Category Archives: aging

On Anti-Aging

from reference 2

Throughout your life, your cells are continually replaced. The replacements are newly differentiated stem cells: cells which have somehow come to a decision regarding their fate in your body, and have thus undergone a transformation from a ready-to-become-something state, to a liver cell, a retinal cell, a skin cell, a brain cell (neuron). This further means that your stem cells (and others) are constantly dividing, a process called mitosis. The most fundamental operation in mitotic division is the replication (copying) of DNA. This is a multifaceted operation involving a large cast of molecular players including (amongst others) enzymes, cofactors, and nucleic acid building blocks.

When DNA is replicated, complementary nucleic acid bases are added one by one to each strand of the double helix as it is unwound, resulting in two copies of the original piece of DNA (chromosome). However, this presents a slight problem. The enzyme complex responsible for adding these base pairs (the process is called elongation) requires a bit of RNA at the end of the strand to get started. The solution is that part of the end of the DNA strand is snipped off and replaced with a chunk of RNA as a jumping off point. This would be an issue if these enzymes were chopping off pieces of “important” (functional) DNA; cells have so called “proofreading” mechanisms to look for the kinds of erroneous DNA sequences that would result from trimming parts off the end, which if found in large enough numbers, result in cellular suicide (apoptosis). Instead, and rather ingeniously, there are long sequences that cap the ends of the important parts of DNA called telomeres. The only function of these sequences is to be snipped apart, slowly ground down over time, by replication so that the important stuff in the middle doesn’t get messed with in this process.

Telomeric DNA has been seen as a potential target for anti-aging therapy. The idea is simple: make telomeres longer, the animal lives longer because the animal’s cells can replicate forever without ever being forced to snip “important” DNA during the replication part and ultimately apoptose. Furthermore, there is an enzyme whose job it is to lengthen telomeric DNA called, unsurprisingly, telomerase. Indeed, it is known that increased telomerase activity extends the lifespan of most human cell types in vitro1. Sadly, high telomerase activity is correlated with the development of cancer, and the exploration of its use as an anti-aging therapy has thus been attenuated.

A recent study, published in the journal Cell, however, has explored the possibility of pumping-up telomerase activity in mice2. The authors of this study enhanced telomerase activity in mice who had also been given a number of tumor-suppressing agents (p53, p16, and p19ARF) to render the rodents cancer resistant. This enhancement “improves the fitness of epithelial barriers, particularly the skin and the intestine, and produces a systemic delay in aging accompanied by extension of the median life span.” (See figure, below.) The real significance of this study is that it is the first to demonstrate the ability of enhanced telomerase activity in extending lifespan in vivo, in a living organism.

from reference 2

Cells can only divide so many times before they become inviable (around 53 for humans). This hints at a fundamental limitation to the replication process. One component of this is surely that described herein of telomere shortening. However, there are many other ways that errors can accrue in DNA. On another note, it will be extremely intriguing to see how these sorts of aging stories regarding DNA and cell division relate to those concerning calorie restriction and associated metabolic pathways.

While the enhancement of telomerase activity is a piece of the aging puzzle, we have a long way to go in understanding the finite quality of cell division, and it may truly be inescapable, to say nothing of aging itself.

References:
1. Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JW, Lichtsteiner S, Wright WE. Extension of life-span by introduction of telomerase into normal human cells. Science 279: 349-352, 1998.
2. Tomás-Loba A, Flores I, Fernández-Marcos PJ, Cayuela ML, Maraver A, Tejera A, Borrás C, Matheu A, Klatt P, Flores JM, Viña J, Serrano M, Blasco MA. Telomerase reverse transcriptase delays aging in cancer-resistant mice. Cell 135: 609-622, 2008.

Life Span

It is somewhat paradoxical that we cannot perform experiments on the animal we are most interested in studing, ourselves. It is difficult enough to deal with the moral implications of experimenting on non-humans. I frequently remind myself that the study of other creatures mitigates the suffering of my own species and this sometimes seems a paltry justification. Humans are investiaged non-invasively, or further when such intrusion is neccessary for medical purposes, but we are still limited in our understanding by such restrictions, the following science included.

It will come as no suprise that there is quite a bit of research into the possibility of extending the length of time that a living thing spends alive. To date, the only effective means of doing so have been based in some way on the concept of Calorie Restriction(CR), see ref. 1 for a review. This simply means that an animal takes in fewer calories than normal while maintaining adequate levels of nutrients. The results are reasonably unequivocal, from nematoads to mammals, lifespan is increased by this method. As one can see from the graph above, increased caloric restriction is effective up to around 65% fewer calories being taken in, at which point it plateaus.

Some recent research, however, (ref. 2) has found a seemingly non-CR-intertwined mechanism that also has an effect on mammalian lifespan. The authors of this study bred mice which lack the gene which codes for adenylyl cyclase 5 (AC5). ACs in general play a key role in beta-adrenergic receptor (β-AR) signaling. In the interest of brevity, I will not delve into the molecular biology of cell-to-cell communications, howiver it is important to know that the blockade of this particular signalling pathway has recently been demonstrated to sucessfully treat mild-to-moderate chronic heart failure (ref. 3). The research into mice which lack the AC5 gene shows that their lifespan is ~30% longer, “are protected from reduced bone density and susceptibility to fractures of aging. Old AC5 KO mice are also protected from aging-induced cardiomyopathy, e.g., hypertrophy, apoptosis, fibrosis, and reduced cardiac function.” (ref. 1)

With both of these examples of extended lifespan, however, a question arises. What quality of life do these animals have? This is perhaps more relevant for the research on calorie restriction, but the animals studied can never report to us how they are feeling though the scientist involved always take pains to minimize any outward signs of discomfort. Until such techniques have been tried in human beings the complete effects of these therapies remains a bit of a quesion mark in my mind. That is not to say that I’m not amazed and optimistic about this direction of progress, I simply find it incredible that such simple things as eating less or disrupting a single gene could have universally positive effects.

References

  1. D.A. Sinclair (2005) Toward a unified theory of caloric restriction and longevity regulation, Mech. Ageing Dev. 126, 987–1002.
  2. Lin Yan, Dorothy E. Vatner, J. Patrick O’Connor, Andreas Ivessa, Hui Ge, Wei Chen, Shinichi Hirotani, Yoshihiro Ishikawa, Junichi Sadoshima, and Stephen F. Vatner (2007) Type 5 Adenylyl Cyclase Disruption Increases Longevity and Protects Against Stress, Cell 130, 247-258
  3. M.R. Bristow (2000) beta-adrenergic receptor blockade in chronic heart failure, Circulation 101, 558–569.