Tag: Biogerontology

The Future of Aging: Pathways to Human Life Extension

This book review was originally published in Cryonics magazine, 1st Quarter, 2011.

Editor-in-chief, cryobiologist, and aging researcher Gregory M. Fahy and his associate editors Michael D. West, L. Stephen Cole and Steven B. Harris have compiled what might be the most impressive collection of articles on interventive gerontology to date in their 866 page collection The Future of Aging: Pathways to Human Life Extension. The book is divided into 2 parts. The first part includes general, scientific, social and philosophical perspectives on life extension. The second part is a collection of proposed interventions, which are organized in chronological order, starting with the (projected) earliest interventions first. Of course, such an organization of the materials necessitates a subjective estimation of when such technologies will be available and is bound to be controversial. The collection closes with a number of appendices about contemporary anti-aging funding and projects (SENS, Manhattan Beach Project).

I have read the book with the following two questions in mind:

1.     Which approaches for increasing the maximum life span show clear near-term potential?

2.     Is meaningful rejuvenation possible without advanced cell repair technologies?

What follows are my comments on selected chapters of the book.

I cannot say that I am a big fan of Ray Kurzweil’s work. His general introduction to life extension, “Bridges to Life,” co-written with Terry Grossman, starts out on a restrained note, discussing the benefits of caloric restriction, exercise, basic supplementation, and predictive genomics. But it then ratchets up into bold claims about the future that rest on controversial premises: about biology and health following the same path as information technology; about the technical feasibility of molecular nanotechnology; and about the nature of mind. One thing that remains a mystery to me is how such an accelerating pace of anti-aging technologies could be validated considering the relatively long life expectancy of humans. Presumably we are expected to adopt a lot of these technologies based on their theoretical merits, success in animal studies, or short-term effects in humans.

Associate Editor Stephen Cole contributes a chapter on the ethical basis for using human embryonic stem cells. I suspect that his argument in favor of these therapies relies on adopting a definition of personhood that has more far-reaching, and more controversial, consequences than just permitting the use of human embryonic stem cells. One of the most disconcerting aspects of the bioethical debate on stem cell research is that many of its advocates seem to feel that if they do not see an ethical case against it, government funding for such research should be permitted.  In essence, this means that opponents of embryonic stem cell research are obliged to financially support it as well. This is a recipe for further aggravating what has already become a passionate political debate.

As someone with relatively limited exposure to the biogerontology literature I should be cautious in singling out one technical contribution for high praise, but Joshua Mitteldorf’s chapter on the evolutionary origins of aging is one of the best and most inspiring articles in the field of aging research I have read and worth the hefty price of the book alone. Mitteldorf outlines a case for the theory that evolution has selected aging for its own sake and presents experimental findings that falsify other explanations for aging such as wear-and-tear and metabolic trade-offs. That aging is firmly under genetic control may appear the most pessimistic finding in terms of the prospects of halting aging but in fact allows for the manipulation of a number of selected upstream interventions that can inhibit or mitigate these programs.

It is clear from this ambitious book that cryobiologist Greg Fahy also has a strong interest in biogerontology but nothing prepared me for the encyclopedic knowledge that he displays in his lengthy chapter on the precedents for the biological control of aging. Fahy’s chapter further corroborates the view that aging is under genetic control. He also reviews a great number of beneficial mutations and interventions in animals and humans that can extend lifespan. Reading all these inspiring examples, however, I found myself faced with the same kind of despair as when reading about all the neuroprotective interventions in stroke and cardiac arrest. There is great uncertainty how such interventions would fare in humans (or other animals) and, more specific to the objective of human life extension, how we ourselves can ascertain that there are no long-term adverse consequences. Fahy does not run away from the most formidable challenge of all, rejuvenation of the brain without losing identity-critical information, but points out that identity-critical information might be retained despite the turnover and replacement of components that a meaningful life extension program for the brain would most likely require. Fortunately, people who make cryonics arrangements can feel a little better about this issue because their survival is not dependent on safe technologies becoming available in their lifetime.

