Chromosome ends and longevity

Chromosome Ends and Longevity
Elizabeth Blackburn
Department of Biochemistry and Biophysics, University of California San Francisco CA
Every cell in our bodies that carries genetic information carries it in the form of 46 chromosomes. Chromosomes in cells carry the genetic information of cells, and every chromosome contains a long linear DNA molecule, with ends that must be protected. Telomeres are the structures that protect and stabilize the ends of chromosomes, ensuring genomic stability. They are so important that it is truism to say: “Lose the telomere, lose the chromosome”. Telomeres consist of simple DNA sequences, which bind protein factors and make a “cap”, thus securing each end of every chromosome. Without telomeric DNA and its special way of replicating, chromosome ends dwindle down as they lose their telomeric DNA, eventually causing cells to stop dividing, a process called cellular senescence. For humans to live a long life, this dwindling down has to be counteracted. Can the understanding of telomeres and telomerase be exploited to improve health and end cancer? New results suggest this is possible. The enzyme telomerase replenishes the DNA at telomeres, partly counteracting the progressive shortening of telomeres throughout the human life span. Telomerase is present in a great many normal cells in human adults, although it was missed in earlier studies because it is often in low amounts. This had led people to conclude, incorrectly, that telomerase is completely absent from normal adult human cells in the body. Although telomerase activity is normally kept in check in adult human cells, throughout life a minimal level of telomerase is still required for replenishment of tissues, such as the immune system. Indeed, our recent collaborative studies showed that the amount of telomerase activity in certain white blood cells of the body (peripheral blood mononucleocytes) is altered depending on the duration (number of years) of caregiving stress in a cohort of caregiving mothers studied: the longer the caregiving situation has lasted, the lower the amount of telomerase activity in these cells, and the shorter their telomeres. We are trying to find out the mechanism of this effect of chronic life stress on telomere maintenance. Furthermore, our recent work with our collaborators has shown that low telomerase in white blood cells is associated with six of the known major risk factors, including chronic psychological stress, for cardiovascular disease in people. In our understanding of human cancers, much is now known about the roles of many molecular players, in both cancer development and progression. In contrast to many normal cells in human adults, in cancer cells telomerase is especially active. As a result, cancer cells can keep dividing indefinitely. Human cancers typically become dependent on these greatly elevated levels of telomerase. Our recent work focuses on targeting telomeres and telomerase, specifically exploiting the high level of telomerase so common in cancer cells, turning it into a liability for the cancer cells. Most enzymes—the catalysts that carry out life’s chemical reactions—are made of protein. In contrast, the telomerase enzyme is made of both protein and RNA. Telomerase adds telomeric DNA to chromosome ends by an unusual enzymatic action involving collaboration between its two core components: a protein that includes a reverse transcriptase portion, and an essential telomerase RNA component. The telomerase RNA molecule contains a short sequence of nucleotides that acts as a built-in RNA template platform, from which telomeric DNA is copied by the reverse transcription action of telomerase, thereby elongating the telomere. In pre-clinical experiments, the template sequence has been engineered to instruct the telomerase to make mutant telomeric DNA. Now, the telomeres became ‘toxic’ to cancer cells, quickly prompting them to undergo self-inflicted cell death. Thus, the overabundant level of telomerase of cancer cells creates vulnerability, because that engineered telomerase now directs the synthesis of a toxic product—namely, telomeric DNA with the wrong DNA sequence. In pre-clinical model tests, this approach had potent effects in blocking tumor growth. While a major known function of the enzyme telomerase is to elongate telomeric DNA, evidence for additional biological roles for telomerase have begun to surface. Stem cells are thought by many to be cells that, when they go awry for various reasons, can generate and regenerate cancer. Telomerase stimulates proliferation of normal stem cells. Conversely, when the high level of telomerase typical of cancer cells is knocked down experimentally, the cells lose proliferative ability and even become less stem cell-like. This has implications for targeting telomerase in cancer, because it is recognized, in a growing number of human cancers, that the persistence of stem cell-like cancer cells may contribute to the recurrence of untreatable cancers. Knocking down the high telomerase inhibits cancer cell growth surprisingly rapidly, even without telomere shortening, and alters the gene-expression profile in a distinctive fashion that is predicted to be associated with diminished cancer progression. Thus, it is now proposed that telomerase has other functions besides mere telomere elongation. A challenge is now to exploit the molecular information available about telomeres and telomerase and translate it into strategies for better health and for cancer therapies.

SIRTUINS, CALORIE RESTRICTION AND LONGEVITY

LEONARD GUARENTE
DEPARTMENT OF BIOLOGY
MIT
CAMBRIDGE MA 02139
Em
Calorie restriction (CR) not only promotes an increase in lifespan in rodents and other creatures, but also mitigates many of the major diseases of aging, such as cancer, cardiovascular disease, diabetes and neurodegenerative disease. Our studies on aging in yeast and roundworms have identified an anti-aging gene SIR2, which we propose mediates the benefits of CR. In this talk I will discuss the mammalian SIR2 ortholog SIRT1 and demonstrate why it is a very good candidate for being the key gene that delivers the benefits of CR. Our findings imply that we can begin to develop drugs that will bind to SIRT and alter its activities and thereby yield the benefits of CR on healthspan and perhaps longevity. By this reckoning, SIRT1 and its related genes may offer us a new therapeutic strategy to combat the major diseases of aging and significantly extend the duration of robust health in humans. CALORIC RESTRICTION MIMETICS: POSSIBLE ANTI-AGING STRATEGY
FOR HUMANS
George S. Roth, GeroScience Inc., Pylesville, MD 21132
Dietary caloric restriction (CR) remains the most robust and reproducible
strategy for maintaining health and vitality, as well as extending lifespan in
a variety of plant and animal species. Although well-controlled human CR
studies have just begun, much anecdotal human data and several nonhuman primate
CR investigations bode well for the possibility that this intervention could
benefit man as well. Unfortunately, except for an extremely dedicated and
relatively small group of human practicioners, very few of us have the will
power to maintain the approximately thirty percent caloric reduction,
necessary over the bulk of the adult lifespan, to implement this strategy.
For this reason, we introduced the concept of CR "mimetics" (means to obtain
the same antiaging effects as CR WITHOUT dieting) in 1998. Two findings
support the legitimacy and reality of mimetics as a practical means for
extending the healthy years of humans.
1) Compounds, such as 2-deoxyglucose and metformin, can elicit some of the same
biological effects as CR (e.g, lower plasma insulin levels/greater sensitivity,
lower body temperature, altered pattern of gene expresion, and possibly
increased lifespan), without reducing food intake in animal models.
2) Some of these same biological endpoints (lower insulin and body temperature)
correlate with increased survival in non-CR humans.
Currently, a number of laboratories in the academic, government, and private
sectors are engaged in a search for candidate CR mimetics for human
application. Some, such as lipoic acid and carnitine, are already commercially
available. Moreover, a number of biological pathways, which mediate CR
effects,
are being targeted. While none of these to date appear to completly mimic the
effects of CR, ultimately a "cocktail" containing several may come very close
and provide the first practical and rational antiaging strategy for humans.

Source: http://tibethouse.us/science_yoga/downloads/longevity_abstract.pdf