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)

Baby boomers confront the reaper

One question that is going to be of great interest is how aging baby boomers will confront aging and death. Where previous generations have found peace in religion and silent resignation, there are reasons to believe that this generation will not be so complacent. The baby boom generation, or at least those who have shaped contemporary culture and politics, have been more secular and less inclined to accept the constraints of nature (as evidenced by the obligatory contempt for views that allow some degree of biological determinism). In a review for the Financial Times, Stephen Cave reports on no fewer than four new books on the topic of death:

In universities around the world, professors are now arguing that the Dark Angel deserves more respect. Contrary to Epicurus, Death is justly to be feared, say today’s academicians – the common folk had it right all along; we should humbly hand him back his scythe and then run for our lives. Four new books insist that we are right to panic when the reaper comes – and that our very civilisation depends upon it.

There is a lot at stake here. Will the dominant opinion become that death gives “meaning” to life, or will death be seen as an outrage that can be pushed back by modern science? As is evident from this review, both perspectives are represented in these books. It almost seems obligatory for philosophers who write about death to present a-priori scholastic arguments against immortality.  Stephen Cave even talks about the “paradox of immortality,” “the fact of death imbues our life with passion and urgency, but it is that very passion for life that makes death tragic.” But what is a paradox  (even a “fact”) to some, is the lack of imagination of a rationalist philosopher to others. It is hard to imagine that (secular) academic pro-death views will persist when medical science has advanced enough to make these rationalizations less important, but it cannot hurt to be vigilant and turn the tools of logic against them.

Herbert Marcuse, one of the heroes of the protest generation that is currently ruling America, made an astute observation about the “ideology of death”:

In the history of Western thought, the interpretation of death has run the whole gamut from the notion of a mere natural fact, pertaining to man as organic matter, to the idea of death as the telos of life, the distinguishing feature of human existence. From these two opposite poles, two contrasting ethics may be derived; On the one hand, the attitude toward death is stoic or skeptic acceptance of the inevitable, or even the repression of the thought of death by life; on the other hand the idealistic glorification of death is that which gives “meaning” to life, or is the precondition for the “true” life of man.

The authoritarian economic and political ideas of Marxists like Marcuse have little to offer to those inclined to critical thinking, but it is time for baby boomers to face the prospect of radical life extension and engage in direct action to fight the grim reaper.

Revival of cryonics patients literature

There is a growing literature that discusses the technical aspects of revival of cryonics patients. The following list of the published literature was compiled by Ralph Merkle and Robert Freitas and published as an appendix of their article on molecular nanotechnology in Cryonics Magazine 2008-4:

Robert C.W. Ettinger, The Prospect of Immortality, Doubleday, NY, 1964

Jerome B. White, “Viral Induced Repair of Damaged Neurons with Preservation of Long-Term Information Content,” Second Annual Cryonics Conference, Ann Arbor MI, 11 April 1969

Michael G. Darwin, “The Anabolocyte:  A Biological Approach to Repairing Cryoinjury,” Life Extension Magazine (July-August 1977):80-83

Thomas Donaldson, “How Will They Bring Us Back, 200 Years From Now?” The Immortalist 12 (March 1981):5-10

K. Eric Drexler, Engines of Creation:  The Coming Era of Nanotechnology, Anchor Press/Doubleday, New York, 1986, pp. 133-138

Brian Wowk, “Cell Repair Technology,” Cryonics 9(July 1988)

Mike Darwin, “Resuscitation: A Speculative Scenario for Recovery,” Cryonics 9(July 1988):33-37

Thomas Donaldson, “24th Century Medicine,” Analog 108(September 1988):64-80 and Cryonics 9(December 1988)

Ralph C. Merkle, “Molecular Repair of the Brain,” Cryonics 10(October 1989):21-44

Gregory M. Fahy, “Molecular Repair Of The Brain: A Scientific Critique, with a Response from Dr. Merkle,” Cryonics 12(February 1991):8-11 & Cryonics 12(May 1991);  “Appendix B. A ‘Realistic’ Scenario for Nanotechnological Repair of the Frozen Human Brain,” in Brian Wowk, Michael Darwin, eds., Cryonics: Reaching for Tommorow, Alcor Life Extension Foundation, 1991

Ralph C. Merkle, “The Technical Feasibility of Cryonics,” Medical Hypotheses 39(1992):6-16

Ralph C. Merkle, “The Molecular Repair of the Brain,” Cryonics 15(January 1994):16-31 (Part I) & Cryonics 15(April 1994):20-32 (Part II)

Ralph C. Merkle, “Cryonics, Cryptography, and Maximum Likelihood Estimation,” First Extropy Institute Conference, Sunnyvale CA, 1994

Ralph Merkle, “Algorithmic Feasibility of Molecular Repair of the Brain,” Cryonics 16(First Quarter 1995):15-16

Michael V. Soloviev, “SCRAM Reanimation,” Cryonics 17(First Quarter 1996):16-18

Mikhail V. Soloviev, “A Cell Repair Algorithm,” Cryonics 19(First Quarter 1998):22-27

Robert A. Freitas Jr., “Section 10.5 Temperature Effects on Medical Nanorobots,” in Nanomedicine, Volume I: Basic Capabilities, Landes Bioscience, Georgetown, TX, 1999, pp. 372-375

Ralph C. Merkle, Robert A. Freitas Jr., “A Cryopreservation Revival Scenario using MNT,” Cryonics 30(Fourth Quarter 2008).