Zheng Sui’s report on using high potency granulocytes to cure cancer in mice is one of the more exciting chapters in the book and a fine example of the role of chance discoveries in biomedical research (Zheng by accident discovered a mouse innately resistant to cancer). With substantial support of the Life Extension Foundation and other private donors, Sui is aggressively pursuing Leukocyte Infusion Therapy (LIFT) human trials instead of pursuing the torturous path of trying to illuminate the biochemical and molecular mechanisms that drive the successful results in mice. I should mention that a unique concern for cryonicists is that eliminating cancer in the absence of other effective anti-aging technologies could increase the likelihood of dying as result of identity-threatening insults such as cardio-vascular complications, ischemic stroke, or Alzheimer’s disease.

I must admit being somewhat disappointed in the chapter about “evolutionary nutrigenomics” by Michael Rose and his collaborators. Michael Rose has always struck me as one of the more level-headed and empirical aging researchers, and his work with fruit flies is a resounding demonstration of using evolutionary tools to investigate and combat aging. His short contribution to this book reads more as a quickly thrown together status update of their company, Genescient, than a rigorous treatment of the issues. Dispersed throughout the text are a number of interesting perspectives on alternative approaches to aging research and the validation of anti-aging interventions, but these issues are not discussed in much detail. Michael Rose’s work is of great interest, but this chapter is neither a good introduction to his work nor an in-depth treatment of the practical applications of his research.

Anthony Atala’s chapter, “Life Extension by Tissue and Organ Replacement,” is a fascinating update on the current status and potential of regenerative medicine and tissue engineering. Unlike most of the chapters in this book, the author reports a number of examples of successful clinical applications. It is a good example of how working with nature (instead of trying to improve upon it) can have meaningful near-term benefits. Unfortunately, there is no discussion of the progress in regenerative medicine for the brain. Obviously, such strategies cannot involve a simple replacement of the brain with a newly grown brain but selected repair technologies can play an important role in brain-damaging diseases and insults. The inclusion of “life extension” in the chapter title seems somewhat artificial to me because there is no distinct treatment about how tissue and organ replacement will be expected to contribute to life extension. Additionally, there is little discussion of contemporary artificial and mechanical alternatives to organs (or biological structural components) in this chapter, or in any other chapters in the book, which I think is a minor oversight.

Robert J. Shmookler Reis and Joan E. McEwen contribute a chapter about identifying genes that can extend longevity. Their discussion of the prospects for mammals includes the sobering observation that “many of the gains we can attain by a single mutation in the simpler organism may already have been incorporated in the course of achieving our present longevities.” Then again, unless aging is firmly under genetic control in simple organisms but the result of wear and tear in humans there should be (unique) approaches in humans that should confer similar benefits as well.

The publication of this book came to my attention when I learned about Robert Freitas’s contribution, “Comprehensive Nanorobotic Control of Human Morbidity (PDF),” so I was quite interested in reading this final chapter of the book. I am not qualified to comment on the technical aspects of his vision of nanotechnology. I think it is fair to say, though, that if resuscitation of cryonics patients is possible they will most likely be resuscitated in a future that has nanomedical capabilities resembling those that are outlined in this chapter. For this reason alone, this chapter should be of great interest to readers of this magazine. Of particular interest is the discussion of cell repair technologies and brain rejuvenation, a topic of great interest to cryonics. Freitas devotes considerable space discussing how anti-aging strategies like SENS can be achieved with medical nanorobots but the chapter falls short of offering a distinct exposition of a nanomedical approach to aging and rejuvenation. With such profound molecular capabilities one would think that such an approach would not just consist of updating existing biotechnological approaches to eliminate aging related damage with more powerful tools. I think that the distinct capabilities that molecular technologies have to offer would have benefitted from a more extensive discussion of their transformative capabilities. In particular, the section on nanorobot-medicated rejuvenation could have benefitted from a more rigorous treatment of the question of how these interventions would produce actual rejuvenation. Rejuvenation will be a practical requirement for most cryonics patients and it would be interesting to see a more detailed technical discussion of this topic.

