Sci. Aging Knowl. Environ., 5 November 2003
Vol. 2003, Issue 44, p. pe30
[DOI: 10.1126/sageke.2003.44.pe30]

PERSPECTIVES

Strategies for Engineered Negligible Senescence

Douglas A. Gray

The author is at the Ottawa Regional Cancer Centre, Ottawa, Canada K1H 1C4. E-mail: Doug.Gray{at}orcc.on.ca

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/44/pe30

Key Words: senescence • bioethics • stem cell • telomere

Introduction

Many of the world's authorities on the biology of aging assembled in storied Cambridge in September 2003 for the 10th Congress of the International Association of Biomedical Gerontology (IABG 10). Under discussion were the scientific feasibility and ethical desirability of extending human life span, not just incrementally but by much more ambitious margins. The word "immortality" was not infrequently heard. This city, where the discovery of the electron is celebrated by a barely noticeable plaque on a back street, is clearly accustomed to scientific bombshells, but the issues under discussion surely held import even by Cantabrigian standards. The subtitle of the meeting--Strategies for Engineered Negligible Senescence: Reasons Why Genuine Control of Aging May Be Foreseeable--and its agenda were set out by its host, Aubrey de Grey (Professor of Genetics, University of Cambridge), a leading proponent of life extension through biological engineering (see de Grey Viewpoint). de Grey argued passionately for an immediate assault on aging, using the best available technologies. In light of the scientific progress reported by the assembled experts, how credible are his claims that researchers have a pressing moral obligation to prepare the public for advances that will "turn society upside-down overnight"? Is the threat of social upheaval truly imminent?

Many more talks were presented at the meeting than could adequately be summarized here, and I have chosen to limit this meeting report to the lectures most closely related to the theme "Strategies for Engineered Negligible Senescence." For Mario Capecchi's (Distinguished Professor of Biology and Human Genetics, University of Utah) strategy to identify genes that contribute to the relative longevity of bats and for many other interesting subjects on offer, I urge the reader to explore the meeting Web site. On this site, de Grey has made available audio recordings of the lectures, and many of the speakers have kindly provided accompanying visuals in PowerPoint format.



View larger version (110K):
[in this window]
[in a new window]
 
Colleagues gather in Cambridge, U.K., the site of IABG 10.

 
Stem Cells

de Grey's vision of engineered negligible senescence is predicated on advances in the key technologies of stem cell manipulation and regulation of telomerase activity. Several speakers at the congress documented the loss of stem cell populations or functions, or both, in a variety of tissues during aging; for example, the perturbation of stem cell function in the small intestine of the mouse. In a visually and conceptually arresting lecture by Tom Kirkwood (Head, Department of Gerontology, University of Newcastle), we learned that, with aging, stem cells defective for cytochrome c oxidase function emerge in intestinal crypts. The subsequent proliferation of progeny cells then generates large sectors of crypts that contain stem cells with defective mitochondria. Nadia Rosenthal (Head, EMBL Mouse Biology Programme, EMBL, Monterotondo, Italy) described experiments in which the function of murine myogenic precursors, which are required to maintain muscle integrity during aging, could be enhanced by insulin-like growth factor 1 and the precursors possibly replaced or their function augmented by bone marrow transplantation. The transplantation of bone marrow stem cells is already routine for the treatment of hematopoietic abnormalities, but replacement of other stem cell types by bone marrow or by totipotent embryonal cells presents much greater technical hurdles. Michael West, the president and CEO of Advanced Cell Technology, described his company's stem cell strategies for the purpose of regenerative medicine. West eschewed use of the phrase "therapeutic cloning," which may be inextricably entangled with reproductive cloning in the public consciousness. He spoke of the desirable attributes of embryonal stem cells, which can be expanded in number and then differentiated into various cell types. In principle, the totipotent character of embryonal stem cells should allow them to be directed to differentiate into any cell type. In an example of what is currently possible, West described the formation of functional synapses by embryonal stem cell-derived neurons, arguing that such synapses were more extensive than those formed from neurons derived from the differentiation of available neuronal stem cell lines. West also discussed his efforts to culture human embryonal stem cells that have utility equal to those produced in mice. Finally, he described various strategies for reprogramming nuclei from somatic cells, including nuclear transfer into oocytes and transfer of oocyte cytoplasm into somatic cells. It would clearly be a boon to regenerative medicine if the requirement for an embryo could be eliminated by such a method. Religious concern over the sacrifice of human embryos would be obviated if reprogramming of somatic cell nuclei proved feasible.

