

Promega tools support a wide range of scientific applications: Apoptosis, Cell Viability, Cloning, Protein Expression & Analysis, Kinase Assays, RT-PCR.

References

1.  Kenyon, C. (2005) The Plasticity of Aging: Insights from Long-Lived Mutants. Science, 120, 449–60.
2. Finkel, T. and Holbrook, N.J. (2000) Oxidant, oxidative stress and the biology of ageing. Nature. 408, 239–47.
3. National Center for Heath Statistics. Centers for Disease Control and Prevention. Trends in Health and Aging. http://209.217.72.34/aging/TableViewer/tableView.aspx (accessed 7/5/2007)
4. Shaffitzel, E. and Hertweck, M. (2006) Recent aging research in Caenorhabditis elegans. Experimental Gerontology. 41, 557–563.
5. Masoro, E.J. (1985) Nutrition and Aging—A Current Assessment. J. Nutr. 115, 842–8
6. Kuro-o, M. et al. (1997) Mutation of the Mouse Klotho Gene Leads to a Syndrome Resembling Ageing. Nature. 390, 45-51.
7. Kurosu, H. (2005) Suppression of Aging in Mice by the Hormone Klotho. Science. 309, 1829–1833.
8. Yamamoto, M. et al. (2005) Regulation of oxidative stress by the anti-aging hormone Klotho. J. Biol. Chem. 280, 38029–34.
9. Syntichaki, P., Troulinaki, K. and Tavernarakis, N. (2007) eIF4E function in somatic cells modulates ageing in Caenorhabditis elegans.Nature. 445, 922–926.

Klotho: An "Aging-Suppressor" Gene

Mice that overexpress Klotho exhibit an extended lifespan and delayed aging, making Klotho unique among the genes found to influence aging to date as an aging suppressor. The exact role of Klotho in regulating aging is still being discovered. A 2005 study published in the Journal of Biological Chemistry by Yamamoto and colleagues shows that Klotho protein protects against oxidative stress and activates the FoxO transcription factors, inducing expression of manganese superoxide dismutase. Klotho is a type I transmembrane protein that is expressed in the distal convoluted tubules of the kidney, the choroid plexus in the brain, and the parathyroid glands. Interestingly these tissues are involved in maintaining calcium homeostasis and has been shown to have glycosidase activity. A 2007 study in Science by Imura et al. demonstrated that α-Klotho binds to Na+/K+ ATPase and may be involved in regulating calcium homeostasis. Additionally, Klotho is also a required cofactor for FGF-23 induction of signaling events. Full-length FGF-23 is involved in phosphate homeostasis. In humans, Klotho activity changes with aging, and its activity is decreases in healthy older individuals. A loss-of-function allele of human Klotho increases individual risk for osteoporosis, hypertension, atherosclerosis, emphysema, cognitive impairment and decreases lifespan. A 2007 study in the Journal of Immunology published by Witkowski et al. looked at Klotho expression in CD4+ T lymphocytes of rheumatoid arthritis patients (RA) and unaffected controls. The results indicate that Klotho expression is especially downregulated in lymphocytes from RA patients, and the authors of the study propose that RA may result from loss-of-function of Klotho in CD4+ lymphocytes.

Citation: Witkowski, J.M. et al. (2007) Klotho—a common link in physiological and rheumatoid arthritis-related aging of human CD4+ lymphocytes. J. Immunol. 178, 771–777.

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Citation: Imura, A. et al. (2007) alpha-Klotho as a regulator of calcium homeostais. Science 316, 1615–8.

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Citation: Yamamoto, M. et al. (2005) Regulation of oxidative stress by the anti-aging homone Klotho. J. Biol. Chem. 280, 38029–34.

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Muscle Decline and Aging

Overexpression of IGF-1 can delay or prevent aging problems in motor neurons and skeletal muscle. A paper published in the Journal of Physiology in 2006 describes a novel method for targeting fusion proteins specifically to motor neurons by using a fusion protein containing tetanus toxin fragment C (TTC). Motor neurons will bind, take up and transport the TTC fragment with no toxicity to the neurons. In this paper IGF-1 was targeted to motor neurons. Muscle weight and fiber size were unaffected by the IGF-1, however single-fiber specific force was significantly increased in mice receiving the IGF-1-TTC fusion over age-matched controls.

Citation: Payne, A.M. et al. (2006). Motor neurone targeting of IGF-1 prevents specific force decline in ageing mouse muscle. J. Physiol. 507, 283-294.

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Oxidative Stresses and Aging

Oxidative stress, exemplified by the accumulation of carbonylated proteins in cells, is linked to age-related decline and diseases. Anti-oxidant response elements (AREs) regulate transcription of many genes that confer protection against oxidative stress. Liu et al. published a study in the Proceedings of the National Academy of Sciences USA in 2007 that describes a genomic screening to look for activators of AREs. They screened a library of 15,000 expression cDNAs in neuroblastoma IMR-32 cells searching for genes that activate the antioxidant response element, ARE. The library was screened using a luciferase reporter construct under the control of an ARE-containing promoter. IMR-32 cells expressing the various cDNAs that activated ARE were more resistant to oxidative stress than controls.

Citation: Liu, Y. et al. (2007) A genomic screen for activators of the antioxidant response element. Proc. Natl. Acad. Sci. USA 104, 5205–5210.

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