Robert Freitas introduces the phrase NENS (Nanomedically Engineered Negligible Senescence) for his vision of how the goals of SENS can be achieved through nanomedicine. This raises an important question: is there any reason to believe that the timeline for “conventional” SENS will be different from the timeline for mature molecular medicine? It is hard to tell, but one could argue that the development of mature nanotechnology is more comprehensive than any strategies designed to deal with the causes or effects of the aging process. So why not just fund the work of biological and mechanical molecular nanotechnologists to accelerate meaningful re-design of the human organism? I think that the best answer is that our current state of knowledge does not justify giving a privileged position to any particular approach and having these visions of the future compete may be the best hope that we have for seeing meaningful rejuvenation and the resuscitation of cryonics patients in the future.

If there is one serious omission in this impressive collection of articles it is a more comprehensive chapter on the topic of biomarkers of aging in humans. As reiterated throughout this review, the gold standard and most rigorous determination of the efficacy of anti-aging therapies and interventions is to empirically determine whether they increase maximum human lifespan. For obvious reasons, most medical professionals and healthcare consumers are pressed to make decisions based on less rigorous criteria and the development of a set of reliable biomarkers of aging is highly desirable. Of course, the most rigorous case for successful biomarkers would require the same kind of long-term studies, leading to an infinite regress problem. How to break out of this predicament while retaining a framework to make rational decisions about life extension technologies is not a trivial problem and can be the topic of a whole new volume of articles. Interestingly enough, one of the most insightful perspectives on this issue is given in Appendix A by SENS researcher Michael Rae when he points out that therapies aimed at rejuvenation can be tested at much more rapid timescales than therapies to retard the aging process or increase the maximum lifespan.

Michael Rae also notes that SENS’s “engineering heuristic” is well established in other fields of biomedicine. It is certainly the case that aging research could benefit from a stronger emphasis on solving problems and repairing damage instead of completely trying to understand the underlying pathologies but it also needs to be pointed out that the engineering approach has not fared much better in areas of research that are notoriously resistant to effective solutions such as neuroprotection in stroke. Ultimately, the SENS approach cannot completely escape studying the mechanisms and metabolic pathways involved when treatments are compared and side-effects are studied. In this sense, the difference between SENS and alternative approaches is a matter of degree, not principle.

I think that the editors are justified in claiming that the prospects for solving the aging challenge have never looked better. A close inspection of all the chapters, however, shows that no significant interventions in the aging process in humans are available now, and I doubt they will become available in the near future. And even if the aging process can be eliminated, there will still be medical conditions and accidents that require placing a person in cryostasis until effective treatment is available. For the foreseeable future there is good reason to agree with Thomas Donaldson’s advice* that making cryonics arrangements is the most fundamental and sensible decision one can make in order to reap the benefits of powerful future life extension therapies.

*Thomas Donaldson – Why Cryonics Will Probably Help You More Than Antiaging, Physical Immortality 2(4) 28-29 (4th Q 2004)


Support real progress in life extension

As we start the new year, it is helpful to draw attention to the sobering fact that no credible human rejuvenation therapies are available today, and it is doubtful that such therapies will see the light of day in the short term. Greg Fahy’s recent monumental collection of  interventive gerontology articles, The Future of Aging: Pathways to Human Life Extension (review forthcoming in Cryonics magazine), leaves little doubt about this predicament. It should also be emphasized that, with the possible exception of Robert Freitas’s comprehensive nanomedical overhaul of human biology, none of the envisioned strategies for life extension and rejuvenation (including SENS) confer increased protection to the brain in the case of severe traumatic insults or accidents. This fact alone highlights the fundamental importance of cryonics as  the core element in life extension. The idea that rejuvenation will make cryonics redundant has been one of the main obstacles for young people to engage in cryonics activism.

There is a broad consensus in the life extension community that more resources need to be allocated to combating aging as such, as opposed to increasingly futile efforts to extend life by treating aging-associated diseases. Unfortunately, the objective to launch a serious rejuvenation research program has limited mass appeal so far. As a consequence, we will have to get involved ourselves. Hopefully we can shift the focus from extensive hypothetical discussion about the consequences of human enhancement technologies to supporting and engaging in real experimental research to make these technologies facts of life.