It has been postulated that senescence depletes stem cell stores, which would make it difficult for organisms to repair worn tissues. Judith Campisi (Head, Department of Cell and Molecular Biology, Lawrence Berkeley National Laboratory) pointed out in a spellbinding lecture that by limiting the proliferative potential of malignant clones, cellular senescence may benefit the young at the expense of the old (see "Dangerous Liasons" and "More Than a Sum of Our Cells"); in the elderly, senescent cells may promote aging and cancer, an example of antagonistic pleiotropy (see Williams Classic Paper). Data presented by Lawrence Donehower (Baylor College of Medicine) demonstrated that in a transgenic mouse mutant, p53 displays antagonistic pleiotropy, with an enhanced ability to block the growth of cells with damaged DNA, but with an apparent acceleration of aging (see Campisi Perspective and "Tumor-Free, But Not in the Clear"). It is important to mention, however, that other results have shown that there is a dose of p53 that acts as a tumor suppressor but doesn't appear to accelerate aging. The most recent data from the Donehower laboratory are consistent with accelerated aging as a consequence of depleted stem cell function. Evidence was presented that hematopoietic stem cell capacity decreased more rapidly in transgenic mice expressing mutant p53 than in wild-type controls. Stem cell capacity may actually be enhanced in mice lacking one copy of the p53 gene. Such mice are prone to cancer, but in the small number of tumor-free animals there was an indication of increased longevity. It will be extremely interesting to see if this finding is borne out in larger numbers of mice.

Telomerase

The other key component in de Grey's proposed assault on senescence is the telomere, and experts on telomeres and senescence were well represented at the speaker's podium (see "More Than a Sum of Our Cells"). Cell senescence requires activation of one or both of the tumor suppressors p53 and the retinoblastoma (Rb) protein. p16 and p21, both cyclin-dependent kinase inhibitors, block progression through the cell cycle (and thus induce senescence) by stalling kinases that phosphorylate and thereby inactivate Rb. One way in which p53 induces senescence is by enhancing the expression of p21. Campisi presented evidence that senescence is irreversible in cell lines that express a large amount of p16. In contrast, senescent lines that express a low amount of p16 could be driven back into the cell cycle by blocking of p53 signaling. Using these findings as a basis, Campisi hypothesized that proliferation of cells that have low concentrations of p16 is blocked by p53 activities that result from telomeric shortening. When p16 is expressed in large amounts, irreversible changes, such as alterations in chromatin structure possibly effected by hypophosphorylated Rb, render senescent cells unsusceptible to growth stimulation by inactivation of p53 (1) (see Sharpless Perspective).

Jerry Shay (University of Texas Southwestern Medical Center) described experiments in which introduction of the catalytic subunit of human telomerase (hTERT) into human keratinocytes and fibroblasts produced organotypic cultures capable of differentiating into skin that could repair wounds in grafted mice. Shay was forceful in asserting that whereas human cancers frequently express telomerase activity to escape senescence, normal cells immortalized by hTERT have none of the hallmarks of cancer.

The dependence of cancer cells on telomerase activity presents a promising target for cancer therapy, as described by Calvin Harley (Geron Corporation, Menlo Park, California). In recently published work, an oligonucleotide has been identified that binds the template region of the telomerase enzyme complex and interferes with telomere synthesis (2). Addition of this oligonucleotide to A431 epidermoid carcinoma cells in culture inhibited their telomerase activity and caused them to rapidly enter crisis, with subsequent apoptosis. Normal BJ fibroblasts, which do not express telomerase, were unaffected by the oligonucleotide. Preliminary experiments using xenografts of DU145 prostate carcinoma cells showed promise, with protection and some regressions reported. No gross toxicity was reported over an 8-week infusion period.

Lengthening Life Span

The dilemma presented by all of this information is that it may be possible, by replacing lost stem cells and by other means, to extend human life (see SAGECrossroads). However, as a consequence of antagonistic pleiotropy, the presence of senescent cells, mutation accumulation, and so forth, at some advanced age a huge proportion of people, perhaps all, would develop cancer (see "Dangerous Liaisons"). The audacious solution to this problem put forward by de Grey is the strategy he has designated "whole-body interdiction of lengthening of telomeres," which reduces to the somewhat unfortunate acronym WILT. He is proposing nothing less than the elimination of cancer-prone stem cells throughout the body and their replacement with tamed stem cells rendered mortal by the genetic engineering of telomerase activity. Such cells would be designed to periodically expire and require replacement, perhaps at 10-year intervals; thus, they could not escape into telomerase-mediated immortality and could not serve as substrates for the generation of oncogenic clones (3).