Robert Freitas discusses the future of nanomedicine

Nanotechnology idea-man Robert Freitas, Jr. has published an article in the January 2009 issue of Life Extension Magazine providing a tutorial in nanomedicine and documenting its progression toward real-world application.

In “Nanotechnology and Radically Extended Life Span,” Freitas describes several theoretical medical nanorobots, such as the microbiovore, which would “act like an artificial mechanical white cell, seeking out and digesting unwanted pathogens including bacteria, viruses, or fungi in the bloodstream.” In addition to fighting infection, medical nanorobots could invigorate old or diseased cells by replacing chromosomes with fresh new ones, correcting the cellular damage and mutations that lead to aging.

Freitas and colleagues have performed many analyses and simulations of the types of technologies and tools that will be necessary to create these nanoscale medical robots, filing two patents for the mechanosynthesis of nanorobots. Together with Ralph Merkle, Freitas founded the Nanofactory Collaboration to “coordinate a combined experimental and theoretical R&D program to design and build the first working diamandoid nanofactory.” This effort has involved many collaborations with researchers from nine different organizations and four countries, and has resulted in a dozen academic articles.

Now Freitas is eager to test his theories with the help of scanning probe microscopist Philip Moriarty, who is attempting to build several of Freitas’ mechanosynthesis tooltips. Presumably, the creation of working tooltips will lead directly to their intended purpose: the creation of nanorobots. Freitas hopes to manufacture medical nanorobots that can contribute to radical life extension therapies by the 2020s.

Of course, most cryonicists are of the opinion that nanotechnological interventions will be necessary for the reversal of aging and disease in cryopreserved patients. As we move closer to reversible cryopreservation with improved stabilization protocol and cryoprotectant solutions, perhaps the maturation of nanomedicine and cryonics will coincide.

In the past Alcor has supported Freitas’ work at the expense of supporting research that could improve the quality of its cryopreservation procedures for existing members. It is therefore encouraging to learn that the Life Extension Foundation has contributed money to support Freitas’ work on nanomedicine.

Warm biostasis through nanotechnology

One concern about chemical fixation as a low cost alternative to cryonics is that current fixatives may not be able to permanently fix all biomolecules that are important to preserve the identity of the person. A related concern is that postmortem delays may not permit adequate perfusion of the brain, resulting in pockets of decomposed tissue. On this issue, biostasis at cryogenic temperatures (cryonics) has a distinct advantage because extreme cold will also preserve tissues that were not, or were poorly, penetrated by the cryoprotectant agent.

But even if cryoprotectant toxicity will be overcome to enable reversible vitrification of humans, the procedures of cryoprotectant perfusion, cryogenic cooldown, long term care, rewarming, and resuscitation may often involve (unintended) imperfections that will require advanced cell repair technologies for successful resuscitation.

Perhaps those same advanced technologies could produce a form of biostasis that avoids the crude consequences of contemporary chemical fixation by making precise modifications within and between cells to arrest metabolism and decomposition.

Looking for discussion of this idea, Brian Wowk pointed this writer to Eric Drexler who envisioned such a form of warm biostasis in Engines of Creation. In chapter 7 (section 5) Drexler calls this form of warm biostasis “anesthesia plus:”

To see how one approach would work, imagine that the blood stream carries simple molecular devices to tissues, where they enter the cells. There they block the molecular machinery of metabolism – in the brain and elsewhere – and tie structures together with stabilizing cross-links. Other molecular devices then move in, displacing water and packing themselves solidly around the molecules of the cell. These steps stop metabolism and preserve cell structures.

This procedure would produce a state in which the person will appear to be dead (and warm) for all practical purposes:

If a patient in this condition were turned over to a present-day physician ignorant of the capabilities of cell repair machines, the consequences would likely be grim. Seeing no signs of life, the physician would likely conclude that the patient was dead, and then would make this judgment a reality by “prescribing” an autopsy, followed by burial or burning.

Such a form of warm biostasis would not only produce a true molecular alternative to cryonics, it would also enable long-duration space travel and could be employed as a means to provide trauma care in emergency situations. These kind of applications of molecular nanotechnology are extremely advanced and, as a result, literature, either fiction or non-fiction, about them is virtually non-existent. It seems that the first rigorous treatment of cellular and whole-body warm biostasis will be published in Robert Freitas’ Nanomedicine Volume IIB and Nanomedicine Volume III (personal correspondence).

Perhaps the future of biostasis will be an advanced form of chemical fixation after all.