In line with the foregoing observations, we suggest to consider the following areas for your support.

1. Cryonics. The first sensible step is making cryonics arrangements. Without cryonics arrangements you may not be able reap the benefits of anti-aging and rejuvenation treatments. Without cryonics arrangements you will remain vulnerable to a large number of personality-destroying diseases and accidents. In addition to making cryonics arrangements, support the major cryonics organizations and their research efforts.

2. Chemical Brain Preservation. Chemical brain preservation is an envisioned alternative (or complement) for human cryopreservation. At this point, there are no organizations offering chemopreservation of the brain but there is a new organization that aims to research the technical feasibility of the procedure.

3. Rejuvenation Research. The emphasis of interventive gerontology should be on rejuvenation as opposed to extending the maximum human lifespan by halting or slowing aging. Interventions aimed at rejuvenation have the distinct advantage that short-term empirical validation of their efficacy is possible. Rejuvenation therapies may include genetic manipulation, regenerative medicine, organ replacement and reversal of accumulated damage. A this stage of our knowledge, no privileged position should be claimed for any approach absent hard empirical breakthroughs in rejuvenation.

4. Nanomedicine Research. The logical evolution of medicine is to intervene at a progressively smaller scales. From “crudely” cutting into tissue, to pharmacology, to manipulating bio-molecules at the molecular level, nanomedical control of morbidity and aging is a prerequisite for resuscitation of cryonics patients and comprehensive rejuvenation. Biological and mechanical pathways to nanomedicine have been outlined. Whatever your position is on the relative technical merits and projected timelines  of such alternative approaches, the evolution of medicine into nanomedicine should be supported and accelerated.

Cryonics Oregon june meeting report

About 35 people attended the Cryonics Oregon-sponsored debate on the subject of SENS. Chana Phaedra was mistress of ceremonies. A show of hands indicated that the great majority of those attending were signed-up cryonicists. There was a sizeable contingent of CI Members who drove down from Seattle for the event. One was Eron Hennessey who bid $100 for an autographed Nanomedicine book by Robert Freitas that was auctioned for the benefit of James Swayze (who also attended the event). The money will be kept by Cryonics Oregon to help pay for equipment  for James. Jordan Sparks has offered to build a portable  ice bath that is large enough for James.

About five people came to the event who were non-cryonicists attending the American Aging Association conference, three of whom I brought in a taxi. A biogerontologist cryobiologist who wishes not to be named also attended.

Dr. de Grey began the debate with his standard presentation explaining the SENS program. After I presented my critique, the cryobiologist took the stage and gave his critique of SENS. Aubrey started by answering the cryobiologist, although he commented on a couple of my points. He and the cryobiologist were soon in an active exchange which went on for a while. It became evident to me the Aubrey was not going to get  around to answering my critique in the remaining 15 minutes of the 2-hour booking for the room. I interrupted Aubrey and the cryobiologist suggesting that questions should  be taken from the floor. Aschwin de Wolf added his critique to the debate, and he was followed by others.

There was not much time for socializing, but there was enough for most of us to have a few brief and rewarding conversations with people we had not seen for a while as well as others we were meeting for the first time.  A few Alcor and CI brochures were taken. One man with a CI brochure expressed interest in having cryonics  arrangements with both CI and Alcor. I told him that CI allows those with dual arrangements to have CI as a backup service provider. Alcor allows dual arrangements, but always insists that Alcor be the primary service provider, and that Alcor can never be the backup.

The case for cryonics

The biology-of-aging blog Ouroboros has posted a skeptical post about cryonics that is highly representative of how most biological scientists respond to questions about cryonics. The discussion of cryonics is largely reduced to a discussion of the technical feasibility of suspended animation and resuscitation requirements. But suspended animation is not cryonics. Cryonics should be discussed in the broader context of decision making under uncertainty. People who have made cryonics arrangements are more than aware that contemporary science is not able to vitrify and resuscitate a complex organism. To them the central question is whether we can reasonably expect that future technologies will be able to repair the injury that is produced by contemporary cryopreservation technologies and rejuvenate the patient. That is the “probabilistic” side of the issue. On the utility side of the equation is nothing less than personal survival.