Even at 10-year intervals, the WILT treatment is unlikely to be a very pleasant experience (particularly in the modality's infancy). But so convinced is de Grey of the eventual implementation of WILT or some equally effective strategy that a session was scheduled wherein he argued that it was the moral duty of congress participants to publicly discuss the time scales involved and, in so doing, diminish the social upheaval precipitated by life extension (see SAGECrossroads de Grey-Sprott Debate). A straw poll of the audience indicated that the majority believed it likely that within a decade or two, it will be possible to extend the life span of a mouse beyond 5 years; de Grey suggested that we consider public reaction to the news that a mammalian life span had been tripled. It is clear that the congress organizer thinks we are very close to mastery of human life span and hopes that this meeting will be remembered as an important milestone along the way. I asked him what he thinks was accomplished in Cambridge. His response:

"It's never certain what an event has achieved until years later, of course, but I have the impression that IABG 10 may well be seen as a turning point in the attitude of mainstream gerontologists, when they began to appreciate that we now know enough about aging to begin to spend a fair proportion of our time designing interventions, rather than spending essentially all our time seeking deeper understanding of aging as a phenomenon. The central goal of a wide-ranging meeting like IABG 10, in which biogerontologists are brought together with scientists who would never think of themselves as biogerontologists, is to have them leave the meeting with a realization of the relevance of each other's work to their own. That's how collaborations begin, how new insights are gained, and how techniques get to be applied in areas other than those for which they were originally designed. I'm sure that that's how aging will be truly cured in the long run. If IABG 10 is seen, years from now, as having been a big step in that direction, I will be extremely happy."

Regeneration and Repair

de Grey's vision, if realized, would not put us entirely in the clear. Manipulation of stem cell and telomere biology might one day achieve life extension, but this would not preclude tissue damage from disease or trauma. Nor would having the latest in genetically engineered stem cells provide insurance against human negligence, and one might reasonably suppose that life-extended people will still find ways to prune off digits or limbs in industrial or recreational mishaps. Quite apart from the issue of life extension, there are widespread diseases (diabetes, for example) where tissue regeneration would be appreciated immediately. What is the barrier to regeneration?

Jeremy Brockes (University College London) is a leading authority in the regenerative powers of newts, remarkable creatures that can regenerate not only severed limbs but also tails, jaws, sections of the heart, and ocular tissues such as the lens and retina. Newts are vertebrates, and their regenerative abilities hold great promise for human applications. Because many metazoan species with regenerative capacity have closely related species in which the ability is absent, Brockes believes that regenerative capacity may be a primitive trait that has been lost in the evolution of vertebrates other than urodele (tailed) amphibians. There are examples in developmental biology where primitive genetic programs are latent, but can be reactivated by appropriate signals (the induction of teeth in birds being a particular favorite of the popular press). It is Brockes' objective to identify the regulatory factors that initiate regeneration in the newt, and in Cambridge he concentrated on his recent investigations into one such factor, thrombin. Thrombin is a protease that one normally associates with the cascade of proteolytic cleavage events in blood clotting, but Brockes has shown that in newt limb regeneration thrombin is pivotal in triggering cell cycle re-entry in multinucleate myotubes (precursors to muscle fibers). The assumption is that thrombin activates some serum factor that serves as a stimulatory ligand for newt myotubes, but why does it not do so in other vertebrates? By fusing mouse and newt myotubes Brockes demonstrated that mouse nuclei were competent to respond to this stimulus, but mouse myotubes apparently lack the receptor stimulated by the thrombin-activated ligand. The identity of this ligand is obviously of great interest to Brockes--it may also figure in the elegant lens regeneration experiments from the Brockes lab (4) presented at IABG10. When the lens was removed from a newt, thrombin could be detected at the dorsal margin of the iris (the site of lens regeneration) and application of a specific thrombin inhibitor was found to preclude formation of a new lens. The axolotl, a salamander that can regenerate limbs but not the lens, was shown to activate thrombin at the site of severed limbs, but not at the site of lentectomy. The axolotl appears to have lost this component of its regenerative program. The reactivation of the latent lens regenerative program in the axolotl is an obvious next step, and these experiments are no doubt in progress. Brockes may be too cautious to speculate, but one cannot help but wonder how much latent regenerative programming lies unexploited in our own genomes.

Bioethics

If de Grey's optimism is not entirely misplaced, if it indeed becomes possible to periodically rejuvenate the human body with "mortalized" stem cells, is this something we should do? Conservative authors in the United States have denounced such objectives as unnatural and dehumanizing. A particularly influential critic of life extension whose arguments were subject to scrutiny at IAGB 10 is Leon Kass (Chair of the President's Council on Bioethics). Kass has argued that by removing life's urgency, added time would only debase the meaning of life (5). Kass is not alone in his opinion; the relationship between life's deadline and life's meaning inspired William Safire's warning that it is "Time to think about the brave new world we're rushing into (6)." Their and others' belief is that one should follow the natural order of things and invest one's efforts and aspirations for immortality in one's children and their children. In this way of thinking, the pursuit of immortality is not just unnatural but vain and self-serving, and its path could only lead to interminable plodding despair. As writer Edward Abbey remarked, "I do not believe in personal immortality; it seems so unnecessary. Show me one man who deserves to live forever."

