Putting Life Back in Your Years

Understanding the Science of Human Aging

Christine Oyugi, BSc
Managing Editor,
Geriatrics & Aging 

"…. it's not the years in your life that counts. It's the life in your years"
Abraham Lincoln

With this in mind, researchers gathered in Toronto on January 16th at The Inaugural Symposium of the Anne and Max Tanenbaum Chair Program in Biomedical Research. The one day symposium provided a good summary of biogerontology and geriatric medicine and a glimpse of our current understanding of the mechanisms of aging.

The field of aging research, biogerontology, is often not distinguished from geriatric medicine--research on age-associated disease. According to Dr Leonard Hayflick, advances in aging research rely on the distinction between these two fields. As people do not actually die from aging, there is a tendency to focus on diseases that afflict the growing elderly population. However, if we do find a resolution to the leading causes of death such as cancer, stroke and cardiovascular diseases, how much will this tell us about the fundamental biology that is involved in aging? The loss of physiological capacity in cells of vital organs is the hallmark of aging and understanding the mechanisms involved could advance our fundamental knowledge of aging and age-associated disease.

There exists abundant evidence linking telomerase to the aging process. Telomerase is a ribonucleoprotein enzyme that extends telomeres by adding hexameric nucleotide repeats to the ends of chromosomes. Without the activity of telomerase, telomeres continue to shrink during cellular division, thereby losing genes that are important for cell function. Telomerase expression is exceptionally high in a variety of animals that appear to age at a negligible rate; these animals include tortoises, lobster, rainbow trout, and sharks. Further research will involve examining the action of telomerase in cells of such animals.

It has been shown that the life span of cultured cells, normally limited to around 50 cell doublings--the so-called Hayflick limit--can be more than doubled by the addition of telomerase. Research shows that the maintenance of telomere length by telomerase is critical to the proliferative ability of some immortalized mammalian cells in culture and in vivo. The catalytic core of telomerase is made up of a reverse transcriptase component (TERT) and RNA component. "It appears that TERT is sufficient for maintenance of telomere-length," says Dr. Lea Harrington from the Department of Medical Biophysics at the University of Toronto.

Evidence from research of systems in the body in which (near critical) loss of telomere has been reported demonstrates that it correlates with disease.

So what is the link between telomerase and aging and how can this be translated into treatment for patients? Evidence from research of systems in the body in which (near critical) loss of telomere has been reported demonstrates that it correlates with disease. These include, the immune system, the liver, the vascular system, skin, kidney and gastrointestinal system. Abnormal telomerase activity has also been linked to all cancers. Potential therapy involves inhibition of telomerase activity, which could be applied to the field of oncology and gene or cell therapy.

The ability of organisms to respond to oxygen and oxidative stress is also connected to aging and life span. Back in the 1950's Denham Harman described the 'free-radical theory' of aging, which states that reactive oxygen species (ROS) cause cellular damage. This cellular damage accumulates with age, eventually leading to disease. Later, the identification of superoxide dismutase (SOD) gave support to this finding. The function of SOD is to promote the conversion of oxygen radicals into the less toxic form, hydrogen peroxide. Studies with SOD knockout Drosophila (Fruit fly) show that flies that lack the gene encoding the SOD 1 protein show signs of neurodegeneration and aging. Furthermore, expressing SOD1 transgene in the motor neurons of knockout flies "rescues " adult lifespan in a dose dependant manner, and the flies live up to 40% longer. The researchers also found that the extension of life span in transgenic SOD flies was not due to lower metabolic rate.

Are there cellular targets for oxidative damage? Evidence gained from studying human degenerative diseases point to the nervous system. Some cases of Alzheimer's disease and Lou Gehrig's disease are linked to mutations involving the SOD protein. Injecting SOD into the motorneurons of knockout mice extends life span; a finding that is not seen when SOD is injected into the muscle or a ubiquitous promoter. "This suggest that the nervous system is a primary target of the aging process," said Dr. Boulianne, professor of molecular and medical genetics at the University of Toronto. She went on to say that future research should determine if there are other cells that may be targets for aging and identify additional genes which may extend lifespan.

the extension of lifespan that is associated with caloric restriction is abolished by mutations in the SIR2, reinforcing the link between SIR2 and aging.

Such genes have recently been identified in budding yeast. Dr. Leonard Guarante, professor of biology at the Massachusetts Institute of Technology, described the link between SIR 2 chromatin silencing and nicotininamide adenine dinucleotide (NAD). SIR2 is a deacetylase enzyme belonging to a complex of silent information regulator proteins. Deacetylase activity of SIR requires NAD, a process that is a universal property of SIR proteins from bacteria to mammals. To date, one of the best indications that we can regulate aging is that caloric restriction can extend the lifespan of yeast. It is likely that this is linked to the increased availability of NAD when metabolic pathways are limited. NAD is essential for capturing electrons in glycolysis. A reduced caloric intake may decrease the need for NAD in the glycolytic pathway, increasing its availability for deacetylation reactions. Interestingly, the extension of lifespan that is associated with caloric restriction is abolished by mutations in the SIR2, reinforcing the link between SIR2 and aging. It remains to be determined whether this effect on aging is conserved up the evolutionary ladder.

A number of human genes have been identified in which mutations can lead to the accelerated emergence of features associated with aging. These cause diseases such as those labeled segmental progerias (e.g. Werner's syndrome) and Alzheimer's disease. Research on these genes and their protein products may lead to a clearer understanding of the aging process and to ways in which aging might be delayed.

Is the goal of aging research to increase the lifespan? Is it likely that we can extend maximum lifespan significantly beyond where it currently stands? There are a number of societal implications of increasing the life-span. For instance, the length of time spent in retirement would increase, perhaps leading to people 'out-living' their old age pensions. Furthermore, it would mean that one would perhaps spend a greater number of years in physical weakness and dependency. The question then becomes one of whether we can improve quality of life, as well as increasing lifespan. At least in part, the development of breakthrough therapies for the treatment of the chronic disease of old age may rely on improvements in our understanding of the fundamental mechanism of human aging.

Suggested Reading

1. Hayflick L.The illusion of cell immortality British Journal of Cancer, Vol. 83, No. 7, Oct 2000, pp. 841-846.
2. Hayflick L. The future of ageing. Nature 2000 Nov 9;408(6809):267-9.
3. Hayflick L. New approaches to old age. Nature 2000 Jan 27;403(6768):365.
4. Harman, D. The aging process. Proc. Natl Acad. Sci. USA 78, 7124&endash;7128 (1981).
5. Kaeberlein, M., McVey, M. & Guarente, L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 13, 2570&endash;2580 (1999).
6. Liu Y, Snow BE, Hande MP ,Yeung D , Erdmann NJ, Wakeham A, et al. The telomerase reverse transcriptase is limiting and necessary for telomerase function in vivo Current Biology 2000, 10:1459-1462.
7. Martin GM, Turker MS Model systems for the genetic analysis of mechanisms of aging. J Gerontol 1988 Mar;43(2):B33-9.
8. Parkes, T., Elia, A.E., Dickinson, D., Hilliker, A.J., Phillips, J.P. & Boulianne, G.L. (1998). Extension of Drosophila lifespan by overexpression of human SOD in motorneurons. Nature Genetics 19:171-174.