This does not mean that cryonics should be approached as a form of Pascal’s Wager in a vacuum. Experimental evidence from fields such as cryobiology, biogerontology and nanotechnology plays an important role in shaping our expectations about the technical feasibility of the resuscitation of cryonics patients. Many biologists, however, feel confident that they can make a case against cryonics without even bothering to examine the current state of the field. For example, how many biologists know that the latest generation of vitrification agents have low enough toxicity to permit vitrification of animal brain slices with retention of electrical activity?

The author writes:

The field could take a lesson from the dawn of modern biogerontology back in the early 1990s: Acknowledge the mind-bending complexity of the challenge. Create model systems for cryonics, using the best tools from the vast edifice of modern biological knowledge.

But that is exactly what the cryonics field has done. Millions of dollars have been devoted to identify low-toxicity vitrification agents and protocols to preserve viability after pronouncement of legal death.  Progress in the cryopreservation of complex organs (including the brain) has been so successful that the vitrification agent that is currently used by the Alcor Life Extension Foundation, 21st Century Medicine’s M22, is the least toxic vitrification agent in the peer reviewed cryobiology literature to date.

The author is correct that the project of cryonics is of “mind-bending complexity.” One major reason for this is that the resuscitation of most cryonics patients will require successful rejuvenation. As a result, cryonics advocates are quite interested in anti-aging research. But whereas modern biogerontology, not unlike macroeconomics, is still plagued by ongoing (technical) debates about even the most basic definitions employed in the field, or engaged in discussions about what constitutes the most effective approach to pursue rejuvenation, the cryonics field has moved from the practice of the crude freezing of patients to the pursuit of long term care at cryogenic temperatures without ice formation and minimal ischemic injury.

Perhaps there is good reason for this difference in success rate. As mathematician and cryonics advocate Thomas Donaldson pointed out, anti-aging research faces conceptual and methodological challenges that cryobiology research does not. Perhaps the time scale to develop and validate effective anti-aging strategies is similar to that of developing a mature technology that can manipulate matter at the molecular level. If this is the case, rejuvenation research could benefit from being pursued as a broader evolutionary bio-nanotechnology research program.

The discussion of cryonics is most fruitful where logic and empirical science meet.  We need to employ the tools of logic to guide coherent decision making and we need the results of experimental science to provide empirical weight to guide those decisions. In a world where knowledge is recognized as probabilistic, and where death is recognized as a biological process that can be halted through the use of low temperatures, the decision to make cryonics arrangements can be rational and life-affirming.

Ben Best on nuclear DNA damage and aging

The June 2009 issue of Rejuvenation Research features an article by Cryonics Insitute President Ben Best about the involvement of nuclear DNA damage in the aging process:

Abstract

This paper presents evidence that damage to nuclear DNA (nDNA) is a direct cause of aging in addition to the effects of nDNA damage on cancer, apoptosis, and cellular senescence. Many studies show significant nDNA damage with age, associated with declining nDNA repair, and this evidence for the decline of nDNA repair with age is also reviewed. Mammalian lifespans correlate with the effectiveness of nDNA repair. The most severe forms of accelerated aging disease in humans are due to nDNA repair defects, and many of these diseases do not exhibit increased cancer incidence. High rates of cellular senescence and apoptosis due to high rates of nDNA damage are apparently the main cause of the elderly phenotype in these diseases. Transgenic mice with high rates of cellular senescence and apoptosis exhibit an elderly phenotype, whereas some strains with low rates of cellular senescence and apoptosis show extended lifespan. Age-associated increases of nDNA damage in the brain may be problematic for rejuvenation because neurons may be difficult to replace and artificial nDNA repair could be difficult.

HT Longevity Meme