On the other side of the argument are equally eloquent philosophers, and the very best of these were invited to Cambridge to present their views. Arthur Caplan (Director, Center for Bioethics, University of Pennsylvania) pointed out that human life expectancy has increased enormously through recorded history and that there was nothing intrinsically natural about dying in one's 20s, as many did at the height of the Roman Empire, nor did he think a Roman would condemn us for living so much longer. Caplan finds it amusing that the "natural order" of things is given such weight by authors who travel to speaking engagements by airplane. [In his writings, Richard Dawkins has made a similar point in reference to those who believe Western science to be but one of many equally valid avenues to truth: "Show me a cultural relativist at 30,000 feet and I will show you a hypocrite," he writes, emphasizing that air travel is made possible by scientists and engineers who "get their sums right" (7).] Caplan rejected out of hand the Kass argument that life extended is life debased. He suggested that increased life expectancy has made possible many undeniably positive features of our lives that would be alien to our predecessors, listing childhood, recreation, the second career, and retirement as examples. Caplan does not find that the desire to live longer is necessarily borne of vanity and greed and made the point that death also deprives family and friends, often cruelly. Nor is he persuaded that life extension will lead to overpopulation. Overpopulation typifies countries with short life expectancy, Caplan argued, and is the result of trying to ensure enough surviving offspring to provide necessary labor.

The issue of unequal access to life-extending technologies was addressed in a lecture given by John Harris (Sir David Alliance Professor of Bioethics, University of Manchester). Life extension will undoubtedly be expensive and, therefore, will not be an option for all, so should it be denied to the affluent citizens of Western cultures who are the most likely beneficiaries? Harris asserted that this position is born of a fundamental misunderstanding of what justice requires. There will always be circumstances in which good cannot be universally applied, but no one, for example, is arguing that the limited supply of donor kidneys be withheld until all potential recipients can receive transplants. Further, Harris argued that the technology for life extension is likely to come to us incrementally through advances in the treatment of specific illnesses, and so the ethical desirability of life extension is not an issue that must be dealt with in "one sitting." He is not much concerned with the issues that so trouble Kass and other authors. In a world where aging is postponed, even indefinitely, people will not stop having children, he asserts. Escape from senescence does not equate with immortality, because it provides no protection from the bus that may be approaching as you step off the curb. Harris pointed out that within this stark truth lies the argument that offsets the imagined cost to society of supporting the chronologically old: The health care costs associated with death by accident are much lower than those associated with death by disease. In other words, if death is sudden and not preceded by a lengthy hospital stay (and does not occur in the hospital at all in most cases), there would be considerable savings to the system. Before they meet with their fatal calamity, would these people endure meaningless lives, endlessly revisiting Disneyland? Perhaps not. "Only the terminally boring are in danger of being terminally bored," Harris quipped.

Science provides powerful protection against boredom, and my hope is that de Grey will be near the front of the line for life extension, so that he can organize many more conferences like IABG 10. That should keep things interesting for the rest of us for a very long time.


November 5, 2003
  1. M. Beausejour, A. Krtolica, F. Galimi, M. Narita, S. W. Lowe, P. Yaswen, J. Campisi, Reversal of human cellular senescence: Roles of the p53 and p16 pathways. EMBO J. 22, 4212-4222 (2003).[CrossRef][Medline]
  2. A. Asai, Y. Oshima, Y. Yamamoto, T. A. Uochi, H. Kusaka, S. Akinaga, Y. Yamashita, K. Pongracz, R. Pruzan, E. Wunder, M. Piatyszek, S. Li, A. C. Chin, C. B. Harley, S. Gryaznov, A novel telomerase template antagonist (GRN163) as a potential anticancer agent. Cancer Res. 63, 3931-3939 (2003).[Abstract/Free Full Text]
  3. M. Counter, W. C. Hahn, W. Wei , S. D. Caddle, R. L. Beijersbergen, P. M. Lansdorp , J. M. Sedivy, R. A. Weinberg, Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization. Proc. Natl. Acad. Sci. U.S.A. 95, 14723-14728 (1998).[Abstract/Free Full Text]
  4. Y. Imokawa, J. P. Brockes, Selective activation of thrombin is a critical determinant for vertebrate lens regeneration. Curr. Biol. 13, 877-881 (2003).[CrossRef][Medline]
  5. L. Kass, L'chaim and its limits: Why not immortality. First Things 113, 17-24 (2001), as viewed at http://www.firstthings.com/ftissues/ft0105/articles/kass.html.
  6. W. Safire, "Of mice and men," New York Times, 20 October 2003.
  7. R. Dawkins, A Devil's Chaplain (Weidenfeld & Nicolson, London, 2003).
Citation: D. A. Gray, Strategies for Engineered Negligible Senescence. Sci. Aging Knowl. Environ. 2003 (44), pe30 (2003).








Science of Aging Knowledge Environment. ISSN 1539-6150